Outline. Update in the Fast Moving World of HIV HISTORY AND GLOBAL EPIDEMIOLOGY. When was the first report describing AIDS released?

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Outline Update in the Fast Moving World of HIV April 21.

1 Outline Update in the Fast Moving World of HIV April Advances in ID Monica Gandhi MD, MPH Professor of Medicine Division of HIV, Infectious Diseases, and Global Medicine Medical director, Ward 86 HIV Clinic, SFGH History of HIV Epidemiology: Global U.S. San Francisco HIV testing: When and how often? HIV Prevention: Where are we in 2015? HIV Treatment and a glimpse of the Cure Where are we in 2015? When was the first report describing AIDS released? 1. June 5, June 5, June 5, June 5, June 5, 1983 HISTORY AND GLOBAL EPIDEMIOLOGY 1

First Clinical Descriptions of AIDS MMWR Where did HIV come from?

Lentivirus means SLOW virus (long interval between initial infection and onset of serious

5 major lineages of primate lentiviruses 1) Chimpanzees; gorillas 2) Monkeys; Mandrills 3)

strain (90% of world infections) HIV 1 Group M Group N Group O Group P SIV from chimpanzees

2 First Clinical Descriptions of AIDS MMWR Where did HIV come from? HIV lentivirus, subgroup of retroviruses Retroviruses means uses RNA as genetic material Lentivirus means SLOW virus (long interval between initial infection and onset of serious symptoms) Where did it come from? 5 major lineages of primate lentiviruses 1) Chimpanzees; gorillas 2) Monkeys; Mandrills 3) African green monkeys; baboons So major types of HIV closest to various SIV strains Pandemic strain (90% of world infections) HIV 1 Group M Group N Group O Group P SIV from chimpanzees SIV from gorillas HIV 2 7 subtypes (A G) SIV from sooty mangabeys 4) Sooty mangabeys 5) Sykes monkeys Hahn BH. AIDS as a Zoonosis: Scientific and Public Health Implications. Science

How did these viruses get from there to here?

(Edward Hooper, 1999) Polish scientist competing with Sabin for first oral

1 million people in Belgiumcontrolled Congo/ Rwanda/ Burundi anyway 1

CHAT oral polio vaccine was not the source of human immunodeficiency virus

Dis 2001 Oral polio vaccines and HIV Theory refuted due to African green

Koprowskisues Rolling Stone for defamation (1992) gets $1 in damages What

Most common prevailing theory is the bushmeat tradehunting primates for food

3 How did these viruses get from there to here? First theory The River The River: A Journey to the Source of HIV and AIDS (Edward Hooper, 1999) Polish scientist competing with Sabin for first oral polio vaccine (Sabin won) Scientist (Koprowski) administered his vaccine to 1 million people in Belgiumcontrolled Congo/ Rwanda/ Burundi anyway 1 Plotkin SA. CHAT oral polio vaccine was not the source of human immunodeficiency virus type 1 group M for humans. Clin. Infect. Dis 2001 Oral polio vaccines and HIV Theory refuted due to African green kidney monkey cells (not chimpanzee) used in making vaccines Timing problem Koprowskisues Rolling Stone for defamation (1992) gets $1 in damages What was the cross over event? Most common prevailing theory is the bushmeat tradehunting primates for food Hunters and other highly exposed populations: many SIV strains incorporated General human population one cross over event and SPREAD due to social disruption, colonization, city growth Hahn BH. AIDS as a Zoonosis: Scientific and Public Health Implications. Science 2000; 3

Bushmeat market in West & Central Africa % of HIV-positive persons in rural villages in Cameroon who report contact with wild animals and primates Hahn BH.

Outbreak in region of origin difficult to distinguish from tropical diseases 1981 first description in U.S.

the lungs Pathologists from Manchester Royal Infirmary (Lancet 1983) claimed his specimens were positive for HIV Methods questioned, apologies to fiancee demanded, no more tissue available To know

4 Bushmeat market in West & Central Africa % of HIV-positive persons in rural villages in Cameroon who report contact with wild animals and primates Hahn BH. AIDS as a Zoonosis: Scientific and Public Health Implications. Science 2000 LeBreton M..Wolfe ND. Exposure to wild primates among HIV infected persons. Emerg Infect. Di 2007 When did it get to us? Outbreak in region of origin difficult to distinguish from tropical diseases 1981 first description in U.S. Case report (Lancet, 1959) 25 year old man (naval seaman) Severely emaciated, Remorseless anal lesion, pneumonia, ulcer eating into upper lip Post mortem revealed cytomegalovirus and pneumocystis in the lungs Pathologists from Manchester Royal Infirmary (Lancet 1983) claimed his specimens were positive for HIV Methods questioned, apologies to fiancee demanded, no more tissue available To know when we need to go back in time and get human specimens! Oldest known stored specimens from Africa: 1213 plasma specimens from Leopoldville, Belgian Congo (now Kinshasa, Zaire DRC), U. of Washington HIV 1 found in 1 patient ( Bantu male, 1959) ZR59 strain intensely studied Phylogenetic analysis How much does this differ from SIV in chimpanzees? How much does ZR59 differ from modern HIV strains? Estimated HIV entered humans ~1930 4

entered humans 1884 1924 Worobey M. Direct evidence of extensive diversity of HIV 1 in Kinshasa by 1960.

