HIV/AIDS UPDATE
From the Medical Management of AIDS, presented December 2005 by the University of California, San Francisco,
School of Medicine
| GLOBAL EPIDEMIOLOGY AND PREVENTION —Harold W. Jaffe, MD, Professor and Head, Department of Public
Health, Oxford University, England
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| Statistics: ≈13,000 new HIV infections daily in 2004; >95% from low- and middle-income countries; ≈1700 children <15
yr of age; in young adults, almost 50% are women; 40 million people living with AIDS worldwide; 85% reside in sub-Saharan
Africa or south and Southeast Asia; South Africa and India have largest number of infected persons, 5 million each;
90% of 3 million deaths occur in sub-Saharan Africa or south and Southeast Asia; World Health Organization (WHO) estimates
5% of all deaths worldwide attributed to HIV/AIDS; countries with highest infection rates clustered in southern
Africa; reason for cluster not clear; perhaps related to patterns of sexual contact in community; unknown whether other
factors (eg, viral factors related to subtype, genetic factors) associated with disease clusters
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| Country comparison: Botswana—almost 50% of pregnant women 25 to 29 yr of age infected with HIV; tuberculosis
(TB) rates have tripled and now exceed 600 per 100,000; life expectancy dropping; in poorer African countries without
high HIV infection rate, life expectancy increasing; HIV affecting population structure; 1985 to 2000, most deaths in
very young and very old; in last 5 yr, many deaths in middle-aged people; family structure now consists of young children
and old people; Uganda—documented decrease in HIV prevalence among pregnant women; dramatic fall from
30% infected in 1991 to 10% in 2000 and 8% in 2002; due to behavioral changes, willingness to discuss problem, and acknowledgement
of deaths due to AIDS; prevention—abstinence controversial; Rakai study—prevalence (proportion of
people testing positive) in teenagers dropped slightly, more dramatic fall in young adults; no significant change in incidence
(rate of new infections per 100 person-years); decrease in infection rates due to AIDS deaths; some increase in
condom use, no increase in abstinence; foreskin—risk factor for HIV infection; contains Langerhans cells susceptible to
HIV infection; predisposes men to other genital ulcer diseases (eg, syphilis, chancroid) that are risk factors for HIV; randomized
study showed circumcision reduced risk for HIV transmission by almost two thirds
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| Emerging infection in China: 840,000 infections, 150,000 deaths; 40% attributed to injection drug use, 30% to unsafe
blood collection practices, ie, paying people for blood donations and reinfusing pooled packed red blood cells
(RBCs); transmission via injection drug use occurs mainly in far west and south China and in Golden Triangle (includes
Thailand and Burma)
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| Recent developments in addressing global AIDS: programs provide antiretroviral therapy to infected people in developing
world; 2003 US Presidential Emergency Plan for AIDS Relief (PEPFAR) main funding source; goals—treat >2
million people in 5 yr, prevent 7 million infections, care for 10 million infected people and AIDS orphans; $15 billion budget;
15 countries (sub-Saharan Africa, Haiti, Guyana, Vietnam); daily cost of 3TC/d4T/nevirapine still too high for individuals
to buy drugs; in Kenya in 2004, 25,000 people received antiretroviral therapy, compared to 2000 people in 2000;
challenges—stigma of disease; profound lack of health care infrastructure (eg, running water, electricity, availability of
medications); introduction of lifelong therapy with potentially toxic drugs requires high degree of adherence; laboratory facilities;
lack of trained personnel; maintenance of supply chain; new models of care—pilot program in Tororo, Uganda using
field workers on mortocycles to provide care visits to patients weekly; 99% adherence rate; unanswered questions—
can focus on prevention be maintained? what happens when antiretroviral resistance (ARV) emerges? will second- and
third-line regimens be available at affordable prices? can ARV programs upgrade medical infrastructure? will staff and resources
be diverted from other critical programs, eg, malaria? can ARV programs be sustained?
