HIV Jack A De Hovitz MD MPH Distinguished

HIV Jack A. De. Hovitz, MD, MPH Distinguished Service Professor Department of Medicine Director, HIV Center for Women and Children

Initial Reports • June 5, 1981: 5 cases of PCP in gay men from UCLA (MMWR) • July 3, 1981: 26 additional cases • Dec 10, 1981: 3 NEJM papers describe cases Gottlieb MS NEJM 2001; 344: 1788 -91

Other Early Developments � 1 • 1982: – Term “AIDS” coined – First cases in women reported – First transfusion and vertically transmitted cases reported • 1983: – Isolation of a retrovirus from a patient with AIDS – by Montagnier’s group • 1984: – Detection of HTLV-III in pts with and at risk for AIDS (Gallo) Sepkowitz K NEJM 2001; 344: 1764 -72

Other Early Developments � 2 • 1985: Proportion surviving – FDA approves first commercial HIV antibody test 1987: – AZT = first antiretroviral approved by FDA 1981 -1987 1. 0 0. 8 0. 6 0. 4 0. 2 0 0 10 20 30 40 50 60 Months after OI diagnosis Source : National AIDS case surveillance data, CDC

Early Antiretroviral Therapy � 1 • 1991 -92: – dd. I, dd. C approved – Sequential monotherapy – Ryan White Care Act passed • 1993: – Concorde: no difference in clinical endpoints over 3 yrs with early vs. deferred AZT

Early Antiretroviral Therapy � 2 • 1994: – ACTG 076: AZT reduces mother-to-child transmission of HIV • 1994– 95: – era of dual combination therapy

The New Treatment Era • 1995 -96: – HIV viral load testing became available • Clinicians could directly assess the effect of antiretrovirals on viral replication (HIV RNA)

The Era of HAART • Paradigm: Aim to achieve durable suppression of HIV viremia • Striking reductions in HIV-related morbidity and mortality • Aggressive treatment guidelines: “Hit hard, Hit early!”

AIDS Mortality Rates: 1996 -2001 40 100 35 Percentage o USE OF ART 30 25 75 DEATHS 20 50 15 10 25 Deaths per 100 Person-Years 5 0 1995 1996 1997 1998 1999 2000 Percentage of patient-days on ART Deaths per 100 person-years Mortality vs. ART utilization 0 2001 Palella F et al. 8 th CROI 2001; abstract 268 b.

1998 - 2000 Realism • HIV eradication is not possible with current therapy – viral “reservoir” in resting T-memory lymphocytes – viral replication continues in lymph nodes even when HIV RNA in plasma is <50 copies/m. L • Awareness that HIV is a chronic disease • Recognition of long-term toxicities: – fat redistribution (lipodystrophy) – metabolic abnormalities (insulin resistance, diabetes, increased lipids) • 2000: Durban AIDS conference – momentum builds to bring antiretrovirals to the developing world

2001 - 2008 • Interest in PI-sparing regimens – Emergence of NNRTI-based regimens • Deferred initiation of antiretroviral therapy followed by earlier initiation of therapy. • Interest in treatment interruption strategies – Ultimately not supported by clinical trials • Simpler, once daily regimens with fewer pills • New classes of drugs • Limited biologic preventive interventions

HIV Epidemiology • • • Etiology/Natural History Distribution of Disease Characteristics of Transmission Prevention Summary

Etiology/Natural History HIV/AIDS

The Causative Agent (s) HIV-1 HIV-2 Discovered 1986 Limited to West Africa Discovered 1983 Evolved from SIV in sooty Lentivirus (subfamily of mangabeys? retrovirus) Less efficient transmission World Wide spread Needs more co-receptors for cell Evolved from Chimpanzee entry virus? Longer incubation period (14 yrs) 12 Subtypes Less pathogenic

Role of Bushmeat • SIV moved from Chimps and sooty mangabeys to humans • Evolved into pathogenic HIV • Exposure to primate blood most likely secondary to bushmeat trade Butchered chimpanzee in middle of photo

Global distribution of HIV-1 subtypes High prevalence: Medium prevalence: C (48%) – southern Africa, Asia A (23%) – Africa B (16%) – North America, western Europe • Other subtypes have low prevalence • Potential implications for vaccines and treatment Quinn TC. 42 nd ICAAC, San Diego 2002, #1191

Distribution of Disease • Worldwide • US

Global estimates for adults and children, 2007 • People living with HIV 33 million [30 – 36 million] • New HIV infections in 2007 2. 7 million [1. 6 – 3. 9 million] • Deaths due to AIDS in 2007 2. 0 million [1. 8 – 2. 3 million] July 2008 e 19

