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ScienceWeek
PUBLIC HEALTH: UPDATE ON HIV IN THE US
The following points are made by T.R. Frieden et al (New Engl. J. Med. 2005 353:2397):
1) Although human immunodeficiency virus (HIV) infection has killed more than half a million people in the US, a comprehensive public health approach that has stopped other epidemics has not been used to address this one. When HIV infection first emerged among stigmatized populations (homosexual men, injection-drug users, and immigrants from developing countries), the discriminatory responses ranged from descriptions of AIDS as "retribution" to violence and proposals for quarantine, universal mandatory testing, and even tattooing of infected persons. This response led to HIV exceptionalism, an approach that advocated special resources and increased funding, but at the same time against the application of standard methods of disease control.[1] The need for extra resources remains essential, but the failure to apply standard disease-control methods undermines society's ability and responsibility to control the epidemic.
2) At present, given the availability of drugs that can effectively treat HIV infection, and progress on antidiscrimination initiatives, perhaps society is ready to adopt traditional disease-control principles and proven interventions that can identify infected persons, interrupt transmission, ensure treatment and case management, and monitor infection and control efforts throughout the population. Doing so will have political and economic costs. The political costs include offending both sides of the political establishment: conservatives who oppose the implementation of effective prevention programs, including syringe exchange and the widespread availability of condoms, and some HIV activists who oppose expansion of testing, notification of the partners of infected persons (also known as partner counseling and referral services), and what some see as inappropriate "medicalization" of the response to the epidemic. The economic costs, particularly to improve population-wide case management and notification of partners, would be substantial. But the human and economic costs of failing to adopt a comprehensive public health approach are much higher.
3) Research and other efforts have identified and elucidated the biology of the virus, established and improved diagnostic tests, and created effective drugs and care systems that have reduced the number of deaths from AIDS in the US by 70 percent since 1995.[2] However, 25 years into the epidemic, progress is stalled. The number of deaths among people with AIDS has not declined since 1998, and the number of newly diagnosed cases is rising slightly.[2] Disease transmission continues at the same or, possibly, a slightly higher rate.[3] High-risk behavior remains common and is increasing in some groups. Late diagnosis of infection is common.[3] Notification of the partners of infected persons is rare.[4] Black and Latino patients are less likely than white patients to receive optimal care.[5] Few patients in care receive counseling about preventing transmission of the virus. All these trends are apparent in New York City, which is home to 1 in 6 of all U.S. patients with AIDS.
4) When HIV testing became available 20 years ago in the absence of treatment and in the context of discrimination, the use of prescriptive regulations mandating counseling and separate written consent, based largely on the genetic-counseling model of testing for untreatable conditions, was reasonable. Today, the existence of these regulations and the separation of counseling and testing from routine medical care result in missed opportunities to diagnose, treat, and stop the spread of HIV infection. Nearly half of black men tested in public venues where men who have sex with men congregate (e.g., bars, bathhouses, and parks) in 2004 and 2005 were HIV-positive, and two thirds of those who were positive were unaware of their status. Our outdated approach to HIV screening means that we not only fail to identify infected patients promptly and thus allow the epidemic to continue to spread, but we may also perpetuate HIV-related stigma by targeting screening only to those perceived to be at risk.
References (abridged):
1. Bayer R. Public health policy and the AIDS epidemic: an end to HIV exceptionalism? N Engl J Med 1991;324:1500-1504
2. Advancing HIV prevention: new strategies for a changing epidemic -- United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52:329-332
3. Cases of HIV infection and AIDS in the United States, 2003. HIV/AIDS surveillance report. Vol. 15. Atlanta: Centers for Disease Control and Prevention, 2004
4. Golden MR, Hogben M, Potterat JJ, Handsfield HH. HIV partner notification in the United States: a national survey of program coverage and outcomes. Sex Transm Dis 2004;31:709-712
5. Palacio H, Kahn JG, Richards TA, Morin SF. Effect of race and/or ethnicity in use of antiretrovirals and prophylaxis for opportunistic infection: a review of the literature. Public Health Rep 2002;117:233-251
New Engl. J. Med. http://www.nejm.org
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EPIDEMIOLOGY: ON THE ORIGINS OF HIV
The following points are made by J. Stebbing et al (New Engl. J. Med. 2004 350:1872):
1) The worldwide dissemination of human immunodeficiency virus (HIV) over the past four decades is one of the most catastrophic examples of the emergence, transmission, and propagation of a microbial genome.(1) We now know that the cellular and anatomical sites of HIV replication influence the course of the infection, the ability of antiretroviral therapy to reduce viremia, and the establishment of the viral reservoir. This highly mutable virus inserts its genome into the genomes of crucially important cells of the host and, despite therapy, maintains a reservoir of latent HIV within the body.(2) The virus has a predilection for activated HIV-specific CD4+ T cells, although other cells are also susceptible to the virus. This tropism for particular cells is determined mainly by cellular receptors to which HIV attaches in order to enter cells.
2) The earliest documented case of HIV infection in humans was identified in a sample of serum from Kinshasa (Democratic Republic of Congo) that was stored in 1959.(3) On the basis of the HIV type 1 (HIV-1) sequences obtained from this and numerous other, more recent isolates, it has been estimated that the main (M) group of HIV-1 strains diversified in humans in about 1931 (95 percent confidence interval, 1911 to 1941).(4) Similarly, the most recent common ancestors of HIV type 2 (HIV-2) subtypes have been dated to the 1940s.(5)
3) There is persuasive evidence that HIV-1 came to humans from the chimpanzee (Pan troglodytes), which harbors the related simian immunodeficiency virus (SIVcpz) and lives in central Africa. HIV-2, whose DNA has 40 to 60 percent homology with HIV-1 DNA, originated from the SIVsm of the sooty mangabey (Cercocebus atys) monkeys of coastal West Africa, from Senegal to the Ivory Coast, the endemic epicenter of HIV-2. In these areas, nonhuman primates are kept as pets and butchered for food, suggesting routes of transmission -- monkey and ape to human -- that are in accord with phylogenetic data implying cross-species infection. Estimates of when HIV was introduced into the human population, on the basis of a molecular clock and the distribution of SIV genomic sequences among the chimpanzees of central Africa, render it highly improbable that contaminated poliovirus vaccines were the source of HIV.
