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Future Directions in HIV Clinical Research

Future Directions in HIV Clinical Research. Eric S. Daar, M.D. Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA. Overview. Diagnosis Prevention Treatment Cure research. Diagnosis. Infected and Unaware.

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Future Directions in HIV Clinical Research

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  1. Future Directions in HIV Clinical Research Eric S. Daar, M.D. Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA

  2. Overview • Diagnosis • Prevention • Treatment • Cure research

  3. Diagnosis

  4. Infected and Unaware CDC and Prevention National HIV Surveillance System1 Females (n=279,200) Males (n=869,000) 85% ~25% Unaware of Infxn Transmission Risk2 81% ~54% New Infections 70% 65% 41% Accounting for: ~75% Aware of Infxn Incidence (%) 36% 35% 32% 26% 25% ~46% New Infections Prescribed ART Linked to Care Viral Suppression Retained In Care Diagnosed People Living with HIV New Sexual Infections n=1,148,200 HIV-infected persons, 18% of whom are unaware of their infection. • Hall HI, et al. 19th IAC. Washington, DC, 2012. Abstract FrLBX05. • Marks et al. AIDS 2006; 20:1447

  5. Revised CDC Recommendations for HIV Testing in Healthcare Settings • Routine testing all 13 to 64 years in healthcare settings • Not based on patient risk • Opt-out testing • No separate consent for HIV • Pretest counseling not required • Repeat HIV testing left to discretion of provider • Based on patient risk Branson BM, et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

  6. Rapid Home HIV Testing(Approved July 2012)

  7. Window Period and HIV Infection

  8. Efficiency of HIV Transmission VL in semen without ARVs VL with intervention (e.g. ARVs) Potential threshold for transmission Cohen MS, et al. JID 2005; 191:1391-3

  9. 4th Generation Antigen/Antibody

  10. Proposed Testing Algorithm CDC. MMWR 2014

  11. Future Directions for Diagnosis • Expand testing • Target high risk populations • Identify early infection • Making diagnosis is just the beginning

  12. Prevention

  13. Adults and Children Estimated to be Living with HIV- 2013 Adults and children estimated to be living with HIV2013 Eastern Europe & Central Asia 1.1 million [980 000– 1.3 million] North America and Western and Central Europe 2.3 million [2.0 million – 3.0 million] Middle East&North Africa 230 000 [160 000 – 330 000] Caribbean 250 000 [230 000 – 280 000] Asia and the Pacific 4.8 million [4.1 million – 5.5 million] Sub-Saharan Africa 24.7 million [23.5 million – 26.1 million] Latin America 1.6 million [1.4 million – 2.1 million] Total: 35.0 million[33.2 million – 37.2 million]

  14. Estimated Number of Adults and Children Newly Infected with HIV- 2013 Estimated number of adults and children newly infected with HIV2013 Eastern Europe & Central Asia 110 000 [86 000 – 130 000] North America and Western and Central Europe 88 000 [44 000 – 160 000] Middle East&North Africa 25 000 [14 000 – 41 000] Caribbean 12 000 [9400 – 14 000] Asia and the Pacific 350 000 [250 000 – 510 000] Sub-Saharan Africa 1.5 million [1.3 million – 1.6 million] Latin America 94 000 [71 000 – 170 000] Total: 2.1 million [1.9 million – 2.4 million]

  15. Estimated New Infection in U.S. (2010) Estimated total= 47,500

  16. Preventing HIV Transmission

  17. Scienceexpress, July 19th 2010. 18th IAC 2010, Vienna, Austria, Abst. TUS505

  18. (N=444) (N=445) High adherers (>80%) effectiveness = 54% Scienceexpress, July 19th 2010.

  19. iPrEx Study (n=2499) N=64 N=36 Cumulative Probability of HIV Infection Risk Reduction 44% (95% CI: 15, 63) P=0.005 Weeks Grant R. et al. NEJM 2010, ePub ahead of press.

  20. iPrEx Protection and Adherence Overall >90% Adherence Detectable Drug Levels Grant R. et al. NEJM 2010, ePub ahead of press.

  21. Conflicting Results with Oral PrEP Trials Efficacy (95% CI) FTC/TDF for HIV discordant couples (Partners PrEP) 75% (55; 87) 67% (44; 81) TDF for HIV discordant couples (Partners PrEP) TDF for young heterosexuals (TDF-2) 63% (22; 83) TDF/FTC for MSM and TW (iPrEx) 44% (15; 63) TDF/FTC for injecting drug users (Bangkok TDF) TDF/FTC for women (FEM-PrEP) TDF/FTC for women (VOICE) TDF for women (VOICE) -4% (-49; 27) 6% (-52; 41) -49% (-129; 3) 49% (10; 72) 0 10 20 30 40 50 60 70 80 90 100% -70 -60 -50 40 -30 -20 -10 Modified from: Abdool Karim SS. Lancet 2013; 381(9883):2060-2.

