HIV Update: Looking Forward, Where are we going? Outline

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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?

1 HIV Update: Looking Forward, Where are we going? 11 th HIV Network Nursing Conference May 15, 2015 Monica Gandhi MD, MPH Professor of Medicine and Medical 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 2015 and looking ahead HIV Treatment: When to start and looking to the future The cure 1

2 EPIDEMIOLOGY Adults and children estimated to be living with HIV 2013 North America and Western and Central Europe 2.3 million [2.0 million 3.0 million] Caribbean [ ] Latin America 1.6 million [1.4 million 2.1 million] Middle East & North Africa [ ] Sub-Saharan Africa 24.7 million [23.5 million 26.1 million] Eastern Europe & Central Asia 1.1 million [ million] Asia and the Pacific 4.8 million [4.1 million 5.5 million] Total: 35.0 million [33.2 million 37.2 million] 2

3 Global summary of the AIDS epidemic 2013 Number of people living with HIV Total Adults Women Children (<15 years) 35.0 million [33.2 million 37.2 million] 31.8 million [30.1 million 33.7 million] 16.0 million [15.2 million 16.9 million] 3.2 million [2.9 million 3.5 million] 2014 epidemiology core slides People newly infected with HIV in 2013 Total Adults Children (<15 years) 2.1 million [1.9 million 2.4 million] 1.9 million [1.7 million 2.1 million] [ ] AIDS deaths in 2013 Total Adults Children (<15 years) 1.5 million [1.4 million 1.7 million] 1.3 million [1.2 million 1.5 million] [ ] Major news from UNAIDS update GOOD NEWS 1.5 million died from HIV 2013, from 2.3 million 2001 New HIV infections among adults by 50% in 26 countries b ,000 children infected 2013 (260K 2012; 330, ) BAD NEWS 77 million infected since epidemic started, 37 million have died Although 9.7 million have access to ARVs, only 34% of people who qualify Any child being infected 3

4 Case 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? % % % % % 4

5 CDC estimates 1,161,600 persons in U.S. 13 yrs living with HIV (~14.5% unaware) Rates of Adults and Adolescents Living with Diagnosed HIV Infection Ever Classified as Stage 3 (AIDS), Year-end 2012 United States and 6 Dependent Areas N = 519,191 Total Rate = Note. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting. 5

75.4% 24.6% Diagnoses of HIV Infection among Adults and Adolescents, by Sex and Race/Ethnicity, 2013 United States and 6 Dependent Areas U.S. Census 2013 estimates: 13.2% Black/African American 17.

6 75.4% 24.6% Diagnoses of HIV Infection among Adults and Adolescents, by Sex and Race/Ethnicity, 2013 United States and 6 Dependent Areas U.S. Census 2013 estimates: 13.2% Black/African American 17.1% Hispanic/Latino 77.7% White Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting. a Hispanics/Latinos can be of any race. 6

7 Case (continued) 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. The Course of Untreated HIV Infection: CD4 cells and HIV RNA Seeding of latent reservoirs CD8 cytotoxic T cells 7

8 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% Persons Living with Diagnosed or Undiagnosed HIV Infection HIV Care Continuum Outcomes, 2009, 2010 and 2011 United States and Puerto Rico Percentage (%) Diagnosed Received medical care Prescribed ART Viral Suppression National HIV Surveillance System,: Estimated number of persons aged 13 years living with diagnosed or undiagnosed HIV infection (prevalence) in the United States at the end of the specified year. The estimated number of persons with diagnosed HIV infection was calculated as part of the overall prevalence estimate. Medical Monitoring Project: Estimated number of persons aged 18 years who received HIV medical care during January to April of the specified year, were prescribed ART, or whose most recent VL in the previous year was undetectable or <200 copies/ml United States and Puerto Rico. 8

9 TESTING CDC 9/21/06 risk-based to routine HIV screening in all health care settings 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 Sep 22;55(RR 14):1 17 ; 2 Wynia MK. Routine screening: informed consent, stigma and the waning of HIV exceptionalism. Am J Bioeth 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

U.S. Preventative Services Task Force Recommendations changed April 2013 Routine testing once for everyone age 15 65 ( grade A

engaged in risky behavior Those living in high prevalence setting Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement.

in home overthe counter saliva test kit (OraQuick In Home HIV test ) Specificity 99.98%; sensitivity 92.

