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The 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention

CME Disclaimer. These slides may not be published, posted online, and/or presented for Continuing Medical Education credit without written permission from Rush University Medical Center and Practice Point Communications. . . Rush University Medical Center is accredited by the Accreditatio

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The 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention

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    1. The 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention Rome, Italy July 17-20, 2011

    2. CME Disclaimer These slides may not be published, posted online, and/or presented for Continuing Medical Education credit without written permission from Rush University Medical Center and Practice Point Communications Slide: CME DisclosureSlide: CME Disclosure

    3. Accreditation and Designation Slide: Accreditation and DesignationSlide: Accreditation and Designation

    4. Faculty: CME Course Director Slide: Faculty: CME Course DirectorSlide: Faculty: CME Course Director

    5. Faculty: Content Development and Training Calvin J. Cohen, MD, MSc Research Director CRI New England Harvard Vanguard Medical Associates Clinical Instructor Harvard Medical School Boston, Massachusetts Ian Frank, MD Professor of Medicine Director, Anti-Retroviral Clinical Research University of Pennsylvania Philadelphia, Pennsylvania W. David Hardy, MD Director, Division of Infectious Diseases Cedars-Sinai Medical Center Associate Professor of Medicine-in Residence David Geffen School of Medicine at UCLA Los Angeles, California Paul E. Sax, MD Clinical Director Division of Infectious Diseases & HIV Program Brigham & Women’s Hospital Associate Professor of Medicine Harvard Medical School Boston, Massachusetts Slide: Faculty: Content Development and TrainingSlide: Faculty: Content Development and Training

    6. Faculty: CME Reviewer Slide: Faculty: CME Course DirectorSlide: Faculty: CME Course Director

    7. Disclosure Information It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content Slide: Disclosure Information It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME. Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months. If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content. Slide: Disclosure Information It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME. Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months. If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content.

    8. Disclosure Information: CME Course Director Harold A. Kessler, MD Grants/Research Support None Consultant None Speakers’ Bureau None Stock Shareholder Abbott Laboratories, GlaxoSmithKline, Merck Other Financial or Material Support None Slide: Disclosure Information: CME Course DirectorSlide: Disclosure Information: CME Course Director

    9. Disclosure Information: CME Course Director Calvin J. Cohen, MD, MSc Grants/Research Support Bristol Myers Squibb, Gilead Sciences, Merck, Tibotec Consultant Bristol Myers Squibb, Gilead Sciences, Merck, Tibotec Speakers’ Bureau Bristol Myers Squibb, Gilead Sciences, Merck, Tibotec Stock Shareholder None Other Financial or Material Support None Slide: Disclosure Information: CME Course DirectorSlide: Disclosure Information: CME Course Director

    10. Disclosure Information: CME Course Director Ian Frank, MD Grants/Research Support GlaxoSmithKline Consultant Gilead Sciences, Tibotec Speakers’ Bureau None Stock Shareholder None Other Financial or Material Support None Slide: Disclosure Information: CME Course DirectorSlide: Disclosure Information: CME Course Director

    11. Disclosure Information: CME Course Director W. David Hardy, MD Grants/Research Support Bionor, Gilead Sciences, GlaxoSmithKline, Pfizer, ViiV Consultant Bionor, Gilead Sciences, GlaxoSmithKline, Pfizer, ViiV Speakers’ Bureau None Stock Shareholder Merck (< $5,000) Other Financial or Material Support None Slide: Disclosure Information: CME Course DirectorSlide: Disclosure Information: CME Course Director

    12. Disclosure Information: CME Course Director Paul E. Sax, MD Grants/Research Support Gilead Sciences, GlaxoSmithKline, Merck, Tibotec Consultant Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Tibotec Speakers’ Bureau None Stock Shareholder None Other Financial or Material Support None Slide: Disclosure Information: CME Course DirectorSlide: Disclosure Information: CME Course Director

    13. Disclosure Information: CME Reviewer David M. Simon, MD, PhD Grants/Research Support None Consultant None Speakers’ Bureau None Stock Shareholder None Other Financial or Material Support None Slide: Disclosure Information: CME ReviewerSlide: Disclosure Information: CME Reviewer

    14. Opinions and Off-Label Discussions Slide: Opinions and Off-Label Discussions The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, University of Florida College of Pharmacy, or Association of Nurses in AIDS Care. The faculty may have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose. Please consult the full prescribing information before using any medication mentioned in this program. Slide: Opinions and Off-Label Discussions The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, University of Florida College of Pharmacy, or Association of Nurses in AIDS Care. The faculty may have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose. Please consult the full prescribing information before using any medication mentioned in this program.

    15. Learning Objectives (CME, CE) Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine: Initiate ARV therapy in ARV-naďve patients based upon the most current clinical data indicating when the potential benefits of ARV therapy outweigh the potential risks. Prescribe ARV therapy in ARV-naďve patients based upon the most current clinical data indicating which ARV regimens are superior regarding efficacy and avoidance of toxicity and adverse events. Utilize recent study results regarding the medical management of HIV-positive patients in your clinical practice to improve patient care. Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients. Slide: Learning Objectives (CME, CE) Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine: Initiate ARV therapy in ARV-naďve patients based upon the most current clinical data indicating when the potential benefits of ARV therapy outweigh the potential risks. Prescribe ARV therapy in ARV-naďve patients based upon the most current clinical data indicating which ARV regimens are superior regarding efficacy and avoidance of toxicity and adverse events. Utilize recent study results regarding the medical management of HIV-positive patients in your clinical practice to improve patient care. Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.Slide: Learning Objectives (CME, CE) Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine: Initiate ARV therapy in ARV-naďve patients based upon the most current clinical data indicating when the potential benefits of ARV therapy outweigh the potential risks. Prescribe ARV therapy in ARV-naďve patients based upon the most current clinical data indicating which ARV regimens are superior regarding efficacy and avoidance of toxicity and adverse events. Utilize recent study results regarding the medical management of HIV-positive patients in your clinical practice to improve patient care. Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.

    16. Learning Objectives (CPE) Upon completion of this activity, the pharmacist should be able to: Determine when the most current clinical data indicates the potential benefits of ARV therapy outweigh the potential risks in ARV-naďve patients. Recommend the most appropriate ARV therapy for ARV-naďve patients based on efficacy and avoidance of toxicity and adverse events according to the most current clinical data. Utilize recent study results regarding the pharmacological management of HIV-positive patients in your clinical practice to improve patient care. Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients. Slide: Learning Objectives (CPE) Upon completion of this activity, the pharmacist should be able to: Determine when the most current clinical data indicates the potential benefits of ARV therapy outweigh the potential risks in ARV-naďve patients. Recommend the most appropriate ARV therapy for ARV-naďve patients based on efficacy and avoidance of toxicity and adverse events according to the most current clinical data. Utilize recent study results regarding the pharmacological management of HIV-positive patients in your clinical practice to improve patient care. Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.Slide: Learning Objectives (CPE) Upon completion of this activity, the pharmacist should be able to: Determine when the most current clinical data indicates the potential benefits of ARV therapy outweigh the potential risks in ARV-naďve patients. Recommend the most appropriate ARV therapy for ARV-naďve patients based on efficacy and avoidance of toxicity and adverse events according to the most current clinical data. Utilize recent study results regarding the pharmacological management of HIV-positive patients in your clinical practice to improve patient care. Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.

    17. Studies in ARV-Naďve Patients W. David Hardy, MD Director, Division of Infectious Diseases Cedars-Sinai Medical Center Associate Professor of Medicine-in-Residence David Geffen School of Medicine at UCLA Los Angeles, CA

    18. As an important part of and embedded in the HPTN 052 study was a randomized, controlled trial of immediate versus delayed ART for the HIV+ member of the serodiscordant couple. The endpoint used in the this study was the previous WHO recommendation of initiating ART at a CD4+ cell count of less than 250 cells/mm3 or diagnosis of an AIDS-defining illness. 886 HIV-infected partners were randomized to immediate ART and 877 HIV-infected partners were randomized to delayed ART to be initiated when their CD4+ cell counts deceased to < 250 or with the occurrence of an AIDS-defining illness. Ultimately, 184 participants in the delayed ART arm initiated therapy. As an important part of and embedded in the HPTN 052 study was a randomized, controlled trial of immediate versus delayed ART for the HIV+ member of the serodiscordant couple. The endpoint used in the this study was the previous WHO recommendation of initiating ART at a CD4+ cell count of less than 250 cells/mm3 or diagnosis of an AIDS-defining illness. 886 HIV-infected partners were randomized to immediate ART and 877 HIV-infected partners were randomized to delayed ART to be initiated when their CD4+ cell counts deceased to < 250 or with the occurrence of an AIDS-defining illness. Ultimately, 184 participants in the delayed ART arm initiated therapy.

    19. HPTN 052: Baseline Characteristics The baseline characteristics of the two study populations were similar with equivalent usage of prophylactic TMP/SMX and INH in both populations. The viral loads and CD4+ cell counts were also well-matched by the randomization scheme on entry considering the global demographics of this population. The baseline characteristics of the two study populations were similar with equivalent usage of prophylactic TMP/SMX and INH in both populations. The viral loads and CD4+ cell counts were also well-matched by the randomization scheme on entry considering the global demographics of this population.

    20. HPTN 052: Virologic and Immunologic Response to ART Virologic Efficacy: Immediate arm: 90% (90% non-Africa; 91% Africa) had viral load <400 cps/mL at 1 year Delayed arm: 93% (96% non-Africa; 85% Africa) had viral load <400 cps/mL at 1 year Virologic failures: Immediate 5.1% vs. 2.7% Delayed 67% began a second regimen (Immediate) vs. 60% (Deferred) Similar virologic responses were seen for both study populations with high proportions (>90%) of subjects achieving undetectable viral loads (<400 copies/mL) at one year of therapy. Note a small drop off in response in the delayed group in subjects in Africa. There were more subjects experiencing virologic failure and use of second ART regimen in the immediate treatment group thought to be due to their longer time on ART. Of note, those in the delayed arm started ART with a much lower CD4 count (median 225 cells/mm3 vs 442 cells/mm3) compared to the immediate arm. While subjects in the delayed arm experienced a robust increase in CD4+ cells at one year of ART (a median of +191 cells/mm3) which was similar to that seen in the immediate arm, it is clear that the CD4+ cell recovery numerically lagged behind that seen not in the immediate arm through the follow-up in this study to date. Similar virologic responses were seen for both study populations with high proportions (>90%) of subjects achieving undetectable viral loads (<400 copies/mL) at one year of therapy. Note a small drop off in response in the delayed group in subjects in Africa. There were more subjects experiencing virologic failure and use of second ART regimen in the immediate treatment group thought to be due to their longer time on ART. Of note, those in the delayed arm started ART with a much lower CD4 count (median 225 cells/mm3 vs 442 cells/mm3) compared to the immediate arm. While subjects in the delayed arm experienced a robust increase in CD4+ cells at one year of ART (a median of +191 cells/mm3) which was similar to that seen in the immediate arm, it is clear that the CD4+ cell recovery numerically lagged behind that seen not in the immediate arm through the follow-up in this study to date.

    21. HPTN 052: Clinical Endpoints 105 individuals had a primary clinical endpoint: Immediate 40 vs. 65 delayed [HR=0.6 (0.4,0.9), P=0.01] Development of extrapulmonary TB was the main difference between the two groups (P<0.002) Increased mortality with delayed treatment, but not significant [HR=0.77, (0.34,1.76), P>0.5] Adverse events: immediate 24% vs. 5% delayed There were significantly greater number of clinical endpoints in the delayed group vs the immediate group (65 vs 40) with a hazard ratio of 0.6, indicating a 40% decrease probability of these events occurring the immediate ART group. This difference was driven principally by the development of extrapulmonary TB which also reached statistical significance. These events occurred in the setting equal use of prophylactic INH. Less severe bacterial infections occurred in the delayed treatment group; this is hypothesized to be due to increased use of prophylactic TMP-SMX instituted in subjects when their CD4+ cells fell below 500 cells/mm3 as per WHO guidelines. There was greater mortality in the deferred group, but these differences were not statistically significant. The greater use of ART also resulted in 24% of the immediate group having adverse events vs 4% in the delayed group. Overall, this study demonstrated a benefit in the developing world of earlier initiation of ART than the current WHO recommendations of < 350 cells/mm3, for those who began at < 550 cells. Please note the following when justifying the number of clinical events reported in the study: 17 subjects experience >1 clinical event - 8 immediate arm (5 had 2 events, 1 had 3 events, and 2 had 4 events) of which 2 had a clinical event followed by death - 9 delayed arm (7 had 2 events, 2 had 3 events) of which 4 had a clinical event followed by death There were significantly greater number of clinical endpoints in the delayed group vs the immediate group (65 vs 40) with a hazard ratio of 0.6, indicating a 40% decrease probability of these events occurring the immediate ART group. This difference was driven principally by the development of extrapulmonary TB which also reached statistical significance. These events occurred in the setting equal use of prophylactic INH. Less severe bacterial infections occurred in the delayed treatment group; this is hypothesized to be due to increased use of prophylactic TMP-SMX instituted in subjects when their CD4+ cells fell below 500 cells/mm3 as per WHO guidelines. There was greater mortality in the deferred group, but these differences were not statistically significant. The greater use of ART also resulted in 24% of the immediate group having adverse events vs 4% in the delayed group. Overall, this study demonstrated a benefit in the developing world of earlier initiation of ART than the current WHO recommendations of < 350 cells/mm3, for those who began at < 550 cells. Please note the following when justifying the number of clinical events reported in the study: 17 subjects experience >1 clinical event - 8 immediate arm (5 had 2 events, 1 had 3 events, and 2 had 4 events) of which 2 had a clinical event followed by death - 9 delayed arm (7 had 2 events, 2 had 3 events) of which 4 had a clinical event followed by death

    22. SENSE: Trial Design Double-blinded, active controlled to Week 48 Inclusion: Treatment naďve, HIV RNA >5,000 copies/mL No genotypic mutations to NRTIs, NNRTIs or PIs Predicted Phenotypic sensitivity to NNRTIs and selected NRTIs The SENSE trial is a small, pilot study. It is unique in that: It evaluated the use of etravirine as an ART regimen in treatment-naive subjects It evaluated etravirine as part of a once-daily (QD)-dosed ART regimen The primary endpoint for this study was not a comparison of virologic efficacy but rather occurrence of neuropsychiatric adverse effects of the two regimens. The SENSE trial is a small, pilot study. It is unique in that: It evaluated the use of etravirine as an ART regimen in treatment-naive subjects It evaluated etravirine as part of a once-daily (QD)-dosed ART regimen The primary endpoint for this study was not a comparison of virologic efficacy but rather occurrence of neuropsychiatric adverse effects of the two regimens.

    23. SENSE: Baseline Characteristics (ITT) The baseline characteristics of the two arms were well-balanced for the parameters shown above. Of note, despite exclusion of subjects with baseline NNRTI, NRTI or PI resistance mutations, significantly more subjects with NNRTI and NRTI mutations were enrolled in the etravirine arm. The baseline characteristics of the two arms were well-balanced for the parameters shown above. Of note, despite exclusion of subjects with baseline NNRTI, NRTI or PI resistance mutations, significantly more subjects with NNRTI and NRTI mutations were enrolled in the etravirine arm.

    24. SENSE: Grade 1 - 4 Drug-related Neuropsychiatric Adverse Event Prevalence through 48 Weeks (ITT) As demonstrated by the graph above, neuropsychiatric adverse effects peaked within the first 2 to 4 weeks of the study in both arms of the study and were significantly more common throughout the 48 week study in the subjects receiving efavirenz As demonstrated by the graph above, neuropsychiatric adverse effects peaked within the first 2 to 4 weeks of the study in both arms of the study and were significantly more common throughout the 48 week study in the subjects receiving efavirenz

    25. SENSE: Summary Efficacy at Week 48 (ITT TLOVR) – by Type of Response (%) In terms of the secondary endpoint of the study, virologic efficacy was numerical comparable at week 48 analyzed by an ITT- TLOVR analysis of % of subjects with HIV RNA less than 50 copies/mL. Similar numbers of subjects discontinued their study medications due to virologic failure, but over twice as many subjects receiving efavirenz discontinued due to adverse events. CD4+ cell increases from baseline were similar between the two study arms.In terms of the secondary endpoint of the study, virologic efficacy was numerical comparable at week 48 analyzed by an ITT- TLOVR analysis of % of subjects with HIV RNA less than 50 copies/mL. Similar numbers of subjects discontinued their study medications due to virologic failure, but over twice as many subjects receiving efavirenz discontinued due to adverse events. CD4+ cell increases from baseline were similar between the two study arms.

    26. SPRING-1: Dolutegravir (DTG, S/GSK1349572) in ART-naďve Adults Phase IIb dose-ranging, partially-blinded, N ~200 ART-naďve patients All arms include 2 NRTI backbone given once daily Primary endpoint: % <50 c/mL at 16 weeks (TLOVR) Spring-1 is a phase II, dose-finding study comparing 3 doses of dolutegravir to efavirenz with an investigator-selected dual NRTI combination (TDF/FTC or ABC/3TC). This study enrolled approximately 50 subjects in each of four treatment arms and was partially blinded—as to the dose of dolutegravir among those three arms only. Spring-1 is a phase II, dose-finding study comparing 3 doses of dolutegravir to efavirenz with an investigator-selected dual NRTI combination (TDF/FTC or ABC/3TC). This study enrolled approximately 50 subjects in each of four treatment arms and was partially blinded—as to the dose of dolutegravir among those three arms only.

