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HIV Prevention and Treatment Guidelines: Update and Implementation

Stay updated on the latest guidelines for HIV prevention and treatment, including recommended regimens and the implementation of pre-exposure prophylaxis (PrEP). Learn about the effectiveness and safety of different antiretroviral therapies, as well as the use of long-acting antivirals for prevention.

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HIV Prevention and Treatment Guidelines: Update and Implementation

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  1. Hot topics: Guidelines, Prevention and cure

  2. Guidelines Update

  3. EACS GUIDELINES UPDATE 9.1 - OCTOBER 2018 Recommended regimens (preferred) • DTG/ABC/3TC • DTG-TFV/FTC • BIC/TAF/FTC • RALqd/bid-TFV/FTC Recommended regimens • RPV/TFV/FTC • DRV/c(r)/TFV/FTC • EFV/TDF/FTC(3TC), EFV-TAF/FTC Alternative • RAL-ABC/3TC • EVG/c/TFV/FTC • ABC/3TC-EFV • TDF/FTC/EFV • ABC/3TC-ATV/c(r) • ABC/3TC-DRV/c(r) • TFV/FTC-ATV/c(r) Other • DTG+3TC • DRV/r(c)+ RAL BID http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html

  4. DHHS GUIDELINES UPDATE - October 2018 Most People with HIV • BIC/TAF/FTC • DTG/ABC/3TC • DTG-TFV/FTC • RAL-TFV/FTC Certain Clinical Situations • EVG/c/TFV/FTC • RAL-ABC/3TC • DRV/c(r)/TFV/FTC • ATV/c(r)/TFV/FTC • DRV/c(r)-ABC/3TC • DOR/TDF/3TC or DOR-TAF/FTC • EFV/TDF/FTC(3TC), EFV-TAF/FTC • RPV/TFV/FTC When ABC, TAF, and TDF Cannot be Used or Are Not Optimal • DTG+3TC • DRV/r + RAL BID • DRV/r + 3TC https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0

  5. PrEP Implementation and Effectiveness

  6. Fast Track Targets 2020 Goal: Reduce number of new infections from 2010 levels by 75% Adapted from: Fitch L, et al. HIVR4P 2018, October 21-25, 2018. Madrid, Spain. Abs OA.04.01.

  7. Global PrEP Implementation 309K+ Initiations 80Implementation Studies 31 in Africa 44 RegulatoryApprovals 2 GlobalGuidelines 1 Global Implementation Guidance 28 National Guidelines 68 countries have PrEP available in some form Fitch L, et al. HIVR4P 2018, October 21-25, 2018. Madrid, Spain. Abs OA.04.01.

  8. World-wide Experience with Daily TDF/FTC for PrEP • 46 projects in countries including 10,609 individuals • 76% men, 20% women, 0.7 transgender • 91 incident infections • 27 more than 30 days after last PrEP dose • 64 infections while potentially on PrEP • 17 within first 3 months of starting Baeten J, et al. HIVR4P 2018, October 21-25, 2018. Madrid, Spain. Abs OA23.01

  9. Meta-Analysis of PrEP Safety • Review of 2306 studies screened, 201 assessed for inclusion • 13 RCT included, 15,678 participants, 22,250 pt/years Serious Adverse Events Bone Fractures • %Events • /Total people • Control: • 16.8% • PrEP: • 17.4% • %Events • /Total people • Control: • 3.3% • PrEP: • 3.7% • More risk onControl • More risk onPrEP • More risk onControl • More risk onPrEP West African Study IPERGAY IAVI Uganda Study FEM-PrEP FEM-PrEP IPERGAY PrEPare PROUD IAVI Kenya Study PrEPare TDF - 2 iPREX VOICE TDF -2 iPREX VOICE BKKTDF Study Partners US Safety Study BKKTDF Study US Safety Study • RD = 0%(-1% to 2%) • RD = 0%(0% to 1%) • p = 0.53 • p = 0.50 • Risk Difference (95% CI) • Risk Difference (95% CI) Pilkington et al Glasgow HIV 2018. Poster 0143.

