Outline. HIV in 2017 GLOBAL EPIDEMIOLOGY. When was the first report describing AIDS released? Epidemiology: Global U.S.

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1 Outline HIV in 2017 March 22, 2017 Advances in Infectious Diseases Monica Gandhi MD, MPH Professor of Medicine Division of HIV, Infectious Diseases, and Global Medicine Medical director, Ward 86 HIV Clinic, SFGH Epidemiology: Global U.S. HIV testing: When and how often? HIV Prevention: Where are we in 2017? HIV Treatment and a glimpse of the Cure Where are we in 2017? When was the first report describing AIDS released? 1. June 5, June 5, June 5, June 5, June 5, 1983 GLOBAL EPIDEMIOLOGY 1

2 First Clinical Descriptions of AIDS Global HIV prevalence in adults, 1985 MMWR Where did it come from? UNAIDS/WHO 1985 Global HIV prevalence in adults, 1995 Global HIV prevalence in adults, 2005 UNAIDS/WHO 1995 UNAIDS/WHO

3 How many people are currently living with HIV worldwide? million million million million million Adults and children estimated to be living with HIV 2015 Total: 36.7 million [34.0 million 39.8 million] People with HIV on antiretroviral therapy Total: 17 million (46%) WHY PEOPLE LIVING WITH HIV ARE BEING LEFT BEHIND THE TOP 4 REASONS 01 Human rights violations, stigma and discrimination 02 Access to treatment and services 03 Gender-based inequalities 04 Criminalization and exclusion

4 U.S. EPIDEMIOLOGY >1.2 million HIV positive individuals in U.S. (1/8 don t know status) Risks in U.S. women cluster with poverty, disempowerment HIV, especially in women clusters with poverty 1,2 ; interpersonal violence 3 ; incarceration 4 7 ; self esteem, alcohol/drugs 8 U.S. Census 2013 estimates: 13.2% Black/African American 17.1% Hispanic/Latino 77.7% White 1 Amidora. STDs 2006; 2 CDC Surveillance 2011; 3 Wyatt. Am J Public Health 2002; 4 Doherty. JAIDS 2009; 5 Doherty. Am J Public Health 2007; 6 Adimora. Am J Public Health 2007; 7 Khan. J Urban Health 2009; 8 Forna. J Natl Med Assoc

5 ARS: What percentage of the HIV population in U.S. has achieved the goal of therapy (complete virologic suppression)? 1. 82% 2. 66% 3. 45% 4. 30% 5. 25% ARS: How often should a patient be tested for HIV infection? TESTING 1. Once, then every time the patient reports risk factors 2. Once every 2 years and with reported risk factors 3. Once yearly and with reported risk factors 4. Once every 6 months and with reported risk factors 5. Every admission 5

6 U.S. Preventative Services Task Force OraQuick ADVANCE HIV 1/2 Test Oral Fluid Application Should test after 90 days Recommendations changed April 2013 Routine testing once for everyone age ( grade A recommendation) Paves way for coverage under ACA Repeat testing based for Those higher risk for HIV infection Those actively engaged in risky behavior Those living in high prevalence setting Swab upper and lower gums once each with flat pad of test device Insert device in developer vial. Read result between 20 and 40 minutes Negative Reactive HIV-1/2 Test Line Positive Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine, April 30, 2013 ARS: What is the most effective modality of HIV prevention? PREVENTION 1. Male and female condoms 2. Circumcision 3. HIV vaccine 4. Pre exposure prophylaxis 5. Treating HIV infected individuals 6