    27. SPRING-1: Baseline Characteristics Baseline characteristics of the study participants were well-balanced across the four arms of the study. Note, the investigator-selected NRTI “backbone” was TDF/FTC in two-thirds of the subjects and ABC/3TC in one-third. Baseline characteristics of the study participants were well-balanced across the four arms of the study. Note, the investigator-selected NRTI “backbone” was TDF/FTC in two-thirds of the subjects and ABC/3TC in one-third.

    28. SPRING-1: Antiviral Activity through Week 48 Mean CD4 cell changes from BL: EFV: +180 cells vs. DTG: +200-240 cells (P=0.076) Resistance: 3/150 (2%) DTG VFs (>400 c/mL); none in 50 mg arm 1 - M184V; No integrase mutations Rapid suppression of HIV RNA was seen with all three doses of dolutegravir with ~90% of these subjects achieving undetectable (HIV RNA <50 copies/mL) by week 16 and maintaining this level of suppression through week 48. The efavirenz-treated subjects achieved viral load suppression more slowly, but did achieve similar proportions of viral load suppression by week 48. CD4+ cell increases from baseline were numerically higher in dolutegravir-treated subjects, but this not statistically significant. Of note, virologic failure occurred in 3/150 (2%) of DTG patients (none in the 50 mg dosage group); no integrase resistance associated mutations were detected. Rapid suppression of HIV RNA was seen with all three doses of dolutegravir with ~90% of these subjects achieving undetectable (HIV RNA <50 copies/mL) by week 16 and maintaining this level of suppression through week 48. The efavirenz-treated subjects achieved viral load suppression more slowly, but did achieve similar proportions of viral load suppression by week 48. CD4+ cell increases from baseline were numerically higher in dolutegravir-treated subjects, but this not statistically significant. Of note, virologic failure occurred in 3/150 (2%) of DTG patients (none in the 50 mg dosage group); no integrase resistance associated mutations were detected.

    29. SPRING-1: Adverse Events Events leading to withdrawal: DTG (n=2): dyspepsia and Burkitt’s lymphoma EFV (n=4): abnormal dreams, suicide attempt, drug intolerance, drug hypersensitivity Small changes in serum creatinine (0.1 – 0.15 mg/dL) observed consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine Small changes in serum creatinine (0.1 – 0.15 mg/dL) observed Observed with both NRTI backbones, did not progress over time No effect of DTG on GFR (as measured by iohexol clearance) In vitro and clinical data are consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine DTG inhibits the organic anion transporter OCT2 (with IC50 of 1.9 µM), like trimethoprim or cimetidine Small changes in serum creatinine (0.1 – 0.15 mg/dL) observed Observed with both NRTI backbones, did not progress over time No effect of DTG on GFR (as measured by iohexol clearance) In vitro and clinical data are consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine DTG inhibits the organic anion transporter OCT2 (with IC50 of 1.9 µM), like trimethoprim or cimetidine Small changes in serum creatinine (0.1 – 0.15 mg/dL) observed Observed with both NRTI backbones, did not progress over time No effect of DTG on GFR (as measured by iohexol clearance) In vitro and clinical data are consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine DTG inhibits the organic anion transporter OCT2 (with IC50 of 1.9 µM), like trimethoprim or cimetidineSmall changes in serum creatinine (0.1 – 0.15 mg/dL) observed Observed with both NRTI backbones, did not progress over time No effect of DTG on GFR (as measured by iohexol clearance) In vitro and clinical data are consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine DTG inhibits the organic anion transporter OCT2 (with IC50 of 1.9 µM), like trimethoprim or cimetidine Small changes in serum creatinine (0.1 – 0.15 mg/dL) observed Observed with both NRTI backbones, did not progress over time No effect of DTG on GFR (as measured by iohexol clearance) In vitro and clinical data are consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine DTG inhibits the organic anion transporter OCT2 (with IC50 of 1.9 µM), like trimethoprim or cimetidine Small changes in serum creatinine (0.1 – 0.15 mg/dL) observed Observed with both NRTI backbones, did not progress over time No effect of DTG on GFR (as measured by iohexol clearance) In vitro and clinical data are consistent with inhibition of the renal transporter responsible for tubular secretion of creatinine DTG inhibits the organic anion transporter OCT2 (with IC50 of 1.9 µM), like trimethoprim or cimetidine

    30. Study A4001078: MVC + ATV/r vs. FTC/TDF + ATV/r in Treatment-naďve Patients Patient Eligibility Criteria R5 HIV at screening =16 years of age HIV-1 RNA =1,000 copies/mL CD4 =100 cells/mm3 No evidence of resistance to ATV/r, TDF, or FTC Study A4001078: an exploratory pilot study of a low pill burden QD dual-therapy regimen, MVC + ATV/r Rationale for MVC + boosted PI regimen: Potential for early use: prevalence of CCR5 tropic virus is greatest in treatment-naďve individuals1 Nucleoside-sparing regimen Good penetration of MVC in CSF and genital secretions2-4 MOTIVATE and PK studies support use of MVC 150 mg QD with selected ritonavir-boosted PIs Study A4001078: an exploratory pilot study of a low pill burden QD dual-therapy regimen, MVC + ATV/r Rationale for MVC + boosted PI regimen: Potential for early use: prevalence of CCR5 tropic virus is greatest in treatment-naďve individuals1 Nucleoside-sparing regimen Good penetration of MVC in CSF and genital secretions2-4 MOTIVATE and PK studies support use of MVC 150 mg QD with selected ritonavir-boosted PIs

    31. Study A4001078: Baseline Characteristics Baseline characteristics were well-balanced between the 2 arms of the study.Baseline characteristics were well-balanced between the 2 arms of the study.

    32. Study A4001078: HIV-1 RNA <50 copies/mL at Week 48 Virologic response was similar between the two study arms when evaluating the % of subjects with HIV RNA less than 400 copies/mL (89.8 % for MVC vs 86.9% for ATV/rtv), however more subjects in the MVC arm experienced virologic failure when the study endpoint of % with less than 50 copies/mL at 48 weeks was examined (74.6% for MVC vs 83.6% for ATV/rtv). Of note, all 7/9 MVC subjects and 3/3 ATV/rtv subjects with viral loads greater than 50 copies/mL at 48 weeks resuppressed virus to less than 50 copies/mL with subsequent monitoring. All viral load measurements greater than 50 copies/mL in the 9 MVC subjects and 2 of 3 in the ATV/rtv subjects were less than 200 copies/mL bringing into question if these were viral “blips”. CD4+ cell increases from baseline were comparable between the two arms and interestingly not greater in the MVC arm as seen in previous MVC studies. Of note, no genotypic nor phenotypic, including viral tropism shifts for the MVC-treated subjects, were detected. Virologic response was similar between the two study arms when evaluating the % of subjects with HIV RNA less than 400 copies/mL (89.8 % for MVC vs 86.9% for ATV/rtv), however more subjects in the MVC arm experienced virologic failure when the study endpoint of % with less than 50 copies/mL at 48 weeks was examined (74.6% for MVC vs 83.6% for ATV/rtv). Of note, all 7/9 MVC subjects and 3/3 ATV/rtv subjects with viral loads greater than 50 copies/mL at 48 weeks resuppressed virus to less than 50 copies/mL with subsequent monitoring. All viral load measurements greater than 50 copies/mL in the 9 MVC subjects and 2 of 3 in the ATV/rtv subjects were less than 200 copies/mL bringing into question if these were viral “blips”. CD4+ cell increases from baseline were comparable between the two arms and interestingly not greater in the MVC arm as seen in previous MVC studies. Of note, no genotypic nor phenotypic, including viral tropism shifts for the MVC-treated subjects, were detected.

    33. Study A4001078: Safety Overall, Aes were well-balanced between the two arms of the study with the exception of the occurrence of grade 3 or 4 increased indirect bilirubin which occurred more commonly inn the MVC arm. This AE accounted for more treatment discontiuations and study treatment switches as allowed per protocol. Overall, Aes were well-balanced between the two arms of the study with the exception of the occurrence of grade 3 or 4 increased indirect bilirubin which occurred more commonly inn the MVC arm. This AE accounted for more treatment discontiuations and study treatment switches as allowed per protocol.

    34. ECHO and THRIVE: 96 Week Follow-Up The ECHO and THRIVE studies were almost identical phase III randomized, controlled, double-blinded, double-dummy trials which compared rilpivirine (TMC 278) with efavirenz. TDF/FTC was used as the dual NRTI exclusively in ECHO while in THRIVE this was selected by the investigator (ZDV/3TC, TDF/FTC, ABC/3TC). The 48 week results were presented a year ago (IAS 2010 in Vienna) and this was extended for 96 weeks, which represents the final analysis. Because the studies were similar, their results are presented in a pooled data set. The ECHO and THRIVE studies were almost identical phase III randomized, controlled, double-blinded, double-dummy trials which compared rilpivirine (TMC 278) with efavirenz. TDF/FTC was used as the dual NRTI exclusively in ECHO while in THRIVE this was selected by the investigator (ZDV/3TC, TDF/FTC, ABC/3TC). The 48 week results were presented a year ago (IAS 2010 in Vienna) and this was extended for 96 weeks, which represents the final analysis. Because the studies were similar, their results are presented in a pooled data set.

    35. Pooled ECHO and THRIVE: VL <50 copies/mL Over 96 Weeks (ITT-TLOVR) The ITT-TLOVR analysis at 96 weeks reveals 79% of rilipivirine subjects and 78 % of efavirenz subjects achieved HIV RNA levels less than 50 copies/ML at 48 weeks. The snapshot analysis which uses the final viral load measurement and does not need confirmation revealed similar results. These results did not exceed the pre-defined 12% difference in the lower bound of the 95 % confidence interval and so these results confirmed that the two treatments were statistically non-inferior. The improvements immunologically were similar as well (RPV +226 vs EFV +219 cells/mm3. The virologic efficacy was stable after 48 weeks and showed a slight decline in both arms. The ITT-TLOVR analysis at 96 weeks reveals 79% of rilipivirine subjects and 78 % of efavirenz subjects achieved HIV RNA levels less than 50 copies/ML at 48 weeks. The snapshot analysis which uses the final viral load measurement and does not need confirmation revealed similar results. These results did not exceed the pre-defined 12% difference in the lower bound of the 95 % confidence interval and so these results confirmed that the two treatments were statistically non-inferior. The improvements immunologically were similar as well (RPV +226 vs EFV +219 cells/mm3. The virologic efficacy was stable after 48 weeks and showed a slight decline in both arms.

    36. Pooled ECHO and THRIVE: Virologic Outcomes and Resistance After 96 Weeks Similar rates of VF in both groups after 48 wks Emergence of mutations after 48 wks was similar in both groups RPV 7 (39%) vs. EFV 6 (43%) Pooled Grade 2-4 adverse events from wk 48-96: RPV 14 (2%) vs. EFV 26 (4%) (P<0.001) Overall through 96 weeks of follow-up, there were more virologic failures in the rilpivirine arm, however there were similar rates of virologic failure in each arm between weeks 48 and 96 with similar rates of rebound in both arms. This was in contrast to the higher rates of virologic failure in greater than 100,000 copies/mL at baseline strata seen at week 48. In this second year of the study the majority of subjects in each arm who achieved virologic suppression at week 48, remained virologically suppressed at week 96. There was similar rates of emergence of viral resistance mutations after week 48 in each arm. Again this was a change from the week 48 results where resistance was seen more frequently in the rilpivirine-failing subjects. Adverse events were similar in the second 48 weeks of the study between the two arms. This was also a change form the first year results in which significantly more adverse events were seen with efavirenz. Overall through 96 weeks of follow-up, there were more virologic failures in the rilpivirine arm, however there were similar rates of virologic failure in each arm between weeks 48 and 96 with similar rates of rebound in both arms. This was in contrast to the higher rates of virologic failure in greater than 100,000 copies/mL at baseline strata seen at week 48. In this second year of the study the majority of subjects in each arm who achieved virologic suppression at week 48, remained virologically suppressed at week 96. There was similar rates of emergence of viral resistance mutations after week 48 in each arm. Again this was a change from the week 48 results where resistance was seen more frequently in the rilpivirine-failing subjects. Adverse events were similar in the second 48 weeks of the study between the two arms. This was also a change form the first year results in which significantly more adverse events were seen with efavirenz.

    37. Treatment Experienced Patients and New Antivirals Calvin J. Cohen, MD, MSc Research Director, CRI New England Harvard Vanguard Medical Associates Clinical Instructor Harvard Medical School Boston, MA

    38. SWIFT: ABC/3TC to TDF/FTC Switch Trial Primary Endpoint was the percentage who had a viral load <200 c/mL through 48 weeks Used TLOVR definition of failure: virologic failure, premature discontinuations, ARV changes -12% margin for definition of Non-inferiority DHHS and IAS-USA Guidelines1 list FTC/TDF as the “preferred” NRTI backbone and 3TC/ABC as an alternative backbone. The DHHS Committee based its recommendations on ACTG 5202, ASSERT, hypersensitivity reactions (HSR) to 3TC/ABC, D:A:D Cohort. EACS Guidelines list both FTC/TDF and 3TC/ABC as recommended and when using ABC, states the need for HLA-B*5701 testing and caution in persons with higher risk of CV disease and baseline high viral load. BICOMBO showed less virologic failures at week 48 and ROCKET I demonstrated lipid benefits in subjects on FTC/TDF compared to 3TC/ABC. These Guidelines and published studies may prompt clinicians to consider switching virologically stable patients from 3TC/ABC to FTC/TDF This study was designed to assess the safety and tolerability of switching from ABC/3TC to TDF/FTC in patients with HIV suppression on a boosted PI based regimen. DHHS and IAS-USA Guidelines1 list FTC/TDF as the “preferred” NRTI backbone and 3TC/ABC as an alternative backbone. The DHHS Committee based its recommendations on ACTG 5202, ASSERT, hypersensitivity reactions (HSR) to 3TC/ABC, D:A:D Cohort. EACS Guidelines list both FTC/TDF and 3TC/ABC as recommended and when using ABC, states the need for HLA-B*5701 testing and caution in persons with higher risk of CV disease and baseline high viral load. BICOMBO showed less virologic failures at week 48 and ROCKET I demonstrated lipid benefits in subjects on FTC/TDF compared to 3TC/ABC. These Guidelines and published studies may prompt clinicians to consider switching virologically stable patients from 3TC/ABC to FTC/TDF This study was designed to assess the safety and tolerability of switching from ABC/3TC to TDF/FTC in patients with HIV suppression on a boosted PI based regimen.

    39. SWIFT: Primary Endpoint Virologic Failure (>200 c/mL): 3 TDF/FTC, 11 ABC/3TC No resistance detected in the subset of virologic failures that qualified for genotyping The % of subject with HIV RNA <200 c/mL through Week 48 by TLOVR was 86% in the FTC/TDF and 83% in the 3TC/ABC arm. Given the 95% confidence interval, FTC/TDF was non inferior to 3TC/ABC and a treatment difference of 3%, ranging from -5 to 11, which was within the predefined confidence interval of 12% to show non inferiority. There were a few pts with virologic failure above 200 c/mL – but no resistance was found in the few pts whose viral load was high enough to allow for resistance testing. The % of subject with HIV RNA <200 c/mL through Week 48 by TLOVR was 86% in the FTC/TDF and 83% in the 3TC/ABC arm. Given the 95% confidence interval, FTC/TDF was non inferior to 3TC/ABC and a treatment difference of 3%, ranging from -5 to 11, which was within the predefined confidence interval of 12% to show non inferiority. There were a few pts with virologic failure above 200 c/mL – but no resistance was found in the few pts whose viral load was high enough to allow for resistance testing.

    40. SWIFT: Changes in Fasting Lipids at Week 48 40 Improvements were noted in lipid fractions to a greater extent for those taking TDF/FTC vs. ABC/3TC. There were significant declines noted for total cholesterol and for LDL fractions. Minimal changes were noted to the HDL component. The clinical significance of these changes is still not certain. Improvements were noted in lipid fractions to a greater extent for those taking TDF/FTC vs. ABC/3TC. There were significant declines noted for total cholesterol and for LDL fractions. Minimal changes were noted to the HDL component. The clinical significance of these changes is still not certain.

    41. SWIFT: Estimated GFR Outcomes Through 48 Weeks 41 There were small changes over the one year noted in the estimated GFR using either the CG or MDRD equations. While there is a statistically significant greater decline in eGFR for TDF/FTC over the one year time period, with nearly overlapping IQRs, the clinical significance of this difference is uncertain. There were small changes over the one year noted in the estimated GFR using either the CG or MDRD equations. While there is a statistically significant greater decline in eGFR for TDF/FTC over the one year time period, with nearly overlapping IQRs, the clinical significance of this difference is uncertain.

