Updates in the fast moving field of HIV medicine 35 th Advances in Infectious Diseases April 25, 2014 Monica Gandhi MD, MPH Professor of Medicine and Clinic Director ( Ward 86 ), Division of HIV/AIDS San Francisco General Hospital Outline Epidemiology: Global and U.S. How are we doing in terms of goals of treatment? HIV testing: When and how often? HIV Prevention: Where are we in 2014? Post exposure prophylaxis HIV Treatment: When to start and updates in 2014 HIV cure: Berlin, the Baby, Boston and Brie EPIDEMIOLOGY 1
Major news from UNAIDS update 9/23/13 Case GOOD NEWS 1.6 million died from HIV 2012, from 2.3 million 2001 New HIV infections among adults by 50% in 26 countries b. 2001 2012 260,000 children infected 2012 (330,000 2011) BAD NEWS 75 million infected since epidemic started, 36 million have died Although 9.7 million have access to ARVs, only 34% of people who qualify Any child being infected 26 yo married woman presents to your 1 o care practice for pre conception visit. She has had sex with men only and has had 3 partners in her life. You tell her that you will be sending an HIV test today in addition to routine pre conception labs and she tells you to not bother as she doesn t think she is at risk for HIV infection. What percentage of the HIV population in U.S. is not aware of their HIV infection? 1. 0 5% 2. 5 10% 3. 15 20% 4. 20 25% 5. 25 30% CDC estimates 1,148,200 persons in U.S. 13 yrs living with HIV, including 207,600 (18.1%) unaware 2
% HIV diagnosis attributable to MSM in 2011 (account for >half in all but 2 states) HIV Testing and Risk Behaviors Among Gay, Bisexual, and Other Men Who Have Sex with Men MMWR Nov 2013 / 62(47);958 962 74.9% 25.1% Case (continued) 74.9% U.S. Census 2011 estimates: 13% Black/African American 17% Hispanic/Latino 78% White 25.1% The patient s rapid HIV Ab test returns as positive, as does her urine pregnancy test. Blood tests verify both findings. She is happy about the pregnancy, but upset about the HIV diagnosis and said she never thought she could be at risk. She also asks if this means that her husband knew about the diagnosis but was not taking medications. 3
The Course of Untreated HIV Infection: CD4 cells and HIV RNA What percentage of the HIV population in U.S. has achieved the goal of therapy (complete virologic suppression)? Seeding of latent reservoirs CD8 cytotoxic T cells 1. 82% 2. 66% 3. 50% 4. 33% 5. 25% CDC vital statistics July 2012: The patient looks terrible Medical Monitoring Project (MMP) 3 surveillance datasets. Testing, linkage, retention, prescription and adherence rates all contribute to poor virologic suppression rate in this country ( Cascade of Care ) TESTING Of the 1.1 million Americans living with HIV, only 25% are virally suppressed 4
How often should a patient be tested at UCSF for HIV infection? 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 CDC 9/21/06 risk-based to routine HIV screening in all health care settings 13 64 yrs after patient notified (opt out screening assent inferred unless patient declines) 1. HIV testing for those high risk at least qyear No written consent, relaxed prevention counseling Pregnancy: Screen in 1 st trimester, repeat in 3 rd trimester if risk factors Routine testing still called grade C recommendation by USPSTF up to April 30, 2013 Branson BM et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health care settings.mmwr Recomm Rep. 2006 Sep 22;55(RR 14):1 17 ; 2 Wynia MK. Routine screening: informed consent, stigma and the waning of HIV exceptionalism. Am J Bioeth. 2006 Jul Aug;6(4):5 8; 3 Burke RC et al. Why don't physicians test for HIV? A review of the US literature. AIDS. 2007 U.S. Preventative Services Task Force Recommendations changed April 2013 Routine testing once for everyone age 15 65 ( 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 Orasure test FDA approved for home testing 5/15/12 FDA panel recommended (17 0) first in home over the counter saliva test kit (OraQuick In Home HIV test ) Specificity 99.98%; sensitivity 92.98% (false negative rate of concern) Cost ~$60; use at least 90 days after exposure Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine, April 30, 2013 5