  10. Meta-Analysis of PrEP Safety (cont’d) Grade 3+ Creatinine Increase Grade 1-4 Creatinine Increase • %Events • /Total people • Control: • 0.1% • PrEP: • 0.1% • %Events • /Total people • Control: • 2.3% • PrEP: • 4.3% • More risk onControl • More risk onPrEP • More risk onControl • More risk onPrEP IPERGAY West African Study PROUD PROUD West African Study FEM-PrEP IAVI Kenya Study IPERGAY IAVI Uganda Study IAVI Uganda Study FEM-PrEP PrEPare PrEPare IAVI Kenya Study iPREX US Safety Study TDF - 2 TDF - 2 US Safety Study Partners VOICE iPREX Partners VOICE BKKTDF Study • RD = 0%(0% to 0%) • RD = 2%(0% to 3%) BKKTDF Study • p = 0.68 • p = 0.04 • Risk Difference (95% CI) • Risk Difference (95% CI) Pilkington et al Glasgow HIV 2018. Poster 0143.

  11. Incident HIV Infection in PrEP Users vs Non-Users, Boston • Between 2012 and 2017, 16,128 HIV-uninfected patients tested for HIV >1 time • 3,965 initiated PrEP • Incident HIV Infection: 163 (1.34%) Non-Users vs 17 (0.43%) Users • 12 discontinued PrEP >1 month prior to infection, 1 infection during 1 month hiatus, 3 possible acute infections, 1 who missed doses infected with virus with M184V Characteristics of PrEP Users vs Non-Users Mayer K, et al. HIVR4P 2018, October 21-25, 2018. Madrid, Spain. Abs OA23.04LB

  12. bNAbS FOR PASSIVE IMMUNOTHERAPY PREVENTION OF VIROLOGIC REBOUND AND INFECTION

  13. bNAb Combinations Delay Virologic Rebound • VL <50 • Virus sensitive to both bNAbs 3BNC117 + 10-1074 (30 mg/kg each) Resume ART: 2 consecutive VL>200 cp/ml ART ATI Rebound -2 0 3 6 12 30Weeks Screen Assessment of latent reservoir P = 0.0003 n=11 Median time to rebound 21 weeks Mendoza P, et al. HIVR4P 2018, October 21-25, 2018. Madrid, Spain. Abs OA08.01

  14. Imaging the Distribution of VRC01 and VRC01-LS in Macaques • Differences in Tissue Distribution • Liver, Small intestine: VRC01 > VRC01LS • Lymph node, large intestine, vagina: VRC01LS > VRC01 VRC01-Wt VRC01-LS Carias AM, et al. HIVR4P 2018, October 21-25, 2018. Madrid, Spain. Abs OA08.06

  15. Long Acting Antivirals for Prevention

  16. HPTN 077: Injectable Cabotegravir for Prevention – The Tail CAB PO 4 weeks 800 mg CAB LA (two 2 mL), weeks 5, 17, 29 Tail Phase 76 weeks N=82 • Levels needed to protect macaques in rectal challenge model • 1>3x PA-IC90: 100% • 1–3x PA-IC90: 97% • <X PA-IC90: 74% • Levels needed to protect macaques in vaginal challenge model • >3x PA-IC90: 98% • 1–3x PA-IC90: 84% • <1X PA-IC90: 80% Cohort 1 PLC PLC Tail Phase 76 weeks N=28 CAB PO 4 weeks 600 mg CAB LA (one 3 mL), weeks 5, 9, 17, 25, 33 Tail Phase 76 weeks N=82 Cohort 2 PLC PLC Tail Phase 76 weeks N=28 199 enrolled (151 CAB, 48 PBO) 135 agreed to 76 week tail phase extension (102 CAB, 33 PBO) 177 received at least 1 injection (133 CAB, 44 PBO) Landowitz RJ et al. HIVR4P Madrid, Spain. Abs OA.15.06LB

  17. HPTN 077: Injectable Cabotegravir for Prevention – The Tail Men 12W n=42 24W n=41 36W n=38 48W n=38 60W n=40 76W n=30 Women 12W n=85 24W n=80 36W n=82 48W n=82 60W n=82 76W n=64 <LLOQ LLOQ - 1x PA-IC90 1x -4x PA-IC90 > 4x PA-IC Landowitz RJ et al. HIVR4P Madrid, Spain. Abs OA.15.06LB

  18. In Situ Forming Implants (IFSI) of Dolutegravir with Very Long Half-Life • Development of soluble polymer incorporating DTG (or other agents) that are liquid when injected and polymerize subcutaneously • Drug slowly eludes from polymer • Removable • Sustained release of drug over 4 months by altering polymer components Benhabour SR, et al. HIVR4P 2018. Madrid, Spain. PD09.01

  19. Key Points • PrEP – coming to a country near you • PrEP – disparities in delivery to populations in greatest need in U.S. are also happening globally • PrEP – it works • PrEP – it’s safe • bNAbs– in development for treatment, prevention, and cure • Cabotegravir– solves some adherence issues, creates others • Several promising long acting strategies in development

