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XIII International AIDS Conference
Myron S. Cohen, MD
HIV is spread from human to human by 3 routes:
Sexual transmission of HIV accounts for more than 75% of infections worldwide.
- blood transmission (contaminated transfusions, needle sharing during drug use, needlestick injuries)
- vertical transmission (mother to offspring during parturition or breast-feeding)
- sexual transmission
Biology of HIV TransmissionThe probability of transmission of HIV by different sexual routes per episode of intercourse was discussed extensively at the XIII International AIDS Conference in Durban, South Africa. Studies of discordant couples in Rakai, Uganda, allowed further calculation of the probability of transmission.[2,3] The transmission rate when serum viral load was less than 3500 copies/mL was estimated at 0.9 per 1000 episodes of intercourse, which increased in a linear fashion to 2.98 per 1000 episodes of intercourse when serum viral load was at or above 50,000 copies/mL. The efficiency of transmission from man to woman and from woman to man was equivalent, despite lower blood viral burden in women.
Clade-Specific Differences in HIV TransmissionThe 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 by Anderson and colleagues) and the susceptibility of the exposed host (reviewed by Vernazza and coworkers).
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.[6,7] In particular, homogeneous viral isolates with envelope sequences that define the slow-growing, macrophage-trophic, non-syncytium-inducing (NSI) phenotype are preferentially transmitted.[8,9]
Moreover, 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 and some other parts of Asia. A variety of clades and a recombinant B-C clade have been identified in 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, Essex 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. However, these results could not be reproduced by other investigators,[13,14] who also emphasized the technical difficulties of this type of study.
Duerr and colleagues presented further 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.
Cofactors That Amplify HIV TransmissionA variety of cofactors appear to amplify HIV transmission, either by increasing the infectiousness of the index case, increasing the susceptibility of the exposed host,[1,16] or both. The most important cofactors are those that cause trauma or inflammation to the genital mucosa. Classical sexually transmitted diseases (STDs) such as 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 classical STDs and HIV is referred to as "epidemiological synergy." Biological studies suggest that STDs may enhance HIV transmission by increasing the concentration of HIV in genital secretions, the number of cells receptive to HIV, or the number of receptors per cell.
More work in this area was presented at the XIII International AIDS Conference. Baeten and colleagues reported that selenium deficiency increases shedding of HIV in the genital tract. An entire session was devoted to the association between STDs and HIV transmission, in which the new presentations continue to confirm the increased risk for HIV transmission ascribed to STDs. Consistent with work from Rakai, Uganda (Gray R, personal communication, 2000), Gwanzura and colleagues 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 of very great importance.
Intervention StrategiesA wide variety of intervention strategies are being pursued, and all were discussed at the XIII International AIDS Conference. It is widely recognized that the strategies must complement one another. The behavior change strategies include safer sex and condoms. Literally scores of presentations addressed these issues, and discussion is beyond the scope of this review. However, it is clear that, while imperfect, this approach to prevention works.
Biological interventions for HIV prevention include vaccines, topical microbicides, use of antiretroviral therapy, and circumcision.
VaccinesVaccines are clearly the most cost-effective way to prevent transmission of infectious diseases. Development of vaccines is particularly important for STDs because change in sexual behavior is so difficult to accomplish and document. 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. Such a vaccine might also increase the incidence of classical STDs.
Work on developing a vaccine against HIV began as soon as the pathogen was identified, but it has proven 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. 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 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.
A plenary session at this meeting was devoted to vaccine development. Vaccine trials are currently being undertaken with HIV envelope proteins, and results will be available within 2 years. Phase I trials with potentially improved vaccine vectors will begin in the near future. There is no way to predict the results of these initial trials. Vaccine trials are clearly essential, but the solid scientific rationale cannot provide any reassurance of eventual success. The movie Contact starring Jodie Foster provides the best metaphor. We are building a giant sphere to be dropped into a hole with little idea of what will happen, and (like in the movie) we are not even sure we will believe the results. But there is no other option.
Topical MicrobicidesThere is a critical need for products that can 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 limited toxicity, allow reproductive function, and be acceptable for sexual behavior. Ideal characteristics of such products would include that they be biodiffusable, 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 the evidence regarding its efficacy is controversial, as discussed below. However, a variety of products in different categories are in development. These products include:
N-9 is the most well-studied and controversial product for the prevention of HIV and other STD infection. 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,[24,25] a film, and sponge. These studies have shown that N-9 may slightly reduce the risk of gonorrhea or chlamydial infections. In 2 studies that looked at N-9's effect on HIV, one found no effect on the rate of acquisition of HIV and an increased rate of genital lesions, while the other showed a trend toward increased HIV transmission, again with increased frequency of genital ulcers and vulvitis.
- 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.
The N-9 controversy will probably end now. Lut van Damme 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 further confirmed that inflammation is observed with frequent use of N-9. The van Damme study 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.
Antiretroviral Therapy to Reduce InfectiousnessThe benefits of antiretroviral drugs to HIV-infected patients have been extremely well documented. Potent combinations, including nucleoside analogue reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs), can be expected to drastically reduce the viral burden in semen as well as in blood. However, differences between HIV isolates from genital secretions compared with blood strongly suggest that virus in the genital tract resides in a unique compartment.
To date, 16 studies on the effects of antiretroviral drugs on HIV in semen have been published. 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;[30,31] in 1 study infectious virus was recovered from the seminal cells of some men who had prolonged HIV-1 suppression with therapy.
In summary, the use of antiretroviral drugs to reduce the concentration of HIV in genital secretions seems to be an important approach to HIV prevention. Considerably more is known about this topic in men than in women. In addition, there have been no large-scale trials to evaluate the cost-benefit ratio of this approach. Such trials are certainly limited by the need to enroll discordant couples who must be counseled to avoid HIV transmission by all known routes.