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| NATIONAL EPIDEMIOLOGY AND PREVENTION —Susan Buchbinder, MD, Director, HIV Research Section, AIDS
Office, San Francisco Department of Public Health
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Data from 2004 Centers for Disease Control and Prevention (CDC) HIV/AIDS Surveillance Report
| Sex with men: predominant transmission mode in United States; in men, about two thirds of cases in men having sex
with men (MSM) or MSM injecting drugs (dual risk); in women, 4 of 5 new AIDS cases occurred through heterosexual
contact; epidemic increasing in MSM (largest number of infections); numbers declining in heterosexuals and injection
drug users; numbers level in dual-risk group; epidemic most heavily affects communities of color; number of newly diagnosed
cases in blacks declining; also small decline in Hispanics; in 2004, 50% of new cases occurring in blacks; disproportionate
number of cases in Hispanics; of persons with newly detected HIV infection in 2003, 39% progressed to AIDS
in <12 mo; factors associated with more rapid progression include older age, injection drug use, and heterosexual orientation;
poor access to early testing; race/ethnicity not leading factor; San Francisco still one of most heavily affected US
cities
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| Epidemic in MSM: prevalence in US urban centers 10% to 40%; 50% of HIV-positive MSM did not know serostatus;
MSM epidemic seen throughout Americas and worldwide in urban centers; attributable risk—combines information on
increment in risk attributable to given risk factor and prevalence of that factor; if common enough, even factors that minimally
increase risk can drive epidemic; estimates potential proportion of new infections avoided by eliminating specific
exposure; data from prospective studies of HIV-negative men at risk of acquiring HIV—25% of cases attributed to
men having larger number of HIV-negative male sex partners; use of alkyl nitrites (poppers) accounted for >25% of infections,
as did unprotected receptive anal sex with partners of unknown serostatus or HIV-positive partners; use of alcohol
or drugs before sex also increased risk
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Role of Behavioral Intervention
| Behavior change works: at beginning of HIV epidemic in United States, sero-incidence in MSM as high as 20% per year;
incidence rates now 2% to 5% per year; behavior change important component of any biomedical prevention strategy, including
vaccines; areas for future development—new HIV testing strategies allowing quicker serostatus results; improving
brief interventions alone or with biomedical interventions; novel strategies using Internet; community level and structural interventions
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| Substance use: high prevalence; data from mid 2004 to mid 2005 show increase in crystal methamphetamine (crystal
meth) use; subgroup of MSM attending circuit parties shows high prevalence of drug use, as well as in noncircuit party
activity; also true for smaller numbers of popper and sildenafil (Viagra) users
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| Drug use augments risk of acquiring HIV: methamphetamine, alkyl nitrites, and sildenafil associated with increase
in anal sex, as well as increase in unprotected anal sex with partner whose serostatus is different from individual’s
own, or where serostatus unknown, ie, high degree of behavioral disinhibition; drugs may enhance transmission biologically;
limited in vitro and animal studies indicate crystal meth associated with increased viral replication; higher viral
loads in crystal meth users on highly active antiretroviral therapy (HAART); perturbations in immune function in meth
users; alkyl nitrites associated with impact on immune function in CD4 and natural killer cells and with vasodilation at
mucosal surfaces that may enhance transmission across surfaces; drugs, including sildenafil, may lead to more prolonged
or traumatic sex, increasing transmission across mucosal barriers; intermittent recreational drug users may need different
treatments from those used for drug addicts
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| Rectal microbicides: chemical barriers to augment physical barrier provided by condom use; unknown variables (eg,
volume of distribution, product durability) affect efficacy; semen in anal sex may travel as high as splenic flexure; political
constraints to conducting studies; future directions of studies—increase understanding of occurrence of rectal transmission
in nonhuman primate and clinical studies; understand what is normal rectal mucosa in setting of anal sex; identify toxic
effects of microbicides; find acceptable and feasible delivery systems
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Interventions Unlinked from Timing of Risk Behavior
| HIV vaccines: could offer lifelong protection against HIV acquisition or disease; collaboration among National Institutes
of Health (NIH) global vaccine trials, International AIDS Vaccine Initiative, CDC, and Walter Reed Army Medical
Center; 6 to 12 new HIV Vaccine Trials Network (HVTN) protocols opening yearly; Merck “test-of-concept” study of
Ad5 trivalent vaccine shows most substantial immune response in clinical trials; >75% of people without prior immunity
to Ad5 responding to at least 2 of HIV-1 gene products; >50% of individuals with prior immunity (neutralizing antibody
titers >200) responding to vaccine
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| Pre-exposure prophylaxis: recommended for occupational and nonoccupational exposures; where mother and child
treated, substantially reduced risk for transmission from mother to child; US Project T study using tenofovir (because of