  20. Studies in Treatment-Naïve Patients

  21. ANRS 12313 NAMSAL Study: Design Phase III, randomized, open-label trial DTG 50mg + TDF/3TC participants HIV-1 Age ≥ 18 years ARV naïve VL> 1000 c/mL Randomly assigned 1:1 EFV 400mg + TDF/3TC Screening Baseline Follow-up (VL W24 & 48) 48 weeks Primary endpoint : Non inferiority DTG- vs EFV400- by proportion with VL<50 c/mL (ITT snapshot, 10% margin) Superiority test planned If non inferiority demonstrated 3 study sites in Yaoundé, Cameroon Delaporte E, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O342.

  22. NAMSAL Study: baseline characteristics Delaporte E, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O342.

  23. NAMSAL Study: HIV RNA suppression at Week 48 (ITT) Treatment difference DTG – EFV: 5.5% (95%CI: -1.6; +12.7) 91.9% <1000 copies/mL 86.5% <1000 copies/mL 89% <200 copies/mL 83.5% <200 copies/mL 74.5% <50 copies/mL 69% <50 copies/mL % HIV RNA suppression TDF/3TC/DTG (n=310) TDF/3TC/EFV (n=303) HIV RNA <50 c/mL 50-200 c/mL 200-1000 c/mL Delaporte E, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O342.

  24. NAMSAL Study: HIV RNA suppression at Week 48 by baseline HIV RNA 93.2% 92.2% 89.5% 83.9% 79.4% 76.4% 91% 84% 55% 57% 75% 64% Baseline HIV RNA level Baseline HIV RNA level HIV RNA <50 copies/mL HIV RNA 50-200 copies/mL Delaporte E, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O342.

  25. NAMSAL Study: Virological Failure > 1000c/mL (WHO) and resistance HIV RNA > 1000 copies copies/mL n=19 DTG n=3 EFV400 n=16 Genotypic resistance testing Baseline R n = 0/3 Baseline R n = 6/16 EFV R n = 5 3TC + TDF + EFV R n =1 At virological failure and susceptible at baseline: EFV R n=3 At virological failure and susceptible at baseline: EFV R n=3 ETC + EFV R n=3 EFV + TDF + 3TC R n=3 Susceptible n=1 Delaporte E, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O342.

  26. Conclusions • DTG was non-inferior to EFV 400 mg, both in combination with TDF/3TC in naïve patients in Cameroon (it was superior to EFV 600 in the SINGLE trial) among pts with high viral loads (median: 5.3 logs) • 9.5% of patients were co-infected with HBV justifying the use of TDFas a backbone • Virologic response rate with DTG only 74.5% vs. responses in the 90% range in registration studies with DTG in naive patients • Patients with BL HIV RNA> 500 000 c/mL had an unsatisfactory virologicalresponse, with only 60% reaching an HIV RNA <50 c/mL at W48 in both arms • The emergence of resistance in the EFV400 mg arm was frequent • No emergence of resistance in the DTG arm but only 3 strains sequenced:long-term follow-up critical • Overall safety and tolerability profile comparable between arms and no discontinuation due to adverse events in the EFV arm confirming the good safety of EFV 400 mg dose • These data support the WHO guidelines of DTG-based regimens as a preferred first line option • These data also support the use of EFV 400 mg when DTG cannot be recommended (women wishing to become pregnant) Delaporte E, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O342.

  27. b/f/tafvSdtg+f/taf in naïve96 week update % Treatment Difference (95% CI) • Mean CD4 increase from baseline at Week 96: • B/F/TAF +237 cells/µL vs DTG + F/TAF +281 cells/µL (p=0.008) • No participant developed treatment-emergent resistance through Week 96 • Few AEs leading to discontinuation occurred (6 vs 5 in the DTG + F/TAF arm) • No discontinuations due to renal AEs and no cases of tubulopathy Favors DTG + F/TAF Favors B/F/TAF -2.3 -7.9 3.2 -12 -6 -0 6 12 269 320 281 325 14 320 9 325 37 320 35 325 Stellbrink H, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O211.

