Table of Contents HIV Transmission Intervention Strategies Biological HIV Prevention Strategies: Reducing Infectiousness, Susceptibility, and the Efficiency of Transmission Antiretroviral Therapy and HIV Transmission Conclusion References Appendix: Talking About Safer Sex With Your Patients _____ HIV Transmission Epidemiology of HIV Transmission HIV is spread from human to human by 3 routes[1]: * blood transmission (contaminated transfusions, needle sharing during drug use, needle-stick injuries) * vertical transmission (mother to offspring during parturition or breastfeeding) * sexual transmission Sexual transmission of HIV accounts for more than 75% of infections worldwide. The probability of transmission of HIV by different sexual routes per episode of intercourse is summarized in Figure 1, using data generated by epidemiologists and mathematical modeling.[1] Transmission of HIV from men to their partners is more efficient than from women to men.[2,3] Transmission of HIV through anal intercourse is more efficient than other sexual behaviors. In addition, transmission per episode of intercourse may well be affected by the stage of disease of the infected subject or innate or acquired immunity of the exposed person as discussed below. Oral sex between women (cunnilingus) appears to confer almost no risk, and fellatio appears to have limited risk relative to sexual intercourse. However, HIV acquisition among gay men has been reported as a result of fellatio alone.[4] Among 122 individuals with primary HIV infection, Dillon and coworkers[5] attributed 6.6% of cases to oral sex. In addition, simian immunodeficiency virus (SIV) has been transmitted to macaques through oral inoculation using similar concentrations of virus as those required for vaginal infection.[6,7] Figure 1. Per-contact probability of HIV transmission. The infectivity ranges for sexual contact are derived from a comprehensive review of the literature (lower and upper bounds are from modeling per-contact transmission in different study populations with different modeling techniques). Each infectivity estimate for the other routes of infection originates from one representative study. The routes of infection are as follows: sexual intercourse, with indicating female-to-male transmission, indicating male-to-female transmission, and indicating male-to-male transmission; needle stick; needle sharing; transmission from mother to infant with and without perinatal zidovudine treatment; and transfusion. Royce RA, Sena A, Cates W Jr, Cohen MS. Current concepts: sexual transmission of HIV. N Engl J Med. 1997;336:1072-1078. Copyright 1997. Massachusetts Medical Society. All rights reserved. The spread of HIV can be assessed at a population level as well. Anderson and May[8] have described the risk of secondary (new) cases of HIV as Ro, where Ro = beta x C x delta, with beta representing the efficiency of transmission, C the number of sexual partners, and delta the duration of infectiousness of the index case. When Ro exceeds 1, new, secondary cases of HIV occur, and the epidemic continues. Successful prevention strategies must reduce Ro to less than 1 and include lowering the rate of partner change, reducing the efficiency of transmission, and shortening the duration of infectiousness. This model offers an excellent conceptual framework to approach HIV prevention and a tool to examine the success of interventions. Biology of HIV Transmission The efficiency of transmission of HIV represents a biological event; transmission either does or does not occur. HIV transmission must depend on the infectiousness of the index case (reviewed in the paper by Vernazza and coworkers[9]) and the susceptibility of the exposed host (reviewed in the paper by Buchacz and colleagues[10]). A schematic representing the transmission of HIV from a male to a female partner is provided in Figure 2. Figure 2. Male-to-female transmission of HIV. Infectiousness of HIV. HIV can be recovered from seminal cells (CD4+ macrophages and lymphocytes) and seminal plasma. Detection of HIV in seminal plasma by RNA polymerase chain reaction amplification techniques has been used as a surrogate for the concentration of HIV in semen, although procedures to eliminate inhibition of amplification must be used.[11] When the concentration of HIV in seminal plasma exceeds 10,000 copies/mL, HIV can usually be grown in seminal cells.[12] However, it is unclear whether HIV is transmitted from seminal cells or seminal plasma; cell-free virions in seminal plasma may be defective (and unfit). The recovery of HIV from cervical mucus and cervicovaginal lavage fluid is similar to semen, although it has only recently been possible to quantify the copy number.[13,14] HIV can be recovered from cervicovaginal lavage fluid cells when the concentration exceeds 10,000 copies/mL.[15] Several lines of evidence suggest that the concentration of HIV in genital secretions can be correlated with risk of sexual transmission. First, there is overwhelming evidence that the concentration of HIV in an infected mother's blood determines the risk of vertical transmission,[16-18] although one must realize that the biologic mechanisms of vertical and sexual transmission are different. Second, a correlation has been demonstrated between increased concentrations of HIV in blood and enhanced transmission by all routes.[18-21] In a remarkable study in Uganda, Quinn and coworkers[22] demonstrated that HIV transmission in HIV serodiscordant couples could be correlated directly with the blood plasma HIV RNA level in the infected subject. No HIV transmission was observed when blood plasma HIV was less than 1500 copies/mL. In a similar study among serodiscordant couples in Rakai, Uganda, Gray and colleagues[23] calculated that when the blood plasma viral load was less than 3500 copies/mL, the transmission probability was 0.0001 (1 per 10,000 episodes of intercourse). When blood viral burden was greater than 50,000 copies/mL, the transmission probability was calculated to be 0.0051 (5.1 per 1000 episodes of intercourse). It should be noted the concentration of HIV in blood can be directly (but imperfectly) correlated with the concentration of HIV in semen[11,12,24] and female genital secretions.[15] Third, the concentration of HIV in genital tract secretions from males and females is increased at times when enhanced transmission is suspected, such as in primary infection or in later stages of HIV disease,[11,12,15,24,25] and in patients with classic sexually transmitted diseases (STDs) (reviewed in the paper by Fleming and Wasserheit[26]). However, recent data suggest that the concentration of HIV in semen during primary infection may not be as high as that in blood[27] and can overlap the concentrations observed in seminal plasma throughout the disease.[28] These data would indicate that primary infection is associated with a higher risk of transmission for reasons other than viral burden in the genital tract or that the model suggesting that most sexual HIV transmission may result from subjects with primary infection is flawed.[29] Empiric data on transmission and stage of disease are desperately needed to inform public health policy.[30] Recent reports[31,32] indicate that individuals with symptomatic primary HIV infection may infect sexual partners as early as 2 days before the onset of the acute retroviral syndrome, or 10-18 days after infection, suggesting that education targeting persons diagnosed with primary HIV infection may be too late, because transmission may have already occurred. Investigators at the University of North Carolina at Chapel Hill have used HIV RNA in semen samples from several hundred men to estimate the effects of semen viral burden on heterosexual transmission.[33,34] They concluded that when HIV RNA in semen was low (<5000 copies/mL) transmission was unlikely to occur, at 1 per 10,000 episodes of intercourse. Conversely, when the concentration of HIV in semen was high (eg, 1 million copies/mL) the probability of transmission rose to 3 per 100 episodes of intercourse. Such high concentrations of HIV RNA have been detected in semen specimens harvested from HIV-positive men in Africa infected with STDs, including trichomonas and gonorrhea. Thus, the magnitude of the AIDS epidemic in Africa likely reflects a variety of factors that dramatically increase genital shedding of HIV. Phenotypic requirements for HIV transmission. HIV recovered from genital secretions is not homogeneous; rather, it consists of a swarm of viral variants that can be separated into discrete quasispecies. Virologic factors required for HIV transmission are only poorly understood, but based on studies of isolates transmitted from infected patients to their partners, it seems clear that some viral quasispecies in a swarm appear to be favored.[35,36] In particular, homogeneous viral isolates with envelope sequences that define the slow-growing, macrophage-trophic, non-syncytium-inducing (NSI) phenotype are preferentially transmitted.[37,38] This observation implies that these variants overwhelm innate or acquired resistance to infection and/or, more likely, that the genital mucosa provide receptors, such as CD4 and CCR-5, that are more appropriate for this viral phenotype than others.[39] Patterson and coworkers[40,41] have demonstrated availability of cells with CD4 and CCR-5 receptors in the endocervix, where infection is likely initiated. These receptors are subject to dynamic regulation by cytokines and other inflammatory stimuli.[42] A key question is whether HIV is transmitted by infected seminal cells or by cell-free virus in the seminal plasma. SIV and SHIV (viral constructs incorporating elements of both simian and human immunodeficiency viruses) are more readily transmitted vaginally to macaques through cell-free virus.[43] In a recent study, DePasquale and colleagues carefully categorized the genotype of HIV variants in the seminal plasma and the seminal cells of an infected patient and that of HIV recovered from the blood of the patient's sexual partner during his primary infection.[36] The results demonstrate that the transmitted variant most likely originated in the seminal cells of the infecting partner. Potent antiretroviral therapy that reduces HIV RNA in blood plasma to below quantifiable levels is almost always effective at reducing HIV RNA in seminal plasma to a similar extent.[9,44] However, the reservoir of HIV in seminal cells may be difficult to eliminate even in the face of potent antiretroviral therapy.