favorable dosing, safety, and resistance profiles) to confirm biologic safety of using products in HIV-negative individuals
and look at risk behavior
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| Herpes suppression: herpes is sexually transmitted infection that most drives HIV epidemic; 2- to 4-fold increase in risk
of transmitting HIV associated with herpes simplex virus 2 (HSV-2) infection; herpes is forever and very common; estimated
25% of HIV-negative MSM in United States have herpes; population-attributable risk increases as herpes prevalence
increases; in sub-Saharan Africa, >75% of women may have herpes; herpes may be contributing to >50% of HIV infections
worldwide; study to determine if treatment of subclinical infection can reduce new HIV infections
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| DECIPHERING HIV PATHOGENESIS —Warner Greene, MD, PhD, Professor of Medicine, Microbiology and Immunology,
and Director, Gladstone Institute of Virology and Immunology, University of California, San Francisco
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| HIV life cycle: mature viral particle binds to cell surface receptors and microinjects core virus components into host cell; ribonucleic
acid (RNA) converted into double-stranded DNA by reverse transcription, enters nucleus through nuclear pore
complexes, and integrates into host chromosomes; recent data suggest that HIV has favored sites of integration within transcriptionally
active genes; once integrated, provirus can assemble new virions from its regulatory, structural, and enzymatic
proteins; virions bud from infected cell surface and infect new CD4 target cells
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| Interventions: introduction of reverse transcriptase inhibitors and protease inhibitors; protease inhibitors block virus
maturation where gag polyprotein cleaved by viral protease; in absence of cleavage, immature viral particles noninfectious;
targeting 2 critical enzymes in virus has changed management of HIV-infected patients from acute to long-term
management of chronic disease; drugs toxic, and virus can rapidly develop resistance, limiting drug utility
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| New drugs: interference with first interaction between mature viral particle and host cell—interaction mediated by
binding of CD4 to glycoprotein (gp) 120; classic “lock (gp120) and key (CD4)” interaction; BMS488043 attachment inhibitor
(small orally bioavailable molecule) most interesting; interplay of HIV with chemokine coreceptor—CCR5
binds R5-tropic viruses, and CXCR4 interacts with X4-tropic viral envelopes; mother-to-child transmission utilizes
CCR5 receptor; individuals lacking CCR5 surface expression highly resistant to HIV infection; Pfizer furthest along in
developing CCR5 antagonist; question remains whether, in presence of CCR5 antagonist, virus will be pushed to shift towards
CXCR4 tropism; fusion inhibitors—HIV fuses at cell surface after conformational changes induced by prior
binding to CD4; enfuvirtide (ENF) commercially available, but must be infused; need fusion inhibitor taken in pill form;
combination of attachment inhibitors, R5 inhibitors, and fusion inhibitors might result in new triple cocktail, attacking
earliest points in HIV life cycle before virus penetrates cell; viral integrase inhibitors—Merck has identified naphthyridine-like
compounds that interfere with integrase-mediated strand transfer (late step in integration reaction); efficacious
in monkeys; now advancing into clinical trials
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| HIV factoids: in untreated HIV infected patient, 50 to 500 billion virions produced daily; replicative rate for HIV is 10,
ie, each infected cell produces enough virus to infect 10 new cells; therapies 90% effective, so if replicative rate reduced
to <1, infection should be extinguished; why are patients not cured? HIV persists in latent proviral state in host, preventing
cure; one important reservoir for HIV latency exists within memory CD4 T lymphocytes; memory cells long-lived
(half-life [T1/2 ] 44 mo); clearance of latent reservoir predicted to require administration of antiretroviral therapy for at
least 60 yr; new approaches needed for dealing with latent reservoir; need biologic modifiers (small molecules) to “rouse
virus from transcriptional slumber” in latently infected cells and stimulate replication, making it sensitive to antiretroviral
therapy as well as to immune response; in clinical studies using histone deacetylase inhibitors, latent proviral pool reduced
by 75% in 1 patient (100% removal required)
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| HIV regulatory proteins: Tat—transcription activator; binds to RNA element within HIV RNA and enables RNA
polymerase to produce full-length genomic RNA; without Tat, polymerase produces short ineffective transcripts; interference
with Tat function prevents viral replication; Rev—without Rev, full-length HIV genomic RNA cannot be exported
from nucleus; Nef—all-purpose protein; viruses lacking Nef have greatly reduced pathogenic potential; down-
regulates CD4 and major histocompatibility complex (MHC) Class 1 antigens; alters state of T cell activation, making
cells more conducive to replication of HIV; inhibits programmed cell death, allowing HIV-infected cell to live long
enough to produce new virions
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Educational Objectives
| The purpose of this program is to provide the listener with information on the nature and management of HIV/AIDS. After
hearing and assimilating this program, the clinician will be better able to:
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 | 1. Review the prevalence and incidence of HIV/AIDS cases worldwide.