4) It is striking that in all known instances of infection of the natural primate host of SIV, neither a disease resembling the acquired immunodeficiency syndrome (AIDS) nor a profound depletion of CD4+ T cells develops, despite the presence of very high viral loads. In contrast, transmission of SIV to unnatural hosts, such as the rhesus macaque (Macaca mulatta) or humans, causes a progressive loss of CD4+ T cells and a high degree of susceptibility to opportunistic infections. The importance of this point cannot be overstated and must surely lie at the core of the pathogenic mechanisms of HIV, which is in effect a zoonotic infection. It is unclear why SIV infection of its natural hosts fails to cause disease, but recent studies have shown that SIV does not elicit the prominent T-cell activation that is seen in chronic HIV infection. Other studies that analyzed polymorphisms in major-histocompatibility-complex genes suggest that present-day animals, which have SIV infection but no disease, may in fact represent the survivors of an ancient retroviral pandemic.
References (abridged):
1. Ho DD, Huang Y. The HIV-1 vaccine race. Cell 2002;110:135-138
2. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003;9:727-728
3. Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature 1998;391:594-597
4. Korber B, Muldoon M, Theiler J, et al. Timing the ancestor of the HIV-1 pandemic strains. Science 2000;288:1789-1796
5. Lemey P, Pybus OG, Wang B, Saksena NK, Salemi M, Vandamme AM. Tracing the origin and history of the HIV-2 epidemic. Proc Natl Acad Sci U S A 2003;100:6588-6592
New Engl. J. Med. http://www.nejm.org
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MEDICAL BIOLOGY: ON HIV DRUG RESISTANCE
The following points are made by F. Clavel and A.J. Hance (New Engl. J. Med. 2004 350:1023):
1) The use of combinations of antiretroviral drugs has proven remarkably effective in controlling the progression of human immunodeficiency virus (HIV) disease and prolonging survival,(1) but these benefits can be compromised by the development of drug resistance.(2,3) Resistance is the consequence of mutations that emerge in the viral proteins targeted by antiretroviral agents. In the US, as many as 50 percent of patients receiving antiretroviral therapy are infected with viruses that express resistance to at least one of the available antiretroviral drugs.(4) Consequently, the transmission of drug-resistant strains is also a growing concern.(5) Because drug-resistant HIV often exhibits resistance to several classes of antiretroviral drugs and because cross-resistance between drugs within a class is frequent, the emergence of resistance always complicates further efforts to control viral replication.
2) The drugs currently used to treat HIV type 1 (HIV-1) infection belong to four distinct classes: nucleoside and nucleotide analogues, which act as DNA-chain terminators and inhibit reverse transcription of the viral RNA genome into DNA, a crucial event occurring at an early stage of the viral life cycle; nonnucleoside reverse-transcriptase inhibitors, which bind and inhibit reverse transcriptase, the viral enzyme that conducts reverse transcription; protease inhibitors, which target the viral protease, the enzyme required for the cleavage of precursor proteins (gag and gag-pol), permitting the final assembly of the inner core of viral particles; and entry inhibitors, which block the penetration of HIV virions into their target cells. Combinations of antiretroviral drugs are now used for the treatment of HIV infection -- so-called highly active antiretroviral therapy (HAART). Current HAART regimens generally comprise three antiretroviral drugs, usually two nucleoside analogues and either a protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor. The use of agents from different classes is instrumental in controlling the development of resistance, but whereas some drug combinations have been shown to be antagonistic, there is no evidence that any combinations of currently available drugs are strongly synergistic in vitro.
3) Two concepts are important to an understanding of the development of drug resistance. First, HIV infection is characterized by high levels of virus production and turnover. In most untreated patients, the total number of productively infected cells in the lymphoid tissue has been estimated to be approximately 10^(7) to 10^(8) cells. During the chronic phase of HIV infection, this number is relatively stable, reflecting the balance between the infection of new target cells and their clearance. Because the half-life of infected cells is remarkably short (one to two days), the maintenance of this steady state requires that HIV infect new target cells at a very high rate. Second, the viral population in an infected person is highly heterogeneous. The reverse transcription of viral RNA into DNA is notoriously prone to error, introducing on average one mutation for each viral genome transcribed. Most of these errors are base substitutions, but duplications, insertions, and recombination can also occur. The high rate of HIV infection, combined with the high mutation rate that occurs during each cycle of infection, ensures that patients have a complex and diverse mixture of viral quasispecies, each differing by one or more mutations.
References (abridged):
1. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853-860
2. DeGruttola V, Dix L, D'Aquila R, et al. The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using a standardized data analysis plan. Antivir Ther 2000;5:41-48
3. Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA 1999;282:2220-2226
4. Richman D, Bozette S, Morton S, et al. The prevalence of antiretroviral drug resistance in the US. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, December 16-19, 2001. Washington, D.C.: American Society for Microbiology, 2001
5. Yerly S, Kaiser L, Race E, Bru JP, Clavel F, Perrin L. Transmission of antiretroviral-drug-resistant HIV-1 variants. Lancet 1999;354:729-733
New Engl. J. Med. http://www.nejm.org
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