[45,46] HIV variants can be divided into subtypes or clades based on the genotypic similarity in the HIV envelope region and in other genes as well. Clade B is the dominant strain in the United States and Europe, whereas clades A and C are dominant in sub-Saharan Africa, though all subtypes are represented. Clades E and B predominate in Thailand[47] and some other parts of Asia. A variety of clades and a recombinant B-C clade have been identified in the People's Republic of China. Given the geographic differences in the magnitude of the HIV epidemic, many investigators have tried to prove that different clades might be transmitted with different efficiency. Stimulated by epidemiological evidence that clade E is more infectious,[48] Soto-Ramirez and coworkers studied growth of different clades of HIV in cervical epithelial cells and dendritic cells. They reported increased growth of clade E HIV in these tissues.[49] However, these results could not be reproduced by other investigators,[50,51] who also emphasized the technical difficulties of this type of study. Duerr and colleagues[52] presented evidence for clade-specific transmission from men to women by comparing the efficiency of transmission of clade B HIV in 51 Italian couples (1.1 per 1000 episodes of intercourse) to clade E in 78 Thai couples (2.4 per 1000 episodes of intercourse); however, these differences were not significant. It seems probable that the actual concentration of HIV in the genital tract is the most important determinant of transmission. We[53] and others[54] have made observations related to clade C HIV that may be relevant to transmission. This clade represents more than half of all HIV infections on the planet and is predominant in hyperendemic regions such as sub-Saharan Africa. Study of clade C variants from several different countries has demonstrated that as patients develop more advanced disease, the virus retains the NSI phenotype. This observation contrasts with evidence regarding subtype B in North America and Europe, where a substantial proportion of infected individuals have a shift in envelope phenotype from NSI to the rapid-growing, lymphotropic, syncytia-inducing (SI) viral phenotype.[55-57] Retention of the NSI phenotype throughout the disease course for most individuals with subtype C could also promote sexual transmission of HIV through the efficient use of the CD4/CCR-5 receptors that are believed critical for sexual transmission (see below and Figure 2). Recently, however, another group has reported a small number of subtype C variants that appear to have the SI phenotype.[58] Susceptibility to HIV Infection Hereditary resistance to HIV. Susceptibility to HIV infection depends on the lack of innate, hereditary resistance or acquired immunity. Recent studies of hereditary resistance have helped to clarify this issue. Soon after the discovery of HIV as the cause of AIDS, binding of the viral envelope to the CD4 molecule on target cells was recognized, but it has been known for some time that at least one additional receptor is also required for cell entry, because CD4-expressing nonhuman cell lines are resistant to HIV infection. Until recently, this receptor had escaped identification, but 2 important second receptors, CCR-5 and CXCR-4, have now been described (reviewed in the papers by Littman[39] and Hoffman and Doms[59]). The CCR-5 receptor is the natural ligand for chemoattractants, including macrophage inflammatory protein 1 alpha and beta and RANTES. The importance of the CCR-5 receptor was quickly demonstrated when individuals who were homozygous for a nonfunctional CCR-5 mutation (a 32-base pair deletion) were found to be underrepresented in HIV-1-infected populations[60] and overrepresented in uninfected exposed populations.[61] Cells from these individuals were shown to be resistant to infection with NSI, macrophage-tropic HIV-1.[60] This CCR-5 mutation is observed in 1 of 100 whites[60] but is much less common among blacks and is associated with a reduced risk of infection after exposure to HIV during intercourse, with no apparent decrement in host defenses.[62] These observations confirmed and explained the critical importance of the NSI phenotype for sexual transmission, as suspected from studies cited earlier that identified that patients with primary HIV infection typically have a homogeneous NSI viral swarm, regardless of the route of transmission. Innate and acquired resistance to HIV. Not every episode of intercourse has an equal risk for HIV transmission. Some exposed, uninfected people do not have the advantage of hereditary resistance, perhaps suggesting the contribution of innate or acquired host defenses against infection.[63] If such defenses exist, they could lead to development of biological prevention strategies. Although a wide variety of innate mucosal defenses have been described (eg, defensins, mucus, zinc, amines, etc), none has demonstrated an ability to prevent HIV transmission. However, "normal" vaginal flora may reduce HIV transmission; women with flora changes characterized as bacterial vaginosis (ie, increased anaerobic bacteria, decreased lactobacilli) have higher rates of HIV acquisition compared with control groups or even with individuals with STDs (see below).[64,65] Acquired immune responses to HIV include specific anti-HIV-1 antibodies and cell-mediated immune responses. From studying exposed, uninfected women, Mazzoli and colleagues[66] reported an association between increased concentrations of vaginal immunoglobulin A directed against the HIV envelope and reduced risk of HIV infection. Kaul and colleagues have reported similar findings with exposed, uninfected commercial sex workers in Nairobi.[67] In addition, both research groups suggest a role for specific cytotoxic lymphocytes harvested from the peripheral blood.[68] These lymphocytes are directed at HIV epitopes that may be conserved across clades.[68] In earlier work, Pinto and coworkers reported observing a cytotoxic response in lymphocytes harvested from health care workers exposed to HIV-1.[69] Not surprisingly, the cytotoxic T-lymphocyte response is being used as a critical milestone in development of preventive HIV vaccines (see below). Acquisition of HIV is reduced in men who have been circumcised.[70,71] In the study by Quinn and colleagues,[22] for example, no circumcised man acquired HIV. The feasibility of circumcision as an HIV prevention intervention is discussed later in this review. Cofactors That Amplify HIV Transmission A variety of cofactors appear to amplify HIV transmission by increasing the infectiousness of the index case, increasing the susceptibility of the exposed host, or both.[1,26] Some of these cofactors are summarized in Table 1.[1] The most important cofactors are those that cause trauma or inflammation to the genital mucosa. Classic STDs (genital ulcers and mucosal inflammatory diseases) occur in the same geographic areas as HIV, and compelling epidemiological evidence supports the view that such diseases increase HIV transmission; indeed, the interaction between classic STDs and HIV is referred to as "epidemiological synergy."[26] For example, Gwanzura and colleagues[72] reported that herpes simplex virus type 2 (HSV-2) appears to increase heterosexual HIV transmission; given the frequency of HSV-2 infection, this cofactor may ultimately prove to be very important. Biological studies suggest that STDs may enhance HIV transmission by increasing the concentration of HIV in genital secretions,[73] the number of cells receptive to HIV,[74] or the number of receptors per cell.[40] Table 1. Biologic Host-Related Factors Affecting Sexual Transmission of HIV.* Biologic Factor Host-Related Infectivity Factors HIV Concentration in Genital Secretions Infectiousness (Transmission) Susceptibility (Acquisition) Mutation of chemokine-receptor gene ? ? Late stage of HIV infection Not applicable Primary HIV infection Not applicable Antiretroviral therapy ? Local infection (inflammation or ulcer of reproductive tract or rectal or oral mucosa) Presence of cervical ectopy ? Presence of foreskin ? Method of contraception Barrier Hormonal contraceptives Spermicidal agents Intrauterine devices Not applicable ? ? ? ? ? Menstruation ? Factors that lower cervicovaginal pH ? ? ? Immune activation ? Genital tract trauma ? Pregnancy ? ? *The associations represented were statistically significant in at least one study. The degrees of positivity ( to ) and negativity ( to ) of the associations are indicated with arrows, with three arrows indicating a very strong association. The symbol denotes that there is evidence in support of both a positive and a negative association. A question mark indicates an unknown or hypothesized association that is not currently supported by data. Royce RA, Sena A, Cates W Jr, Cohen MS. Current concepts: sexual transmission of HIV. N Engl J Med. 1997;336:1072-1078. Copyright 1997. Massachusetts Medical Society. All rights reserved. A study in Malawi of HIV-infected men with urethritis found that levels of HIV in their semen were 10 times higher than in subjects without urethritis (Figure 3).[73] After single-dose antibiotic treatment, HIV excretion gradually decreased to a level similar to the control group. Likewise, men with genital ulcers also demonstrate increased excretion of HIV in semen.[75] Phenotypic analysis of HIV in semen compared with blood suggests that the increased levels of HIV caused by genital tract inflammation result from local replication, perhaps influenced by local cytokines.[76-78] It is not yet clear whether the observed increase in HIV excretion results from increased numbers of infected cells, increased replication per cell, or both. Figure 3. HIV excretion in semen of HIV-infected men with and without urethritis. Sexually transmitted diseases also increase excretion of HIV in female genital secretions,[79,80] which can be reduced by effective antimicrobial therapy.[80] HIV excretion in women is also influenced by hormones, and oral contraceptives may have a highly significant effect.[81,82] Medroxyprogesterone acetate (Depo-Provera) use by commercial sex workers in Kenya resulted in an increased risk of HIV acquisition in a multivariate analysis. In addition, use of oral contraceptives was associated with an increased relative risk of HIV acquisition that did not reach statistical significance in a multivariate analysis.[83] Hormones can also increase susceptibility. Using macaques, Sodora and coworkers[43] demonstrated a considerable increase in susceptibility to SIV in animals treated with progesterone, albeit in doses and a schedule inconsistent with contraception. Conversely, estrogen therapy reduces the likelihood of vaginal acquisition of SIV.[84] Two studies have examined the relationship between the presence of STDs and cells that are receptive to HIV infection. Using cervicovaginal lavage, Levine and coworkers[74] found an increase in CD4+ lymphocytes in women with a variety of STDs. Patterson and colleagues[40] noted increased concentration of CCR-5 messenger RNA in endocervical biopsy specimens harvested from women with STDs. As indicated above, women with bacterial vaginosis are at greatly increased risk of acquisition of HIV. Bacterial vaginosis cannot be readily reversed with antibacterial therapy in women in developing countries.