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| 2. Describe recent developments in addressing global AIDS.
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| 3. Summarize the transmission modes and mechanisms for acquiring HIV/AIDS in the United States.
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| 4. Discuss the relationship of substance abuse to HIV/AIDS.
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| 5. Review the molecular biology of the HIV infection process with a view to development of new therapies for treating
HIV/AIDS.
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Discussed on This Program
Clotrimazole [several trade names]
Enfuvirtide [Fuzeon]
Isoniazid (isonicotinic acid hydrazide; INH) [Nydrazid]
Nevirapine [Viramune]
Sildenafil citrate [Viagra]
Tenofovir disoproxil fumarate (PMPA) [Viread]
Suggested Reading
Amberg SM et al: Expanded tropism and altered activation of a retroviral glycoprotein resistant to an entry inhibitor peptide.
J Virol 80:353, 2006; Asamoah-Odei E et al: HIV prevalence and trends in sub-Saharan Africa: no decline and
large subregional differences. Lancet 364:35, 2004; Buchbinder SP et al: Sexual risk, nitrite inhalant use, and lack of circumcision
associated with HIV seroconversion in men who have sex with men in the United States. J Acquir Immune Defic
Syndr 39:82, 2005; Celum CL et al: Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral
therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis 191:S107, 2005; Cohen J: ABC in Uganda:
success or subterfuge? HIV AIDS Policy Law Rev 10:23, 2005; Creek TL et al: Declining syphilis prevalence among
pregnant women in northern Botswana: an encouraging sign for the HIV epidemic? Sex Transm Infect 81:453, 2005; Douek
DC et al: The rational design of an AIDS vaccine. Cell 124:677 2006; Flanigan TP et al: Public health principles for the
HIV epidemic. N Engl J Med 354:877, 2006; Freeman EE et al: Herpes simplex virus 2 infection increases HIV acquisition
in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 20:73, 2006; Gray RH et al:
Increased risk of incident HIV during pregnancy in Rakai, Uganda: a prospective study. Lancet 366:1182, 2005; Gregson S
et al: HIV decline associated with behavior change in eastern Zimbabwe. Science 311:664, 2006; Khurana S et al: Human
immunodeficiency virus (HIV) vaccine trials: a novel assay for differential diagnosis of HIV infections in the face of vaccine-generated
antibodies. J Virol 80:2092, 2006; Mills E: Tenofovir trials raise ethical issues. HIV AIDS Policy Law Rev
10:31, 2005; Paul JP et al: Viagra (sildenafil) use in a population-based sample of U.S. men who have sex with men. Sex
Transm Dis 32:531, 2005; Sterne JA et al: Long-term effectiveness of potent antiretroviral therapy in preventing AIDS
and death: a prospective cohort study. Lancet 366:378, 2005; Strizki JM et al: Discovery and characterization of vicriviroc
(SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob Agents
Chemother 49:4911, 2005; Wald A et al: Reactivation of genital herpes simplex nirus type 2 infection in asymptomatic seropositive
persons. N Eng J Med 342:844, 2000; Zuckerman RA et al: Higher concentration of HIV RNA in rectal mucosa
secretions than in blood and seminal plasma, among men who have sex with men, independent of antiretroviral therapy. J
Infect Dis 190:156, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reports
nothing to disclose.
Drs. Jaffe, Buchbinder, and Greene addressed The Medical Management of AIDS, held December 8-10, 2005, in San
Francisco, and sponsored by the University of California, San Francisco, School of Medicine. The Audio-Digest
Foundation thanks the speakers and the University of California, San Francisco, School of Medicine, for their cooperation
in the production of this program.
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