10 U.S. Preventative Services Task Force 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 Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine, April 30, 2013 Orasure test FDA approved for home testing 5/15/12 FDA panel recommended (17 0) first in home overthe 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 Walgreens, CVS, Wallmart, Rite Aide, Target 24 o line, $43 million sales 10

11 PREVENTION Case (continued) 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. 11

12 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 (Increasingly negative data) 2. Circumcising the male partner (Effective for men) 3. Pre exposure prophylaxis for HIV negative partner (Effective, complicated, will discuss) 4. HIV vaccine (Some glimmers of hope, but no definitive candidate) 5. Using HIV treatment for HIV+ partner (Effective, will discuss) 6. Post exposure prophylaxis for HIV partner (will discuss occupational PEP) 12

13 Pre exposure prophylaxis: PrEP Preexposure prophylaxis (PrEP) is giving an HIVnegative individual a pill (daily, or coitally?) to prevent HIV infection (studied: Tenofovir +/ emtricitabine) PrEP Adherence everything Trial Population/Setting Intervention Reduction in HIV Infection Rate, % iprex [1] (N = 2499) MSM, 11 sites in US, S. America, Africa, Thailand Daily oral TDF/FTC 44% (95% CI 15 63, p 0.005) Partners PrEP [2] (N = 4747) TDF2 [3] (N = 1219) Bangkok TFV Study [6] (N= 2413) FEM PrEP [4] (N = 2120) VOICE [5] (N = 5029) PROUD (N=523) [7] 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 High risk men, U.K. 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 , p 0.01) Daily oral TDF/FTC Daily oral TDF Daily oral TDF/FTC 1% TFV gel Daily oral TDF/FTC, immediate vs deferred Study stopped early due to futility (adherence) 1% TDF gel & daily oral TDF arm both stopped early, futile Daily TDF/FTC arm no efficacy (adherence) 86% (90% CI 58 96%, p=0.0002) 1. Grant RM. N Engl J Med Baeten JM. N Engl J Med Thigpen MC. N Engl J Med. 2012; 4. Van Damme. N EnglJ Med Marrazzo J, N. EnglJ. Med. 2015; 6. ChoopanyaLancet June 2013; 7. McCormack. CROI

14 Ipergay: Event based PrEP Intervention Preventive de l Exposition aux Risques avec et pour les Gays TDF/FTC vs. placebo with dosing around the time of sex HIV uninfected MSM; UAI with 2 partners 6 months 2 24 hours before sex: 2 tabs 24 hours after 1 st dose: 1 tab 48 hours after 1 st dose: 1 tab Monday Tuesday Wednesday Thursday Friday Saturday Sunday Ongoing risk: continue 1 tab daily until 48 hours after last exposure Molina, et al. CROI 2015, Abs 23LB. Probability of HIV-1 Infection N at Risk: Placebo 201 TDF/FTC 199 Ipergay Placebo TDF/FTC D Arm Infections (N) Incidence per 100 PY Placebo TDF/FTC Months Reduction in incidence: 86% (95% CI: 40 99%), p=0.002 Molina, et al. CROI 2015, Abs 23LB. viraled.com. 14

Treatment as prevention 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%

15 Treatment as prevention 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: 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 Cohen MS et al. Prevention of HIV 1 infection with early antiretroviral therapy. NEJM August 2011 (HPTN 052) 15

16 HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 (Africa, Asia, Americas) Randomization Immediate ART CD 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 The Data safety and monitoring board announced April 28, 2011 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 16

HPTN 052: HIV 1 Transmission Total HIV-1 Transmission Events: 39 Immediate Arm: 1 Linked Transmissions: 28 p < 0.

17 HPTN 052: HIV 1 Transmission Total HIV-1 Transmission Events: 39 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 Blood Risks Semen/vaginal CSF, synovial, pleural, pericardial, amniotic Feces, saliva, nasal, sputum, sweat, tears, urine, vomitus Risk Yes Yes, not occupational Unknown (presumed) No, unless bloody 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);

18 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); TREATMENT 18

19 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 19

20 When to Begin Treatment for asymptomatic patients - U.S. guidelines 3/27/12 HIV Infection Prior to 3/12, start when CD4 count <500 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: Last updated 5/1/14 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 20

21 W.H.O. guidelines June 30, 2013 HIV Infection >500 Asymptomatic CD4+ T cells/mm 3 <500 Don t treat 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) 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: CD4 nadir: % < 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

SMART Study # Events Relative Risk (95% CI) Progression of Disease/Death 164 2.5 Death 84 1.9 Serious HIV events 21 Severe non-hiv Complications 114 1.5 (Cardiac/CVA/renal/hepatic) 6.