[83] Intervention Strategies As indicated above, sexual transmission of HIV has been described in a mathematical model as Ro = beta x C x delta:, where beta is efficiency of transmission, C is partner change rate, and delta is duration of infectiousness.[8] When Ro exceeds 1, new secondary cases of HIV occur, so successful prevention strategies must reduce Ro to less than 1. To accomplish this goal, prevention strategies should include overlapping behavioral and biological approaches. Behavioral interventions aim to lower the rate of partner change (or to reduce the number of partners with whom risk behaviors take place), and biological interventions aim to reduce the efficiency of transmission or to shorten the duration of infectiousness. Comprehensive HIV prevention strategies are now multisectoral and are aimed not only at individuals but at families, communities, institutions, and the contextual barriers to behavior change.[85-90] Approaches have been broadened to address the social, political, infrastructural, and environmental factors that influence risk behaviors.[89,90] Behavior Change Interventions Perhaps the most difficult area of STD/HIV prevention lies in the area of behavior change. Behavior change is certainly difficult to inspire and extremely hard to measure. Furthermore, the theoretical basis for behavior change has been difficult to characterize. Challenges in behavior change programs include (1) the most effective way to measure intermediate stages of change to assess a program's effectiveness and (2) how to sustain behavior change. A comprehensive behavior change intervention strategy must be designed to address specific target groups in which HIV is being transmitted,[90] to take account of the stage and the progress of the epidemic, and to combine an array of media and interpersonal methods. In addition, behavior changes at the societal level are essential.[89] Given these limitations, the kinds of behavior changes desired are obvious. Such changes are intended to reduce acquisition HIV infection by promoting the following: * sexual abstinence * delayed sexual debut * sexual monogamy * correct and consistent condom use * avoidance of injection drug use or safe drug-injecting habits * health-seeking behavior for rapid treatment of sexually transmitted infections Methods used to inspire behavior change range from intensive education aimed at individuals to mass advertising as offered on commercial television. Behavior change interventions generally draw on contemporary marketing principles such as the following: 1. audience segmentation based on variables such as age, sex, attitudes, and values 2. audience research 3. concept development and pretesting 4. multiple message development to target various segments of the audience 5. design of messages that offer benefits meaningful to the audience, ensuring accessibility to needed services or products.[91] Behavior change has been documented in high-risk individuals both in the United States and in developing countries.[92,93] It is clear that as early as the mid-1980s, before the initiation of large-scale public education campaigns, gay men enrolled in cohort studies modified their sexual behavior in response to growing awareness of the existence of AIDS and education campaigns mounted by gay community-based groups. However, only more recently have different types of prevention intervention been rigorously evaluated in properly controlled settings, which have begun to shed light on the type and frequency of interventions required. Examples of controlled studies of prevention interventions include the following: Project Respect. follow-up study is now under way. San Antonio study. Investigators in San Antonio, Texas, enrolled 617 Mexican American and black women in a randomized study comparing 3 small-group behavioral-cognitive interventions vs standard counseling about STDs. Rates of chlamydial and gonorrheal infections were significantly lower in the intervention group at 6 and 12 months.[93] Project Light. This randomized controlled trial compared a 1-hour education session with a 7-session program focused on attitudes about safer sex, skills building, and risk reduction strategies and enrolled 3706 people at 37 STD or primary care clinics across the United States. During 1-year follow-up, participants who received the 7-session intervention reported less unprotected sex, increased condom use, and more consistent condom use.[94] The HEROES Project. An alternative strategy for producing individual behavior change is to attempt to influence group norms. Kelly and colleagues[95] evaluated this type of HIV prevention intervention in 3 different cities in sequence. Popular trendsetters who frequented gay bars and clubs were trained in peer education techniques and contracted to communicate risk reduction recommendations and endorsements to their friends and acquaintances. In each of the cities, the incidence of unprotected anal intercourse after intervention decreased by 15% to 29% compared with baseline levels. Successes in developing countries such as Thailand and Uganda deserve special attention and are discussed in the context of condom use below. Prevention Initiatives for HIV-Infected Individuals Ever since the recognition that AIDS is caused by HIV infection, HIV prevention initiatives developed by public health agencies in the United States have focused almost entirely on encouraging "harm reduction" behavior in HIV-negative risk groups or the entire US population. While this is an important objective, prevention services for HIV-infected individuals are also essential.[96] At the beginning of the epidemic, diagnosis of HIV infection resulted in intense stigma with virtually no personal medical benefit. However, with the availability of effective, life-saving treatment it makes perfect sense to try to detect virtually all HIV-infected people, so that provision of treatment could be combined with strategies to prevent further transmission. Furthermore, as discussed in this review, most experts believe that treatment with highly active antiretroviral regimens reduces an individual's infectivity, decreasing the probability of HIV transmission. Recognizing the importance of this approach, in February 2001 the US Centers for Disease Control and Prevention (CDC) launched a new prevention strategy called Serostatus Approach to Fighting the HIV Epidemic (SAFE). This project has 5 goals: * To create an environment in which people know their HIV status. A variety of studies suggest that people who know their status are more likely to engage in safer sex behavior. To achieve this goal, the CDC is launching a campaign entitled "Know Now" which will use radio ads in HIV high-transmission areas to inspire voluntary testing. * People with newly diagnosed HIV infection will need to be provided easy access to healthcare. Some studies have demonstrated a long lag time between recognition of infection and appropriate healthcare. * HIV-infected subjects need to be provided with appropriate therapy at reasonable cost. * Adherence to therapy must be emphasized. * Safer sex behavior in this population must be achieved and sustained. The CDC estimates that perhaps 200,000-300,000 HIV-infected people are unaware of their status, and an equal number of HIV-infected people remain untreated. In addition, there are 40,000 new (incident) cases of HIV each year in the United States. The CDC hopes to increase the percentage of infected people who know their status to 90%, and to reduce incident cases by 50% by 2005. The CDC plans to garner $300 million for this program from its own resources and through collaborative partnerships with other governmental agencies. Sadly, these resources will likely fall far short of what is required for success. In addition, the program may not sufficiently emphasize the critical importance of healthcare workers in the private sector. More than 90% of prescriptions for HIV drugs are written by only 2000 doctors. These doctors have no incentive to participate in HIV prevention programs, nor have they received any training for this purpose. Indeed, there are almost no data to inform the best approach for prevention in HIV-infected people. Conversely, there are compelling data to show that HIV-infected people often continue to engage in unprotected intercourse, putting their partners at grave risk. The latter issues were addressed extensively in a CDC-supported report[97] by the Institute of Medicine designed as a comprehensive blueprint for HIV prevention. An entire chapter of this report is devoted to prevention of transmission from HIV-infected people, with considerable emphasis on strategies to draw in, re-educate, and compensate treatment providers from the private sector. The latter approach may ultimately be most critically important to the success of SAFE. Focusing on HIV-infected individuals can have a dramatic effect on the epidemic but should be pursued within an ethical framework that respects both the rights and responsibilities of infected individuals. Cuba appears to have avoided an HIV epidemic, at least temporarily, through mass screening and quarantine and re-education of HIV-infected individuals, an approach used by other totalitarian countries to control STDs.[98] Obstacles to Individual Behavior Change Although considerable progress has been made in this arena, population level factors may ultimately prove limiting both in the United States and abroad. Studying sexual behavior in black women, Adimora and coworkers[99] proposed that risky sexual behavior among this population is largely secondary to the unavailability of appropriate male sexual partners. The disproportionate number of black men incarcerated and the low birth rate and high death rate in this community essentially force women to share men. Change in individual behavior becomes a less effective intervention in this setting. In developing countries already ravaged by HIV, another problem surfaces. HIV prevention strategies are incompatible with conceiving children, and the high prevalence of HIV means that transmission commonly occurs as a direct result of attempts toward reproduction. In this context, the availability of therapy to reduce vertical transmission of HIV is also a critical health consideration but one destined to increase the number of "AIDS orphans" already so visible throughout sub-Saharan Africa. Improving the Availability and Use of Condoms The effectiveness of condoms in preventing many STDs has been well established.[100] The ability of condoms to prevent HIV transmission has also been extensively evaluated. Ten cohort studies conducted among high-risk populations in 7 countries, in which both the level of condom use (HIV exposure) and HIV incidence (outcome) were prospectively measured, have shown that consistent use of condoms by men reduces HIV acquisition by between 50% and 100%.