Adults and children estimated to be living with HIV, 2007 Western & Eastern Europe Central Europe & Central Asia 730 000 North America 1. 2 million [760 000 – 2. 0 million] Caribbean 230 000 1. 5 million [580 000 – 1. 0 [1. 1 – 1. 9 million]East Asia million] Middle East & North Africa [210 000 – 270 000] Latin America 1. 7 million [1. 5 – 2. 1 million] 380 000 [280 000 – 510 000] Sub-Saharan Africa 22. 0 million [20. 5 – 23. 6 million] 740 000 [480 000 – 1. 1 million] South & South-East Asia 4. 2 million [3. 5 – 5. 3 million] Oceania 74 000 [66 000 – 93 000] Total: 33 million (30 – 36 million) July 2008 e 20

Over 7400 new HIV infections a day in 2007 • More than 96% are in low and middle income countries • About 1000 are in children under 15 years of age • About 6300 are in adults aged 15 years and older of whom: — almost 50% are among women — about 45% are among young people (15 -24) July 2008 e 21

Estimated Number of People Living with HIV (Panel A) and HIV Prevalence among People 15 to 49 Years of Age (Panel B), Globally and in Sub-Saharan Africa, 1990 -2007 Steinbrook R. N Engl J Med 2008; 359: 885 -887

Source of Infections with HIV-1 by Region MTCT Medical Injections Blood Transfusions Marital Sex Casual Sex Workers MSM IDU 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Asia Sub-Saharan Africa Latin America and the Caribbean Eastern Europe U. S. Department of Health and Human Services National Institutes of Health National Institute on Drug Abuse Cohen, M. S. , et al. J. Clin. Invest. , Vol 118, 1244 -1254, 2008

Categorization of HIV/AIDS Pandemic I - Low Level epidemic • HIV Prevalence < 5% in risk groups II - Concentrated epidemic • HIV prevalence > 5% in risk groups III - Generalized epidemic • HIV Prevalence in Adults > 1 %

AIDS in Africa 70% of all AIDS patients live in Sub. Saharan Africa 66% of patients with tuberculosis in Africa are co-infected with HIV 40% of deaths in Africa are secondary to AIDS 12. 1 million African children orphaned

Impact of HIV on life expectancy in Africa Low HIV prevalence: Madagascar Senegal Mali Life expectancy (years) High HIV prevalence: Zimbabwe South Africa Botswana Source: UN Department of Economic and Social Affairs (2001) World Population Prospects, The 2000 Revision

The Worst is Yet to Come: The AIDS Orphans

Numbers of HIV positive cases in Estonia and Lithuania, 1991 - 2000 (06/2000)*

Rapid HIV spread among IDUs Prevalence quickly rising to 40% or more Myanmar 60 Manipur & Yunnan Edinburgh 40 Ho Chi Minh City Bangkok 20 1995 1993 1991 1989 1987 1985 Odessa 1983 HIV prevalence (%) 80

HIV-1 infection-US • Almost 1, 000 infected in US • Highest rates in MSM, IDUs, and their sexual partners. • Approximately ¼ not aware of HIV status • HIV-2 rare • Approximately 55, 000 new infections/yr

Estimated New Human Immunodeficiency Virus (HIV) Infections, Extended Back-Calculation Model, 50 US States and the District of Columbia, 1977 -2006 Hall, H. I. et al. JAMA 2008; 300: 520 -529. Copyright restrictions may apply.

Number of AIDS cases, deaths and persons living with AIDS in the US Science 305; 2004: 1243

Public Health Need for Rapid HIV Tests • High rates of non-return for test results • Need for immediate information or referral for treatment choices – Perinatal settings – Post-exposure treatment settings • Screening in high-volume, high-prevalence settings

HIV/AIDS in New York City • 94, 495 New Yorkers are known to be living with HIV or AIDS – 60, 807 diagnosed with AIDS (15% of all U. S. cases) – 33, 688 diagnosed with HIV (non-AIDS) • NYC has highest AIDS case rate in U. S. – 3 x national average, 60 x HP 2010 target – More AIDS cases than Los Angeles, San Francisco, Miami & Washington DC combined • Estimated 20, 000 more are HIV-positive, but do not know their status Data complete as of 12/31/04

HIV Prevalence in NYC Now 1. 5% But Higher in Many Subgroups Note: Data include estimates of undiagnosed cases, rounded to nearest 0. 5%

Transmission of HIV • • • Sexual Perinatal Transfusion Occupational Injection Drug use

Per-Contact Probability of HIV Transmission Royce, R. A. et al. N Engl J Med 1997; 336: 1072 -1078

Sexual Transmission of HIV • Worldwide epidemic driven by sexual transmission • HIV isolated from semen and vaginal secretions • Risk of transmission directly related to viral load and acute infections • Heterosexual transmission occurs more readily from male to female

Cohen et al, JID 2005; 191: 1391 -1393

Perinatal Transmission • 25% transmission rate in pre AZT era • All children born to HIV infected women are antibody + at birth • Breast feeding is proscribed in developing nations after birth • Combination of C-section and ART in women has reduced transmission to less than 3% • Transmission, if it occurs, typically occurs at birth.