22 SMART Study # Events Relative Risk (95% CI) Progression of Disease/Death Death Serious HIV events 21 Severe non-hiv Complications (Cardiac/CVA/renal/hepatic) 6.1 Increased risk for all clinical outcomes, including death, HIV and non-hiv events with interrupted therapy Favors off and on Favors continuous therapy Balance now tipped (permanently) on earlier treatment 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 22

23 Therapies now available for HIV infection 3) Integration Integrase RT DNA 2) Reverse transcriptase RNA 4) Transcription 5) Translation 6) Cleavage 1) Virus Entry CD4 receptor (CXCR4, CCR5) 9) Re-infection Protease 8) Maturation 7) Packaging Therapies now available for HIV 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 8) Maturation 7) Packaging 23

24 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 (EVG) Dolutegravir (DTG) 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/TDF) Complera (RPV/FTC/TDF) Stribild (EVG/cobicistat/TDF/ FTC) Protease inhibitors: Indinavir, IDV (Crixivan) Saquinavir, SQV (Invirase, hgc) Nelfinavir, NFV (Viracept) Amprenavir, APV (Agenerase) Atazanavir, ATV(Reyataz) Fosamprenavir, FPV (Lexiva) Kaletra (lopinavir/ritonavir) Tipranavir (Aptivus) Darunavir (Prezista) Prezcobix (Darunavir/cobicistat) Evotaz (ATV/cobicistat) Triumeq (DTG/FTC/TFV) red combination agents What to start DHHS guidelines 2015 INSTI + 2 NRTI PI + 2 NRTI Recommended Dolutegravir/abacavir/lamivudine Dolutegravir + tenofovir/emtricitabine Elvitegravir/cobicistat/tenofovir/emtricitabine Raltegravir + tenofovir/emtricitabine Darunavir/ritonavir + tenofovir/emtricitabine 24

NNRTI + 2 NRTI PI + 2NRTI Alternative Regimen Options Efavirenz/tenofovir/emtricitabine Rilpivirine/tenofovir/emtricitabine* Atazanavir with ritonavir or cobi plus TDF/FTC Darunavir with ritonavir or

25 NNRTI + 2 NRTI PI + 2NRTI Alternative Regimen Options Efavirenz/tenofovir/emtricitabine Rilpivirine/tenofovir/emtricitabine* Atazanavir with ritonavir or cobi plus TDF/FTC Darunavir with ritonavir or cobi plus ABC/3TC Darunavir/cobi plus TDF/FTC if CrCl >70 Effective and tolerable but have potential disadvantages when compared with Recommended Regimens *Don t use with vl >100LK or CD4 <200 An alterative regimen may be preferred regimen for some patients 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) 25

for an SPC given Need for multiple pills Can t be started sequentially; must be simultaneous Stigma, depression, other

26 Case (cont.) The patient would like to start on a regimen that is new, has few pills and won t hurt my baby. She also asks if there is just one pill she can take HIV and single pill combinations 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 26

27 Which SPCs are currently available? TFV/FTC/efavirenz, approved 2006 TFV/FTC/rilpivirine, approved 2011 TFV/FTC/elvitegravir/ cobicistat, approved 2012 ABC/3TC/dolutegravir, approved 8/22/

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29 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 Persaud. NEJM

graveyard sequences) No Western blot reactivity for child (remains reactive for mother) Baby (~42 months) still negative (CROI March, 2014) Major announcement 7/21/14: Baby with viremia (16,750

30 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) Major announcement 7/21/14: Baby with viremia (16,750 copies/ml with repeat testing 72 hours later 10,564 copies/ml), HIV 1 antibody positive CD4+ T cells/mm Year RNA copies/ml 14 patients in France: 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

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

31 2 patients cured s/p stem cell transplants, Boston no 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) Cure research initiative 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 31

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Outline Epidemiology: Global and U.S. How are we doing in terms of goals of treatment? Updates in the fast moving field of HIV medicine EPIDEMIOLOGY

Outline Epidemiology: Global and U.S. How are we doing in terms of goals of treatment? Updates in the fast moving field of HIV medicine EPIDEMIOLOGY 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