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This overview discusses the diagnosis, prevention, treatment, and cure research for HIV. It covers topics such as expanding testing, targeting high-risk populations, and optimizing treatment and prevention strategies. The article also explores the potential for vaccines and other future directions in HIV clinical research.
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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
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
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.
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
Proposed Testing Algorithm CDC. MMWR 2014
Future Directions for Diagnosis • Expand testing • Target high risk populations • Identify early infection • Making diagnosis is just the beginning
Adults and Children Estimated to be Living with HIV- 2013 Adults and children estimated to be living with HIV2013 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]
Estimated Number of Adults and Children Newly Infected with HIV- 2013 Estimated number of adults and children newly infected with HIV2013 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]
Estimated New Infection in U.S. (2010) Estimated total= 47,500
Scienceexpress, July 19th 2010. 18th IAC 2010, Vienna, Austria, Abst. TUS505
(N=444) (N=445) High adherers (>80%) effectiveness = 54% Scienceexpress, July 19th 2010.
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.
iPrEx Protection and Adherence Overall >90% Adherence Detectable Drug Levels Grant R. et al. NEJM 2010, ePub ahead of press.
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.
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]
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
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
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.
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
DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Revision March 27, 2012. DHHS Guidelines May 2014: What to Start
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
Brain Liver Kidney Cardiovascular System Genitourinary Tract Bone
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
Inflammatory biomarkers remain elevated during long-term ART Neuhaus JID 2010
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
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)
Studies of Neuropathogenesis Central Nervous System • Timing of treatment • Reducing inflammation • Select or enhanced CNS active ART
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
Healthy aging requires aggressive risk factor management (in middle age), exercise and diet
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
Obstacle to cure: At least one…. • Control • Purge • Minimize • Combination interventions Siliciano JD, et al. Nature Med 2003;9:727-8
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
ANRS VISCONTI-14 Saez-Cirion A, et al. PLOS Pathogen 2013; 9:e1003211