Incidence of Perinatally-Acquired AIDS United States, 1985 -June 2000* 81% PACTG 076 No. of Cases 500 decline USPHS ZDV recs 400 300 200 100 Half Year of Diagnosis *Reported through December 2000 00 99 98 97 96 95 94 93 92 91 90 89 88 87 86 85 0

Transmission of HIV 14% 25% 40%

Occupational HIV Infection • Occupationally acquired HIV infection among HCW reported through 6/99 – 137 possible cases of HIV transmission – 57 documented cases of HIV infection • Most exposures do not result in infection • Risk is approximately 1/250

Prevention • • Behavior Microbicide Cervical Barriers Therapy to suppress HSV-2 Male Circumcision Pre-exposure prophylaxis with ART Expanded access to therapy Vaccine

Trends in HIV prevalence in selected populations in Kampala, Uganda; Dakar, Senegal; and Thailand; 1989 to 1999 30 Kampala, <20 year old ANC Thailand, 21 year old military conscripts HIV prevalence (%) 25 Dakar, all ages ANC 20 15 10 5 0 89 90 91 92 93 94 95 96 97 Source: National STD/AIDS Control Programmes, Senegal and Uganda Armed Forces Research Institute of Medical Sciences, Thailand 98 99

Proportion of sex workers and sex workers’ clients always using condoms with commercial partners, Cambodia, 1997 to 1999 90 Proportion reporting consistent condom use (%) 80 70 brothel-based sex workers 60 military/police 50 motorbike taxi drivers beer promotion women 40 30 20 10 0 1997 1998 1999 Source: National AIDS Programme, Cambodia, and Family Health International, 2000

Increasing rates of high-risk behavior and STDs in San Francisco Percent STDs, high-risk behavior, HIV incidence in MSM 1 Unprotected anal sex 40 35 30 25 20 15 10 5 0 Unprotected anal sex, multiple partners 97 98 99 2000 2001 No. patients 250 200 Rectal gonorrhea 150 100 50 Early syphilis 0 97 98 99 2000 2001 Predictors of high-risk behavior among HIV+ individuals 2 • Belief that undetectable VL reduces transmission vs no change in transmission: AOR 5. 9 (95% CI 1. 9– 19) • Most recent VL undetectable vs detectable: AOR 9. 3 (95% CI 2. 3– 37) 1. Gibson S, et al. XIV Int AIDS Conference, 2002, #3430; 2. Colfax G, et al. ibid, #3445

Possible Actions of a Vaginally Administered Topical Microbicide Moore, J. P. N Engl J Med 2005; 352: 298 -300

Kaplan-Meier Estimate of the Proportion of Adult and Adolescent Patients Surviving after the Initiation of Antiretroviral Therapy Severe P et al. N Engl J Med 2005; 353: 2325 -2334

Haitian Patient, before and after Receiving Free Treatment for HIV Infection and Tuberculosis Kim J and Farmer P. N Engl J Med 2006; 355: 645 -647

Geneva, Dec 5, 2006 Evidence on male circumcision and HIV prevention Strategies and Approaches for Male Circumcision Programming Hankins UNAIDS

MALE CIRCUMCISION AND POPULATION BASED HIV PREVALENCE IN AFRICA High (>80%) male circumcision Low (<20%) male circumcision Sources: ORC/MACRO, 2005, USAID, 2002

Biological Rationale for HIV link Biological plausibility n Inner mucosa of foreskin is rich in HIV target cells, ie Langerhans, dendritic, CD 4+, macrophages n External foreskin/shaft keratinized and not vulnerable n After circumcision, only vulnerable mucosa is meatus Foreskin is retracted over shaft during intercourse n Large inner mucosal surface exposure n Micro-tears, especially of frenulum Intact foreskin associated with infections n Genital ulcer disease n Balanitis/phimosis n Possible increased HIV entry or shedding

AIDS Vaccine Development • Rational, empiric approaches to vaccine development have not been successful to date • Fundamental questions regarding HIV disease and the host response to the virus need to be answered. • Fresh new ideas beyond the scope of classic vaccinology are urgently needed.

Candidate Vaccines Currently in Clinical Trials Johnston M, Fauci A. N Engl J Med 2007; 356: 2073 -2081

Potential Scientific Obstacles • The window of opportunity for the immune system to clear the initial infection is narrow, since HIV integrates and establishes latent infection within days or weeks • Viral diversity • Animal models • Conserved antibody targets on the outer envelope protein are "hidden" from immune recognition. • Destruction of CD 4+ T cells begins early after infection.

Logistical and Ethical Challenges • Behavioral factors in exposure • Efficacy trials in the U. S. • Clinical trials in developing countries • Lack of consensus on ethical issues such as treatment • Potential social harms to volunteers

Conclusions • Increasing number of HIV+’s in US as a result of new infections and new therapy. • Epidemic in developing world continues • Challenge of integrating prevention and therapy • Prevention efforts in US need to be maintained and focused on individuals known to be HIV+