[101] Two studies involving HIV-discordant couples were compelling. In a study of serodiscordant couples in Europe, none of the 123 HIV-negative partners who prospectively reported consistent condom use became infected.[102] In Haiti, only 1 of 42 seronegative partners who consistently used condoms with their seropositive partners became infected.[103] Among HIV-discordant couples who either used condoms inconsistently or did not use them at all, between 7% and 14% became infected. Targeting condom use to populations where HIV is spreading rapidly can have a marked impact. The 100 Percent Condom Program in Thailand is a remarkable success story. In 1991, the Thai government implemented a national strategy to encourage condom use in commercial sex facilities. The proportion of commercial sex acts in Thailand where condoms were used increased from 25% in 1989 to 94% in 1995. During the same interval, the incidence of curable STDs reported to the government clinics decreased dramatically, as did HIV prevalence among Thai military recruits.[104] In the United States, Nevada brothels that have instituted similar policies have not had a single reported case of HIV transmission during the epidemic in this country.[105] The latex condom for men is available in many countries through private pharmacies, maternal and child health and family planning clinics, STD services, community-based distribution systems linked with peer education programs, and condom social marketing initiatives. The latter have been extremely successful in vastly improving access to condoms by making them available to consumers at an affordable, usually subsidized price and in convenient, nontraditional outlets, such as bars, taxis, and hotels. For example, condom sales in Ethiopia increased from 300,000 in 1990 to 19.8 million in 1995, with more than 90% of the condoms sold in nontraditional outlets. Moreover, the aggressive promotion of condoms in condom social marketing programs makes them more acceptable. Social marketing approaches are also being used to increase use of STD treatment and prevention services.[106] Although the latex condom for men is a key element in HIV prevention programs, it can only be used at the discretion of the male partner. "Female condoms" for women are now available in some countries. Their efficacy against HIV transmission has not been proven. The female condom for women is currently expensive (several times the cost of a latex condom for men) and can only be used once. The high cost and issues of acceptability have limited its use. However, in a group of 99 high-risk couples in Zambia who were counseled and given supplies of female condoms, spermicides, and male condoms, during 1-year follow-up the female condom continued to be used by most couples and was used in about one quarter of the coital acts.[107] Increasing Health-Seeking Behavior In addition to reduced partner change and condom use, a third component of desirable behavior change is improved health-seeking behavior. This is considered likely to affect the rate of sexual HIV transmission, because people exposed to HIV may be at increased risk of infection if they have an untreated STD or other cause of inflammation[26] and because people with HIV may transmit the virus more efficiently if they have an STD. Cost-effectiveness analysis is necessary to determine which STDs deserve the most attention, given limited resources.[108] In many cases, currently available research results are insufficient to enable us to reach firm conclusions. Biological HIV Prevention Strategies: Reducing Infectiousness, Susceptibility, and the Efficiency of Transmission Biological interventions to prevent sexual transmission of HIV include interventions to reduce susceptibility (eg, vaccines, topical microbicides) and infectiousness and/or susceptibility (eg, elimination of transmission cofactors, use of antiretroviral therapy). Vaccines Vaccines are clearly the most cost-effective way to prevent transmission of infectious diseases. Development of vaccines is particularly important for STDs, since change in sexual behavior is so difficult to accomplish and document.[109] Unfortunately, vaccine development is time-consuming and expensive. An ideal vaccine for HIV would work by increasing immunity of the susceptible host to prevent mucosal or systemic infection (primary prevention). Even a vaccine that did not completely protect against infection but that did provide enough immunity to reduce the initial viral burden (secondary prevention) could make a significant contribution to limiting the epidemic by making transmission to the next sexual partner less likely. Conversely, there is concern that a vaccine that is less than 100% effective could increase overall rates of HIV transmission if it resulted in an increase in risk-taking behavior.[110] Such a vaccine might also increase the incidence of classic STDs. Work on developing a vaccine against HIV began as soon as the pathogen was identified, but it has proved a daunting task because of the variability of the virus and our limited understanding of the immune responses required to prevent infection. Also, vaccines have been generated using antigens derived from viral strains in blood, which are not always the same as antigens recovered in semen.[111] Vaccine efforts to date have focused primarily on the clade B virus represented in the United States and Western Europe, whereas other viral clades (especially clades A, E, and C) predominate in the epicenters. It will take a considerable time to complete studies of clade B vaccines in the United States because of the low prevalence and limited transmission of HIV in that country. Accordingly, trials of vaccines against clade B and other clades will also be conducted in Uganda, Thailand, and other developing countries. Vaccines generally include critical viral immunogens (ie, pieces of the HIV envelope, gag, or other proteins) delivered directly with an adjuvant or by means of genes inserted in a live viral vector to improve the immune response.[112] Several novel approaches, such as DNA vaccines and alternative vectors and adjuvants, are also being evaluated. The appropriate immunological milestone required to justify full-scale effectiveness trials is not known, since a protective immune response has not been documented -- the work of Clerici's group and others notwithstanding.[66] Nevertheless, cytotoxic lymphocyte responses and serum neutralizing antibody responses have been carefully studied in vaccine recipients and have been selected de facto as surrogates of immunity. There is little evidence to support a role for immunoglobulin G antibody-mediated protection from HIV. Also, the cytotoxic lymphocyte response being measured is extremely difficult to quantitate and has limited duration in vaccine recipients. Prevention of sexual HIV acquisition must depend on immune defenses present at mucosal surfaces. However, clinical HIV vaccine development to date has focused almost entirely on systemic immune responses after inoculation. In large part, this disconnection between the research being undertaken and the data we actually need may be due to the extreme complexity of studying mucosal immunity. Collection of specimens is difficult, and the samples acquired are always limited. In addition, few vaccinologists or immunologists have expressed interest in mucosal immunity. Despite the enormous interest and investment in an HIV vaccine, the study of mucosal immunity remains in its infancy. Topical Microbicides As noted in the earlier discussion of condoms for women, there is a critical need for products that could be used by women to protect themselves from STDs and HIV. Such products must be active against a range of sexually transmitted pathogens, have very few toxic effects, allow reproductive function, and be acceptable for sexual behavior. Idealistically, such products would be biodiffusable and bioadhesive and have long duration of effect. In addition, such products should leave vaginal flora unchanged. They must not be absorbed systemically, and they must be able to be maintained at room temperature so that no special storage is required. Currently, the only topical microbicide in widespread use is nonoxynol-9 (N-9), and its use is now contraindicated, as discussed below. However, a variety of products in different categories are in development. These products include the following: * other detergents in various formulations * polymers that are designed to block HIV attachment * compounds that would be expected to change the pH of the vaginal fluids * antiretroviral agents * suppositories designed to increase the concentration of hydrogen peroxide-producing lactobacilli in the vagina, in the belief that such bacteria contribute to innate resistance to HIV and other STD pathogens N-9 is the most well-studied product for the prevention of acquisition of HIV and other STDs. This compound was developed as a spermicide without consideration of its effects on vaginal flora or disease acquisition. Randomized controlled trials have compared 3 different N-9 products: a gel,[113,114] a sponge,[115] and a film.[116] These studies have shown that N-9 slightly reduces the risk of gonorrhea or chlamydial infections. In 2 studies that looked at HIV acquisition, one found a trend toward increased HIV transmission with increased frequency of genital ulcers and vulvitis,[115] whereas the other found no effect on the rate of acquisition of HIV but again, an increased rate of genital lesions.[116] The controversy over the use of N-9 controversy was effectively ended at the XIII International AIDS Conference in Durban, South Africa, in July 2000. Lut van Damme[118] reported that in a multicenter trial women using an N-9 gel had a higher rate of HIV acquisition than women using a placebo gel. Exposed women were also more likely to have vaginal inflammation. No protection from STDs was observed. Work from Hoffman and colleagues[119] further confirmed that inflammation is observed with frequent use of N-9. The van Damme study[118] can be criticized for loss to follow-up and the lack of a true, third-arm control group using no topical application (to address the possibility that the placebo gel had an effect). However, the results suggest that inflammation caused by detergents applied frequently may offset any antiviral benefit observed in vitro. There are other special problems encountered in trials of topical microbicides. First, the use of a placebo is a challenge if the preservative(s) present in the placebo could affect the vaginal flora. Second, condom use, which must be recommended to all subjects, complicates interpretation. Third, product use is difficult to record. Finally, men are exposed to these products without informed consent. These limitations notwithstanding, the need for a topical microbicide is evident, and ongoing or planned trials are likely to generate important results. Treatment of Cofactors That Facilitate Transmission The concentration of HIV in the genital tract is increased by vitamin A deficiency,[117,120] high-dose oral contraceptives,[117] and classic STDs.