African history No city in region of crossspecies transmission before 1910 had population > 10,000 Kinshasa (and other) populations in 2 nd half of 20 th C.

first probable outbreak in Kinshasa (OIs seen) Worobey M. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature 10/08 What happened from there?

Africa (especially in areas bordering Lake Victoria), reached epidemic form in early 80 s Labor migration (35% truck drivers positive Uganda 88) High ratio of men urban centers

5 Found another human specimen! Lymph node in paraffin found, adult female, Kinshasa, 1960 DRC60 DRC60 very different than ZR59 Family tree constructed, rate of mutation calculated Ancestor of HIV 1 M probably entered humans Worobey M. Direct evidence of extensive diversity of HIV 1 in Kinshasa by Nature 455 (October 2008) Population ( x 1000) Time to the most recent common ancestor ( ) period of HIV slow growth City, founding date Kinshasa The rest is West African history No city in region of crossspecies transmission before 1910 had population > 10,000 Kinshasa (and other) populations in 2 nd half of 20 th C. (trade, colonial) HIV 1 M from Cameroon brought by traveler down river to Kinshasa entered urban sexual network and spread By 1960 s, ~2000 people infected in Africa By 1970s, first probable outbreak in Kinshasa (OIs seen) Worobey M. Direct evidence of extensive diversity of HIV-1 in Kinshasa by Nature 10/08 What happened from there? Carried from West to Eastern Africa in 70 s Long distances between cities, difficulty in travel, violence, insecurity limited spread in W. Africa Spread fast in E. Africa (especially in areas bordering Lake Victoria), reached epidemic form in early 80 s Labor migration (35% truck drivers positive Uganda 88) High ratio of men urban centers Low status of women Low rates circumcision Sexually transmitted infections (STIs) Sex work (85% Nairobi sex workers infected by 86) By mid and late 80 s, on to sub Saharan Africa Tanzamroad between Tanzania and Zambia high prevalence in 88, devastating proportions in South Global HIV prevalence in adults, 1985 Piot P. Retrospective seroepidemiology of AIDS virus infection in Nairobi populations. Journal of Infectious Diseases 1987 UNAIDS/WHO

Global HIV prevalence in adults, 1995 Global HIV prevalence in adults, 2005 UNAIDS/WHO 1995 UNAIDS/WHO 2005 How many people are currently living with HIV worldwide? 1. 15 million 2.

6 Global HIV prevalence in adults, 1995 Global HIV prevalence in adults, 2005 UNAIDS/WHO 1995 UNAIDS/WHO 2005 How many people are currently living with HIV worldwide? million million million million million 8 million (1990) Number of people living with HIV Estimated number of people living with HIV globally, million (2014) UNAIDS Nov Year 6

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

9 2014 HIV prevalence in school boys & girls in rural South Africa (Grades 9 & 10) Age Group (years) HIV Prevalence (2010) % (95% Confidence Interval) Male (n=1252) Female (n= 1423) 15 1.0 (0.0-2.

. In some settings, up to 45% of adolescent girls report that their first sexual experience was forced In sub Saharan Africa, only 15% of young women aged 15 24 are aware of their HIV status. 16-17 1.

7 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 Number of People Living With HIV, millions Children (< 15 y) 2.6 Women 17.4* Adults 34.3 Total HIV prevalence in school boys & girls in rural South Africa (Grades 9 & 10) Age Group (years) HIV Prevalence (2010) % (95% Confidence Interval) Male (n=1252) Female (n= 1423) ( ) 2.6 ( ) Gender-based inequalities Infection rates among young women are twice as high as among young men in sub Saharan Africa.. In some settings, up to 45% of adolescent girls report that their first sexual experience was forced In sub Saharan Africa, only 15% of young women aged are aware of their HIV status ( ) (0-3.7) (0-3.9) 6.1 ( ) 13.6 ( ) 24.7 ( ) In LIMC, average HIV prevalence among sex workers is ~12%, with an OR for HIV infection of 13.5 compared to all women aged (violence and criminalization big contributors) Kharasany AB. AIDS Source: Res Hum Abdool Retroviruses. Karim Q, al Sex 2014; Transm Slide Infect 2014 courtesy Diane Havlir

U.S. AND SAN FRANCISCO EPIDEMIOLOGY 75.4% 24.

