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Current Challenges in the Management of HIV

Current Challenges in the Management of HIV. Sharon Walmsley Professor of Medicine University of Toronto Senior Scientist, Toronto Hospital Research Institute. Objectives. Review the advances achieved in the management of HIV especially the impact on morbidity and mortality

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Current Challenges in the Management of HIV

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  1. Current Challenges in the Management of HIV Sharon Walmsley Professor of Medicine University of Toronto Senior Scientist, Toronto Hospital Research Institute

  2. Objectives • Review the advances achieved in the management of HIV especially the impact on morbidity and mortality • Discusses the challenges that continue despite the advances with HAART therapy • Describe the increasing epidemic of comorbidity • Describe the impact of the changing management of HIV and the importance of considerations of drug interactions

  3. Triumphs Improved morbidity and mortality • Improved antiretroviral formulations to optimize adherence • Improved short term tolerability and decreased some long term adverse events of therapy • Prevention of maternal to child transmission • Decreased drug resistance • Ability to better manage the treatment experienced patient

  4. The impact of HAART on Survival Survival from age 25 yearsN = 3,990 1 0.75 Population controls Probability of survival 0.5 Late HAART (2000–2005) 0.25 Early HAART (1997–1999) Pre-HAART (1995–1996) 0 25 30 35 40 45 50 55 60 65 70 Age (years) Adapted from Lohse N, et al. Ann Intern Med 2007;146:87–95

  5. ARVs: 2011 Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6

  6. US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; Thompson MA, et al. JAMA 2010;304(3):321-333; www.eacs.eu.

  7. Improved ARV formulations • Fixed-dose combinations - the standard of care One pill once a day for HIV is a reality

  8. Toxicity Was a Major Reason for Discontinuation of First-Line ARV ICONA study group (March 1997 - June 1999) Median follow-up:45 weeks Study population: 862 ARV-naive patients 84.3% receiving unboosted PI + NRTIs Discontinuations: n = 312 (36%) Cause of Discontinuation Toxicity Nonadherence Failure Other 8% 20% 58% 14% d’Arminio Monforte A, et al. AIDS. 2000;14:499-507.

  9. Safety and Tolerability of Select Current Regimens Are Improved 1. Pozniak AL, et al. JAIDS. 2006. 2. Eron J Jr, et al. Lancet. 2006. 3. Ortiz,et al AIDS 2008. 4. Molina JM, et al. Lancet, 2008. 5. Smith K, et al.AIDS, 2009. 6. Gathe J, et al. JAIDS, 2009, 7. Walmsley SL, et al. JAIDS, 2009. 8. Lennox et al, Lancet 2009, 9. Cooper et al, JID, 2010

  10. Therapy works for most for the long term7 year follow-up Study 720: LPV/RTV Study 903E: EFV 95% 81% 59% Murphy HIV Clin Trials 2008;9:1-10 Cassetti IAS 2008, abstract #TUPE0057

  11. Not only in clinical trials but also in practice Raboud, Walmsley, 2010

  12. Can I Have Children? Contraception and Pregnancy Issues in HIV

  13. TriumphsTrends in reduction of MTCT: results over time in the field 35 30 25 20 15 % Transmission 10 5 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 USA and Europe Thailand Africa McIntyre J, et al 12th CROI 2005; #8

  14. PRIMARY RESISTANCEHas continued at low levels Canada ~8.5%1 UK: ~181† USA: ~10%1 France: ~123‡ Europe:~112* Spain: ~9.51 Mexico: ~7%1 Brazil0-30% Australia: ~131 Argentina 7-15% 1 XIII IHDRW, Tenerife, June 2004; 2 Wensing AMJ, XII IHDRW, June 2003, #117; 3 Delfraissy JF,Rapport 2004

  15. Kaplan-Meier curves for the proportion of patients without virologic failure by the presence of minority HIV-1 drug-resistant variants 0.0 0.2 0.4 0.6 0.8 1.0 p <0.001 Proportion without virologic failure Minority variants not detected Minority variants detected 0.0 250 500 750 1000 1250 1500 Days

  16. The proportion of patients in North America who experience failure of at least two distinct regimens has declined dramatically (n ~ 30,000) aRR=1.46 REF aRR=0.82 aRR=0.51 aRR=0.54 Adjusted RR from cohort-stratified Cox model adjusting for time from HAART initiation, sex, age, AIDS, CD4 and VL at HAART initiation and switch, type of ARV (PI, NNRTI, NRTIs only) at initiation Deeks CID 2009;49:1582