  28. Safety and Efficacy of DOR/3TC/TDF in Treatment-Naïve HIV-1 Infected Adults With Transmitted NNRTI Resistance Mutations • Transmitted mutations associated with resistance to NNRTIs have an estimated prevalence ranging from 3% to 10% in treatment-naïve patients • The most common transmitted NNRTI-resistance mutation is K103N, followed by Y181 and G190 • Doravirine (DOR) is a novel NNRTI recently approved in the US for the treatment of HIV-1 which demonstrated non-inferior efficacy to ritonavir-boosted darunavir and to EFV/FTC/TDF and a superior CNS safety profile • DOR is active in vitro against both wild-type HIV-1 and the most common NNRTI-resistant variants at concentrations achieved with 100 mg once-daily dosing • This study examined the efficacy and safety of DOR in treatment-naïve adults with HIV-1 and transmitted NNRTI resistance mutations Wong A, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. P050.

  29. Study Design • Phase 2, multicenter, open-label, single-arm trial • HIV-1 infected adults naïve to antiretroviral therapy • Plasma HIV-1 RNA ≥1000 copies/mL and CD4+ ≥100 cells/mm3 • A single NNRTI mutation consisting of RT K103N, Y181C, or G190A • Calculated creatinine clearance (CrCL) ≥50 mL/min • The trial was designed to enroll 60 participants but enrollment was discontinued early due to lack of feasibility • Participants received a fixed-dose combination of DOR 100 mg, TDF/3TC once daily for up to 48 weeks Wong A, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. P050.

  30. Results and Conclusions • Nine participants were included in the efficacy analysis (8 K103N and 2 G190A) with a median BL plasma HIV RNA level of 17,000 cp/ml • All 8 participants who completed the week 48 visit achieved HIV-1 RNA <50 copies/mL • The mean increase from baseline in CD4+ T-cell count was 132 cells/mm3 at week 48 • One participant was excluded from the analysis because the presence of baseline NNRTI mutation (K103N) could not be confirmed by the central lab. This participant achieved HIV-1 RNA <40 copies/mL at week 16 and was subsequently lost to follow-up • One participant (with G190A mutation) experienced viral rebound at week 24 (HIV-1 RNA of 5393 copies/mL), which was attributed to non-adherence and genotyping revealed no additional resistance mutations • These data in addition to those from the DRIVE-Shift switch study suggest that Doravirine may also have activity in vivo against NNRTIs resistant strains of HIV Wong A, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. P050.

  31. Studies in treatment-experienced patients

  32. GEMINI studies subgroup analyses: Design Screening(~28 days) Double-blindphase Open-labelphase Continuation phase 1:1 • ART-naive adults • VL 1000-500,000 c/mL DTG + 3TC (N=716) DTG + 3TC • DTG + TDF/FTC (N=717) Orkin C, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. P021.

  33. GEMINI studies subgroup analyses:Baseline characteristics 3-Drugregimen 2-Drugregimen -1,7 -1,5 -3,0 -0,8 -2,3 -1,7 -1,6 -0,4 -0,1 -3,8 -2,8 1,9 -0,9 5,6 -0,7 -13,4 Orkin C, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. P021.

  34. GEMINI studies subgroup analyses:outcomes Orkin C, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. P021.

  35. ACTG A5353: Comparable viral decay with DTG+3TC vs dolutegravir-based triple therapy ACTG A5353: Initial DTG + 3TC in Treatment – Naïve Patients • Design: Phase II, single-arm, open-label pilot • Population: Antiretroviral treatment naïve (N = 120) • HIV-1 RNA 1000 – 500,000 c/mL • 31% > 100,000 c/mL • Primary Result: Virologic success (HIV RNA <50 c/mL) was approximately 90% at Wk 24 with no idfference between viral load strata • Sample Size: 2-drug regimen of DTG + 3TC in ACTG 5353 (N=120); and the 3-drug DTG-based regimens in SPRING-1 (N=51) and SINGLE (N=417) Taiwo B, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O213.

  36. ACTG A5353: results Taiwo B, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O213.

  37. ACTG A5353: results – Decay rates Study / Baseline VL A5353, < 100k A5353, > 100K SPRING-1 / SINGLE, < 100k SPRING-1 / SINGLE, > 100k Taiwo B, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O213.

  38. No significant changes to residual viremia after switch to DTG and 3TC Switch to DTG 50 mg + 3TC 300 mg qd (n=44) Baseline Characteristics: • Male: 88% • Age: 47 years • White/black/Hispanic: 60%/38%/15% • CD4: 680 cells/µL • Time on ART: 5.7 years • Current ART: • NNRTI (30%), PI/r (33%), INSTI (37%) • FTC/TDF (86%), ABC/3TC (14%) Randomization 1:1 Continue Triple Therapy (n=45) Week 0 24 48 Primary Endpoint Li J, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O145.