No studies related to usage of antiretroviral therapy were presented at the Durban meeting. However, Quinn and colleagues provided a population model demonstrating the potential benefits. Quinn predicts that if serum viral burden is reduced to less than 3500 copies/mL, HIV transmission will be reduced by 81.4%. Previous studies[30,31] have demonstrated that antiretroviral therapy reduces blood and semen viral load below this threshold, again endorsing the potential for antiretroviral therapy to prevent sexual transmission of HIV.
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, and a substantial proportion of patients with primary HIV infection have acquired virus that is resistant to 1 or more antiretroviral agents.[34,35] A sobering abstract demonstrated drug resistance in 2 of 8 clade C HIV isolates from KwaZulu-Natal in South Africa. The fact that resistance is observed in this region, where antiretroviral therapy is rarely available, adds a note of caution to this intervention strategy.
Antiretroviral Therapy as Postexposure ProphylaxisTwo lines of evidence suggest that antiretroviral therapy can prevent acquisition of HIV following sexual exposure to an infected individual. First, rhesus macaques given antiretroviral therapy before or considerably after exposure to SIV can be protected from infection, regardless of the route of exposure. Second, a single large study appeared to demonstrate that zidovudine reduced the acquisition of HIV in exposed healthcare workers. However, prevention of HIV acquisition following exposure of a mucosal surface to HIV in genital secretions may require different interventions from those that may be effective following exposure through a needlestick injury.
Two sessions at the XIII International AIDS Conference were devoted to further consideration of postexposure prophylaxis, including 5 papers related to sexual transmission of HIV. None of the papers addressed the ability of a prophylactic regimen to prevent infection, because to date it has been impossible to develop a study design with adequate power to answer this critical question.
The French government has reportedly legislated that women who survive rape should be offered antiretroviral prophylaxis, along with appropriate counseling services. Benaise and coworkers described 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.
A second study was conducted in Rouen, France, by Debab and colleagues. Between June 1995 and December 1999, a total of 248 subjects were studied, 63.6% after occupational exposure and 28.4% after sexual exposure to HIV. The majority of subjects were seen within 24 hours of exposure. Antiretroviral therapy was prescribed to 68.4% of subjects, three quarters of whom received 3 drugs. In 27.6% of cases, therapy was stopped early when the index source proved HIV-negative; of the remainder, 81.9% completed the 28-day course. Adverse events occurred more commonly in people with occupational exposure than sexual exposure. Again, no study subject became infected with HIV.
A study focused on sexual assault was conducted in San Francisco, California, USA, where postexposure prophylaxis has been offered to all victims of rape since April 1998. 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 postexposure prophylaxis. 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 postexposure prophylaxis should be offered to all victims of a rape as part of comprehensive counseling.
Finally, Friedman and colleagues offered postexposure prophylaxis as part of an HIV prevention study among homosexual men in Brazil. The study subjects received a 4-day supply of coformulated zidovudine/lamivudine to be used as chemoprophylaxis immediately after high-risk sexual exposure. Subjects who fulfilled exposure criteria (unprotected vaginal, anal, or oral receptive intercourse within the previous 48 hours) were provided with 24 days of additional therapy. Among the cohort of 202 subjects, 47 individuals initiated postexposure prophylaxis 53 times, although none of the subjects thought postexposure prophylaxis more desirable than condoms. The authors concluded that many subjects are exposed to HIV despite counseling, and that perception of risk differs greatly from individual to individual.
These presentations demonstrate the intense interest in postexposure prophylaxis, especially for victims of rape. While the rate of acquisition of HIV through sex is too low to allow assessment of the benefit of postexposure prophylaxis, even the small degree of risk justifies the option of therapy in many cases. 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 drug therapy 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 postexposure prophylaxis regimens, and in the rare subject who was exposed, drug resistance might evolve. In summary, it seems unlikely that postexposure prophylaxis after unknown sexual exposure will become routine public health policy in the foreseeable future. Postexposure prophylaxis after high-risk or known exposure will probably become commonplace, even without definitive supportive data. Given the large number of women who are raped, biological strategies to determine the HIV status of the perpetrator are desperately needed.
CircumcisionSome 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, and (2) dendritic cells receptive to HIV can be found in the mucosal surface of the glans. 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.
An entire session of the XIII International AIDS conference was devoted to discussion of circumcision to prevent acquisition of HIV.
Evidence of the benefit of circumcision was provided by Buve and coworkers. 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 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 hundred patient-years. In a related analysis from the same group, Serwadda estimated that circumcision could prevent as much as 44.8% of cases of HIV acquisition.
Controlled trials to evaluate the benefit of circumcision may be necessary. In preparation for such trials, Taljaard and coworkers 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 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).
Results from these presentations add further support to a potential important health benefit from male circumcision. However, many authors[50-52] have cautioned about the costs and complications of circumcision, especially in adults; these costs must 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.
ConclusionsThe XIII International AIDS Conference was remarkable in many ways, including the setting, the science, the tone, and the sense of expectation. It seems clear that treatment and prevention are likely to wed, and that antiretroviral therapy for infected individuals will be used to prevent both vertical and sexual transmission During the meeting, the US National Institutes of Health announced the award of the HIV Prevention Trial Network Grants, providing 26 sites around the world with funding for the next 5 years. These sites will redouble research efforts in virtually all the categories addressed in this report. However, like vaccine research, development of these interventions is a laborious, time-consuming, iterative process. Furthermore, prevention requires a marriage between behavioral, biological, and political approaches. All this having been said, it seems realistic to expect advances in these approaches by the time of the next International AIDS Conference in Barcelona, Spain, in 2002.
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