7 Focus on pre exposure prophylaxis: PrEP Preexposure prophylaxis (PrEP) is giving an HIVnegative individual a pill (daily, or coitally?) to prevent HIV infection (studied: Tenofovir +/ emtricitabine) We know this works if the person takes it Recommended by the CDC, approved by FDA, recommended by WHO Clinical trials of TDF/FTC based PrEP Trial Population, Location Reduction in HIV infections (95% CI) iprex 1 Partners PrEP 2 TDF2 3 FEM PrEP 4 VOICE 5 PROUD 6 IPERGAY 7 MSM, transwomen Americas, South Africa, Thailand Mutually disclosed serodiscordant heterosexual couples; Kenya, Uganda Heterosexual men, women Botswana Women Kenya, South Africa, Tanzania Women Uganda, South Africa, Zimbabwe MSM (open label) UK MSM (intermittent PrEP) France, Canada Men, transwomen 44% (15 63) 84% (54 94) 80% (25 97) Cisgender women 66% (28 84) 49% ( 21 81) 6% ( 52 41) 4% ( 49 27) 86% (58 96) 86% (40 98) % of Adults with PrEP Indication No. of Adults with PrEP Indication , , , , , , MSM PWID Hetero. Men Hetero. Women Slide courtesy of Catherine Koss MD 200, , , ,000 MSM PWID Hetero. Men Hetero. Women Cohen MS et al. Prevention of HIV 1 infection with early antiretroviral therapy. NEJM August 2011 (HPTN 052) 7

8 HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 (Africa, Asia, Americas) HPTN 052: HIV 1 Transmission Total HIV-1 Transmission Events: 39 Immediate ART CD Randomization Delayed ART CD4 <250 Primary Transmission Endpoint Transmission events that were linked to that primary partnership Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death Immediate Arm: 1 Linked Transmissions: 28 p < % reduction Delayed Arm: 27 Unlinked or TBD Transmissions: 11 People have sex outside of their partnerships.. 23/28 (82%) transmissions in sub Saharan Africa 18/28 (64%) transmissions from female to male partners 238 pregnancies People have unprotected sex. Occupational exposure PEP Fluid Risks Blood Semen/vaginal CSF, synovial, pleural, pericardial, amniotic Feces, saliva, nasal, sputum, sweat, tears, urine, vomitus Percutaneous: 0.3% (95% CI %) rate (deep vs superficial; large bore vs not; blood in tip or not; HIV end stage or not but still offer if viral load suppressed) Mucous membrane/non intact skin: 0.09% (95% CI %) infection rate CDC guidelines: last updated 9/2013 Kuhar DT. Infection Control and Hospital Epidemiology 2013; 34(9); Risk Yes Yes, not occupational Unknown (presumed) No, unless bloody Occupational PEP now simplified Decide on case by case basis Try within 72 hours of exposure (1 week if high risk) 28 days Tenofovir + emtricitabine + raltegravir (no 2 drug vs 3 drug PEP) well tolerated, minimal interactions and resistance (consult expert if?) No nevirapine Follow up testing at 6 wks, 12 wks and done at 6 months (4 months if 4 th generation combination HIV p24 antigen HIV antibody test available) Kuhar DT. Infection Control and Hospital Epidemiology 2013; 34(9);

9 April 18, 2016 TREATMENT Health care providers should evaluate persons rapidly for npep when care is sought 72 hours after a potential nonoccupational exposure that presents a substantial risk for HIV acquisition All persons considered for npep should have HIV status checked- rapid combined Ag/Ab, or antibody blood tests 28 day course of TDF/FTC + raltegravir (alternative TDF/FTC + darunavir/ritonavir) ARS: What are the recommendations to start treatment worldwide and in the U.S.? 1. Start HIV treatment when the CD4 count is <500 in U.S. and <350 globally 2. Start HIV treatment when CD4 <500 both sets of recommendations 3. Start HIV treatment regardless of CD4 in U.S. and <500 worldwide 4. Start HIV treatment regardless of CD4 worldwide When to start treatment for HIV? Recommendations NO LONGER differ by resources 9