[73,79,121] In addition, STDs probably increase susceptibility to HIV by reducing mucosal resistance to HIV and recruiting cells that are receptive to infection with HIV to the genital mucosa.[40,74] Recent studies suggest that the changes in the vaginal flora that characterize bacterial vaginosis also increase women's susceptibility to acquiring HIV.[64,65] Several studies have demonstrated that treatment of STDs reduces excretion of HIV.[117] Syndromic algorithmic treatment of STDs in Tanzania reduced incident cases of HIV by 42%,[122] an extremely cost-effective approach to HIV prevention.[123] In Wellcome, South Africa, monthly use of azithromycin by sex workers serving a mining community led to lower levels of gonorrhea and Chlamydia in both the sex workers themselves and their male clients.[124] In rural Uganda, mass therapy administered every 9 months to community-based sociosexual networks decreased the incidence of gonorrhea, syphilis, and trichomoniasis[83]; however, HIV transmission was not reduced. The difference between the studies in Uganda and Tanzania may reflect the enrollment of different populations with different STDs.[125] In addition, the study in Tanzania focused on treatment of symptomatic STDs, which may be of greatest importance in HIV transmission. These concerns notwithstanding, it is hard to argue against detection of treatment of STDs, which cannot help but benefit reproductive health. Circumcision Some classical STD pathogens such as gonorrhea and chlamydia infect the anterior urethra, whereas those that cause ulcers (eg, syphilis) infect the shaft or the mucosa of the glans penis. Two lines of evidence suggest that HIV might be transmitted to men in the same way as pathogens that cause ulcers: (1) men with genital ulcers appear to have an increased susceptibility to HIV infection,[26] and (2) dendritic cells receptive to HIV can be found in the mucosal surface of the glans.[126] When men are circumcised, the mucosal tissue of the glans keratinizes and evolves into stratified squamous epithelium, which would be expected to be more resistant to STD pathogens. The foreskin itself may represent an important route by which HIV can gain access to the body. Bailey and coworkers[127] have shown that the foreskin contains a variety of the cellular elements potentially important for HIV acquisition and can be successfully infected with HIV in vitro. Langerhans cells represent 4.7% of foreskin cells and express both the CD4 and the CCR5 receptors required for HIV acquisition. An entire session of the XIII International AIDS conference in Durban, South Africa, in July 2000 was devoted to discussion of circumcision to prevent acquisition of HIV. Evidence of the benefit of circumcision was provided by Buve and coworkers.[128] They reported on a community-based, cross-sectional study comparing African communities with high and low HIV prevalence. Two thousand people were studied in each of 4 towns. Subjects were interviewed, examined, and tested for STD pathogens and HIV. The investigators found that in Yaounde, Cameroon, and Cotonou, Benin, the prevalence of HIV was 3.8% and 4.4%, respectively. Ninety-nine percent of the men studied were circumcised. Conversely, in Kisumu, Kenya, and Ndola, Zambia, where the HIV prevalence was 21.9% and 25.9%, respectively, only 26.8% (Kisumu) and 7.6% (Ndola) of men were circumcised. Statistical analysis, including adjustment for sexual behavior, marital status, ethnic group, herpes simplex virus-2 antibodies, and syphilis, demonstrated that circumcision appeared to provide significant protection from HIV acquisition. The authors concluded that at least some of the regional variation in HIV prevalence in Africa could be ascribed to circumcision, and that this procedure might be introduced as an HIV prevention measure. Using a very different study design, Gray and coworkers[129] also reported on the protective effects of circumcision. These investigators studied HIV acquisition in a cohort of 5507 men in rural Uganda. Of the men in the study, 16.5% were circumcised. Ninety-nine percent of the circumcised men were Muslims; 3.7% of non-Muslims were circumcised. Circumcision was associated with a significant decrease in acquisition of HIV in the cohort. Because Muslim and non-Muslim men may engage in very different sexual behaviors, the study results must be interpreted with caution. The time of circumcision was important because protection was observed only in men who were circumcised before puberty. A total of 187 HIV-negative men were in sexual partnerships with HIV-infected women. In the discordant couples, none of 50 circumcised men acquired HIV from his female partner. HIV was acquired in the uncircumcised men at a rate of 16.7 per 100 patient-years. Controlled trials to evaluate the benefit of circumcision may be necessary. In preparation for such trials, Taljaard and coworkers[130] evaluated social factors affecting the likelihood of circumcision in a community in South Africa. The data emphasize the wide variation in circumcision and the reasons for circumcision in different tribal groups. Some groups use circumcision as part of a ritual of manhood, perhaps too late to offer protection from HIV. The potential health benefits of circumcision were also widely appreciated by respondents in this study. In preparation for an intervention trial, acceptance of circumcision was studied in the Nyanza Province in Kenya, where circumcision is not traditionally practiced. Bailey and colleagues[131] interviewed 106 men, 110 women, and 45 clinicians. The results strongly suggest that this community would accept circumcision. Most respondents thought the procedure should be performed on boys at 8.6 years (range, 1-22 years). This group now intends to conduct a randomized, controlled trial of circumcision in Kenya. The study will compare HIV acquisition rates in 1000 control subjects who will remain uncircumcised with those of 1000 subjects who will be circumcised as part of the study. The investigators estimate that a study of this size will demonstrate the benefits of the approach within 2 years. The study will enroll men over 18 years of age, which represents a potential limitation because some investigators have indicated that circumcision has its greatest impact on rates of HIV acquisition when performed before puberty. The study will also determine the costs, limitations, and complications of circumcision in a resource-poor setting. These latter factors have been a source of concern to many authors,[70,71,132] especially with regard to circumcision of adults. It will be important for these costs to be compared with the benefits expected. Developing an infrastructure and public and governmental support for routine circumcision in infants, children, or adults would be no small undertaking, and the benefit (ie, protection from HIV) would not be realized for years or decades. This being said, many countries suffering from an HIV epidemic (or threatened epidemic) that is likely to continue for decades would do well to consider this intervention now. Antiretroviral Therapy and HIV Transmission As discussed earlier, it is increasingly clear that the concentration of HIV in genital secretions helps to determine the efficiency of transmission. There are 2 ways that antiretroviral drugs may be used to prevent transmission: * First, use of effective antiretroviral therapy by index cases typically results in a reduction in HIV in blood, semen, and, possibly, vaginal secretions and thus may be expected to reduce infectivity. In a retrospective study, Musicco and coworkers[133] reported that when index cases were receiving the antiretroviral drug zidovudine transmission to exposed partners was reduced. However, the ability of antiretroviral drugs to reduce sexual transmission of HIV has not been demonstrated prospectively. * Second, antiretroviral agents can be given to uninfected people as pre-exposure or postexposure prophylaxis. However, there are no data on the efficacy of these strategies in preventing sexual HIV transmission in humans. Availability of antiretroviral therapy for prevention could lead to increased risk-taking behavior in both HIV-positive and HIV-negative individuals. There have been a number of anecdotal reports suggestive of such increased risk taking among gay and bisexual men. Several studies examining this possibility are in progress. Antiretroviral Drugs to Reduce Infectiousness The benefits of antiretroviral drugs for HIV-infected patients have been extremely well documented. Potent combinations, including nucleoside analogue reverse transcriptase inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs) and protease inhibitors, can be expected to drastically reduce the viral burden in semen and blood. However, as described earlier, differences between HIV isolates from genital secretions compared with blood strongly suggest that virus in the genital tract resides in a unique compartment. The male ejaculate is composed of secretions from testes (10%), the seminal vesicles (50%-70%), and the prostate (20%-30%). Secretions from the urethra, epididymis, and ampulla contribute 10% to the overall ejaculate volume. The exact mechanisms for distribution of drugs into these secretions are not known. It seems most likely that the boundary between the blood and semen is a lipid barrier and that most drugs will enter into the secretions by passive diffusion. Physical chemical properties likely to regulate the rate at which compounds passively diffuse from blood into semen include the dissociation constant, partition coefficient, and plasma protein binding. Table 2 summarizes these parameters for existing antiretroviral drugs and the predicted concentrations of antiretroviral drugs in different seminal secretions based on available data. In addition, active transport of compounds into genital secretions is possible, as mediated by adenosine 5'-triphosphate-dependent p-glycoprotein transporters. The effects of p-glycoprotein transporters on the concentrations of HIV in genital secretions is not known. Table 2. Physicochemical and Pharmacokinetic Parameters of Representative Antiretroviral Agents Potentially Influencing Seminal-Compartment Distribution Drug pKa Lipid solubility (partition coefficient) Time to C max a (h) Elimination half-life in serum (h) Protein binding (%) Nucleoside reverse transcriptase inhibitors Zidovudine Lamivudine Didanosine Zalcitabine Stavudine Abacavir 9.7 4.3 9.1 4.4 10.0 0.4, 5.1 Slightly lipophilic (1.15) Hydrophilic (NA b ) Slightly lipophilic (NA) Hydrophilic (0.04) Hydrophilic (NA) Lipophilic (NA) 0.6-0.8 1-1.5 0.5-4.6 0.5-2 3.8 0.7-1.7 0.6-1.7 3-5 0.6-2.9 1-3 1-1.5 0.9-1.7 20-38 10-50 < 5 < 4 Negligible 50 Nonnucleoside reverse transcriptase inhibitors Nevirapine Delavirdine Efavirenz 2.8 4.3-4.6 10.2 Slightly lipophilic (1.8) Slightly lipophilic (2.98) Lipophilic (NA) 4 1 2-5 25-30 4.4-11 40-52 c 60 98 99.5 Protease inhibitors Ritonavir Saquinavir Indinavir Nelfinavir Amprenavir 2.8 1.1, 7.1 6.2 6.0, 11.1 1.9 Lipophilic (4) Lipophilic (NA) Hydrophilic (NA) Lipophilic (NA) 2-4 NA 0.5-1.1 2-4 1.2 3-5 6 1-3 3.5-5 7-10 98 > 98 60 99 95 a C max, maximum concentration of drug in serum. b NA, not available. c At steady state. Kashuba AD, Dyer JR, Kramer LM, Raasch RH, Eron JJ, Cohen MS. Antiretroviral-drug concentrations in semen: implications for sexual transmission of human immunodeficiency virus type 1. Antimicrob Agents Chemother. 