    42. Subanalysis of MOTIVATE 1 and 2: Maraviroc QD or BID Plus boosted-PI in Treatment-Experienced Patients MOTIVATE 1 and 2: Maraviroc vs. placebo in treatment experienced patients Comparison of MVC 150 mg QD, MVC 150 mg BID and placebo in pts also taking a boosted PI PK exposures to MVC 150 mg QD in presence of most ritonavir boosted PIs similar to currently approved dose in treatment-naďve patients Analysis restricted to those confirmed R5 by ESTA test There is recent interest in the use of maraviroc once daily when starting treatment with a boosted PI only. This analysis of the MOTIVATE studies was done to assess the results of MVC 150 QD vs MVC 150 BID when given with a boosted PI in the motivate trials. This analysis is restricted to those with R5 virus as determined by the current enhanced sensitivity R5 assay. The analysis confirms that both doses resulted in similar rates of suppression of HIV at one year, and both were superior to placebo results. These data support further development of the MVC 150 mg QD strategy when given with a boosted PI. There is recent interest in the use of maraviroc once daily when starting treatment with a boosted PI only. This analysis of the MOTIVATE studies was done to assess the results of MVC 150 QD vs MVC 150 BID when given with a boosted PI in the motivate trials. This analysis is restricted to those with R5 virus as determined by the current enhanced sensitivity R5 assay. The analysis confirms that both doses resulted in similar rates of suppression of HIV at one year, and both were superior to placebo results. These data support further development of the MVC 150 mg QD strategy when given with a boosted PI.

    43. Elvitegravir vs. Raltegravir: Study Design Background: Elvitegravir is an investigational once-daily integrase inhibitor with a long half life, and robust PK with trough levels of over 10-fold in excess of IC95. Methods: Adults with plasma HIV-1 RNA =1,000 copies/mL, and either resistance or six months experience to > 2 classes of antiretroviral drugs were randomized to receive blinded elvitegravir (EVG) 150 mg QD (85 mg if with atazanavir/lopinavir) or raltegravir (RAL) 400mg BID, in addition to a background regimen (BR) of a fully active ritonavir-boosted protease inhibitor and a second agent (investigator choice). The primary endpoint was the proportion of subjects achieving and maintaining HIV RNA < 50 copies/mL through Week 48 by TLOVR algorithm, with a non-inferiority threshold set at -10% (EVG-RAL). Background: Elvitegravir is an investigational once-daily integrase inhibitor with a long half life, and robust PK with trough levels of over 10-fold in excess of IC95. Methods: Adults with plasma HIV-1 RNA =1,000 copies/mL, and either resistance or six months experience to > 2 classes of antiretroviral drugs were randomized to receive blinded elvitegravir (EVG) 150 mg QD (85 mg if with atazanavir/lopinavir) or raltegravir (RAL) 400mg BID, in addition to a background regimen (BR) of a fully active ritonavir-boosted protease inhibitor and a second agent (investigator choice). The primary endpoint was the proportion of subjects achieving and maintaining HIV RNA < 50 copies/mL through Week 48 by TLOVR algorithm, with a non-inferiority threshold set at -10% (EVG-RAL).

    44. EVG vs. RAL: Baseline Characteristics and Background Regimens 44 This slide summarizes the baseline characteristics and main components of the optimized background regimens in the entire study population. The majority of patients had two or more class resistance, while only about one third had PI resistance. The most common PIs used were darunavir, and then lopinavir. The most common third drug was a nucleoside RT inhibitor and the most common one was tenofovir. About a quarter used TDF/FTC instead and patients whose resistance assay showed the M184V or M184I were allowed to add 3TC or FTC to their regimen without counting as a fourth antiviral.This slide summarizes the baseline characteristics and main components of the optimized background regimens in the entire study population. The majority of patients had two or more class resistance, while only about one third had PI resistance.

    45. EVG vs. RAL: Week 48 Results 45 Key 48 Week Results: for Elvitegravir vs. Raltegravir HIV RNA < 50 copies/mL(TLOVR) Responder, n (%) 207/351 (59%) 203/351 (58%) 95% CI, -6.0% to 8.2%, * p= 0.001 for non inferiority Increase in CD4 cells/mm3, mean 138 vs 147 cells/mm Development of Integrase Resistance 16/62 vs 15/76 Discontinuations due to Adverse Events, n (%) 9/354 vs. 15/358   Adverse events (AE) and laboratory abnormalities were similar. Conclusion: This study demonstrated that once daily EVG was non-inferior to twice daily RAL in treatment-experienced HIV-1 infected subjects with similar AE profiles overall. Key 48 Week Results: for Elvitegravir vs. Raltegravir HIV RNA < 50 copies/mL(TLOVR) Responder, n (%) 207/351 (59%) 203/351 (58%) 95% CI, -6.0% to 8.2%, * p= 0.001 for non inferiority Increase in CD4 cells/mm3, mean 138 vs 147 cells/mm Development of Integrase Resistance 16/62 vs 15/76 Discontinuations due to Adverse Events, n (%) 9/354 vs. 15/358  

    46. EVG vs. RAL: Select Adverse Events and Labs 46 Discontinuations due to Adverse Events, n (%) 9/354 (3%) 15/358 (4%)   Adverse events (AE) and laboratory abnormalities were similar. There was a 5% higher rate of diarrhea observed with EVG vs RAL. Lipid outcomes were similar. There was a lower rate of transaminase elevations noted on EVG. Conclusion: This study demonstrated that once daily EVG was non-inferior to twice daily RAL in treatment-experienced HIV-1 infected subjects with a safety profile that shows few adverse events and few differences of the two compounds tested.

    47. Lersivirine in ARV-Naďve Patients: Phase 2b Trial Design Planned interim analysis at week 24 Primary endpoint at week 48: HIV RNA <50 c/mL Pts followed to week 96 Eligibility criteria HIV-1 RNA =1,000 c/mL CD4 >200/mm3 Absence of any RT mutations (using standard genotyping) Randomization stratified by: Viral load (< or =100,000 c/mL) Geographic region 47 Background: Lersivirine is a second-generation NNRTI with a unique resistance profile, currently under development. Methods: Study A5271015 is an ongoing 96-week, international, double-blind, randomised, Phase IIb study in HIV-1 infected, treatment-naďve patients to assess antiviral activity and safety of lersivirine (500/750mg once daily [QD]) or efavirenz (600mg QD), each combined with tenofovir DF/emtricitabine (300mg/200mg QD). Primary endpoint was percentage of patients with HIV-1 RNA < 50 copies/mL (missing/discontinuation=failure) at 48 weeks. Background: Lersivirine is a second-generation NNRTI with a unique resistance profile, currently under development.Methods: Study A5271015 is an ongoing 96-week, international, double-blind, randomised, Phase IIb study in HIV-1 infected, treatment-naďve patients to assess antiviral activity and safety of lersivirine (500/750mg once daily [QD]) or efavirenz (600mg QD), each combined with tenofovir DF/emtricitabine (300mg/200mg QD). Primary endpoint was percentage of patients with HIV-1 RNA < 50 copies/mL (missing/discontinuation=failure) at 48 weeks.

    48. Lersivirine: Week 48 Virologic Outcomes 48 Results: Overall, 193 patients were randomised 1:1:1 and received study treatment. Baseline mean viral load was 4.7 log10 copies/mL; median CD4+ cell count 310 cells/mm3. Percentage of patients with HIV-1 RNA < 50 copies/mL was 51/65 (79%), 51/65 (79%) and 54/63 (86%) in lersivirine 500mg, 750mg and efavirenz groups, respectively. CD4+ cell count changes from baseline were similar across groups: lersivirine 500mg: +194.2 cells/mm3, 750mg: +199.4 cells/mm3, efavirenz: +196.7cells/mm3 Results: Overall, 193 patients were randomised 1:1:1 and received study treatment. Baseline mean viral load was 4.7 log10 copies/mL; median CD4+ cell count 310 cells/mm3. Percentage of patients with HIV-1 RNA < 50 copies/mL was 51/65 (79%), 51/65 (79%) and 54/63 (86%) in lersivirine 500mg, 750mg and efavirenz groups, respectively. CD4+ cell count changes from baseline were similar across groups: lersivirine 500mg: +194.2 cells/mm3, 750mg: +199.4 cells/mm3, efavirenz: +196.7cells/mm3

    49. Lersivirine: Reported Adverse Events 49 Most common adverse events (AEs, all causalities) with efavirenz were abnormal dreams (8% lersivirine 500mg, 8% 750mg, 19% efavirenz) and dizziness (8% lersivirine 500mg, 6% 750mg, 21% efavirenz). Most common AEs with lersivirine were nausea (23% lersivirine 500mg, 42% 750mg, 13% efavirenz) and headache (23% lersivirine 500mg, 17% 750mg, 14% efavirenz). Rash and grade 3/4 AEs were less frequent with lersivirine than efavirenz (rash: 5% lersivirine 500mg, 2% 750mg, 11% efavirenz; grade 3/4 AEs: 6% lersivirine 500mg, 14% 750mg, 22% efavirenz). AE-related discontinuations occurred in 3 (lersivirine 500mg), 3 (750mg) and 5 (efavirenz) patients. Few clinically significant laboratory abnormalities were reported. Lersivirine was not associated with increases in total cholesterol, low-density lipoprotein cholesterol, or triglycerides (+0.9, -1.7, -1.5 mg/dL lersivirine 500mg; -4.2, -4.6, -3.1 mg/dL 750mg; +15.5, +4.0, +10.6 mg/dL efavirenz). Most common adverse events (AEs, all causalities) with efavirenz were abnormal dreams (8% lersivirine 500mg, 8% 750mg, 19% efavirenz) and dizziness (8% lersivirine 500mg, 6% 750mg, 21% efavirenz). Most common AEs with lersivirine were nausea (23% lersivirine 500mg, 42% 750mg, 13% efavirenz) and headache (23% lersivirine 500mg, 17% 750mg, 14% efavirenz). Rash and grade 3/4 AEs were less frequent with lersivirine than efavirenz (rash: 5% lersivirine 500mg, 2% 750mg, 11% efavirenz; grade 3/4 AEs: 6% lersivirine 500mg, 14% 750mg, 22% efavirenz). AE-related discontinuations occurred in 3 (lersivirine 500mg), 3 (750mg) and 5 (efavirenz) patients. Few clinically significant laboratory abnormalities were reported. Lersivirine was not associated with increases in total cholesterol, low-density lipoprotein cholesterol, or triglycerides (+0.9, -1.7, -1.5 mg/dL lersivirine 500mg; -4.2, -4.6, -3.1 mg/dL 750mg; +15.5, +4.0, +10.6 mg/dL efavirenz).

    50. Metabolic and Other Adverse Events Paul E. Sax, MD Clinical Director, Division of Infectious Diseases and HIV Program Brigham and Women's Hospital Associate Professor of Medicine, Harvard Medical School Boston, MA

    51. Aging of HIV Population: San Francisco Population-based HIV registry from 2006-2010 Registry increased from 9,001 to 9,673 mostly due to decline in deaths Those older than 50 now 53% of population, up from 41% in 2006 --fastest growing subset of patients Background: Increased use of anti-retroviral therapy has resulted in significant declines in mortality and an increased survival time from HIV to AIDS. As a result, older persons are the fastest growing population of people living with AIDS. Methods: We used San Francisco's (SF) population-based HIV/AIDS surveillance registry to examine trends among persons diagnosed and living with AIDS. AIDS case reporting has been validated as over 95% complete. Death ascertainment is continually updated with National and State death index matches and local death certificate reviews. The national death index match is complete through 2008. Results: The number of persons living with AIDS (PLWA) in SF steadily increased from 9,001 in 2006 to 9,673 in 2010. Of PLWA, 92% were male, 6% women and 2% transgender. Between 2006-2009, 23% of cases newly diagnosed with AIDS were over 50 years old compared to 27% in 2010. Deaths declined from 288 in 2006 to 228 in 2008. By 2010, the proportion of PLWA over age 50 had increased to 53% from 41% in 2006. (See Figure.) [Trends in persons living with AIDS by age] Conclusion: In 2010, for the first time the majority of PLWA in SF were over the age of 50. The aging nature of the HIV/AIDS epidemic is significant and will continue given trends in older age at diagnosis and declining deaths. Faced with both HIV/AIDS-related and age-related co-morbidities, the growing population of older persons with AIDS presents new challenges for research, medical care and support services. Background: Increased use of anti-retroviral therapy has resulted in significant declines in mortality and an increased survival time from HIV to AIDS. As a result, older persons are the fastest growing population of people living with AIDS. Methods: We used San Francisco's (SF) population-based HIV/AIDS surveillance registry to examine trends among persons diagnosed and living with AIDS. AIDS case reporting has been validated as over 95% complete. Death ascertainment is continually updated with National and State death index matches and local death certificate reviews. The national death index match is complete through 2008. Results: The number of persons living with AIDS (PLWA) in SF steadily increased from 9,001 in 2006 to 9,673 in 2010. Of PLWA, 92% were male, 6% women and 2% transgender. Between 2006-2009, 23% of cases newly diagnosed with AIDS were over 50 years old compared to 27% in 2010. Deaths declined from 288 in 2006 to 228 in 2008. By 2010, the proportion of PLWA over age 50 had increased to 53% from 41% in 2006. (See Figure.) [Trends in persons living with AIDS by age] Conclusion: In 2010, for the first time the majority of PLWA in SF were over the age of 50. The aging nature of the HIV/AIDS epidemic is significant and will continue given trends in older age at diagnosis and declining deaths. Faced with both HIV/AIDS-related and age-related co-morbidities, the growing population of older persons with AIDS presents new challenges for research, medical care and support services.

    52. ECHO/THRIVE: Change in Lipids through 96 Weeks The Echo and thrive studies compared efavirenz with rilpivirine;96 week data demonstrate a continued favorable lipid profile of rilpivirine, with smaller increases in total cholesterol, LDL cholesterol, and triglycerides. Since HDL cholesterol increased more in the efavirenz arm, the total to HDL cholesterol ratio was not significantly different between study arms.The Echo and thrive studies compared efavirenz with rilpivirine;96 week data demonstrate a continued favorable lipid profile of rilpivirine, with smaller increases in total cholesterol, LDL cholesterol, and triglycerides. Since HDL cholesterol increased more in the efavirenz arm, the total to HDL cholesterol ratio was not significantly different between study arms.

    53. RADAR: Fasting Lipids and Renal Function In this small prospective randomized trial in treatment naďve patients, once daily boosted darunavir was combined with either tenofovir/FTC or raltegravir. Virologic outcomes were similar, although the small sample size (n=80 total) makes it impossible to draw firm conclusions about the efficacy of these 2 approaches. In general, lipid changes from baseline to week 24 were numerically greater in the raltegravir than in the tenofovir FTC arm In this small prospective randomized trial in treatment naďve patients, once daily boosted darunavir was combined with either tenofovir/FTC or raltegravir. Virologic outcomes were similar, although the small sample size (n=80 total) makes it impossible to draw firm conclusions about the efficacy of these 2 approaches. In general, lipid changes from baseline to week 24 were numerically greater in the raltegravir than in the tenofovir FTC arm

    54. SENSE: Lipid Abnormalities at 48 Weeks Although not FDA approved for treatment naďve patients, etravirine once daily as a potentially attractive option given its potency, relatively high genetic barrier for an NNRTI, and the newly available 200 mg tablet. In the SENSE study, patients randomized to receive etravirine at a lower rate of grade 3 or 4 lipid abnormalities at 48 weeks then patients receiving efavirenz.Although not FDA approved for treatment naďve patients, etravirine once daily as a potentially attractive option given its potency, relatively high genetic barrier for an NNRTI, and the newly available 200 mg tablet. In the SENSE study, patients randomized to receive etravirine at a lower rate of grade 3 or 4 lipid abnormalities at 48 weeks then patients receiving efavirenz.