Case (continued) PREVENTION The patient asks whether there was anything she could have done to protect herself from HIV infection (even while trying to conceive) if she had known her no good husband s status. Of the following interventions, which has the highest efficacy (level I RCT data) in preventing heterosexual HIV transmission? 1. Microbicides 2. Circumcising the male partner 3. Pre exposure prophylaxis for HIV negative partner 4. HIV vaccine 5. Using HIV treatment for HIV+ partner 6. Post exposure prophylaxis for HIV negative partner Of the following interventions, which has the highest efficacy (level I RCT data) in preventing HIV transmission? 1. Microbicides Jury out (CAPRISA 004 yes on 1% tenofovir gel; VOICE no with same product) 2. Circumcising the male partner (Yes, helps men; no efficacy for women partners) 3. Pre exposure prophylaxis for HIV negative partner 4. HIV vaccine (no viable candidate; recent failures) 5. Using HIV treatment for HIV+ partner 6. Post exposure prophylaxis for HIV partner 6
PrEP Adherence everything, esp in women Pre exposure prophylaxis: PrEP Preexposure prophylaxis (PrEP) is giving an HIVnegative individual a pill (daily, or coitally?) to prevent HIV infection (studied: Tenofovir +/ emtricitabine) Trial Population/Setting Intervention iprex [1] (N = 2499) Partners PrEP [2] (N = 4747) TDF2 [3] (N = 1219) Bangkok TFV Study [6] (N= 2413) FEM PrEP [4] (N = 2120) VOICE [5] (N = 5029) MSM, 11 sites in US, S. America, Africa, Thailand Serodiscordant couples in Africa Heterosexual males and females in Botswana IDU (use in last year) in Bangkok High risk women, Africa High risk women, Africa Reduction in HIV Infection Rate, % Daily oral TDF/FTC 44% (95% CI 15 63, p 0.005) Daily oral TDF Daily oral TDF/FTC Daily oral TDF/FTC Women: 71%; men: 63% Women: 66%; men: 84% 62%* (underpowered for sex differences) Daily oral TDF 49% (95% CI 9.6 72.2, p 0.01) Daily oral TDF/FTC Daily oral TDF Daily oral TDF/FTC 1% TFV gel Study stopped early due to futility 1% TDF gel & daily oral TDF arm both stopped early, futile Daily TDF/FTC arm no efficacy Grant RM, et al. N Engl J Med. 2010;363: 2587 2599. 2. Baeten JM, et al. N Engl J Med. 2012;367:399 410. 3. Thigpen MC, et al. N Engl J Med. 2012;367:423 434. 4. Van Damme L, et al. N Engl J Med. 2012;367:411 422.; 5. Marrazzo J, et al. CROI 20th, March 4, 2013, Atlanta, GA; 6. ChoopanyaK et al. Lancet June 2013: 381: 9883: 2083 2090 PrEP approved July 2012 by FDA Treatment as prevention Voted 19 3 in favor of Truvada as PrEP for MSM Heterosexual women and men in serodiscordant partnerships Other individuals at risk for HIV infection Some controversy Behavioral disinhibition, relies on adherence, side effects, should be focusing on treatment Only 20% of HIV+ pts in low or middle income countries know status Model predicts reduction of HIV incidence & mortality to <1 case/1000 people in 10 yrs (prevalence to <1% within 50 yrs) Rights, feasibility, costs all concerns Granich RM et al. Jan 2009:373:48-57 MMWR 2012; 61: 586 589; MMWR 2011; 60: 65 68 1980 2000 2020 2040 de Cock AM et al. Can antiretroviral therapy eliminate HIV transmission?; 2 Garnett GP et al. Treating our way out of the HIV pandemic: could we, would we, should we? Lancet; Jan 3 2009 7
HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 (Africa, Asia, Americas) Randomization Immediate ART CD4 350 550 Delayed ART CD4 <250 Cohen MS et al. Prevention of HIV 1 infection with early antiretroviral therapy. NEJM August 2011 (HPTN 052) 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 The Data safety and monitoring board announced April 28, 2011 HPTN 052: HIV 1 Transmission Total HIV-1 Transmission Events: 39 The Board recommends that the results of the trial be announced as soon as possible (was supposed to go until 2014) HPTN 052 continues to follow couples, but all HIVinfected participants are being offered ART Immediate Arm: 1 Linked Transmissions: 28 p < 0.001 96% 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. 8
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 0.2 0.5%) 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 0.009 0.6%) infection rate CDC guidelines: last updated 9/2013 Kuhar DT. Infection Control and Hospital Epidemiology 2013; 34(9); 875-892 Risk Yes Yes, not occupational Unknown (presumed) No, unless bloody New guidelines for PEP - Simple 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); 875-892 Case (cont.) TREATMENT The patient is very worried about her fetus and asks about her baby s chances of getting HIV now that she knows she is infected 9