10 When to Begin Treatment for asymptomatic patients - U.S. guidelines 3/27/12 & 2/13/13 When to Begin Treatment for asymptomatic patients WHO guidelines September 30, 2015 HIV Infection Prior to 3/12, start when CD4 count <500 HIV Infection Prior to 9/30/15, start when CD4 count <500 ART is recommended for all HIV positive individuals ART is recommended for all HIV positive individuals Universal ART policy adopted in San Francisco through HIV Division leadership (Havlir, Hare) and SFDPH January 2010 DHHS. Guidelines for the use of antiretroviral agents in HIV 1 infected adults and adolescents; Available at: May 2015 Prioritize CD4 <350 or stage 3, 4; pregnant and breastfeeding women; all children especially < 1 year World Health Organization. Guidelines on when to start antiretroviral therapy and on pre exposure prophylaxis for HIV. September 30, th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com START: Immediate vs Deferred ART International, randomized phase IV study 215 sites in 35 countries Randomized 1:1 ART-naive adults with CD4+ cell count > 500 cells/mm 3 (N = 4685) Immediate ART* Delayed ART* (until CD4+ cell count 350 cells/mm 3 ) Interim results: serious AIDS and non-aids events, n 41 Study stopped by data and safety monitoring board following results of interim analysis Risk of serious illness or death reduced by 53% with immediate ART Rates of serious AIDS-related and non AIDS-related events lower in immediate ART arm START NEJM *Any licensed ART allowed, according to national guidelines. 86 START NEJM START study Although rates of serious AIDSrelated events and serious non AIDS related events were both lower, risk reduction was more pronounced for the AIDS related events Benefits similar in low, mid and highincome countries START and IPERGAY endorsed by Anthony Fauci, NIAID director, today on WAD 10

11 WHEN TO DELAY THERAPY Hardly EVER (TB meningitis, other space-occupying lesions with inflammation, cryptococcal meningitis) HIV Life Cycle and Antiretroviral Targets 3) Integration 4) Transcription RT 6) Cleavage 7) Packaging 5) Translation DNA 2) Reverse transcriptase RNA 8) Maturation 1) Virus Entry CD4 receptor (CXCR4, CCR5) 9) Re-infection HIV Life Cycle and Antiretroviral Targets DNA 3) Integration Nucleos(t)ide reverse 2) Reverse transcriptase transcriptase RT inhibitors (NRTIs): Integrase RNA strand transfer Non-nucleoside inhibitors reverse transcriptase (INSTI): inhibitors (NNRTIs): 4) Transcription 6) Cleavage 5) Translation Protease inhibitors (PIs): 1) Virus Entry Fusion (entry) inhibitor: CD4 receptor e.g. enfuvirtide (CXCR4, CCR5) CCR5 receptor antagonist: 9) Re-infection e.g. maraviroc The history of ARV approvals- the ascent of the integrase inhibitor and the descent of EFV/Atazanavir Golconda Dolutegravir Elvitegravir 8) Maturation 7) Packaging

12 Cumulative problems for EFV (CNS side effects) EFV as Initial Therapy: Increased Risk for Suicidal Ideation Review of 4 ACTG studies in ART naïve patients Compared 3241 patients starting EFV vs 2091 patients starting non EFV based ART Median duration f/u 96 weeks First suicidal ideation OR attempted OR completed suicide in each group 8.08 events per 1000 PY in EFV group vs 3.66 events per 1000 PY in EFV free group (HR: 2.28; 95% CI, ; P=.006) Mollan KR, et al. Ann Intern Med. 2014;161:1-10. Cumulative problems for ATV: ACTG A5257 ATV/r + FTC/TDF HIV+ adults, no previous ART (n=1809) Randomized 1:1:1. Open Label Therapy RAL + FTC/TDF DRV/r + FTC/TDF RAL superior to both PI/r regimens for combined tolerability and virologic efficacy; DRV/r superior to ATV/r; ATV/r lost due to tolerability issues Lennox J et al, Ann Int Med, 2014 Ascent of the integrase inhibitor Three and one in phase III trials Dolutegravir Elvitegravir Raltegravir Current Guidelines: What to Start 2016 INSTI (n=5) PI (n=1) Recommended Regimens (n=6) Dolutegravir/ABC/3TC Dolutegravir + TDF/FTC Elvitegravir/cobi/TDF/FTC Elvitegravir/cobi/TAF/FTC added 11/15 Raltegravir +TDF/FTC Darunavir/ritonavir +TDF/FTC Only if CrCl >70 David Lazar The Ascent 12