  39. Virologic Outcomes (FDA Snapshot) Difference (%): 2.0 (-12.6, 16.5) Difference (%): 2.1 (-11.2, 15.3) 93% 91% 91% 89% Patients (%) 2% 2% 2% 0% Dolutegravir + lamivudine (n=44) Continue triple therapy (n=45) Li J, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O145. Week 48 Week 24 Week 48 Week 24 HIV RNA <50 Copies/mL Virologic Failure

  40. Study Results • Integrase Single Copy Assay (iSCA) with a 0.5 HIV-1 RNA copies/mL limit of detection • At baseline, mean residual viremia did not differ between arms • 4.9 c/ml (DTG+3TC) vs. 5.3 c/ml (cART) diff = -0.5 c/ml, 95% CI [-3.8, 2.8], p=0.78 HIV viral load by iSCA by Treatment Arm at Baseline, 24 and 48 Weeks copies/ml Treatment DTG+3TC ART Li J, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O145.

  41. Study Results: By Duration and CD4 Count ART Duration CD4 Count study week study week Treatment DTG+3TC ART Li J, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O145.

  42. The impact of M184V/I mutation on the efficacy of ABC/3TC/DTG regimens prescribed in treatment-experienced patients • Methods: Cohort analysis in treatment experienced patients switched to ABC/3TC/DTG containing regimens with previous resistance profile but an HIV-RNA below 50 copies/ml at the time of the switch 1626 patients were included Ratio presence: absence of M184 V/I mutations 1:11 List of the TAMs found for both groups: 41L, 67N, 70R, 210W, 215Y, 215F, 219Q, 219E *= median Olearo F, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O214.

  43. Study Outcomes Small incidence rate difference : 0.016 (95%CI -0.014 0.05) *Virological blips: any viral load measurement >50 copies/ml, with viral load subsequently undetectable. Olearo F, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O214.

  44. Adverse events

  45. Rio Cohort: Weight gain on first ARTAdjusted analysis Factors Associated with Weight Change During the First ART Regimen *missing values imputed Bakal DR, et al. 20th Intl. Workshop on Co-Morbidties and AdverseDrug Reactions in HIV; 13-14 October 2018; New York, NY. Oral presentation.

  46. NA-ACCORD: Weight gain after initiation of different ART n=21867 86 DTG RAL PI EVG NNRTI 84 Predicted weight (kgs) 82 80 0.0 0.5 1.0 1.5 2 Years since ART initiation Lake J et al Adverse Event workshop Oral

  47. NEAT 22: Modelled Change in weight after Immediate vs Delayed PI/r to DTG n=415 • Factors associated with BMI gain on DTG in multivariable analysis: • Framingham >15% (P=0.042) & hypertension (P=0.035) • Protective factors were switching from PIs other than DRV or ATV (P=0.032), • current smoking (P=0.006), daily exercise (P=0.036), and HDL-chol (P<0.001) • From W0-W48: +0.82kg in DTG-I arm vs+0.25kg in DTG-D arm; (p=0.008) • From W48-W96: +0.03kg in DTG-I arm vs+0.98kg in DTG-D (p=0.002) +0.033 +0.979 +0.818 0.252 Waters L, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. P102.

  48. NEAT 22: PI/r to DTGMedian % change in biomarkers from baseline to week 48 P<0.001 P=0.264 P=0.481 P=0.405 1 -11 P=0.382 P=0.391 P=0.408 P=0.572 P=0.064 P=0.448 P=0.714 P=0.675 -13 -4 P=0.222 P=0.059 P<0.001 P=0.574 0 -14 0 -11 PI/r DTG NEAT22 Biomarkers week 48 data Martinez E, et al. HIV Glasgow; 28-31 October 2018; Glasgow, UK; Abst. O113.

  49. D:A:D, Framingham RS and Pooled Cohorts Equations best fit ATHENA cohort data, but still yield a statistically significant lack of fit SCORE-NL D:A:D GND chi2 = 30.00 GND P = 0.0004 GND chi2 = 119.22 GND P < 0.0001 D:A:D 5-year CVD risk D:A:D 10-year CVD risk SCORE 10-year CDS risk FRS PCE GND chi2 = 24.57 GND P = 0.0035 GND chi2 = 34.22 GND P < 0.0001 FRS 10-year CVD risk PCE 10-year CVD risk GND = Greenwood-Nam-D’Agostino test Van Roest RA, et al. 20th Intl. Workshop on Co-Morbidties and AdverseDrug Reactions in HIV; 13-14 October 2018; New York, NY. Oral presentation.

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