What is rate of maternal to child transmission of HIV (with appropriate management) in 2014 in the U.S.? 1. 25% 2. 10% 3. 5% 4. 2.5% 5. <1% Case (cont.) At your recommendation, the patient decides to start antiretroviral therapy right away in the context of pregnancy. Her CD4 and viral load is pending. She asks you If I wasn t pregnant, doc, when would you suggest I start HIV therapy? What are the current U.S. guidelines on when to start antiretroviral therapy? 1. As soon as the patient is diagnosed with HIV 2. When CD4 count 200 cells/mm 3 3. When CD4 count 350 cells/mm 3 4. When CD4 count 500 cells/mm 3 5. When the HIV RNA level (viral load) >100,000 copies/ml When to Begin Treatment for asymptomatic patients - U.S. guidelines 3/27/12 & 2/13/13 HIV Infection ART is recommended for all HIV positive individuals Prior to 3/12, start when CD4 count <500 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: http://aidsinfo.nih.gov;, March 27, 2012 and February 13, 2013 10
What are the current W.H.O. guidelines on when to start antiretroviral therapy? 1. As soon as the patient is diagnosed with HIV 2. When CD4 count 200 cells/mm 3 3. When CD4 count 350 cells/mm 3 4. When CD4 count 500 cells/mm 3 5. When the HIV RNA level (viral load) >100,000 copies/ml W.H.O. guidelines June 30, 2013 >500 Don t treat Asymptomatic CD4+ T cells/mm 3 HIV Infection <500 Treat Prior to 6/30/13, start when CD4 count <350 All children <5 yrs, pregnant and breastfeeding women, HIV in relationship with HIV+, active HepB or TB Treat W.H.O. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection", June 30, 2013 (updated guidelines) Was there ever a clinical trial that randomized patients to starting HIV therapy upon diagnosis versus CD4 <500? 1. Yes how could the recommendations have changed otherwise? 2. No Recommendations changed due to pathogenesis Given toxicities, one idea was to reduce total duration on therapy by going off and on Strategies for Management of Antiretroviral Therapy (SMART) Eligibility: CD4> 350 (N=5472) Continuous Treatment Baseline CD4: 596-599 CD4 nadir: 250-252 % < 400 copies/ml viral load: 71% Mean follow-up: 14 months (2% LFU) No Treatment until CD4 <250, then treatment until >350, then stop The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count guided interruption of antiretroviral treatment. NEJM 2006 11
SMART Study Balance now tipped (permanently) on earlier treatment Progression of Disease/Death 164 Death 84 Serious HIV events 21 Severe non-hiv Complications 114 (Cardiac/CVA/renal/hepatic) Increased risk for all clinical outcomes, including death, HIV and non-hiv events with interrupted therapy # Events Relative Risk (95% CI) 1.5 1.9 2.5 6.1 0.1 1 10 Favors off and on Favors continuous therapy WHY WAIT? Avoid drug-related toxicity Preserve future drug options Delay development of drug resistance WHY NOT WAIT? Possibility of irreversible immune system depletion Drugs easier to take now Increased possibility of progression to AIDS Increased risk of HIV transmission Some observational cohort data showing survival advantage HIV as chronic inflammatory condition more CV disease, CA, hepatic, renal Therapies now available for HIV infection Therapies now available for HIV infection 3) Integration Integrase 4) Transcription RT 5) Translation 6) Cleavage DNA 2) Reverse transcriptase RNA 1) Virus Entry CD4 receptor (CXCR4, CCR5) 9) Re-infection 3) Integration Integrase inhibitors 4) Transcription DNA Nucleoside reverse transcriptase RT inhibitors 2) Reverse transcriptase (NRTIs) RNA Nonnucleoside reverse transcriptase inhibitors (NNRTIs) 5) Translation Protease inhibitors 6) Cleavage 1) Virus Entry Fusion (entry) inhibitors (T20, CD4 envelope receptor protein gp41) (CXCR4, CCR5) CCR5 9) receptor Re-infection antagonist Protease 8) Maturation 8) Maturation 7) Packaging 7) Packaging 12