    55. Prevalence of Lipodystrophy in Current ART Era Cross-sectional study of HIV patients at Australian clinic, comparing 1998 to 2010 Definition of lipodystrophy (LD) from original case definition Results: Participants older, healthier from HIV and CV risk factor perspective Prevalence of study-defined LD has declined from 69 to 58% In multivariate analysis, use of tenofovir or abacavir associated with significantly lower risk Conclusion: Although prevalence of LD has declined, it remains relatively common – especially in long-term survivors Current antiretrovirals are less likely to induce changes in body habitus than those used in the early antiretroviral therapy. In the study, the cross-sectional prevalence of lipodystrophy in 2010 was compared to that reported in 1998. As shown on the table, while the patients not surprisingly have aged, they are healthier from the HIV and the cardiovascular risk factor perspective. In addition, the prevalence of lipodystrophy has declined, although remained somewhat common especially for those who have been living with HIV for a long time. Among treatment effects, use of tenofovir or abacavir was associated with a significantly lower risk. Background: The prevalence of lipodystrophy is unknown. Potent antiretroviral drugs with improved long term tolerability, trend to earlier initiation of ART, combined with an ageing cohort have influenced the prevalence of lipodystrophy. The aim of this study was to compare the prevalence and predictors of lipodystrophy using methodology used in 1998, when last evaluated in the HIV Ambulatory Clinic at Alfred Hospital, Melbourne, Australia. Methods: HIV-infected males underwent dual energy X-ray absorptiometry (DEXA) scanning, plasma lipids and questionnaire in a cross-sectional study. Lipodsytrophy was defined according to Australian National Centre for HIV Epidemiology and Clinical Research definition. 2010 cohort data was compared to original 1998 cohort. Predictors of lipodystrophy in 2010 were assessed: univariate and multivariate regression. Results: Lipodystrophy Prevalence; 1998= 68.5% 2010= 53.5% (p= 0.02) Variable 1998 (mean/median) 2010 (mean/median) Variable 1998 (mean/median) 2010 (mean/median) Age (years) * 41.7 ± 9.2 51.8 ± 8.7 Weight (kg) 76.0 ± 9.8 79.2 ± 12.8 HIV duration (months)* 81.0 (IQR 35, 144) 157.5 (IQR 78, 220) Waist (cm) * 89.9 ± 8.0 95.5 ± 10.2 ART duration (months)* 38.0 (IQR 22, 73) 129.5 (IQR 51, 168) DEXA total fat (%)* 17.5 ± 6.8 22.1 ± 8.2 CD4 count (cells/mL)* 304 (IQR 170, 507) 585 (IQR 403, 754) Cholesterol (mmol/L)* 5.6 ± 2.6 5.0 ± 1.2 Viral load (copies/mL)* 250 (IQR 250, 12800) 250 (IQR 250, 250) Triglyceride (mmol/L)* 2.2 (IQR 1.6, 4.0) 1.7 (IQR 1.2, 2.3) [1998 vs. 2010] *p< 0.05 Antiretroviral therapy 1998 2010 p- value Current PI use % 92.0 50.0 < 0.005 Current d4T use % 53.8 0 < 0.005 Current AZT use % 26.8 12.0 0.007 [Antiretroviral Therapy 1998 vs. 2010] 2010 cohort: univariate analysis: Lipodystrophy predictors; Metabolic syndrome, Framingham risk, HIV duration. Metabolic Syndrome (OR:6.3CI: 2.2-17.7) remained significant after multivariate analysis. Tenofovir was associated with reduced risk of Lipodystrophy (OR:0.8,CI 0.68-0.99)* Conclusion: Despite aging, longer HIV and ART duration, the prevalence of lipodystrophy over 12 years has declined. In 2010 there is a significant reduction in the current use of stavudine, zidovudine and PI backbones with the availability of 'metabolically friendlier' ART. Lipodystrophy defined according to the National Centre HIV Epidemiology and Clinical Research (NCHECR) with both major and minor criteria: Major: < 20% total body fat on DEXA ± Waist Circumference>90cmPLUS-Minor: Cholesterol>5.5mmol/L±Triglycerides>2.0mmol/L Patient defined Lipoatrophy subjective questionnaire reflecting on presence or absence of facial or arm, leg and/ or buttocks fat wasting Patient defined Lipodystrophy patient report of peripheral lipoatrophy and dorsocervical or abdominal fat accumulation/ hypertrophy were evident. Metabolic Syndrome: NCEP ATP III criteria. 3 or more of the following: Waist circ > 102cm, HDL-Chol < 1.03mmol, Trigs > 1.7mmol (or on treatment for same), Syst BP >135mg/Hg, Diast BP > 85mg/Hg (or on treatment for same). Framingham Cardiovascular Disease (CVD) risk score: High risk > 15%, Intermediate 10-15%, Low < 10%Current antiretrovirals are less likely to induce changes in body habitus than those used in the early antiretroviral therapy. In the study, the cross-sectional prevalence of lipodystrophy in 2010 was compared to that reported in 1998. As shown on the table, while the patients not surprisingly have aged, they are healthier from the HIV and the cardiovascular risk factor perspective. In addition, the prevalence of lipodystrophy has declined, although remained somewhat common especially for those who have been living with HIV for a long time. Among treatment effects, use of tenofovir or abacavir was associated with a significantly lower risk. Background: The prevalence of lipodystrophy is unknown. Potent antiretroviral drugs with improved long term tolerability, trend to earlier initiation of ART, combined with an ageing cohort have influenced the prevalence of lipodystrophy. The aim of this study was to compare the prevalence and predictors of lipodystrophy using methodology used in 1998, when last evaluated in the HIV Ambulatory Clinic at Alfred Hospital, Melbourne, Australia. Methods: HIV-infected males underwent dual energy X-ray absorptiometry (DEXA) scanning, plasma lipids and questionnaire in a cross-sectional study. Lipodsytrophy was defined according to Australian National Centre for HIV Epidemiology and Clinical Research definition. 2010 cohort data was compared to original 1998 cohort. Predictors of lipodystrophy in 2010 were assessed: univariate and multivariate regression. Results: Lipodystrophy Prevalence; 1998= 68.5% 2010= 53.5% (p= 0.02) Variable 1998 (mean/median) 2010 (mean/median) Variable 1998 (mean/median) 2010 (mean/median) Age (years) * 41.7 ± 9.2 51.8 ± 8.7 Weight (kg) 76.0 ± 9.8 79.2 ± 12.8 HIV duration (months)* 81.0 (IQR 35, 144) 157.5 (IQR 78, 220) Waist (cm) * 89.9 ± 8.0 95.5 ± 10.2 ART duration (months)* 38.0 (IQR 22, 73) 129.5 (IQR 51, 168) DEXA total fat (%)* 17.5 ± 6.8 22.1 ± 8.2 CD4 count (cells/mL)* 304 (IQR 170, 507) 585 (IQR 403, 754) Cholesterol (mmol/L)* 5.6 ± 2.6 5.0 ± 1.2 Viral load (copies/mL)* 250 (IQR 250, 12800) 250 (IQR 250, 250) Triglyceride (mmol/L)* 2.2 (IQR 1.6, 4.0) 1.7 (IQR 1.2, 2.3) [1998 vs. 2010] *p< 0.05 Antiretroviral therapy 1998 2010 p- value Current PI use % 92.0 50.0 < 0.005 Current d4T use % 53.8 0 < 0.005 Current AZT use % 26.8 12.0 0.007 [Antiretroviral Therapy 1998 vs. 2010] 2010 cohort: univariate analysis: Lipodystrophy predictors; Metabolic syndrome, Framingham risk, HIV duration. Metabolic Syndrome (OR:6.3CI: 2.2-17.7) remained significant after multivariate analysis. Tenofovir was associated with reduced risk of Lipodystrophy (OR:0.8,CI 0.68-0.99)* Conclusion: Despite aging, longer HIV and ART duration, the prevalence of lipodystrophy over 12 years has declined. In 2010 there is a significant reduction in the current use of stavudine, zidovudine and PI backbones with the availability of 'metabolically friendlier' ART. Lipodystrophy defined according to the National Centre HIV Epidemiology and Clinical Research (NCHECR) with both major and minor criteria: Major: < 20% total body fat on DEXA ± Waist Circumference>90cmPLUS-Minor: Cholesterol>5.5mmol/L±Triglycerides>2.0mmol/L Patient defined Lipoatrophy subjective questionnaire reflecting on presence or absence of facial or arm, leg and/ or buttocks fat wasting Patient defined Lipodystrophy patient report of peripheral lipoatrophy and dorsocervical or abdominal fat accumulation/ hypertrophy were evident. Metabolic Syndrome: NCEP ATP III criteria. 3 or more of the following: Waist circ > 102cm, HDL-Chol < 1.03mmol, Trigs > 1.7mmol (or on treatment for same), Syst BP >135mg/Hg, Diast BP > 85mg/Hg (or on treatment for same). Framingham Cardiovascular Disease (CVD) risk score: High risk > 15%, Intermediate 10-15%, Low < 10%

    56. Raltegravir Substitution for Lipohypertrophy Prospective study of women (n=37) with VL <50 on 2NRTIs + PI or NNRTI and lipohypertrophy – randomized to continue current ART or switch PI to RAL Results at 24 weeks: No statistically significant changes in adipose tissue, anthropometrics, or glucose metabolism Improvement in lipids observed in those switching from PI Lipohypertrophy remains one of the more vaccine challenges in HIV care. In the study of 37 women with virologic suppression and lipohypertrophy, fat distribution was assessed after 24 weeks of remaining on their current treatment versus substituting raltegravir for their third drug. As shown in the figure, there were no significant changes in adipose tissue distribution; similarly, anthropometrics and glucose metabolism were unchanged. There was a decline in lipids for those women who switched from a boosted PI to raltegravir. This study is one of several demonstrating no improvement in lipohypertrophy from antiretroviral switches. Background: Lipohypertrophy is a common problem associated with multiple metabolic abnormalities. Raltegravir (RAL) has not been associated with fat changes or severe metabolic perturbations. We assessed changes in adipose tissue (AT) volumes, anthropometric measurements, and fasting glucose and lipids 24 weeks following a switch to RAL vs. continued PI or NNRTI in HIV-infected women with lipohypertrophy. Methods: HIV-infected women with lipohypertrophy and HIV-1 RNA < 50 copies/ml were randomized to continue their NRTI backbone and switch to RAL vs. continue PI or NNRTI. Subcutaneous (SAT) and visceral (VAT) AT volumes were measured using L4-L5 single-slice CT scan. 36 subjects provided 80% power to detect a 10% improvement in VAT over 24 weeks. Results: 37 of 39 enrolled subjects completed Week 24. 59% African American, 24% Caucasian, 16% Hispanic, 3% Asian. Mean age 42 years, CD4 count 635 cells/µL, weight 88.6 kg, BMI 33.2. 43% current tobacco use. No statistically significant changes in: absolute or percent VAT or SAT, VAT: TAT, anthropometrics, or glucose were observed. Significant improvements in total and LDL cholesterol (both p=0.03) were seen with RAL (AT and lipid data presented in Table 1). No virologic failures, changes in CD4 count, or related Grade 3-4 adverse events occurred. In sub-analyses of subjects with BMI< 30, a switch to RAL led to similar improvements in lipids but no statistically significant AT improvements. 24-week Median Change (IQR) % VAT VAT (cm2) %SAT SAT (cm2) VAT: TAT Total Cholesterol (mg/dL) LDL (mg/dL) HDL (mg/dL) Triglycerides (mg/dL) Raltegravir (n=17) -3.57 (-11.87, 21.6) -6.58 (-15.54, 17.60) -0.12 (-8.03, 3.15) -0.50 (-31.20, 20.07) -0.01 (-0.03, 0.04) -17.0 (-31.0, -7.0) -12.0 (-23.9, 1.6) -1.3 (-5.0, 2.0) -16.0 (-29.0, 2.0) Control (n=20) 1.85 (-6.44, 5.53) 1.75 (-9.31, 8.08) -0.005 (-7.35, 3.96) -3.44 (-40.47, 20.49) 0.01 (-0.01, 0.02) 2.0 (-13.0, 15.5) 3.0 (-9.0, 16.0) 2.2 (-3.8, 7.0) 3.0 (-50.0, 24.0) P value (Raltegravir vs. Control) 0.43 0.52 0.93 0.85 0.39 0.03 0.03 0.19 0.35 [Table 1] Conclusions: Compared to continued PI or NNRTI use, switch to RAL demonstrated a statistically significant improvement in total and LDL cholesterol but not AT volumes after 24 weeks in this cohort of women with lipohypertrophy.Lipohypertrophy remains one of the more vaccine challenges in HIV care. In the study of 37 women with virologic suppression and lipohypertrophy, fat distribution was assessed after 24 weeks of remaining on their current treatment versus substituting raltegravir for their third drug. As shown in the figure, there were no significant changes in adipose tissue distribution; similarly, anthropometrics and glucose metabolism were unchanged. There was a decline in lipids for those women who switched from a boosted PI to raltegravir. This study is one of several demonstrating no improvement in lipohypertrophy from antiretroviral switches. Background: Lipohypertrophy is a common problem associated with multiple metabolic abnormalities. Raltegravir (RAL) has not been associated with fat changes or severe metabolic perturbations. We assessed changes in adipose tissue (AT) volumes, anthropometric measurements, and fasting glucose and lipids 24 weeks following a switch to RAL vs. continued PI or NNRTI in HIV-infected women with lipohypertrophy. Methods: HIV-infected women with lipohypertrophy and HIV-1 RNA < 50 copies/ml were randomized to continue their NRTI backbone and switch to RAL vs. continue PI or NNRTI. Subcutaneous (SAT) and visceral (VAT) AT volumes were measured using L4-L5 single-slice CT scan. 36 subjects provided 80% power to detect a 10% improvement in VAT over 24 weeks. Results: 37 of 39 enrolled subjects completed Week 24. 59% African American, 24% Caucasian, 16% Hispanic, 3% Asian. Mean age 42 years, CD4 count 635 cells/µL, weight 88.6 kg, BMI 33.2. 43% current tobacco use. No statistically significant changes in: absolute or percent VAT or SAT, VAT: TAT, anthropometrics, or glucose were observed. Significant improvements in total and LDL cholesterol (both p=0.03) were seen with RAL (AT and lipid data presented in Table 1). No virologic failures, changes in CD4 count, or related Grade 3-4 adverse events occurred. In sub-analyses of subjects with BMI< 30, a switch to RAL led to similar improvements in lipids but no statistically significant AT improvements. 24-week Median Change (IQR) % VAT VAT (cm2) %SAT SAT (cm2) VAT: TAT Total Cholesterol (mg/dL) LDL (mg/dL) HDL (mg/dL) Triglycerides (mg/dL) Raltegravir (n=17) -3.57 (-11.87, 21.6) -6.58 (-15.54, 17.60) -0.12 (-8.03, 3.15) -0.50 (-31.20, 20.07) -0.01 (-0.03, 0.04) -17.0 (-31.0, -7.0) -12.0 (-23.9, 1.6) -1.3 (-5.0, 2.0) -16.0 (-29.0, 2.0) Control (n=20) 1.85 (-6.44, 5.53) 1.75 (-9.31, 8.08) -0.005 (-7.35, 3.96) -3.44 (-40.47, 20.49) 0.01 (-0.01, 0.02) 2.0 (-13.0, 15.5) 3.0 (-9.0, 16.0) 2.2 (-3.8, 7.0) 3.0 (-50.0, 24.0) P value (Raltegravir vs. Control) 0.43 0.52 0.93 0.85 0.39 0.03 0.03 0.19 0.35 [Table 1] Conclusions: Compared to continued PI or NNRTI use, switch to RAL demonstrated a statistically significant improvement in total and LDL cholesterol but not AT volumes after 24 weeks in this cohort of women with lipohypertrophy.

    57. Pooled ECHO and THRIVE: DEXA Substudies In the ECHO and Thrive studies, a subset of patients underwent DEXA scans to assess fat distribution. As shown in the figure on the right, most patients gained fat, representing a return to health that is physically seen when treatment naďve patients begin HIV therapy; this was a statistically significant change from baseline for both groups, but not different between RPV or EFV. A subset of patients did lose another 10% or 20% of subcutaneous fat in the limbs, as shown in the table. Rates are similar to those described in other studies, such as A5224 (McComsey et al, Clin Infect Dis. 2011 Jul;53(2):185-96). In the ECHO and Thrive studies, a subset of patients underwent DEXA scans to assess fat distribution. As shown in the figure on the right, most patients gained fat, representing a return to health that is physically seen when treatment naďve patients begin HIV therapy; this was a statistically significant change from baseline for both groups, but not different between RPV or EFV. A subset of patients did lose another 10% or 20% of subcutaneous fat in the limbs, as shown in the table. Rates are similar to those described in other studies, such as A5224 (McComsey et al, Clin Infect Dis. 2011 Jul;53(2):185-96).