  17. Tribulations • We still debate when to start therapy • Response rates not increased above 80% at 48 week • Short and long term adverse events • Difficult to treat patients- depression, IVDU • Emerging co-morbidities • HIV as an inflammatory condition • Inability to eradicate the reservoir • Costs and access

  18. When to Start ART ? • Much better ARV drugs - Potency - Simplicity Tolerability • Larger number of options • Deleterious effect of HIV • Reduction HIV transmission Later • Long term ART Complications • Cost • Uncertainty ? EARLY Fewer arguments not to start ART early

  19. What is the impact of starting late? • Impaired immunological response to HAART1 • Increased HIV-related and non-HIV related mortality2 • Increased HIV-related sequelae3 • Increased HAART-related complications4 • Increased onward transmission5 • Increased health care costs6 1. Robbins GK et al. Clin Infect Dis 2009; 48:350–361 2. Marin B, et al AIDS 2009;23:1743–53 3. Sabin CA et al. AIDS 2004;18:2145–51 4. Florence et al. HIV Medicine 2003;4:255–262 5. Marks G, et al. AIDS 2006;20:1447–50 6. Fimpel et al. Eur J Health Econ 2009; epub.

  20. CD4 Nadir Impacts Ability of Effective HAART Treatment to Increase CD4 >500 cells/mm3 Kelly CF et al. CID 2009;48:787-794.

  21. NA-ACCORD study: Higher mortality when deferring treatment 0.20 CD4 count >500 cells/mm3& defer HAART (N=6,539) Kaplan-Meier survival estimates 0.15 0.10 CD4 count >500 cells/mm3& initiate HAART (N= 2,616) 0.05 0.00 0 2 4 6 8 10 Years after 1996 Kitahata M, et al CROI 2009. Abstract 71

  22. When to start antiretroviral therapy ? • Treatment recommended if • hepatitis C co-infection, • HBV, • HIVAN • VL>105 c/ml and/or CD4 decline >50-100/mm3/year or age >50 or, pregnancy, • high cardiovascular risk, malignancy.

  23. Pathogenesis of HIV HIV Immune activation Inflammation Immune deficit Cardiovascular risk Bone Cognitive disorders HBV/HCV Cancers Immune deficit Accelerated aging Cancers AIDS Cancers HIV is deleterious - immune suppression and activation

  24. SMARTandDARTHIV replication is associated to increased mortality and morbidity Treatment interruption vs continuing therapy Event STI CT RR P N /100py N /100 py AIDS/death 3.3 1.3 2.6 <10-4 AIDS (WHO stage 4) 8.3 3.2 2.6 0.003 NEJM 2006;355: 2283-96

  25. SMART : Risk of Death and increases in markers of inflammation and coagulation Marker Un-adjusted Adjusted OR (4th/1st) P-Value OR (4th/1st) P-Value Hs-CRP 2.0 0.05 2.8 0.03 Amyloid A 2.2 0.07 2.6 0.09 Amyloid P 0.7 0.39 1.1 0.84 IL-6 8.3 <0.0001 11.8 <0.0001 D-Dimer 12.4 <0.0001 26.5 <0.0001 F1.2 1.0 0.92 1.2 0.66 *Adjusted for age, race, ART, VL, BMI, Cholesterol, Smoking, Hepatitis, Statins, BP med’s Kuller LH, et al. PLoS Med. 2008;5:e203.doi;10.1371/journal.pmed.0050203

  26. HIV- HIV+ INCIDENCE Non HIV related Comorbidities appear to occur earlier 10-15 years AGE

  27. Patients HIV+ with CD4 >500 cp/ml Early Therapy Start cART immediately n=600 in the initial phasen=1500 (estimation) in the final phase Deferred therapy Start cART when CD4 <350 cells/µL or symptoms n=600 in the initial phasen=1500 in the final phase The START studyWhen to start ART therapy? Gordin et al. IAS 2007, MOSY205 oral presentation

  28. Tribulations:Recent Randomized ARV Trials

  29. Triumph: Randomized ARV Trials in Treatment Experienced Patients % VL< 50/ml at week 48 Patients with >2 active agents All Patients

  30. Difficult to Treat Populations Impact of DepressionWIHS and MACS Cohorts 1. Anastos K, et al. J Acquir Immune Defic Syndr. 2005;39:537-544. 2. Cook JA, et al. AIDS Care. 2006;18:93-100. 3. Li X, et al. J Acquir Immune Defic Syndr. 2005;38:320-328.