Many options... Fewer toxicities Nucleoside and nucleotide RTIs Zidovudine, AZT (Retrovir) Abacavir, ABC (Ziagen) Lamivudine, 3TC (Epivir) Didanosine, ddi (Videx) Stavudine, d4t (Zerit) Tenofovir, TFV (Viread) Emtricitabine, FTC (Emtriva) Combivir (AZT/3TC) Trizivir (AZT/3TC/ABC) Epzicom (3TC/ABC) Truvada (FTC/TFV) CCR5 receptor blocker Maroviroc (Selzentry) Integrase inhibitor Raltegravir (Isentress) Elvitegravir (ELV) Dolutegravir NNRTI s: Delavirdine (DLV) Nevirapine, NVP (Viramune) Efavirenz, EFV (Sustiva) Etravirine (Intelence) Rilpivirine (Edurant) Fusion inhibitors: Enfuvirtide, ENF or T20 (Fuzeon) SPC (1 pill once daily) Atripla (EFV/FTC/TFV) Complera (RPV/FTC/TFV) Stribild (ELV/cobicistat/TDF/ FTC) Protease inhibitors: Indinavir, IDV (Crixivan) Saquinavir, SQV (Invirase, hgc) Nelfinavir, NFV (Viracept) Amprenavir, APV (Agenerase) Atazanavir, ATZ (Reyataz) Fosamprenavir, FPV (Lexiva) Kaletra (lopinavir/ritonavir) Tipranavir (Aptivus) Darunavir (Prezista) red combination agents Circled DHHS recommended ARVs for naives What to start DHHS guidelines Preferred regimens Efavirenz/ tenofovir/emtricitabine (Atripla ) Raltegravir + tenofovir/emtricitabine (Truvada ) Elvitegravir/cobicistat/tenofovir/emtricitabine (Stribild ) Dolutegravir + abacavir/lamivudine (Epzicom ) Dolutegravir + tenofovir/emtricitabine Ritonavir + atazanavir + tenofovir/emtricitabine Ritonavir + darunavir + tenofovir/emtricitabine DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available at: http://aidsinfo.nih.gov;, February 13, 2013; Update October 30, 2013 What to start WHO guidelines (updated 6/30/13) Preferred regimens Efavirenz + tenofovir + emtricitabine (Atripla ) Efavirenz + tenofovir + lamividudine (generic FDC) 9.7 million currently being treated worldwide Under WHO guidelines of treating CD4 <350, 17 million in need Now 26 million in need of treatment (only 34% getting) Case (cont.) The patient would like to start on a regimen that is new, has few pills and won t hurt my baby. You decide to just tell her and this audience about the newest medication available for HIV infection since there is not time to go over all 30 13
What is the name of the newest drug approved for the treatment of HIV infection in adults? 1. Darunavir 2. Maraviroc 3. Elvitegravir 4. Dolutegravir 5. Something vir Dolutegravir New integrase inhibitor, approved 8/12/13 by FDA n HIV infected adults and children > 12, 40kg Once daily, pregnancy class B Broad indications naives (SINGLE, SPRING 2, FLAMINGO studies), treatment experienced without integrase inhibitor resistance (SAILING study) treatment experienced with integrase inhibitor resistance (to RAL and ELV; VIKING 3 study) latter group 50mg po bid Pharmacokinetic bioequivalence :ABC/3TC + dolutegravir vs. single pill combination (SPC) Walmsley S. NEJM 2013; Raffi F. et al. Lancet 2013 (48 wks), Lancet ID (96 weeks); Cahn P. Lancet 2013 (48 wks); Eron JJ. JID 2013 & Castagna JID 2014; Clotet B. Lancet 2014 HIV and single pill combinations Which SPCs are available? HIV may be the perfect disease for an SPC given Need for multiple pills Can t be started sequentially; must be simultaneous Stigma, depression, other adherence barriers can make multiple pill taking difficult Mistakes in taking one pill and not another can lead to resistance TFV/FTC/Efavirenz (Atripla ), approved 2006 TFV/FTC/Rilpivirine (Complera ), approved 2011 TFV/FTC/elvitegravir/ cobicistat (Stribild ), approved 2012 ABC/3TC/dolutegravir (maybe 2014?) 14
If you are the most optimistic person ever, how many people in the world have been cured of HIV? 1. 0 2. 1 3. 3 4. 17 5. 20 6. Many 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 15
Typical biphasic decay Persaud. NEJM 2013 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) Another baby in Long Beach treated within 4 hours of birth no HIV at 9 months (still on ARVs) CD4+ T cells/mm3 2000 1500 1000 500 101 0 100 99 01 02 03 04 05 06 07 08 09 Year 109 108 107 106 105 104 103 102 RNA copies/ml 14 patients in France cured? Visconti trial 14 pts diagnosed with primary HIV infection (acute) late 90 s early 00s (12 pts symptoms) Started on standard ART < 10 weeks, continued x 3 years, then interrupted (6 9.6 years out) 14 patients ( post treatment controllers ) 8 with no detectable viremia off treatment (6/14 have occasional blips ) Early treatment meant low resting CD4 sets (but inducible) is this cure? Sáez Cirión A, Plos Pathogen 2013 2 patients cured s/p stem cell transplants, Boston Boston cure? 2 HIV+ men on ARVs with lymphoma Allogeneic stem cell transplants (donors didn t have CCR5 32 deletions) After STCs, host cells <0.001% of PBMCs, on sirolimus Continued ARVs for 2 and 5 years longer, then d/c d July 3, 2013: 9 and 27 weeks after stopping, no HIV RNA in bloodstream December 6, 2013: Virus reported to have come back in both (12 and 32 weeks) 16
Cure research initiative (Steve Deeks) 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 17