    58. Aquitaine Cohort: Risks for Chronic Kidney Disease Aquitaine cohort, 2004-2008 Eligible: Baseline creatinine clearance >60 mL/min/1.73m2 by MDRD CKD definition 2 consecutive measurements <60 Incidence: 10.1 cases per 1,000 person-years Risks by MV analysis: preexisting mild renal dysfunction, female, older age, DM, HTN, lower CD4, TDF exposure – risk increased if also given with PI/r The Aquitaine cohort is a Hospital-based cohort from France.in the study, they evaluated risks for chronic kidney disease among over 2600 patients receiving care from 2004 2008. the definition of chronic kidney disease was a decline in estimated creatinine clearance using the MDRD method from > 60 to < 60. the overall incidence was 10.1 cases per 1000 person-years. Risk factors by multivariate analysis included pre-existing mild renal dysfunction, female sex, older age, diabetes, hypertension, lower CD4, and tenofovir exposure. The risk of chronic kidney disease with tenofovir exposure was increased when it was given with a boosted protease inhibitor. WEPDB0104 - Poster Discussion Antiretroviral drugs and incidence of chronic kidney disease, ANRS CO3 Aquitaine cohort (2004-2008) Presented by Philippe Morlat (France). P. Morlat1,2, A. Vivot3, F. Dauchy1, J. Asselineau3, M.-A. Vandenhende1, E. Lazaro1, Y. Gérard4, F. Bonnet1,2, D. Neau1, P. Mercié1,2, E. Déti2, G. Chęne2,3, Groupe d'Epidémiologie Clinique du SIDA en Aquitaine 1CHU de Bordeaux, Services de Médecine Interne et Maladies Infectieuses, Bordeaux, France, 2Université Bordeaux Segalen, INSERM U 897, Bordeaux, France, 3CHU de Bordeaux, USMR, Bordeaux, France, 4CH de Dax, Service de Maladies Infectieuses, Dax, France Background: We examined the role of antiretroviral drugs (ART) on the incidence of chronic kidney disease (CKD) in HIV-infected patients. Methods: Creatinine clearance (CC) was estimated using the modification of diet in renal disease formula in a multicenter cohort. CKD was defined as a CC< 60 ml/min/1.73m2 (two consecutive measurements = 3 months apart). A Poisson regression model was used to investigate determinants of CKD measured at baseline, or updated [CD4+ lymphocytes count, HIV-RNA, cumulative exposure to ART]. Results: From January 2004 until December 2008, 2692 patients (76% men) with baseline CC>60 ml/min/1.73m2 were included and followed for a median of 3.4 years. Mean age was 42 years and median delay since HIV diagnosis 9.2 years; 21% had a history of AIDS; 80% were treated by ART. At the end of follow-up, 95% had received ART (mean cumulative exposure 7.5 years) among whom 35% received jointly (>6 months) tenofovir and a protease inhibitor (PI) [mainly atazanavir/r or lopinavir/r]. The average incidence rate of CKD was 10.1 cases per 1000 persons-years. 95% of those developing CKD had a baseline CC between 60 and 90. Incidence of CKD was higher (p< 0.05) among women (HR=1.94), older patients (>60 y: HR=3.68 and 45-60y: HR=1.95), with diabetes (HR=2.19), hyperlipidemia (HR=2.07), low baseline CC (HR=48 for 60< CC< 70 ; HR=19 for 70< CC< 80), latest CD4+< 200 cells/mm3 (HR=3.72), and exposure to tenofovir (HR=2.34 for >6 months). After 1 year of exposure, tenofovir was associated with a higher risk of CKD when co-administered with PI (HR=2.4 for 1-2 years; HR=3.4 for >2 years).  Conclusion: Cumulated exposure to tenofovir was associated with a higher incidence of CKD, as was true for preexisting mild renal impairment, traditional risk factors of CKD, severe immunodeficiency and female gender. Concomitant use of tenofovir and PI requires particular vigilance to prevent occurrence of CKD. The Aquitaine cohort is a Hospital-based cohort from France.in the study, they evaluated risks for chronic kidney disease among over 2600 patients receiving care from 2004 2008. the definition of chronic kidney disease was a decline in estimated creatinine clearance using the MDRD method from > 60 to < 60. the overall incidence was 10.1 cases per 1000 person-years. Risk factors by multivariate analysis included pre-existing mild renal dysfunction, female sex, older age, diabetes, hypertension, lower CD4, and tenofovir exposure. The risk of chronic kidney disease with tenofovir exposure was increased when it was given with a boosted protease inhibitor. WEPDB0104 - Poster Discussion

    59. Risk of Chronic Kidney Disease: Role of PI/r CANOC cohort, 2000-2010 (n=965)1 Eligible: ARV Tx naďve, starting TDF (682) or ABC (283) based ART; normal renal function After controlling for known causes of renal impairment: LPV/r and ATV/r associated with increased risk of CKD No association with TDF use (vs. ABC) Chelsea-Westminster Cohort: Among 2,115 patients (86% also on TDF), exposure to ATV/r and LPV/r (but not DRV/r) associated with increased risk of CKD2 2 additional cohort studies found associations between chronic kidney disease and some boosted protease inhibitors. In a group of 965 patients from Canada, all of whom were treatment naďve, after controlling for known causes of renal impairment investigators found that lopinavir/ritonavir and atazanavir ritonavir were associated with increased risk of chronic kidney disease. In this study, there was no association between tenofovir versus abacavir use. A second cohort, from England, which included over 2000 patients also demonstrated an association between LPV/r and ATV/r use and CKD. The mechanism by which boosted protease inhibitors could increase the risk of chronic kidney disease is not known. Tupe254: Background: Although potent antiretroviral therapy (ART) can significantly extend survival, concerns remain about long- term safety. Renal safety is an emerging issue in the treatment of chronic HIV infection and eGFR is an important clinical tool for assessing renal function. This study investigates whether use of atazanavir or lopinavir correlates to progression to impaired eGFR among patients on NRTI backbone containing either tenofovir (TDF) or abacavir (ABC). Methods: Treatment-naďve HIV-1-infected participants with initial ART regimens containing TDF or ABC were prospectively followed since 2000 across Canada. Regular assessments of viral load, CD4+ cell count, co-infections, creatinine, and lipid parameters were conducted. MDRD equations were used to calculate eGFR. Cox regression analysis was used for time to impaired eGFR (defined as < 60 mL/min). Results: A total of 965 patients were included in this analysis (87% male, 13% female), median age 39 years (IQR 33- 45), 14% known IDU, 18% hepatitis C positive, median CD4 219 cells/mm3 (IQR 137-290), median VL 4.8 log10 copies/ ml (IQR 4.3-5.0). Baseline NRTI use included 283 on ABC and 682 on TDF; initial third agents included 384 on atazanavir, 192 on lopinavir, and 389 on non-PI. In a multivariable proportional hazards model adjusting for province, baseline CD4, baseline VL, age, year therapy started, baseline eGFR and rate of eGFR testing, TDF use was not associated with increase risk of impaired eGFR (aHR 1.16, 95% CI 0.94-1.43, p=.177) compared to ABC use. Both lopinavir (aHR 1.32, 95% CI 1.04-1.69, p=.024) and atazanavir (aHR 1.46, 95% CI 1.18-1.81, p< .001) were associated with impaired eGFR relative to non-PI use. Conclusion: Results from this cohort suggest that treatment-naďve HIV-positive patients who are given PI-based regimens, particularly atazanavir, appear to be at increased risk for mild-to-moderate renal toxicity. We plan further analyses to explore this finding. A comparative analysis of risk factors associated with efavirenz, darunavir/ritonavir, lopinavir/ritonavir, atazanavir/ritonavir and renal impairment N. Rockwood, M. Nelson, S. Mandalia, B. Gazzard Chelsea and Westminster, HIV/GUM, London, United Kingdom Background: The long term effect of Protease Inhibitors(PIs) on renal function is unknown. We compared the effect of efavirenz(EFV) and boosted PIs atazanavir(ATZ), lopinavir(LPV) and darunavir(DRV) on reaching first eGFR< 60. Methods: 2115 patients were prescribed HAART containing 2NRTI+ EFV or PIs and had a baseline eGFR available between 06/06-02/10. Univariate and adjusted Cox's hazards regression model were used to show likelihood of renal impairment (eGFR< 60). Proportion of renal recovery after first eGFR< 60 was examined. Results: 386(18%) reached eGFR< 60. On univariate analysis, female gender(HR 1.51,p0.002), baseline age(p< 0.001), baseline eGFR(p< 0.001),DRV(HR1.53,p< 0.001), ATZ(HR 1.27,p0.036), LPV(HR 1.71,p< 0.001), prior Tenofovir(TFV) exposure(HR 1.68,p< 0.001), Hep B Sag +ve status(HR1.21,p< 0.001) and total duration TFV exposure(HR 1.09,p< 0.001) were associated with significantly increased risk of eGFR< 60. Ethnicity, baseline CD4 count, baseline viral load(VL), VL blips >500, prior EFV exposure and Hep C+ve status were not. EFV was linked with significantly decreased risk of eGFR< 60(HR 0.6,p< 0.001). Risk of eGFR< 60 increased by 9% per year exposure to TFV. Multivariate analysis with comparison to EFV showed DRV(HR 1.3,p0.014) and LPV(HR 1.8,p< 0.001) but not ATZ to have significantly increased risk of eGFR< 60. [ : This is different in the poster.]There were no significant differences between the EFV group(N=50) and PI group(N=160) in a subgroup analysis of traditional risk factors for renal impairment. Post first eGFR< 60, at 12months, 50% of patients had eGFR>60. Between 0-30months, there was a mean 31% increase in proportion of patients with renal recovery in those who stopped TFV compared to those who continued TFV(p< 0.001). Conclusion: There was significant risk of renal impairment with boosted LPV and DRV in the study. The effect of boosted ATZ on renal impairment was no longer significant after adjusting for TFV exposure. In individuals developing eGFR< 60, cessation of TFV was associated with higher rate of renal recovery. 2 additional cohort studies found associations between chronic kidney disease and some boosted protease inhibitors. In a group of 965 patients from Canada, all of whom were treatment naďve, after controlling for known causes of renal impairment investigators found that lopinavir/ritonavir and atazanavir ritonavir were associated with increased risk of chronic kidney disease. In this study, there was no association between tenofovir versus abacavir use. A second cohort, from England, which included over 2000 patients also demonstrated an association between LPV/r and ATV/r use and CKD. The mechanism by which boosted protease inhibitors could increase the risk of chronic kidney disease is not known. Tupe254: Background: Although potent antiretroviral therapy (ART) can significantly extend survival, concerns remain about long- term safety. Renal safety is an emerging issue in the treatment of chronic HIV infection and eGFR is an important clinical tool for assessing renal function. This study investigates whether use of atazanavir or lopinavir correlates to progression to impaired eGFR among patients on NRTI backbone containing either tenofovir (TDF) or abacavir (ABC). Methods: Treatment-naďve HIV-1-infected participants with initial ART regimens containing TDF or ABC were prospectively followed since 2000 across Canada. Regular assessments of viral load, CD4+ cell count, co-infections, creatinine, and lipid parameters were conducted. MDRD equations were used to calculate eGFR. Cox regression analysis was used for time to impaired eGFR (defined as < 60 mL/min). Results: A total of 965 patients were included in this analysis (87% male, 13% female), median age 39 years (IQR 33- 45), 14% known IDU, 18% hepatitis C positive, median CD4 219 cells/mm3 (IQR 137-290), median VL 4.8 log10 copies/ ml (IQR 4.3-5.0). Baseline NRTI use included 283 on ABC and 682 on TDF; initial third agents included 384 on atazanavir, 192 on lopinavir, and 389 on non-PI. In a multivariable proportional hazards model adjusting for province, baseline CD4, baseline VL, age, year therapy started, baseline eGFR and rate of eGFR testing, TDF use was not associated with increase risk of impaired eGFR (aHR 1.16, 95% CI 0.94-1.43, p=.177) compared to ABC use. Both lopinavir (aHR 1.32, 95% CI 1.04-1.69, p=.024) and atazanavir (aHR 1.46, 95% CI 1.18-1.81, p< .001) were associated with impaired eGFR relative to non-PI use. Conclusion: Results from this cohort suggest that treatment-naďve HIV-positive patients who are given PI-based regimens, particularly atazanavir, appear to be at increased risk for mild-to-moderate renal toxicity. We plan further analyses to explore this finding. A comparative analysis of risk factors associated with efavirenz, darunavir/ritonavir, lopinavir/ritonavir, atazanavir/ritonavir and renal impairment N. Rockwood, M. Nelson, S. Mandalia, B. Gazzard

    60. Bone Turnover Markers in SMART SMART study: Bone density decreased more in virologic suppression (VS) than drug conservation (DC) group Markers of bone formation and resorption both higher in VS group In the SMART study, the only benefit of the drug conservation versus virologic suppression strategy was that the former was associated with less bone mineral density loss. In this analysis of markers of bone formation and bone resorption, there is clearly an increase in the virologic suppression group compared with the drug conservation group. This suggests that antiretroviral therapy and/or the immunologic or virologic changes induced by treatment increase bone metabolism with a relative imbalance favoring bone resporption. Bone alk phos Osteocalcin: Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a noncollagenous protein found in bone and dentin Definition for p1np: Amino-terminal procollagen propeptides of type I collagen, used as a marker for bone formation.. In the SMART study, the only benefit of the drug conservation versus virologic suppression strategy was that the former was associated with less bone mineral density loss. In this analysis of markers of bone formation and bone resorption, there is clearly an increase in the virologic suppression group compared with the drug conservation group. This suggests that antiretroviral therapy and/or the immunologic or virologic changes induced by treatment increase bone metabolism with a relative imbalance favoring bone resporption. Bone alk phos Osteocalcin: Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a noncollagenous protein found in bone and dentin Definition for p1np: Amino-terminal procollagen propeptides of type I collagen, used as a marker for bone formation..

    61. Risk of Osteoporotic Fractures Data Source: Veterans Affairs’ Clinical Case Registry Predictors: Antiretroviral exposure: PY of exposure to NRTIs (TDF, ABC, AZT or D4T), NNRTI, boosted PI. Age, race, smoking, BMI, type 2 diabetes, HCV co-infection, chronic kidney disease Outcome: Incident osteoporotic fracture defined as any vertebral, hip, or wrist fracture by ICD-9 codes While several studies have documented a decline in bone mineral density with initiation of antiretroviral therapy – with a more pronounced effect from tenofovir – thus far most studies have not demonstrated an increase in fracture risk based on antiretroviral exposure. While several studies have documented a decline in bone mineral density with initiation of antiretroviral therapy – with a more pronounced effect from tenofovir – thus far most studies have not demonstrated an increase in fracture risk based on antiretroviral exposure.

    62. VA: Antiretroviral Exposure and Risk of Osteoporotic Fractures In the univariate analysis, exposure to tenofovir or a ritonavir boosted parties inhibitor was significantly associated with increased risk of osteoporotic fracture. In the first multivariable model, controlling for known causes of osteoporosis, the risk from the stroke exposures was reduced, but remained statistically significant. In a second MV model, controlling for medical risk factors for fracture plus ARV drug exposure, the risk of fracture remained significant only for tenofovir. Of note, the hazard ratio for fracture for tenofovir is between 1.1 and 1.2. MOAB0101 - Oral Abstract Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents Presented by Roger Bedimo (United States). R. Bedimo1,2, S. Zhang2, H. Drechsler1,2, P. Tebas3, N. Maalouf2 1VA North Texas Health Care System, Medicine, Dallas, United States, 2UT Southwestern Medical Center, Medicine, Dallas, United States, 3University of Pennsylvania, Medicine, Philadelphia, United States Background: Decreased bone mineral density is increasingly reported in the aging HIV-positive population. While tenofovir exposure has been associated with decreased bone mineral density, it remains unclear whether it´s associated with increased risk of osteoporotic fractures (OF).  Methods: Patients with any OF (defined as wrist, vertebral or hip fracture) occurring after HIV diagnosis were identified by ICD9 code in the Veterans Affairs´ Clinical Case Registry from 1984 to 2009. Pharmacy records were used to calculate cumulative exposure to different antiretroviral drugs prior to the first OF event or end of follow-up; controlling for race, age, tobacco use, diabetes, and body mass index (BMI). Results: 56,660 HIV-infected patients (98.1% male; mean age: 45.0 years) contributed 305,237 patient-years of follow-up (median: 4.5 years/patient). During this period, 951 patients sustained at least one OF(124 vertebral, 486 wrist and 341 hip). The following table summarizes the risk of OF by type of antiretroviral therapy (ART): Drug or Drug CategoryPY of ExposureHazard Ratio per Year of Exposure (95% Confidence Interval; p value)  Univariate AnalysisMulti-variable Model 1Multi-variable Model 2Tenofovir (TDF)460621.08 (1.02-1.15; 0.010)1.04 (0.98-1.11; 0.168)1.01 (0.93-1.10; 0.771)Abacavir (ABC)242510.99 (0.93-1.05; 0.737)0.95 (0.89-1.02; 0.157)0.95 (0.88-1.02; 0.141)ART with boosted protease inhibitors (rPI)327861.09 (1.03-1.16; 0.003)1.06 (0.998-1.126; 0.057)1.07 (0.99-1.16; 0.091)ART with NNRTI492800.99 (0.95-1.04; 0.715)0.96 (0.91-1.01; 0.077)0.98 (0.92-1.04; 0.420)ART with thymidine analogues704721.01 (0.98-1.05; 0.496)0.97 (0.94-1.01; 0.121)0.98 (0.93-1.04; 0.554)[Cumulative antiretroviral exposure and OF risk] Model 1: Controlling for CKD, are, race, tobacco use, diabetes and BMI Model 2: Controlling Model 1 variable + concomitant exposure to other antiretrovirals. Other factors independently associated with increased risk of OF included older age (HR=1.478), non-Black race (HR=1.614), tobacco use (HR=1.491) and BMI < 20 (HR=1.480). Conclusion: Cumulative exposure to TDF and rPI was associated with a modest increase in OF risk, which was no longer significant after controlling for traditional OF risk factors. In the univariate analysis, exposure to tenofovir or a ritonavir boosted parties inhibitor was significantly associated with increased risk of osteoporotic fracture. In the first multivariable model, controlling for known causes of osteoporosis, the risk from the stroke exposures was reduced, but remained statistically significant. In a second MV model, controlling for medical risk factors for fracture plus ARV drug exposure, the risk of fracture remained significant only for tenofovir. Of note, the hazard ratio for fracture for tenofovir is between 1.1 and 1.2. MOAB0101 - Oral Abstract