United States and 6 Dependent Areas U.S. Census 2013 estimates: 13.

women cluster with poverty, disempowerment HIV in women clusters with poverty 1,2 ;

Data include persons with a diagnosis of HIV infection regardless of stage of disease at

All displayed data have been statistically adjusted to account for reporting delays, but not

8 U.S. AND SAN FRANCISCO EPIDEMIOLOGY 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 Risks in U.S. women cluster with poverty, disempowerment HIV in women clusters with poverty 1,2 ; interpersonal violence 3 ; incarceration 4 7 ; self esteem, alcohol/drugs 8 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. 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

San Francisco: New HIV Diagnosis, Living HIV cases and Deaths Trends in New HIV Diagnosis for males by

deaths Persons of color disproportionately affected in San Francisco as well 2014 San Francisco Epidemiology

Report August 2015, slide courtesy of Susan Scheer PhD and Diane Havlir MD Getting to Zero in San Francisco

9 San Francisco: New HIV Diagnosis, Living HIV cases and Deaths Trends in New HIV Diagnosis for males by infection/100,000 persons 15,979 living with HIV 302 new diagnosis (still about 1 new infection a day) 177 deaths Persons of color disproportionately affected in San Francisco as well 2014 San Francisco Epidemiology Report August 2015, slide courtesy of Susan Scheer PhD and Diane Havlir MD 2014 San Francisco Epidemiology Report August 2015, slide courtesy of Susan Scheer PhD and Diane Havlir MD Getting to Zero in San Francisco Consortium Zero new HIV infections Zero HIV deaths Zero stigma and discrimination Website: Launched in 2013 by Diane Havlir MD and Susan Buchbinder MD; Now involves UCSF, DPH, Mayor s Office, community organizations, Supervisors, Kaiser, public, foundations (MAC); meetings and town halls, truly multidimensional consortium 9

How often should a patient be tested for HIV infection at SFGH? TESTING 1. Once, then every time the patient reports risk factors 2. Once every 2 years and with reported risk factors 3.

10 How often should a patient be tested for HIV infection at SFGH? 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 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 ( 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,

11 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 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 7 major daily PrEP trials iprex [1] (N = 2499) Partners PrEP [2] (N = 4747) TDF2 [3] (N = 1219) Bangkok TFV Study [4] (N= 2413) FEM PrEP [5] (N = 2120) VOICE [6] (N = 5029) Population/Setting 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, 20% female High risk women, Africa High risk women, Africa Intervention Daily oral TDF/FTC Daily oral TDF Daily oral TDF/FTC Daily oral TDF/FTC Daily oral TDF Daily oral TDF/FTC Daily oral TDF Daily oral TDF/FTC 1% TFV gel Reduction in HIV Infection Rate, % 44% (95% CI 15 63%), no ciswomen 67% (44 81%) reduction with TDF; 75% (55 87%) reduction with TDF/FTC (more efficacious in women than men) 62% (22 83%) (underpowered for sex differences) Overall efficacy 49% ( %); Women 78.6% (p 0.03); men 37.6% (p 0.15) Study stopped early, no significant efficacy 1% TDF gel & daily oral TDF arm both stopped early (HR 0.34 gel with detectable drug) Daily TDF/FTC arm. no significant efficacy PROUD [7] MSM in U.K. PROUD 86% (64 96%) effective, no ciswomen PROUD: Daily 1. Grant RM. NEJM 2010; (immediate 2. Baeten vs JM, deferred) NEJM. 2012; 3. Thigpen MC. NEJM Choopanya K Lancet 2013: 5. Van Damme L. NEJM. 2012; 6. Marrazzo J. NEJM 2015; 7. McCormack Lancet 2015; 8. Molina. NEJM

30 % of Adults with PrEP Indication No. of Adults with PrEP Indication 600,000 TREATMENT 25 24.7 500,000 492,000 468,000 20 18.

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.

12 30 % of Adults with PrEP Indication No. of Adults with PrEP Indication 600,000 TREATMENT , , , , , , , , , MSM PWID Hetero. Men Hetero. Women Slide courtesy of Catherine Koss MD 0 MSM PWID Hetero. Men Hetero. Women 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 12

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

13 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 13

How many single pill combinations for the treatment of HIV are there now? WHEN TO DELAY THERAPY Hardly EVER (TB meningitis, other space-occupying lesions with inflammation, cryptococcal meningitis) 1.

14 How many single pill combinations for the treatment of HIV are there now? WHEN TO DELAY THERAPY Hardly EVER (TB meningitis, other space-occupying lesions with inflammation, cryptococcal meningitis) TFV/FTC/efavirenz, approved 2006 TFV/FTC/elvitegravir/ cobicistat, approved 2012 A new era TFV/FTC/rilpivirine, approved 2011 TAF/FTC/rilpivirine approved 4/4/16 TAF/FTC/elvitegravir/ cobicistat approved 11/5/15 ABC/3TC/dolutegravir, approved 8/22/2014 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) Genvoya (TAF/FTC/ELV/Cobi) Odefsey (TAF/FTC/RPV) 14

15 The Mississippi Baby Typical biphasic decay 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 Persaud. NEJM

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

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.

16 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) CD4+ T cells/mm Year 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 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

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

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