  22. HPTN 052: Treatment as Prevention 96%reduction in risk of transmission from those on treatment Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3* (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]

  23. Future Directions for Prevention • Expand testing and early diagnosis • Optimize treatment as prevention strategies • Linkage and retention into care • Adherence with therapy • Refine PrEP strategies • Microbicide (e.g. dosing frequency, long acting forms) • Systemic (adherence interventions, dosing, long acting therapy) • Vaccine research

  24. Treatment

  25. Projected Impact of ART on Survival of a 20-yo in a High Income Country Source: UNAIDS / Lohse et al / Hoog et al / May et al / Hogg et al

  26. When to Start Treatment *Unless elite controller (HIV RNA <50 copies/mL) or has stable CD4 cell count and low-level viremia in absence of therapy. The IAS-USA guidelines also recommends initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision March 27, 2012; Thompson MA, et al. JAMA. 2012;308:387-402.

  27. HIV replication cycle and sites of drug activity Protease New HIV particles Capsid proteins and viral RNA CD4 Receptor Viral RNA Fusion Inhibitor T-20 (Enfuvirtide, Fuzeon) Integrase Inhibitor Raltegravir (Isentress) Elvitegravir /COBI Dolutegravir (Trivicay) CCR5 Antagonist Maraviroc (Celsentri) Reverse Transcription Attachment Translation Uncoating Integration Transcription Protease Inhibitors Indinavir (Crixivan) Ritonavir (Norvir) Saquinavir (Fortovase) Nelfinavir (Viracept) Lopinavir/ritonavir (Kaletra) Atazanavir (Reyataz) Fos Amprenavir (Lexiva) Tipranavir (Aptivus) Darunavir (Prezista) NNRTIs Efavirenz (Sustiva) Delavirdine (Rescriptor) Nevirapine (Viramune) (XR) Etravirine (Intelense) Rilpivirine (Edurant) NRTIs AZT (Zidovudine-Retrovir) ddI (Didanosine-Videx) ddC (Zalcitabine-Hivid) d4T (Stavudine-Zerit) 3TC (Lamivudine-Epivir) ABC(Abacavir-Ziagen) FTC (Emtricitabine, Emtriva) nRTI Tenofovir DF (Viread) Cellular DNA Nucleus HIV Virions Reverse Transcriptase Integrase Unintegrated double stranded Viral DNA gag-pol polyprotein Integrated viral DNA Viral mRNA 6 5 1 3 4 2 Assembly and Release

  28. DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Revision March 27, 2012. DHHS Guidelines May 2014: What to Start

  29. HIV Cascade

  30. Physical Manifestations of Fat Redistribution Syndromes

  31. Increased age-related complications on ART Mean AMI events per 1000 person years Increased risk of AMI in HIV compared to HIV uninfected HR = 1.48 (CI = 1.27 – 1.72) Further increase HR if CD4<200 or HIV RNA>500 N=82,459; Veterans Ageing Cohort Study Virtual Cohort Frieberg et al., JAMA Internal Med 2013

  32. Brain Liver Kidney Cardiovascular System Genitourinary Tract Bone

  33. Etiology of non-AIDS-related events Non-AIDS-related events are more common in HIV disease, even after adjustment for age, cART exposure and traditional risk factors cART toxicity Non-AIDS events Lifestyle Persistent inflammation(immune activation) (e.g. smoking) Deeks SG, Phillips AN.Br Med J 2009;338:a3172

  34. Inflammatory biomarkers remain elevated during long-term ART Neuhaus JID 2010

  35. Early ART is associated with less inflammation during ART ART-naïve with CD4+ count > 500 cells/mm3 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm3 N=2,300 Early ART Group Initiate ART immediately N=2,300

  36. 100 90 80 70 60 50 % HIV-1 RNA <50 c/mL 40 30 20 10 0 16 24 2 12 4 8 Time (Weeks) TAF/FTC/EVG/COBI Tenofovir alenofenamide (TAF): reduced toxicity TDF/FTC/EVG/c 90% (n=58) TAF/FTC/EVG/c 88% (n=112) Rx-naïve, VL >5000, CD4 >50 (N=170)

  37. Studies of Neuropathogenesis Central Nervous System • Timing of treatment • Reducing inflammation • Select or enhanced CNS active ART

  38. Prevention of non AIDS events • Lifestyle modifications • Reduce smoking, healthy diet, exercise • Reduce modifiable risk factors • Assessment of blood pressure, glucose and lipids • Counselling and screening for common cancers • Enhance CD4 recovery and reduce inflammation

  39. Healthy aging requires aggressive risk factor management (in middle age), exercise and diet

  40. Future Directions for Treatment • Enhancing linkage and retention into care • Outreach, patient navigators, incentives • Defining benefits of early therapy • Prevent end-organ dz, delay non-AIDS events, transmission • Optimizing treatment • New treatments/new formulations • Minimize toxicity • Target end-organs (e.g. CNS) • Direct interventions to address chronic inflammation • Antiinflammatory • Target underlying pathogenesis

  41. Cure Research

  42. Obstacle to cure: At least one…. • Control • Purge • Minimize • Combination interventions Siliciano JD, et al. Nature Med 2003;9:727-8

  43. Hutter G, et al. N Engl J Med 2009; 360:692-8. • Procedure and Events • Ablative chemotherapy • Total body XRT • Graft vs. host • Transplant with CCR5∆32 homozygous donor

  44. ANRS VISCONTI-14 Saez-Cirion A, et al. PLOS Pathogen 2013; 9:e1003211

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