    63. STEAL: Changes in BMD by Switch to TDF/FTC or ABC/3TC In virologically suppressed patients, the STEAL study randomized subjects to either tenofovir/FTC or abacavir/3TC while maintaining the rest of their regimen. 48 week data already published showed a small but statistically significant decline in bone mineral density for those receiving tenofovir. We can 96 data presented here are largely similar. Of note, bone density changes appear to be relatively stable in both treatment groups. There is no significant difference in incident fractures. Small overall changes from baseline in BMD but differences between arms are significant at week 96 when t-tested. In %: The mean % change for ABC patients was +0.4% (SD 2.9) over 96 weeks in the hip and +0.75% (SD 3.9) BMD gain in the spine. While TDF patients lost -0.6% (SD 3.9) in the hip and -0.3% (SD 4.8) in the spine over 96 weeks. At week 48: ABC lost -0.6% (SD 5.5) in the hip and gained 0.4% (SD 3.8) in the spine, while patients on TDF lost -1.1% (SD 3.9) in the hip and lost -1.2% (SD 3.6) In virologically suppressed patients, the STEAL study randomized subjects to either tenofovir/FTC or abacavir/3TC while maintaining the rest of their regimen. 48 week data already published showed a small but statistically significant decline in bone mineral density for those receiving tenofovir. We can 96 data presented here are largely similar. Of note, bone density changes appear to be relatively stable in both treatment groups. There is no significant difference in incident fractures. Small overall changes from baseline in BMD but differences between arms are significant at week 96 when t-tested. In %: The mean % change for ABC patients was +0.4% (SD 2.9) over 96 weeks in the hip and +0.75% (SD 3.9) BMD gain in the spine. While TDF patients lost -0.6% (SD 3.9) in the hip and -0.3% (SD 4.8) in the spine over 96 weeks. At week 48: ABC lost -0.6% (SD 5.5) in the hip and gained 0.4% (SD 3.8) in the spine, while patients on TDF lost -1.1% (SD 3.9) in the hip and lost -1.2% (SD 3.6)

    64. Progress: BMD Changes by LPV/r + RAL or TDF/FTC The PROGRESS study was a randomized trial in treatment naďve patients of lopinavir/ritonavir plus either tenofovir/FTC or raltegravir. Presented here for the first time are the changes in bone mineral density. Total BMD increased at weeks 48 and 96 in the lopinavir/ritonavir plus raltegravir arm, while declining in the tenofovir/FTC arm. Notably, in study A5224, ABC/3TC (with either ATV/r or EFV) had intermediate changes between these 2, with an overall decline in BMD but not to the same degree as TDF/FTC. While these results are interesting from the pathogenesis of changes in BMD in HIV perspective, they do not warrant changes in clinical practice regarding management of treatment-naďve patients. TULBPE021 - Bone mineral density (BMD) analysis in antiretroviral (ART)-naďve subjects taking lopinavir/ritonavir (LPV/r) combined with raltegravir (RAL) or tenofovir/emtricitabine (TDF/FTC) for 96 weeks in the PROGRESS study R. Qaqish, R. Trinh, M. Tian, L. Fredrick, T. Podsadecki, M. Norton, A. Nilius Abbott, Abbott Park, United States Background: An increased prevalence of reduced BMD and bone fracture has been reported among HIV-infected patients. Longitudinal studies observed BMD decrease of 2-6% in the first 48-96 weeks after ART initiation. The PROGRESS study has previously shown LPV/r+RAL to have noninferior antiretroviral activity to LPV/r+TDF/FTC at 48 and 96 weeks and similar safety and tolerability in ART-naďve patients. Methods: This sub-study evaluated the change in BMD in ART-naďve subjects initiating LPV/r 400/100 mg twice- daily combined with either RAL 400 mg twice-daily or TDF/FTC 300/200 mg once-daily. Total BMD (tBMD) and spine BMD (sBMD) were assessed by whole body dual-energy x-ray absorptiometry (DXA) scans. Any subject who had a baseline (BL) and 96 week DXA was included (48 week DXA not required for inclusion). Results: Of 206 subjects randomized to LPV/r+RAL or LPV/r+TDF/FTC, 160 (78%) subjects had DXA scans at BL and 96 weeks. BL characteristics including mean tBMD were similar between groups: 1.18 grams/cm2 (LPV/r+RAL), 1.19 grams/cm2 (LPV/r+TDF/FTC). LPV/r+RAL LPV/r+TDF/FTC Week 48 96 48/96 48 96 48/96 48/96 N=77 N=78 Within group P- value1 N=80 N=82 Within group P- value1 Between group P- value Mean %? from BL in tBMD +0.68 +0.68 0.136/0.158 -1.19 -2.48 0.009/<0.001 0.004/ <0.0011 Mean %? from BL in sBMD -1.88 -1.34 0.005/0.053 -3.95 -4.61 <0.001/<0.001 0.028/ <0.0011 Percentage of subjects with =5%? from BL in tBMD 1.3 3.8 NA 8.8 19.5 NA 0.064/ 0.0032 1. One-way ANOVA 2. Fisher's exact test; NA: Not Applicable Conclusion: ART-naďve patients initiating LPV/r+RAL had no significant loss of total body BMD and significantly smaller reduction in spine BMD compared to those who received LPV/r+TDF/FTC. The minimal effect of RAL, in combination with LPV/r, on BMD with ART initiation warrants confirmation through further study. Presenting author email: roula.qaqish@abbott.comThe PROGRESS study was a randomized trial in treatment naďve patients of lopinavir/ritonavir plus either tenofovir/FTC or raltegravir. Presented here for the first time are the changes in bone mineral density. Total BMD increased at weeks 48 and 96 in the lopinavir/ritonavir plus raltegravir arm, while declining in the tenofovir/FTC arm. Notably, in study A5224, ABC/3TC (with either ATV/r or EFV) had intermediate changes between these 2, with an overall decline in BMD but not to the same degree as TDF/FTC. While these results are interesting from the pathogenesis of changes in BMD in HIV perspective, they do not warrant changes in clinical practice regarding management of treatment-naďve patients. TULBPE021 - Bone mineral density (BMD) analysis in antiretroviral (ART)-naďve subjects taking lopinavir/ritonavir (LPV/r) combined with raltegravir (RAL) or tenofovir/emtricitabine (TDF/FTC) for 96 weeks in the PROGRESS study R. Qaqish, R. Trinh, M. Tian, L. Fredrick, T. Podsadecki, M. Norton, A. Nilius Abbott, Abbott Park, United States Background: An increased prevalence of reduced BMD and bone fracture has been reported among HIV-infected patients. Longitudinal studies observed BMD decrease of 2-6% in the first 48-96 weeks after ART initiation. The PROGRESS study has previously shown LPV/r+RAL to have noninferior antiretroviral activity to LPV/r+TDF/FTC at 48 and 96 weeks and similar safety and tolerability in ART-naďve patients. Methods: This sub-study evaluated the change in BMD in ART-naďve subjects initiating LPV/r 400/100 mg twice- daily combined with either RAL 400 mg twice-daily or TDF/FTC 300/200 mg once-daily. Total BMD (tBMD) and spine BMD (sBMD) were assessed by whole body dual-energy x-ray absorptiometry (DXA) scans. Any subject who had a baseline (BL) and 96 week DXA was included (48 week DXA not required for inclusion). Results: Of 206 subjects randomized to LPV/r+RAL or LPV/r+TDF/FTC, 160 (78%) subjects had DXA scans at BL and 96 weeks. BL characteristics including mean tBMD were similar between groups: 1.18 grams/cm2 (LPV/r+RAL), 1.19 grams/cm2 (LPV/r+TDF/FTC). LPV/r+RAL LPV/r+TDF/FTC Week 48 96 48/96 48 96 48/96 48/96 N=77 N=78 Within group P- value1 N=80 N=82 Within group P- value1 Between group P- value Mean %? from BL in tBMD +0.68 +0.68 0.136/0.158 -1.19 -2.48 0.009/<0.001 0.004/ <0.0011 Mean %? from BL in sBMD -1.88 -1.34 0.005/0.053 -3.95 -4.61 <0.001/<0.001 0.028/ <0.0011 Percentage of subjects with =5%? from BL in tBMD 1.3 3.8 NA 8.8 19.5 NA 0.064/ 0.0032 1. One-way ANOVA 2. Fisher's exact test; NA: Not Applicable Conclusion: ART-naďve patients initiating LPV/r+RAL had no significant loss of total body BMD and significantly smaller reduction in spine BMD compared to those who received LPV/r+TDF/FTC. The minimal effect of RAL, in combination with LPV/r, on BMD with ART initiation warrants confirmation through further study. Presenting author email: roula.qaqish@abbott.com

    65. CASTLE: Changes in Bone Density Randomized comparison of ATV/r and LPV/r, both with TDF/FTC DEXA performed at baseline and weeks 48, 96; paired results available on 176 study subjects to assess bone mineral density (BMD) Results: Both study arms experienced decline in BMD ATV/r was associated with smaller declines in BMD compared to LPV/r, with differences of 0.8%, 0.8%, and 1.1% for arms, legs, and total body, respectively (P=NS) The CASTLE study compared ATV/r and LPV/r, both with tdf/ftc. Here DEXA results of BMD show declines for both treatment arms, with numerically greater decreases with LPV/r than ATV/r. The authors postulate that LPV/r-induced increases in TDF exposure may account for the observed differences. Background: Initiation of antiretroviral therapy is associated with declines in bone mineral density (BMD). This effect appears greatest with tenofovir DF/emtricitabine (TDF/FTC) containing regimens but differences between protease inhibitors have not been systematically studied. The objective of this open-label, randomized, multicenter CASTLE sub-study was to compare changes in BMD between atazanavir/ritonavir (ATV/r) and lopinavir/ritonavir (LPV/r) from baseline to Week 96 by dual energy x-ray absorptiometry (DXA). Methods: DXA was performed at baseline, Week 48 and Week 96, and obtained from arms, legs, trunk and total body. Measurements were expressed as g/cm2; mean percent change from baseline was computed using log scale, and back transformed to the original scale. Because of methodology, T-scores were not calculated. Results: 224 subjects were enrolled in the sub-study. Paired BMD data from baseline and Week 96 were available for 106 subjects on ATV/r and 70 subjects on LPV/r. Compared to baseline, subjects receiving either the ATV/r or LPV/r regimens had significant decreases of BMD at Week 96 in legs, trunk and total body (P< 0.0001). In the ATV/r regimen, trunk BMD decreased at Week 48 (-4%) but did not progress through Week 96 (-3%); BMD also decreased on LPV/r at Week 48 (-4%) but did progress through Week 96 (-5%); these differences were not statistically significant. ATV/r was associated with smaller declines in BMD compared to LPV/r, with differences of 0.8%, 0.8%, and 1.1% for arms, legs, and total body, respectively (P=NS), and 1.9% for trunk (P< 0.05, NS with Bonferroni's correction). Conclusion: Loss of BMD was noted with both regimens with relatively smaller declines in BMD with ATV/r at Week 96. Higher exposure of TDF with the greater ritonavir dose in the LPV/r arm may explain differences between regimens. The CASTLE study compared ATV/r and LPV/r, both with tdf/ftc. Here DEXA results of BMD show declines for both treatment arms, with numerically greater decreases with LPV/r than ATV/r. The authors postulate that LPV/r-induced increases in TDF exposure may account for the observed differences. Background: Initiation of antiretroviral therapy is associated with declines in bone mineral density (BMD). This effect appears greatest with tenofovir DF/emtricitabine (TDF/FTC) containing regimens but differences between protease inhibitors have not been systematically studied. The objective of this open-label, randomized, multicenter CASTLE sub-study was to compare changes in BMD between atazanavir/ritonavir (ATV/r) and lopinavir/ritonavir (LPV/r) from baseline to Week 96 by dual energy x-ray absorptiometry (DXA). Methods: DXA was performed at baseline, Week 48 and Week 96, and obtained from arms, legs, trunk and total body. Measurements were expressed as g/cm2; mean percent change from baseline was computed using log scale, and back transformed to the original scale. Because of methodology, T-scores were not calculated. Results: 224 subjects were enrolled in the sub-study. Paired BMD data from baseline and Week 96 were available for 106 subjects on ATV/r and 70 subjects on LPV/r. Compared to baseline, subjects receiving either the ATV/r or LPV/r regimens had significant decreases of BMD at Week 96 in legs, trunk and total body (P< 0.0001). In the ATV/r regimen, trunk BMD decreased at Week 48 (-4%) but did not progress through Week 96 (-3%); BMD also decreased on LPV/r at Week 48 (-4%) but did progress through Week 96 (-5%); these differences were not statistically significant. ATV/r was associated with smaller declines in BMD compared to LPV/r, with differences of 0.8%, 0.8%, and 1.1% for arms, legs, and total body, respectively (P=NS), and 1.9% for trunk (P< 0.05, NS with Bonferroni's correction). Conclusion: Loss of BMD was noted with both regimens with relatively smaller declines in BMD with ATV/r at Week 96. Higher exposure of TDF with the greater ritonavir dose in the LPV/r arm may explain differences between regimens.

    66. Management Ian Frank, MD Professor of Medicine Director, Anti-Retroviral Clinical Research University of Pennsylvania Philadelphia, PA

    67. The Rome Statement for an HIV Cure Major HIV/AIDS Stakeholders Call for HIV Cure Research to be Accelerated The year 2011 marks 30 years since the first AIDS cases… development of efficient antiretroviral drugs and their expanding availability have ensured that millions of people living with HIV live a healthy life… Nevertheless…This life-long requirement is both an individual and public health burden…Investments to develop new therapeutic strategies that will ultimately allow HIV infected patients to discontinue their treatment are of the utmost urgency. A functional HIV cure can only be achieved through an increased and concerted international effort engaging not only the scientific community but also stakeholders involved in the HIV/AIDS response and global health. Now, more than ever, it is time to seriously start looking for an HIV cure. As StatedAs Stated

    68. Early or Late Initiation of ARVs to Prevent Transmission: HPTN 052 Design: Early vs. delayed ART (start when CD4 count <250 cells/mm3) to infected partner in discordant couple with CD4+ count of 350-550 cells/mm3 at enrollment Population – 1,763 couples 98% heterosexual DSMB stopped trial April 28, 2011 Number of transmissions Total - 39 4 early therapy (0.3/100 py) 35 delayed therapy (2.2/100 py) Linked - 28 Transmissions linked by pol sequences 23/28 linked transmissions in African sites Conclusion: Treatment is prevention Objectives: 1. To determine if ART reduces HIV-1 transmission magnitude? durability of benefit? 2. To determine if ART is used “earlier” to reduce HIV-1 transmission personal health benefit(s)? Criteria: healthy, serodiscordant couples, sexually active, CD4 count: 350 to 550 cells/mm3 Recruitment: 10,838 screened; 3058 HIV+ but CD4 count out of range Median F/U 1.7 years At enrollment median CD4 count ~430 cells; median viral load 4.4 log Other facts about transmissions: 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm3 23/28 (82%) transmissions in sub-Saharan Africa 18/28 (64%) transmissions from female to male partners Objectives: 1. To determine if ART reduces HIV-1 transmission magnitude? durability of benefit? 2. To determine if ART is used “earlier” to reduce HIV-1 transmission personal health benefit(s)? Criteria: healthy, serodiscordant couples, sexually active, CD4 count: 350 to 550 cells/mm3 Recruitment: 10,838 screened; 3058 HIV+ but CD4 count out of range Median F/U 1.7 years At enrollment median CD4 count ~430 cells; median viral load 4.4 log Other facts about transmissions: 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm3 23/28 (82%) transmissions in sub-Saharan Africa 18/28 (64%) transmissions from female to male partners

    69. High Drug Concentrations and Low Amounts of Virus in Cervicovaginal Fluid of Women on ART Goal: Evaluate the level of HIV RNA and drug concentrations in blood and CVF in women on TDF/FTC + ATV/r Design: 20 women had samples collected at 6 time points during menstrual cycle (absence of menses) HIV RNA >50 c/mL detected in blood in 13/119 (11%) of evaluations and in CVF in 0/119 (0%) HIV DNA detected in 100% of blood specimens and 36% of CVF specimens Conclusions: Low levels of HIV and high levels of drug in female genital secretions Design: 20 women on TDF/FTC/ATV/r, with undetectable viral loads in plasma at one time point over the past 90 days, had blood and genital secretions sampled at 6 time points over a single menstrual cycle. Women completed 119 of the scheduled 120 visits. Cervicovaginal fluid collected by lavage and TearFlo strips. Drug concentrations taken at 24 hrs post preceding dose. Subjects: 19/20 AA, median age 36, 94% with one partner, current CD4+ count mean 412, median 14 months on current regimen Conclusions: Levels of HIV RNA In CVF are likely to be undetectable in women with undetectable VL in blood. Several commonly used ARVs are concentrated in genital tract. Design: 20 women on TDF/FTC/ATV/r, with undetectable viral loads in plasma at one time point over the past 90 days, had blood and genital secretions sampled at 6 time points over a single menstrual cycle. Women completed 119 of the scheduled 120 visits. Cervicovaginal fluid collected by lavage and TearFlo strips. Drug concentrations taken at 24 hrs post preceding dose. Subjects: 19/20 AA, median age 36, 94% with one partner, current CD4+ count mean 412, median 14 months on current regimen Conclusions: Levels of HIV RNA In CVF are likely to be undetectable in women with undetectable VL in blood. Several commonly used ARVs are concentrated in genital tract.