1999;43:1817-1826. Copyright 1999. American Society for Microbiology. All rights reserved. Only a limited number of studies have been undertaken to determine the actual concentrations of antiretroviral drugs in semen (reviewed in the paper by Kashuba and associates[44]). Henry and colleagues[134] studied 6 men who received 800 to 1200 mg of zidovudine per day. The ratio of semen concentrations of zidovudine to serum concentrations ranged from 1.3 to 20.4, demonstrating that zidovudine is concentrated in male genital secretions. These results suggest that there may be active transport or trapping of zidovudine in the male reproductive tract and that the theoretical calculations in Table 2 may be inaccurate. We studied 71 semen and plasma samples collected from 9 men during the first 200 days of antiretroviral therapy. The blood-plasma ratio of zidovudine was 5.9 (25th to 74th percentile, 0.95-15.5). For lamivudine, the blood-semen ratio was 9.1 (2.3-16.1).[135] More recently, ritonavir and saquinavir have been studied. These agents appear to achieve very low concentrations in seminal plasma.[136] Amprenavir and indinavir appear to penetrate into the male genital tract, and indinavir concentrations were enhanced by ritonavir.[137,138] The poor penetration of some protease inhibitors into seminal plasma might be ascribed to high levels of protein binding or other factors that remain unknown. Kim and colleagues[139] conducted a detailed study of the penetration of efavirenz into semen. Blood and semen samples from 14 men were collected 6 times during a 24-hour period postdose. Efavirenz achieved 2-fold higher concentrations in seminal plasma than in blood. The blood plasma area under the curve (AUC) was predictive of the seminal plasma AUC, and AUC measurements were more reliable than random ratios. For the NRTIs, the critical parameter is the intracellular level of the active metabolite, after appropriate phosphorylation. Although the positive effects of antiretrovirals in genital secretions (see below) would strongly suggest that phosphorylated products are available, phosphorylation in seminal cells has not been directly measured. Indeed, by examining this question it might be possible to determine whether antiretroviral drugs are inhibiting HIV in the semen itself or before it ever gets into the semen. To date, 16 studies on the effects of antiretroviral drugs on HIV in semen have been published (Table 3). When the most potent combinations of drugs were used, HIV-1 could only rarely be detected in seminal plasma. However, 2 studies demonstrated that HIV-1 DNA can be recovered from seminal cells despite suppression of HIV-1 RNA in blood and seminal plasma[45,46]; in one study, infectious virus was recovered from the seminal cells of some men who had prolonged HIV-1 suppression with therapy.[46] Table 3. Summary of Published Studies Evaluating the Effects of Antiviral Therapy on HIV-1 Shedding in Semen a Reference [yr] n Study type Drug therapy and no. of subjects Anderson et al. [1992] 95 Cross-sectional None, 64; AZT, 31 14 Longitudinal (5-8 mo) None, 9; AZT, 5 Delwart et al. [1998] 5 Cross-sectional None, 2; AZT, 2; AZT + ddI, 1 Eron et al. [1998] 11 (5 ARV naïve, 6 NA experienced) Longitudinal (8-58 wk) Naïve patients, single or dual NA or NA PI; experienced patients, 2 NAs + 1 PI Gilliam et al. [1997] 11 on newly initiated therapy, 11 on stable therapy Longitudinal (up to 90 wk in the new TX group, up to 26 wk in the stable TX group) New TX; AZT or ddI ± DLV; stable TX; no TX, 6; mono-TX, 1; combination TX, 4 Gupta et al. [1997] 6 Longitudinal (0-28 wk) IND ± efavirenz Hamed et al. 36 Cross-sectional ART naïve, 9; AZT, 19; ddl, 4; AZT + ddl, 4 6 Longitudinal (8 wk after TX initiation) AZT or ddl, AZT + ddl, or AZT + ddC Krieger et al. [1991] 34 Cross-sectional None, 30; AZT, 22 Krieger et al. [1995] 56 Mixed (single samples from 22 subjects; multiple samples from 34 subjects) None, 8; AZT or ddI, 30; AZT + ddC 2, unknown, 16 Kroodsma et al. [1994] 16 Cross-sectional AZT, 7; ddI, 6; AZT + ddI, 3 Musicco et al. [1994] 436 couples (HIV-1-infected men and their monogamous seronegative female sexual partners) Cohort (740 person-year follow-up) AZT, 64 Vernazza et al. [1997] 101 Cross-sectional ARV-naïve, 53; 1 or 2 NAs, 29; no therapy, 19 discontinued Vernazza et al. [1997] 4 (19 TX naïve, 25 experienced) Longitudinal (0-10 wk) AZT, 1; IND, 1; AZT + 3TC, 5; 2 NAs + PI, 16; 1 or 2 NAs ± SQV or DLV, 21 Vernazza et al. [1999] 114 cases, 55 historical controls Case control Cases: 2 NAs PI, 97; 2 NAs, 16; ddI + HU, 1; controls; drug naïve Zhang et al. [1998] 7 Cross-sectional 2 NAs + PI for 5-41 mo prior to study Table 3 (continued) Reference [yr] STD screening HIV-1 detection Results Anderson et al. [1992] Yes Microculture Median AZT concn 0.004 (0-0.019) ng/ml; AZT associated with a decrease in detection of seminal HIV-1 (adjusted OR, 0.04; 95% CI, 0-0.63) Yes Microculture HIV-1 detected in 43% of men without AZT TX and in 0% of men with AZT TX Delwart et al. [1998] Unknown HIV-1 RNA sequence analyses by nested PCR Distinct variant populations in BP and SP in 3/5 subjects; no semen-specific signature amino acid sequence detected Eron et al. [1998] Yes HIV-1 RNA by NASBA, HIV-1 RNA sequence analysis by Affymetrix Median BP and SP HIV-1 RNA levels before TX, 5.1 and 5.7 log10 copies/ml; median maximal change in BP and SP HIV-1 RNA levels with TX, -0.95 and -1.41 log10 copies/ml; baseline SP RT resistance mutations in 3/6 NA-experienced subjects (vs 1/5 for TX-naïve subjects); 8/11 subjects developed resistance mutations during TX (to NAs and PIs in BP; to NAs in SP) Gilliam et al. [1997] Yes Microculture of seminal cells, HIV-1 RNA by NASBA Before TX, 50% seminal-cell culture positive; after TX, 0.1% seminal-cell culture positive; median SP HIV-1 RNA reduction, 1.01 log10 (78% BLQ); in 55%, decrease in SP HIV RNA was > BP HIV RNA decrease; in stable TX group, median SP HIV-1 RNA, 1.45 log10 lower than that in patients on TX (P = 0.05), with less within-subject variability Gupta et al. [1997] Unknown HIV-1 RNA by NASBA SP RNA decreased 5- to 10-fold after 2 wk (n = 3), SP RNA decreased 4- to 150-fold after 4 wk (n = 6), HIV-1 RNA remained undetectable in BP and SP for duration of study Hamed et al. Yes RT-PCR HIV-1 DNA detected in semen in 67% of untreated patients and 78% of treated patients, HIV-1 RNA detected in semen in 44% of untreated patients and 48% of treated patients Yes RT-PCR Before TX, HIV-1 DNA detected in blood in 6/6 patients and in semen in 4/6 and remained stable over 8 wk of TX; before TX, HIV-1 RNA detected in BP 4/6 in patients and in SP of 2/6 patients and decreased to BLQ during 8 wk of TX Krieger et al. [1991] Unknown Mixed-lymphocyte culture method, with HIV p24 antigen detection 16/55 semen samples HIV positive (10 in cellular fraction only, 3 in plasma fraction only, 3 in both fractions); no difference in HIV isolation between TX and no TX (41 vs 23%) or between symptomatic and asymptomatic (28 vs 32%) Krieger et al. [1995] Yes Mixed-lymphocyte culture method, with HIV p24 anigen detection by ELISA 36/215 semen samples HIV positive (24 in cellular fraction only, 5 in plasma fraction only, 7 in both fractions); CD8 + in BP predictive of HIV-1 in semen (OR, 5.0; 95% CI, 1.0-23.9); TX not associated with HIV-1 in semen (OR, 1.7; 95% CI, 0.6-5.1) Kroodsma et al. [1994] Unknown RT-PCR Recovery of HIV-1 RNA, 68% in BP and 44% in SP; 25% of paired semen and blood samples had discordant genotypes (codon 215 or 74) Musicco et al. [1994] Unknown Seroconversion measured by ELISA with Western blot confirmation Incidence rates of seroconversion with and without AZT TX, 4.4 and 3.8, respectively, per 100 person-years; relative risk of sexual transmission of HIV with AZT TX, 0.5 (95% CI, 0.1-0.9) Vernazza et al. [1997] Yes NASBA Seminal HIV lower in treated vs untreated patients (P = 0.03); treatment was an independent inverse predictor of HIV RNA detection (OR, 0.38; P = 0.054) Vernazza et al. [1997] Yes RT-PCR (blood), NASBA (semen), and microculture At baseline, 68% had HIV-1 RNA in SP and 37% had HIV-1 in coculture; at follow-up, 27% had HIV-1 RNA in SP and 12% had HIV-1 in coculture; the 27% with undetectable BP RNA also had undetectable SP RNA and culture Vernazza et al. [1999] Yes HIV-1 RNA by Nuclisens (114 cases, 55 controls) HIV-1 DNA by nested PCR (67 cases, 55 controls) 67% detection frequency of HIV RNA in controls vs 2% in cases (OR, 0.01; 95% CI, 0.0-0.3); 38% detection frequency of HIV DNA in controls vs 16% in cases (OR, 0.32; 95% CI, 0.12-0.80) Zhang et al. [1998] Unknown HIV-1 RNA by RT-PCR, p24 antigen ELISA of mixed-lymphocyte coculture, DNA sequence analysis HIV-1 RNA in BP and SP BLQ; HIV-1 DNA in PBMC of 7/7 and in seminal cells of 4/7; replication-competent HIV-1 in PBMC of 3/7 and in seminal cells of 2/3 (1 macrophage tropic and 1 dual tropism) a Only Anderson et al. 2 in the cross-sectional study measured antiretroviral-drug concentrations, in 19 of 31 patients. BP, blood plasma; SP, seminal plasma; RT, reverse transcriptase; TX, antiretroviral therapy; NA, nucleoside analogue; PI, protease inhibitor; AZT, zidovudine; ddI; didanosine; ddC, zalcitabine; IND, indinavir; SQV, saquinavir; DLV, delavirdine; HU, hydroxyurea; BLQ, below limit of quantitation; STD, sexually transmitted disease; ELISA, enzyme-linked immunosorbent assay; OR, odds ratio; CI, confidence interval; ARV, antiretroviral; NASBA, nucleic acid sequence-based amplification. Kashuba AD, Dyer JR, Kramer LM, Raasch RH, Eron JJ, Cohen MS. Antiretroviral-drug concentrations in semen: implications for sexual transmission of human immunodeficiency virus type 1. Antimicrob Agents Chemother. 