  31. Difficult to Treat Populations IVDU • Prospective study (interview) of Hopkins cohort (N = 764) of patients with nadir CD4+ count < 500 cells/mm³ or peak HIV-1 RNA > 30,000 copies/mL • Adherence, virologic, and immunologic outcomes poorer among current IDUs Nonadherence CD4+ Count Increase Change in HIV-1 RNA 122 0 50 125 116 P < .05 P < .001 100 -0.5 40 34 P = .11 65* 75 -1.0 -0.8† 30 Change HIV RNA-1 (log10 copies/mL) Change in CD4+ Count (cells/mm³) Patients Reporting Nonadherence (%) 24 50 -1.5 20 17 -1.6 25 -2.0 -1.7 10 Nonusers Former users -2.5 0 0 Active users *P = .003 vs nonusers and former users; †P < .001 vs nonusers and former users. Lucas G, et al. J Acquir Immune Defic Syndr. 2001;27:251-259.

  32. The drugs are better butOngoing issues with toxicity • Anemia • Lipoatrophy/ lipohypertrophy • Renal problems • Osteoporosis • Cardiovascular diseases • Impact of HIV, inflammation, aging, ARV

  33. Are we seeing more Neurocognitive Disorders (HAND)? HIV-Associated Dementia (HAD) Mild Neurocognitive Disorder (MND) Asymptomatic Neurocognitive Impairment (ANI) No Neurocognitive Impairment

  34. Emerging co-morbidities in HIV Neurocognitive dysfunction Renal dysfunction Neurological impairment present in ≥50% HIV+ patients3 30% of HIV+ patients have abnormal kidney function1 Cardiovasculardisease Reduced bone mineral density 75% increase in risk of acute MI4 Increased prevalence of osteoporosis or osteopenia in spine, hip or forearm: 63% of HIV+ patients2 Cancer Increased risk of non-AIDS-defining cancers e.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal5 Gupta SK et al. Clin Infect Dis 2005;40:1559–1585. ,Brown TT et al. J Clin Endocrinol Metab 2004;89(3):1200–1206, Clifford DB. Top HIV Med 2008;16(2):94–98 Triant VA et al. J Clin Endocrinol Metab 2007;92:2506–2512, Patel P et al. Ann Intern Med 2008;148:728–736

  35. Nature Medicine • Volume: • 16, • Pages: • 460–465 • Year published: • (2010 • Nature Medicine • Volume: • 16, • Pages: • 460–465 • Year published: • (2010 • Nature Medicine • Volume: • 16, • Pages: • 460–465 • Year published: • (2010 Tribulations: We have failed to Eliminate the Viral ReservoirIntensification with Raltegravir We will not solve the problem with antivirals alone Buzon et al, Nature Medicine, 2010

  36. Multi-Class Failure: Tomorrow Heavily NRTI experienced with multiple mutations + failure on ENF and RAL

  37. ARV therapy in the developing world

  38. Access is Improving but not good enough

  39. Treatment for Prevention • Can it work • Will it work • Can we afford it?

  40. Viral Load as a predictor of Heterosexual HIV transmission Quinn et al, N Engl J Med. 2000;342:921-929

  41. HAART stops HIV replication  HIV load falls to undetectable levels in plasma as well as in sexual fluids  Sharp reduction in HIV transmission

  42. Impact of ART Sero-discordant Heterosexual Couples 92% reduction in HIV Transmission Risk from 5.64 to 0.46 transmissions per 100 person-years S Attia, M Egger, M Muller, M Zwahlen and N Lowa. AIDS. 2009 Jul 17;23(11):1397-404

  43. Conclusions • HAART has dramatically improved the lives of persons with HIV • Despite our advances problems remain as we continue to cope with challenges of adverse events both short and long term, the increase in comorbidity, aging, and issues around adherence • The difficult to treat population needs new management strategies • We need to go beyond the virus, and think of the deleterious impact of inflammation • We have made some inroads into prevention

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