    70. Benefit of PrEP in Heterosexual Men and Women in Botswana: TDF2 Study Design: Placebo-controlled, trial of daily TDF/FTC Population 1,200 followed for seroconversion 33% did not complete study 45% women 94% married Results 33 seroconverters 21 women (7 on TDF/FTC and 14 PLC) 12 men (2 on TDF/FTC and 10 PLC) Conclusions PrEP beneficial in this population Protection in women in contrast with results of FEM-PrEP trial Randomize, placebo controlled trial of daily TDF/FTC Concern for lack of benefit in FEM-PrEP trial Eligibility criteria: HIV neg, 18-39, sexually active in past 3 months, otherwise healthy, women must use hormonal contraception Procedures Tested at months 1, 2 and every 3 months thereafter with rapid oral test Positives confirmed by standard tests Lots of negative publicity of trial in Botswana in news; general suspicion; may account for high rate of non-completion Use of contraception required by IRB because of concern for TDF/FTC exposure if women conceived Randomize, placebo controlled trial of daily TDF/FTC Concern for lack of benefit in FEM-PrEP trial Eligibility criteria: HIV neg, 18-39, sexually active in past 3 months, otherwise healthy, women must use hormonal contraception Procedures Tested at months 1, 2 and every 3 months thereafter with rapid oral test Positives confirmed by standard tests Lots of negative publicity of trial in Botswana in news; general suspicion; may account for high rate of non-completion Use of contraception required by IRB because of concern for TDF/FTC exposure if women conceived

    71. PrEP among Heterosexual Africans: The Partners PrEP study Phase III, placebo-controlled comparison of oral TDF, TDF/FTC and placebo to prevent HIV transmission in heterosexual discordant couples 4,758 couples enrolled; HIV neg partner - 38% women, 62% men Safety: no difference in renal function; more diarrhea with active agents Study performed in Kenya and Uganda HIV+ participants seen every 3 months with labs every 6 months HIV- partner tested monthly for HIV and pregnancy with every 3 month safety labs Adherence counseling to uninfected participant monthly DSMB stopped trial July 10, 2011 Median CD4+ count of partner 495 (IQR 375,662) Adherence 97% mITT analysis excludes 12 infections at enrollment No difference between TDF and TDF/FTC effect Transmissions by gender Women 42 Infections: 8 TDF; 9 TDF/FTC, 25 PLC Men 36 infections: 10 TDF, 4 TDF/FTC, 22 PLC Study performed in Kenya and Uganda HIV+ participants seen every 3 months with labs every 6 months HIV- partner tested monthly for HIV and pregnancy with every 3 month safety labs Adherence counseling to uninfected participant monthly DSMB stopped trial July 10, 2011 Median CD4+ count of partner 495 (IQR 375,662) Adherence 97% mITT analysis excludes 12 infections at enrollment No difference between TDF and TDF/FTC effect Transmissions by gender Women 42 Infections: 8 TDF; 9 TDF/FTC, 25 PLC Men 36 infections: 10 TDF, 4 TDF/FTC, 22 PLC

    72. Risk Compensation among MSM Following iPrEx Internet surveys of MSM in San Francisco1 and Boston2 asking about knowledge and attitudes of PrEP SF – 1155 responders Heard of PrEP: 70.0% post-iPrEx Would use PrEP: 69% somewhat to extremely likely to use Similar findings among 4,325 responders Boston 0.8% have used PrEP 78.4% would use PrEP Men would obtain PrEP from PCP (40.9%) Internet (28.3%) or other provider (22.7%) Boston Group Rationale: To better understand their response to the first PrEP efficacy data, online surveys of HIV-uninfected American MSM were conducted before and after the iPrEx publication Methods: MSM members of a large sexual/social networking site were invited to complete a survey about PrEP knowledge, interest and experience in September-October, 2010 and January, 2011 Results: Pre-iPrEx, 458 MSM responded to the survey, and afterwards, 4,325 did. Their median age was 40. Most participants were Caucasian (83.6%). Most (73%) reported at least one unprotected anal sex episode in the prior 3 months. - MSM surveyed after iPrEx data release were much more likely to have heard about PrEP than those surveyed before (18.6% vs. 12.7%, p< .05). - The majority reported they were likely to use PrEP if it were available either time (78.4% vs. 76.9%, NS). - Only 0.8% of post-iPrEx men reported having already used PrEP, and only 1.8% had used PEP. More than 80% of the men in either wave indicated they did not think they would decrease condom use during anal sex while taking PrEP. Although most men (82.0%) had a primary care provider, the majority (66.5%) had not discussed having anal sex without condoms with providers. The men's preference's for obtaining PrEP included their primary care providers (40.9%), other healthcare settings (22.7%) or via the internet (28.3%). San Francisco Methods: Online survey to US MSM recruited from Facebook and Black Gay Chat from 11/30/10-12/14/10. Participants were told about PrEP efficacy and answered questions about risk practices with/out TDF/FTC. Results: Overall, 1,155 HIV-negative MSM responded: 73% white, 7% African-American, 12% Hispanic. Mean age was 33 and 38% completed college. - Seven percent anticipated less frequent condom use with PrEP, 75% anticipated no change in condom use, 8% anticipated more condom use, and 10% wouldn't use PrEP. However, 21% perceived less risk of HIV infection from unprotected anal insertive sex and 39% perceived less risk from unprotected anal receptive sex (UAR) with PrEP versus no PrEP. - Likelihood of PrEP use was positively associated with perceptions that PrEP decreases HIV risk of both UAI (AOR=1.63; 95%CI 1.20-2.21) and UAR (AOR=1.88; 95%CI 1.46-2.42). - One-third believed they would feel increased pressure from others to have unprotected anal sex were they on PrEPBoston Group Rationale: To better understand their response to the first PrEP efficacy data, online surveys of HIV-uninfected American MSM were conducted before and after the iPrEx publication Methods: MSM members of a large sexual/social networking site were invited to complete a survey about PrEP knowledge, interest and experience in September-October, 2010 and January, 2011 Results: Pre-iPrEx, 458 MSM responded to the survey, and afterwards, 4,325 did. Their median age was 40. Most participants were Caucasian (83.6%). Most (73%) reported at least one unprotected anal sex episode in the prior 3 months. - MSM surveyed after iPrEx data release were much more likely to have heard about PrEP than those surveyed before (18.6% vs. 12.7%, p< .05). - The majority reported they were likely to use PrEP if it were available either time (78.4% vs. 76.9%, NS). - Only 0.8% of post-iPrEx men reported having already used PrEP, and only 1.8% had used PEP. More than 80% of the men in either wave indicated they did not think they would decrease condom use during anal sex while taking PrEP. Although most men (82.0%) had a primary care provider, the majority (66.5%) had not discussed having anal sex without condoms with providers. The men's preference's for obtaining PrEP included their primary care providers (40.9%), other healthcare settings (22.7%) or via the internet (28.3%). San Francisco Methods: Online survey to US MSM recruited from Facebook and Black Gay Chat from 11/30/10-12/14/10. Participants were told about PrEP efficacy and answered questions about risk practices with/out TDF/FTC. Results: Overall, 1,155 HIV-negative MSM responded: 73% white, 7% African-American, 12% Hispanic. Mean age was 33 and 38% completed college. - Seven percent anticipated less frequent condom use with PrEP, 75% anticipated no change in condom use, 8% anticipated more condom use, and 10% wouldn't use PrEP. However, 21% perceived less risk of HIV infection from unprotected anal insertive sex and 39% perceived less risk from unprotected anal receptive sex (UAR) with PrEP versus no PrEP. - Likelihood of PrEP use was positively associated with perceptions that PrEP decreases HIV risk of both UAI (AOR=1.63; 95%CI 1.20-2.21) and UAR (AOR=1.88; 95%CI 1.46-2.42). - One-third believed they would feel increased pressure from others to have unprotected anal sex were they on PrEP

    73. Higher Clearance Rate Than Expected of HCV in MSM Prospective survey of acute HCV in MACS cohort (n = 6,972 MSM) 103 seroconverters: 83% HIV+, 16% with IVDU history Conclusion: HCV clearance rate considerably higher than previously reported The mean age among the 103 seroconverters was 40.2 years, 74% were Caucasian, 83% were HIV positive, and 16% had a history of IDU. The clearance rate was 45%; higher among HIV uninfected (59%) vs. infected (43%) men (p=0.048). In regression analyses, HIV infection (HR=0.21), moderate to heavy alcohol use (HR=0.50), and unprotected anal receptive intercourse with =2 partners during the prior 6 months (HR=0.44) were independently associated (p< 0.05) with a lower HCV clearance rate. Among HIV-infected men, HIV RNA >400 copies/ml was significantly associated with a lower HCV clearance rate (HR=0.14). The mean age among the 103 seroconverters was 40.2 years, 74% were Caucasian, 83% were HIV positive, and 16% had a history of IDU. The clearance rate was 45%; higher among HIV uninfected (59%) vs. infected (43%) men (p=0.048). In regression analyses, HIV infection (HR=0.21), moderate to heavy alcohol use (HR=0.50), and unprotected anal receptive intercourse with =2 partners during the prior 6 months (HR=0.44) were independently associated (p< 0.05) with a lower HCV clearance rate. Among HIV-infected men, HIV RNA >400 copies/ml was significantly associated with a lower HCV clearance rate (HR=0.14).

    74. Factors Associated with SVR on Boceprevir Therapy in HCV Monoinfected Patients SPRINT-2 IFN naďve BOC vs. Placebo + IFN + RBV x 24 (RGT) or 44 week RESPOND-2 Previous IFN failure BOC vs. Placebo + IFN + RBV x 32 (RGT) or 44 week IL28B CC genotype and >1 log decline in HCV RNA at week 4 predictive in both studies Boceprevir (BOC) significantly increases SVR rates in treatment-naďve (SPRINT-2) and prior-treatment-failure (RESPOND-2) HCV Genotype 1 patients when added to peginterferon (P) and ribavirin (R). To optimize clinical use of this treatment regimen, it is necessary to better understand factors that predict successful outcomes in BOC-treated patients. Methods: Logistic regression models assessed baseline factors as predictors of SVR Approximately 60% of patients from both trials were genotyped for IL28B polymorphisms. Results: Multivariate regression analyses of SPRINT-2 patients revealed the baseline factors significantly associated with SVR were BOC assignment, low viral load, absence of advanced liver fibrosis, and race. In RESPOND-2, BOC assignment, historical classification as a relapser, low viral load, and absence of advanced fibrosis were associated with SVR. Additional analyses indicated that IL28B CC polymorphism was a predictor of SVR when only baseline factors were considered. on-treatment PR response was the strongest predictor of SVR in both studies. Poor interferon responders (< 1 log10 viral load decline) and interferon responders (=1 log10 viral load decline) after PR lead-in had substantially increased SVR rates when BOC was added to PR (poor responders: 0-4% PR vs 28-38% BOC + PR; responders: 50% PR vs 75-80% BOC + PR). Interferon responders achieved 75-82% SVR rates regardless of IL28B polymorphism (Figure). Poor interferon responders benefited from BOC therapy regardless of IL-28B polymorphism, with SVR rates for CC > CT and TT. Conclusion: On treatment interferon response was a stronger predictor of SVR than any baseline variable, including IL28B polymorphism. However, IL28B used in conjunction with lead-in response offers the clinician early predictability of SVR. Boceprevir (BOC) significantly increases SVR rates in treatment-naďve (SPRINT-2) and prior-treatment-failure (RESPOND-2) HCV Genotype 1 patients when added to peginterferon (P) and ribavirin (R). To optimize clinical use of this treatment regimen, it is necessary to better understand factors that predict successful outcomes in BOC-treated patients. Methods: Logistic regression models assessed baseline factors as predictors of SVR Approximately 60% of patients from both trials were genotyped for IL28B polymorphisms. Results: Multivariate regression analyses of SPRINT-2 patients revealed the baseline factors significantly associated with SVR were BOC assignment, low viral load, absence of advanced liver fibrosis, and race. In RESPOND-2, BOC assignment, historical classification as a relapser, low viral load, and absence of advanced fibrosis were associated with SVR. Additional analyses indicated that IL28B CC polymorphism was a predictor of SVR when only baseline factors were considered. on-treatment PR response was the strongest predictor of SVR in both studies. Poor interferon responders (< 1 log10 viral load decline) and interferon responders (=1 log10 viral load decline) after PR lead-in had substantially increased SVR rates when BOC was added to PR (poor responders: 0-4% PR vs 28-38% BOC + PR; responders: 50% PR vs 75-80% BOC + PR). Interferon responders achieved 75-82% SVR rates regardless of IL28B polymorphism (Figure). Poor interferon responders benefited from BOC therapy regardless of IL-28B polymorphism, with SVR rates for CC > CT and TT. Conclusion: On treatment interferon response was a stronger predictor of SVR than any baseline variable, including IL28B polymorphism. However, IL28B used in conjunction with lead-in response offers the clinician early predictability of SVR.

    75. A5269: Nitazoxanide Increases Rate of Early Virologic Response When Added to Peg-IFN + RBV for HCV Genotype 1 Infection: Single-arm, open-label study with historical comparison Nitazoxanide 500 mg BID x 4 wks, then add Peg-IFNa-2a + RBV 1,000 – 1,200 mg QD 68 subjects enrolled 78% men, 48% AA 91% on ART 73% HIV RNA <detectable Response rates RVR – 10.4% cEVR – 38.8% EVR – 65.7% GI toxicity – diarrhea, nausea, vomiting most common Conclusion: Nitazoxanide can potentiate the effects of IFN+RBV compared to historical populations cEVR and EVR: Comparison with prior study – A5178 at week 12 In ACTG 5178 genotype 1 HCV treatment-naďve subjects: 51.4% had EVR and 39.9% complete EVR (cEVR) (using Roche Cobas Amplicor HCV Monitor with undetectable HCV RNA< 600 IU/mL). Nitazoxanide (NTZ) plus PEG-IFN and WBR has demonstrated improved efficacy in HCV monoinfected subjects Methods: HIV/HCV genotype 1 coinfected subjects naďve to HCV treatment received a 4-week lead-in of NTZ followed by 12 weeks of therapy with NTZ (1000 mg/day), PEG-IFN alfa-2a (180 µg/week) and WBR (1000-1200 mg/day). EVR was defined as undetectable serum HCV RNA (< 43 IU/mL, Roche TaqMan HCV, v2.0) or =2-log10 decrease from entry at week 12 of triple therapy, cEVR was defined as undetectable serum HCV RNA at week 12 of triple therapy. Results: Demographics of 67 enrolled subjects included 78% male, 48% black, 31% white, 18% Hispanic and median age 50. At entry, median CD4+ was 452 cells/mm3, and 73% had undetectable HIV RNA. The median entry HCV RNA was 6.38 log10IU/mL. EVR was achieved in 44 subjects (66%, 90% CI: 55-75%), cEVR in 26 subjects (39%, CI:29-50%), and 30 subjects (45%, CI:34-56%) had HCV RNA < 600 IU/mL at 12 weeks of triple therapy. 12(18%) subjects did not complete 16 weeks of therapy due to: noncompliance(3), thrombocytopenia(1), anemia(1), diarrhea(1), hypersensitivity to NTZ(1), and subjects' decision based on toxicities(5). Conclusion: In genotype 1 HCV treatment-naďve HIV/HCV coinfected subjects, the addition of NTZ to PEG-IFN and WBR results in improved EVR and similar cEVR rates when compared to historical rates with PEG-WBR. In ACTG 5178 genotype 1 HCV treatment-naďve subjects: 51.4% had EVR and 39.9% complete EVR (cEVR) (using Roche Cobas Amplicor HCV Monitor with undetectable HCV RNA< 600 IU/mL). Nitazoxanide (NTZ) plus PEG-IFN and WBR has demonstrated improved efficacy in HCV monoinfected subjects Methods: HIV/HCV genotype 1 coinfected subjects naďve to HCV treatment received a 4-week lead-in of NTZ followed by 12 weeks of therapy with NTZ (1000 mg/day), PEG-IFN alfa-2a (180 µg/week) and WBR (1000-1200 mg/day). EVR was defined as undetectable serum HCV RNA (< 43 IU/mL, Roche TaqMan HCV, v2.0) or =2-log10 decrease from entry at week 12 of triple therapy, cEVR was defined as undetectable serum HCV RNA at week 12 of triple therapy. Results: Demographics of 67 enrolled subjects included 78% male, 48% black, 31% white, 18% Hispanic and median age 50. At entry, median CD4+ was 452 cells/mm3, and 73% had undetectable HIV RNA. The median entry HCV RNA was 6.38 log10IU/mL. EVR was achieved in 44 subjects (66%, 90% CI: 55-75%), cEVR in 26 subjects (39%, CI:29-50%), and 30 subjects (45%, CI:34-56%) had HCV RNA < 600 IU/mL at 12 weeks of triple therapy. 12(18%) subjects did not complete 16 weeks of therapy due to: noncompliance(3), thrombocytopenia(1), anemia(1), diarrhea(1), hypersensitivity to NTZ(1), and subjects' decision based on toxicities(5). Conclusion: In genotype 1 HCV treatment-naďve HIV/HCV coinfected subjects, the addition of NTZ to PEG-IFN and WBR results in improved EVR and similar cEVR rates when compared to historical rates with PEG-WBR.