13 NNRTI (n=2) PI (n=5) Alternative Regimens Efavirenz/TDF/FTC Rilpivirine/TDF/FTC* ATV/r or cobi + TDF/FTC DRV/cobi + TDF/FTC DRV/r or cobi + ABC/3TC *Only if VL <100K and CD4 >200. Only if Cr Cl >70 Effective and tolerable but have potential disadvantages, have limitations for use in certain patient populations, or have less supporting data than Recommended Regimens ARS: How many single pill combinations for the treatment of HIV are there now? An alternative regimen may be the preferred regimen for some patients Currently available SPCs Picture of SPC Drugs in SPC Approval Food effects date TDF/FTC/efavirenz (Atripla ) 2006 Food levels TDF/FTC/rilpivirine (Complera ) TDF/FTC/elvitegravir/ cobicistat (Stribild ) ABC/3TC/dolutegravir (Triumeq ) TAF/FTC/elvitegravir/ cobicistat (Genvoya ) TAF/FTC/rilpivirine (Odefsey ) 2011 Take with solid meal (390kcal) 2012 Take with food (373kcal) 2014 Food levels 2015 Take with food (373kcal) 2016 Take with solid meal (390kcal) Examining questions of dual therapy NRTI intolerance (HLA B5701 and renal failure) or NRTI mutations Minimize pill burden Minimize toxicities Minimize cost Preserve treatment options for future INSTIs (e.g. dolutegravir, cabotegravir) potent and medium high genetic barrier to resistance will this allow the possibility? Allow for long acting therapy (just 2 available right now; in phase III trials) 13

14 SWORD 1 and 2: Switch to Dolutegravir Plus Rilpivirine Noninferior to Remaining on Baseline ART at Week 48 in Virologically Suppressed Patients CROI 2017 #44LB 2 true virologic failures in SWORD arm one developed K103K/E (NNRTI mutation), no INSTI mutations 14

15 The Mississippi Baby 28 month old child (now 37 mo) born at 35 weeks gestation (2.5kg) via NSVD Rapid HIV test positive in mother during labor (CD4 644; viral load 2423 copies/ml) No antiretrovirals in labor (precipitous delivery) HIV viral load (~20,000 copies/ml) at 30 hours of age AZT/3TC/NVP (usually 1 drug) started as prophylaxis by 31 hours of age (31 hrs 7d), therapeutic dose of NVP used; latter switched to LPV/r (protease inhibitor) (7d 18 months) after 1 week Persaud. NEJM 2013 Typical biphasic decay What happened to baby? Mother and baby lost to follow up when baby 18 months old Baby off treatment Re appeared ~24 months Plasma HIV RNA remained undetectable (off therapy) Super low HIV DNA in PBMC, no infectious virus ( graveyard sequences) No Western blot reactivity for child (remains reactive for mother) Baby (~42 months) still negative (CROI March, 2014) Baby (nearly 4 yrs) on 7/10/14 announced to have HIV viremia (16,750 copies/ml) Persaud. NEJM

16 Cure research initiative (Steve Deeks and team) Strategies being pursued Early ART may be curative Stem cell transplants to reduce reservoir Drugs to flush out HIV from latent reservoirs Vaccines to enhance host clearance Barriers anticipated Current ART not fully suppressive No high through put reliable assays to examine reservoir Flush out drugs may not work as monotherapy 16