1999;43:1817-1826. Copyright 1999. American Society for Microbiology. All rights reserved. In summary, the use of antiretroviral drugs to reduce the concentration of HIV in genital secretions seems to be one important approach to HIV prevention. Quinn and colleagues[140] provided a population model demonstrating the potential benefits; they estimated that if serum viral burden is reduced to less than 3500 copies/mL, HIV transmission will be reduced by 81.4%. Previous studies[45,46] have demonstrated that antiretroviral therapy does indeed reduce blood and semen viral load below this threshold. Considerably more is known about this topic in men than women (although Hart and colleagues[141] recently demonstrated a reduction in HIV RNA in female genital secretion in response to antiretroviral therapy). In addition, there have been no large-scale trials to evaluate the cost-benefit ratio of this approach. Using a mathematical model, Blower and coworkers[142] demonstrated that the benefit of antiretroviral therapy that reduces but does not eliminate transmissibility might be offset by increased risky sexual behavior. Compelling empirical data are not available. Trials to demonstrate a reduced rate of transmission of HIV by patients receiving antiretroviral therapy are limited by the need to enroll discordant couples who must be counseled to avoid HIV transmission by all known routes. The study of this subject in animal models has also been difficult; nevertheless, it is clearly possible to use antiretroviral drugs to reduce the burden of feline immunodeficiency virus in blood and semen in cats, and this model probably holds some promise for study of lentivirus transmission (H. Jordan, unpublished observation, 2000). HIV Transmission and Resistance to Antiretroviral Agents The public health considerations of the use of antiretroviral therapy should certainly receive increasing attention. Drug-resistant viral isolates are clearly fit enough to be transmitted successfully,[143] and a substantial proportion of patients with primary HIV infection have acquired virus that is resistant to 1 or more antiretroviral agents.[144,145] The factors that might be expected to lead to antiretroviral resistance are as follows: * biological (partial penetration of drugs into the genital tract) * behavioral (poor adherence to therapy) * metabolic (poor absorption of drugs or drug interactions that reduce blood plasma concentrations, etc) On account of 1 or more of these factors, HIV in semen may be only partially suppressed by antiretrovirals, and hence drug-resistant isolates are likely to be selected. Although it is standard practice to measure viral burden in blood and to combat the evolution of resistance aggressively, this is not the case in genital secretions. Several small-scale studies have examined this problem. Eron and coworkers[143] have recently examined blood and semen viral isolates from men undergoing antiretroviral therapy and demonstrated emergence of resistance in both compartments that was not always concordant (see below). Mayer and colleagues[146] and Byrn and associates[147] have made similar observations. Eron and colleagues[143] studied 11 patients in whom potent antiretroviral therapy failed to suppress HIV in blood plasma. Variants resistant to NRTIs evolved in both blood and semen, although in these subjects some differences in evolution of resistance variants were noted between the blood and the semen. Interestingly, although several patients were taking protease inhibitors and protease inhibitor resistance mutations evolved in blood, such mutations were not detected in semen, supporting the idea that the protease inhibitors may not achieve adequate concentrations in the genital tract to provide selective pressure for the evolution of resistance.[143] However, other groups have now reported evolution in semen of HIV-1 variants with resistance to certain protease inhibitors.[148] In addition, the ability of protease inhibitors to penetrate into semen is variable.[44,137,138] The recognition of resistant HIV isolates in blood and semen of patients receiving antiretroviral therapy begs the question of the potential role of resistance testing. In many but not all infectious diseases, the choice of therapy is guided by sensitivity testing. Recent data suggest that testing the drug sensitivity of viral isolates from the blood can benefit patient management and response to therapy,[149] albeit at considerable cost. However, since drug resistance may evolve independently in blood and semen, the public health benefits of such testing are unproved. Postexposure Prophylaxis Antiretroviral agents could be given to those at risk before or shortly after exposure to HIV. Work with macaques demonstrates that pre-exposure and early postexposure prophylaxis can work well, depending on the timing and the agent(s) chosen.[150] There is no clinical experience with pre-exposure prophylaxis, although trials among selected commercial sex workers are in the planning stages. Prompt use of antiretroviral drugs after occupational exposure to HIV in health care settings has been associated with a reduced risk of acquiring HIV. In a single, large case-control study, Cardo and colleagues[151] compared acquisition of HIV in 33 health care workers infected by occupational exposure compared with 665 exposed but uninfected controls. The use of zidovudine as postexposure prophylaxis appeared to be protective, with significantly fewer cases than controls having used zidovudine. Galvanized by these findings, several organizations have recommended that subjects exposed to HIV through unprotected intercourse under very specific circumstances might receive postexposure prophylaxis (PEP). Specifically, both the Centers for Disease Control and Prevention and an expert panel recommended that subjects exposed to high-risk patients, especially after rape, should consider using antiretroviral drugs.[152] However, these authorities also recognize the lack of data to support the efficacy of this approach, and it is unclear whether data regarding occupational exposures can be extrapolated to other types of exposure, where the biological mechanisms of transmission may be quite different. Indeed, the only available data on PEP for sexual exposure come from a limited study of the use of drugs in macaques exposed to intravaginal HIV introduced through cell-free virus. The drug PMPA appeared to offer protection when provided either before or even 24 hours after introduction of the virus.[150] On the other hand, some investigators have explored the possibility of more routine use of PEP. In a series of articles, Gerberding and Katz[153,154] investigated the rationale for PEP after nonoccupational exposures and tried to analyze the cost-benefit ratio for the use of such drugs. Unfortunately, although it is possible to estimate the financial cost of the medical intervention, it is not possible to reliably estimate the likelihood that a random sexual partner will be infected with HIV or the likely benefit of PEP in reducing the risk of transmission. Indeed, because the pharmacology of antiretroviral drugs in the genital tract is only poorly understood and because semen can persist in vaginal secretions for a very long period, assumptions cannot be made. Investigators in San Francisco, California, have launched a multicenter program to provide access to counseling, PEP (if appropriate), and HIV antibody testing for individuals reporting recent unsafe sexual or drug-injecting behaviors.[155] However, although data are being gathered on types of risk exposure, uptake of PEP, adherence, drug adverse effects, and longitudinal trends in risk-taking behavior, the study design does not allow assessment of the efficacy of PEP. Currently, it seems very unlikely that a study in the United States could properly evaluate the potential benefit of PEP in subjects exposed to HIV. Accordingly, to try to evaluate this approach, the Centers for Disease Control and Prevention has recently launched a registry to assess PEP after nonoccupational HIV exposure. There is particular interest in the use of PEP following rape. The French government has reportedly legislated that women who survive rape should be offered antiretroviral prophylaxis, along with appropriate counseling services. Benais and coworkers[156] have reported their experience in 5 emergency medicolegal units in Paris that have been in operation since June 1999. A total of 2550 victims of rape were offered triple-drug antiretroviral therapy with stavudine, didanosine, and nelfinavir within 48 hours of the assault, but only 100 subjects were treated. No biochemical toxicities were recognized, but many patients discontinued therapy and 25% failed to return for follow-up. No patient acquired HIV. Another study focused on sexual assault was conducted in San Francisco, California, where PEP has been offered to all victims of rape since April 1998.[157] Subjects who present within 72 hours of potential exposure are offered a 10-day supply of coformulated zidovudine/lamivudine (Combivir) with an additional 18 days of therapy provided in a follow-up visit. A total of 376 patients were evaluated, 3% of whom were found to HIV-positive at baseline, and 213 subjects were offered PEP. Only 32.4% of these subjects chose to initiate therapy, and only 12% returned to complete the course of therapy. White, college-educated males with stable housing and subjects reporting anal penetration were the most likely to initiate prophylaxis. A course of therapy cost $327. The authors concluded that PEP should be offered to all victims of a rape as part of comprehensive counseling. However, it is clear that even when offered therapy, many patients -- even victims of rape -- choose not to accept it, and furthermore, therapy may not be completed by those who do initiate it. Routine use of drugs after sexual exposure is fraught with additional concerns. First, the drugs are expensive. Second, the drugs have substantial toxicity, and the long-term consequences of taking them are not known. Third, one might predict that, in cases where it is unclear whether exposure to HIV has occurred, subjects might be poorly adherent to PEP regimens, and in the rare subject who was exposed, drug resistance might evolve. In summary, it seems unlikely that PEP after unknown sexual exposure will become routine public health policy in the foreseeable future.[158] Postexposure prophylaxis after high risk or known exposure will probably become commonplace, even without definitive supportive data.[159] Conclusion The recognition of HIV as the etiological agent responsible for AIDS quickly led to a serologic test and a misplaced belief that a preventive vaccine would soon follow. However, the search for a vaccine has led to an explosion in knowledge about the behavior and biology of HIV transmission by all routes. This information has informed development of other interventions: safer sex behaviors, condoms, and better treatment of STDs. Alternative biological interventions, including protective microbicides and antiretroviral agents, are progressing rapidly. From this review it should be clear that biomedical and behavioral approaches to HIV prevention are being simultaneously developed. 