    76. Maraviroc to Prevent HCV-Related Liver Fibrosis in HIV Coinfection Proof of concept, open-label trial of maraviroc to prevent acceleration of liver fibrosis HIV/HCV coinfection with undetectable VL on TDF/FTC + ATV/r Addition of maraviroc 150 mg BID vs. maintenance therapy x 96 wk Liver stiffness measured by elastography Results of safety on first 60 patients prior to continued enrollment Possible delay in fibrosis as evidenced by shift towards Stage I and II fibrosis after 24 weeks of therapy In HIV/HCV patients (pts) LS is faster than in HCV-monoinfected.. The CC chemokines MIP-1alpha,MIP-1beta and RANTES and their receptors CCR1 and CCR5 are strongly upregulated in experimental mouse models of fibrogenesis. Methods: HIV/HCV pts, anti HCV treatment naďve,on stable effective HAART with atazanavir /ritonavir 300/100 mg + tenofovir/emtricitabina QD and Child-Pugh score < A6 were enrolled in a 96 weeks(W), prospective, randomized, pilot study. LS has been evaluated with biochemical markers of liver fibrosis and transient elastometry, performed by standard methods. Eligible subjects have been randomized 1:1 to maintain the current regimen (arm A) or to add MVC 150 mg BID (arm B). Clinical, virologic, immunologic, hepatic and metabolic parameters are recorded at baseline (BL) and every three months. LS was measured every 24W and staged following the standardized categories I:< 7.1 kPa; II:7.1-9.4; III:9.5-12.4; IV:=12.5. A preliminary 24W analysis has been assessed. The Mann Whitney/Wilcoxon test has been used to compare the median of LS variations from BL through 24W in two groups .Results: Up to September 2010, 54 pts were enrolled: 28 in arm B,77% males, median age 46 (IQR 43-48)years,CD4 506(405-654)cell/mm3, AST 43(31-59)IU/ml,ALT 68(45-92)IU/ml,HCV5,8(5,4-6,2)log10 IU/ml. LS was 7.2 kPa (4.2-10.2) in arm B and 5,7 kPa (4,7-7.4) in arm A (p=NS). Twenty four subjects achieved week 24 (12 patients in each arm). From BL to week 24 LS decreased [-0.5(-1.7;+0.3)] in subjects enrolled in arm B (p=0.03) and increased [+ 0.35 KPa(-0.2;+1.4)] in subjects enrolled arm A. Seven of 24 patients (3 in arm A and 4 in arm B) (29,1%) changed the stage of LS : three out of 4 pts enrolled in arm B had a LS improvement switching from stage III to stage II .In all 3(100%)patients enrolled in arm A,LS worsened, switching from stage I to stage II. In HIV/HCV patients (pts) LS is faster than in HCV-monoinfected.. The CC chemokines MIP-1alpha,MIP-1beta and RANTES and their receptors CCR1 and CCR5 are strongly upregulated in experimental mouse models of fibrogenesis. Methods: HIV/HCV pts, anti HCV treatment naďve,on stable effective HAART with atazanavir /ritonavir 300/100 mg + tenofovir/emtricitabina QD and Child-Pugh score < A6 were enrolled in a 96 weeks(W), prospective, randomized, pilot study. LS has been evaluated with biochemical markers of liver fibrosis and transient elastometry, performed by standard methods. Eligible subjects have been randomized 1:1 to maintain the current regimen (arm A) or to add MVC 150 mg BID (arm B). Clinical, virologic, immunologic, hepatic and metabolic parameters are recorded at baseline (BL) and every three months. LS was measured every 24W and staged following the standardized categories I:< 7.1 kPa; II:7.1-9.4; III:9.5-12.4; IV:=12.5. A preliminary 24W analysis has been assessed. The Mann Whitney/Wilcoxon test has been used to compare the median of LS variations from BL through 24W in two groups .Results: Up to September 2010, 54 pts were enrolled: 28 in arm B,77% males, median age 46 (IQR 43-48)years,CD4 506(405-654)cell/mm3, AST 43(31-59)IU/ml,ALT 68(45-92)IU/ml,HCV5,8(5,4-6,2)log10 IU/ml. LS was 7.2 kPa (4.2-10.2) in arm B and 5,7 kPa (4,7-7.4) in arm A (p=NS). Twenty four subjects achieved week 24 (12 patients in each arm). From BL to week 24 LS decreased [-0.5(-1.7;+0.3)] in subjects enrolled in arm B (p=0.03) and increased [+ 0.35 KPa(-0.2;+1.4)] in subjects enrolled arm A. Seven of 24 patients (3 in arm A and 4 in arm B) (29,1%) changed the stage of LS : three out of 4 pts enrolled in arm B had a LS improvement switching from stage III to stage II .In all 3(100%)patients enrolled in arm A,LS worsened, switching from stage I to stage II.

    77. Tryptophan Catabolism Correlates with CD4+ T Cell Recovery and Survival Background: Tryptophan depletion can diminish T cell proliferation Goal: Evaluate the relationship between tryptophan catabolism and CD4 count increases after ART initiation and survival Design: Measurement of kynurenine:tryptophan (K/T) ratio in 500 Ugandans starting ARVs Results: Higher K/T ratio associated with higher baseline VL and lower CD4 count Conclusion: Tryptophan catabolism may be cause, or just another marker, of immune activation HIV-induced indoleamine 2,3-dioxygenase (IDO) expression in activated monocytes results in tryptophan catabolism, which may inhibit T cell proliferation and IL-17 production. Methods: HIV-infected adults initiating antiretroviral therapy (ART) were sampled from the Uganda AIDS Rural Treatment Outcomes cohort. Levels of IDO-induced tryptophan catabolism (ratio of the downstream catabolite kynurenine to tryptophan in plasma, KT ratio) were assessed before and during ART, and related to subsequent mortality and the rate of subsequent CD4 recovery during confirmed viral suppression Results: Of 435 evaluable participants, 70% were women and median pre-ART values were: age, 34 years; CD4 count, 133 cells/mm3; plasma HIV RNA level (VL), 5.0 log10 copies/ml; tryptophan, 18 uM; and KT ratio, 0.13. Higher pre-ART KT ratio was associated with higher VL (rho: 0.38, P< 0.001), lower CD4+ T cell count (rho: -0.16, P< 0.001), and after adjustment for VL and CD4 count, female gender (P=0.038). Through month 12 of ART-mediated viral suppression, plasma tryptophan increased (P< 0.001) and KT ratio decreased (P< 0.001), but pre-ART levels remained strongly predictive of month 12 levels (rho: 0.42 and 0.54, P< 0.001 for both). After adjustment for pre-ART CD4 count, VL, age, and gender, higher pre-ART KT ratio predicted a slower rate of CD4 recovery after month 12 (P=0.008). Thirty-nine participants died. After adjustment for pre-ART CD4 count and BMI, lower tryptophan and higher KT ratio both pre-ART and at month 6 of viral suppression predicted earlier mortality (P=0.022 for all). While lower self-reported dietary protein sources were associated with lower tryptophan levels (P=0.007), adjustment for dietary protein strengthened the association between tryptophan levels and mortality. HIV-induced indoleamine 2,3-dioxygenase (IDO) expression in activated monocytes results in tryptophan catabolism, which may inhibit T cell proliferation and IL-17 production. Methods: HIV-infected adults initiating antiretroviral therapy (ART) were sampled from the Uganda AIDS Rural Treatment Outcomes cohort. Levels of IDO-induced tryptophan catabolism (ratio of the downstream catabolite kynurenine to tryptophan in plasma, KT ratio) were assessed before and during ART, and related to subsequent mortality and the rate of subsequent CD4 recovery during confirmed viral suppression Results: Of 435 evaluable participants, 70% were women and median pre-ART values were: age, 34 years; CD4 count, 133 cells/mm3; plasma HIV RNA level (VL), 5.0 log10 copies/ml; tryptophan, 18 uM; and KT ratio, 0.13. Higher pre-ART KT ratio was associated with higher VL (rho: 0.38, P< 0.001), lower CD4+ T cell count (rho: -0.16, P< 0.001), and after adjustment for VL and CD4 count, female gender (P=0.038). Through month 12 of ART-mediated viral suppression, plasma tryptophan increased (P< 0.001) and KT ratio decreased (P< 0.001), but pre-ART levels remained strongly predictive of month 12 levels (rho: 0.42 and 0.54, P< 0.001 for both). After adjustment for pre-ART CD4 count, VL, age, and gender, higher pre-ART KT ratio predicted a slower rate of CD4 recovery after month 12 (P=0.008). Thirty-nine participants died. After adjustment for pre-ART CD4 count and BMI, lower tryptophan and higher KT ratio both pre-ART and at month 6 of viral suppression predicted earlier mortality (P=0.022 for all). While lower self-reported dietary protein sources were associated with lower tryptophan levels (P=0.007), adjustment for dietary protein strengthened the association between tryptophan levels and mortality.

    78. Hydroxychloroquine (HCQ) to Treat Immune Activation – No Benefit in ARV Naďve Patients HCQ is a candidate drug to decrease immune activation HCQ 400 mg vs. placebo in ARV naďve patients x 48 weeks Activation markers, CD4 counts and HIV RNA levels tracked hydroxychloroquine (HCQ), a long-established and safe anti-inflammatory and immunomodulatory drug .Methods: prospective, randomised, double-blind, placebo controlled trial in asymptomatic, ART-naive HIV-infected patients with a CD4 count above 400 cells/mm3. Patients were randomised to receive HCQ 400mg or placebo once daily for 48 weeks. The primary endpoint was change in immune activation from baseline to week 48, measured by the proportion of CD8 T-cells expressing CD38+ and HLA-DR+ (CD8CD38DR+). Results: 83 patients (41 placebo, 42 HCQ); 93% male, 88% white; median baseline CD4 count 492 cells/mm3, VL 4.2 log10 copies/ml, and CD8CD38DR+ 23%. There was no difference between the groups in change from baseline in CD8CD38DR+, IL-6 or D-dimer, but the HCQ group showed a trend towards higher VL and more rapid loss of CD4 cells. In the HCQ group 16 patients discontinued treatment (9 started ART, 1 SAE, 6 patient decision), and in the placebo group 7 discontinued treatment (1 started ART, 1 SAE, 2 AE, 3 patient decision) hydroxychloroquine (HCQ), a long-established and safe anti-inflammatory and immunomodulatory drug .Methods: prospective, randomised, double-blind, placebo controlled trial in asymptomatic, ART-naive HIV-infected patients with a CD4 count above 400 cells/mm3. Patients were randomised to receive HCQ 400mg or placebo once daily for 48 weeks. The primary endpoint was change in immune activation from baseline to week 48, measured by the proportion of CD8 T-cells expressing CD38+ and HLA-DR+ (CD8CD38DR+). Results: 83 patients (41 placebo, 42 HCQ); 93% male, 88% white; median baseline CD4 count 492 cells/mm3, VL 4.2 log10 copies/ml, and CD8CD38DR+ 23%. There was no difference between the groups in change from baseline in CD8CD38DR+, IL-6 or D-dimer, but the HCQ group showed a trend towards higher VL and more rapid loss of CD4 cells. In the HCQ group 16 patients discontinued treatment (9 started ART, 1 SAE, 6 patient decision), and in the placebo group 7 discontinued treatment (1 started ART, 1 SAE, 2 AE, 3 patient decision)

    79. Acyclovir Delays CD4 Decline in HIV/HSV2 Co-Infection Objective: Compare effect of acyclovir 400 mg BID vs. placebo on progression to CD4+ count <250 cells/mm3 or WHO Stage IV endpoints 440 HIV/HSV2 coinfected participants with CD4 counts 300 – 400 cells/mm3 Benefits only seen for those with BL VL >50,000 c/mL Change in VL over time Placebo +0.402 log ACV -0.061 log Difference -0.46 log (P=0.001) Conclusion: Use of acyclovir can slow progression of HIV HSV-2 most common cause of GUD, seroprevalence rates 70-90% among HIV-1 infected, HSV-2 reactivation common and known to increase HIV-1 replication Results of 7 RCTs: daily acyclovir or valacyclovir reduced plasma HIV-1 by 0.33 (95% CI; -0.56, -0.10) log10 copies/ml (AIDS, 2011; 25) Valacyclovir has an even greater impact on HIV VL (IAS abstract B0106) 24 months follow-up, participants seen monthly for adherence assessment (pill-counts), examination for GUD if symptomatic, women provided self-administered vaginal swabs Every 6 months, laboratory visit (CBC, CD4, HIV VL), quality of life survey and full physical examination Secondary post-hoc analysis examined impact of ACV on disease progression among participants with low (<50000 copies/ml) versus high (>=50000 copies/ml) baseline HIV VL 14 (3.1%) subjects lost to follow-up during study 12 (2.7%) subjects died on study Excellent follow-up, of those participants remaining on study, 99% of expected study visits completedHSV-2 most common cause of GUD, seroprevalence rates 70-90% among HIV-1 infected, HSV-2 reactivation common and known to increase HIV-1 replication Results of 7 RCTs: daily acyclovir or valacyclovir reduced plasma HIV-1 by 0.33 (95% CI; -0.56, -0.10) log10 copies/ml (AIDS, 2011; 25) Valacyclovir has an even greater impact on HIV VL (IAS abstract B0106) 24 months follow-up, participants seen monthly for adherence assessment (pill-counts), examination for GUD if symptomatic, women provided self-administered vaginal swabs Every 6 months, laboratory visit (CBC, CD4, HIV VL), quality of life survey and full physical examination Secondary post-hoc analysis examined impact of ACV on disease progression among participants with low (<50000 copies/ml) versus high (>=50000 copies/ml) baseline HIV VL 14 (3.1%) subjects lost to follow-up during study 12 (2.7%) subjects died on study Excellent follow-up, of those participants remaining on study, 99% of expected study visits completed

    80. Therapeutic Vaccines – May Be Possible Vacc-4x is peptide vaccine with highly conserved and immunogenic p24 domains Design: Vacc-4x or placebo (2:1) at weeks 1, 2, 3, 4, 16, 18 with analytical STI at week 28 for up to 24 weeks Treatment resumed for fall in CD4+ count to <350 cells/mm3 Results 135 enrolled (92 Vacc-4x, 43 PLC) Vacc-4x safe and well tolerated Conclusion: More effective control of HIV following vaccination Difference in viral load at week 52: 44 Vacc-4x and 18 PLC off ART HIV RNA 0.55 log10 c/mL lower in Vacc-4x recipients (P=0.0003) Vacc-4x is a peptide-based HIV therapeutic vaccine to conserved domains on p24Gag. The co-primary endpoints of this study were to compare changes in CD4 counts and return to ART between treatment and placebo groups during a 24 week treatment interruption. Secondary endpoints included safety, viral load and immunogenicity .Methods: prospective, randomized, double blind phase IIB clinical study (NCT00659789) was carried out in 13 European and 5 US centers recruiting 135 patients on ART. 6 immunizations on ART over 28 weeks, treatment was interrupted for up to 24 weeks (to week 52) (Vacc-4x n=88; placebo n=38). Results: There were no Vacc-4x-related serious adverse events. Of the 135 patients recruited (male n=92; female n=43), 126 patients completed the study. Median prestudy CD4 count was 712 (Vacc-4x) and 619 cells/mm3 (placebo), and median CD4 nadir 300 (Vacc-4x) and 285 cells/mm3 (placebo). There was no statistically significant difference between the two groups regarding change in CD4 counts (p=0.12) or ART resumption (p=0.89) during treatment interruption. A statistically significant treatment difference between Vacc-4x and placebo groups for viral load (VL) was found for patients who achieved a 6 month ART-free period (p=0.0022). Post-hoc analyses for patients with preART VL values showed a statistically significant reduction in VL from the pre-ART level (0.55 log, p=0.0003) in the Vacc-4x group (n=44) at week 52 (off ART) compared to a non-statistically significant VL reduction (0.08 log, p=0.89) in the placebo group (n=18) Vacc-4x is a peptide-based HIV therapeutic vaccine to conserved domains on p24Gag. The co-primary endpoints of this study were to compare changes in CD4 counts and return to ART between treatment and placebo groups during a 24 week treatment interruption. Secondary endpoints included safety, viral load and immunogenicity .Methods: prospective, randomized, double blind phase IIB clinical study (NCT00659789) was carried out in 13 European and 5 US centers recruiting 135 patients on ART. 6 immunizations on ART over 28 weeks, treatment was interrupted for up to 24 weeks (to week 52) (Vacc-4x n=88; placebo n=38). Results: There were no Vacc-4x-related serious adverse events. Of the 135 patients recruited (male n=92; female n=43), 126 patients completed the study. Median prestudy CD4 count was 712 (Vacc-4x) and 619 cells/mm3 (placebo), and median CD4 nadir 300 (Vacc-4x) and 285 cells/mm3 (placebo). There was no statistically significant difference between the two groups regarding change in CD4 counts (p=0.12) or ART resumption (p=0.89) during treatment interruption. A statistically significant treatment difference between Vacc-4x and placebo groups for viral load (VL) was found for patients who achieved a 6 month ART-free period (p=0.0022). Post-hoc analyses for patients with preART VL values showed a statistically significant reduction in VL from the pre-ART level (0.55 log, p=0.0003) in the Vacc-4x group (n=44) at week 52 (off ART) compared to a non-statistically significant VL reduction (0.08 log, p=0.89) in the placebo group (n=18)

    81. Outcomes Measurement Reminder CME providers are required to assess “changes in learners competence, performance or patient outcomes achieved as a result of their participation in a CME sponsored educational activity” As a result of this requirement you will receive via e-mail a short 1-page survey 2 to 3 months after completing this course We consider the survey to be an additional component of your overall participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey Please be certain that you have correctly written your e-mail address on the CME evaluation form that you complete at the end of today’s activity Slide: Outcomes Measurement ReminderSlide: Outcomes Measurement Reminder

    82. The 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention Rome, Italy July 17-20, 2011

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