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Postexposure prophylaxis after nonoccupational HIV exposure: clinical, ethical and policy considerations. JAMA. 1998;280:1769-1773. 159. France D. Emergency treatment to stop AIDS virus. New York Times. October 19, 1999: D7. Appendix: Talking About Safer Sex With Your Patients (Reproduced with permission from a brochure written by Marshall Miller, Kenneth Mayer, MD, and Harvey J. Makadon, MD, published by The Fenway Institute/Fenway Community Health, 7 Haviland Street, Boston, MA 02115. Copyright 1999. The brochure was made possible through a grant from the Kaiser Family Foundation, Putting HIV Prevention Into Clinical Practice, Harvey J. Makadon, MD, Principal Investigator.) Think Prevention Health care providers can play an important role in HIV prevention. Many people consider their doctor the person they most trust to give advice about the issues around health and sexuality. Some health care providers find that the most useful approach to talking about safer sex with their patients is to include it in a broader discussion about all aspects of healthier living. Just as a physician may discuss with his or her patient the importance of exercise or seat belts, or the health benefits of quitting smoking, he or she may discuss ways the patient can reduce the risk for HIV infection. Communicate About Sexuality In our culture, sexuality is rarely talked about in honest, open terms. Given this, few people have experience asking and responding to questions about sex. One way to overcome this barrier is to assess and then speak about sexuality in terms that are familiar and comfortable for the patient. These terms may vary based on the age, race, gender, sexual orientation, and other identities of the patient. If you develop a communication style that works for you both, it will enable you to ask the questions and get the answers you need to provide your patients with appropriate education, support, and referral. Workshops and trainings on this issue are offered at conferences and other locations throughout the country. Build Trust People at risk for HIV are diverse; many have a wide range of sexual experiences. Some may have experienced prejudice or discrimination because of their sexuality. In order to be an effective HIV educator for your patients, it is important to earn their trust. One way to do this is to have brochures, posters, pamphlets and other information in your office that are welcoming to people of all sexual orientations. This serves as positive reinforcement for patients that they will be respected for who they are. Another means of building trust is to not make any assumptions about the type or amount of sex a person is having. Just because a person is married, for example, does not mean that he or she is monogamous or heterosexual. Effective trust-building results in a patient feeling comfortable talking about his or her risks around HIV regardless of sexual orientation or past sexual experience. Communicate the Risks Patients may have questions about the risk of being infected with HIV as a result of engaging in particular sexual activities. For example, a patient might ask, "How risky is oral sex?". Questions like this provide a good opportunity to engage patients in a discussion about what risks they are taking and how to reduce their overall risk for HIV. One way of responding to the oral sex question above is to ask the patient "Riskier than what?". Answering this question helps the patient probe deeper into how they understand the risk of oral sex in the context of their own lives. Oral sex is safer than unprotected vaginal or anal sex Recognize the Links When counseling patients about safer sex, it is important to help patients make connections between their sexual risk-taking and other issues in their lives. Substance use, for example, can put a person at higher risk for HIV. A client concerned about his or her unsafe sex while under the influence of alcohol or other drugs, would need counseling about substance use as well as about safer sex. Other issues, including domestic violence, sex for drugs or money, and sexual assault are opportunities for counseling, support, and referral. The Biology of Safer Sex HIV is present in semen and cervicovaginal secretions, both as cell-free and cell-associated virus. Genital tract secretions may contain millions of particles of HIV, especially in individuals who are acutely infected, who have advanced disease, and who are not receiving antiretroviral therapy. HIV inhabits white blood cells, particularly CD4 lymphocytes, and monocyte-macrophages In some individuals who are asymptomatic, there may be more than a million of these white blood cells in genital secretions. Other sexually transmitted diseases, including gonorrhea, chlamydia, trichomonas, and herpes may increase the number of genital tract white cells and may make HIV infected people more infectious to their partners. Thus, people with HIV infection may range in their level of infectiousness to potential partners. The Impact of Antiretroviral Therapy Antiretroviral therapy usually decreases the amount of HIV in the genital tract as well as the blood. There are individuals, however, who have been shown to have undetectable levels of virus in the blood, and yet have virus found in the genital tract, Therefore individuals cannot assume that because the virus is suppressed in the blood due to therapy, they are not potentially infectious to their partners. There are individuals who have received antiretroviral therapy and have transmitted multi-drug resistant HIV to their partners. Thus, although people taking combination antiretroviral therapy may be less likely to be infectious, they need to be counseled that for any given sex act, they are potentially infectious, and thus should practice safer sex. Susceptibility May Vary Just as the level of infectiousness of HIV may vary, the level of susceptibility to HIV may vary between different groups of people, and the same person has different levels at separate times. Sexually transmitted diseases in HIV uninfected people may enhance susceptibility, either by causing ulcerations in which the mucous members are exposed (eg, herpes), or the enhanced inflammation of infections like gonorrhea or chlamydia, may result in more target cells for HIV to infect. In addition, genital infections result in the production of cytokines, which increase the ability of HIV to multiply at the site of sexual contact. Some individuals may be genetically more resistant to HIV because they lack or have decreased amounts of some of the receptors to which HIV binds in order to enter cells. Other factors that may influence the efficiency of HIV transmission include the absence of circumcision and cervical ectopy. Both the human foreskin and the endocervix contain cells that have increased number of receptors to bind HIV. Hormonal contraception may also increase HIV susceptibility. Sexual practices that increase trauma and/or inflammation in the genital tract, like certain douching products, may also increase risk for HIV transmission. Sexual Practice and Risk Not all sexual practices are equally likely to result in HIV transmission. The most efficient ways are through the rectal mucous membranes, or the cervical vaginal mucosa. These tissues seem to have more receptors to bind HIV, and in the case of the rectal mucous membranes, the tissue is more easily traumatized, leading to more easy access for HIV transmission. Because cervicovaginal secretions contain less HIV on the average than semen, and because the amount of exposed tissue of the male urethra is limited for HIV binding, it is more efficient for men to transmit HIV to women through heterosexual contact than vice-versa. Likewise, it is harder for an insertive partner to acquire HIV through anal intercourse than a receptive partner. As mentioned above, there are many factors that may influence the amount of virus in genital tract secretions and the susceptibility of individuals at risk for HIV to acquire HIV. Therefore, it is impossible to give precise numbers for the individual risks of each sexual act between an infected person and an uninfected person. It is clear from many epidemiological and biological studies, that most HIV transmission between men who have sex with men occurs via unprotected anal intercourse, either to the insertive or receptive partner; and for heterosexuals, most of the contact is through unprotected penile-vaginal intercourse. Well-documented cases of HIV transmission through oral exposure to semen or cervicovaginal secretions have been documented so that fellatio and cunnilingus cannot be considered to be safe practices. However, the relative inefficiency of HIV transmission in the upper digestive system suggests that the likelihood of HIV transmission by the oral route is several logs less likely than penile-vaginal or penile-anal intercourse. For these higher risk practices, the per contact risk of HIV acquisition, ranges from less than 1/1000 to more than 1/10. There is wide biological variability for each behavior, in terms of the amount of risk for each act. Other sexual practices are substantially less likely to transmit HIV. For example, although HIV has been shown to be present in minute quantities in pre-ejaculate, there are documented reports that suggest exposure to pre-ejaculate has resulted in transmission. Other body fluids such as saliva have been shown to contain substances that inhibit HIV transmission, so in the absence of visible blood, there has been no incidence of HIV transmission by kissing. HIV can be transmitted via blood contact, and thus shared sharp objects, piercing, shared sex toys, etc have the potential to transmit HIV. Intimate skin contact, mutual masturbation, and other practices, which do not result in genital secretions coming directly into contact with mucus membranes or abraded skin have not been documented to transmit HIV (ie, the intact skin is a good barrier to HIV transmission). Other practices may not transmit HIV, but may result in other health problems. For example, although anal-oral contact without blood present has not been shown to result in HIV transmission, it can result in the transmission of enteric parasites, and serious bacterial infections, like salmonella. Practices involving other bodily fluids may transmit STDs as well, and need to be evaluated on a case-by-case basis. _____ Author Affiliations and Disclosures Myron S. Cohen, MD Professor of Medicine, Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine; Chief, Division of Infectious Diseases, UNC Hospitals, Chapel Hill, North Carolina Joseph J. Eron, MD Associate Professor of Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill Edward E. Rylander, M.D. Diplomat American Board of Family Practice. Diplomat American Board of Palliative Medicine.