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Chemoprophylaxis of HIV Infection: Moving Forward with Caution
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The Journal of Infectious Diseases Oct 1, 2006;194:874-876
Robert M. Grant1 and Mark A. Wainberg2
1Gladstone Institute of Virology and Immunology, University of California, San Francisco; 2McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada
The study by Subbarao et al. [1] in this issue of the Journal advances the rationale for HIV chemoprophylaxis, or the use of antiretroviral drugs in preexposure prophylaxis (PrEP) for HIV disease. Most research is focused on the use of tenofovir disoproxil fumarate (TDF) [2, 3], because of its long half-life, its excellent safety record, and the findings of earlier research that involved nonhuman primates and showed some efficacy in the prevention of infection by simian immunodeficiency virus (SIV) [4-6]. The new study by Subbarao et al. [1] used a more stringent model to study viral transmission and suggested that TDF may not be sufficient for the prevention of HIV disease when used as a single agent.
The study by Subbarao et al. [1] set the bar much higher for chemoprophylaxis agents, by using repeated viral challenges weekly for 14 weeks. Repeated exposures may simulate the experience of sexually active people who are exposed to HIV through sexual contact with >1 partner. Of 12 macaques studied, 2 groups of 4 macaques each received TDF via an oral route, either once daily or once weekly, whereas the remaining 4 macaques served as untreated control animals. The results revealed that the control animals became infected at a median of 1.5 weeks after initiation of the study, whereas the groups receiving TDF once daily or once weekly became infected after a median duration of 6 weeks and 7 weeks, respectively. At the end of 14 weeks, all animals were infected.
The predictive value of nonhuman primate models of chemoprophylaxis is not yet established. The virus used was a recombinant simian human immunodeficiency virus (SHIV), which is more similar to HIV-2 than HIV-1. In fact, HIV-2 has not spread extensively outside of West Africa, and it is probably not as pathogenic as HIV-1. The route of exposure to SHIV was rectal; such exposure may be associated with more efficient infection, possibly because the rectal epithelium is columnar and is rich with lymphoid and dendritic target cells.
This issue of the Journal also contains an important report by Kaizu et al. [7], who have developed a vaginal system that involves the use of SIV-infected lymphocytes to establish reproducible and persistent infection of cynomolgus macaques. This model demonstrates the feasibility with which cell-associated virus, rather than free virus, can cause infection, and it should be valuable for scientists evaluating chemoprophylaxis concepts. This new model also emphasizes that either cell-associated or free virus may be the vector of transmission, and it suggests that inhibitors of viral expression may have a role in prevention.
Unlike previous researchers who used parenteral dosing of TDF in nonhuman primates, Subbarao et al. [1] orally administered the prodrug to animals that were awake. Although masking the drug in peanut butter was a novel and clever approach, the use of oral dosing for monkeys is less reliable than parenteral dosing, because the animals may either refuse or spit out some foods and many drugs. In this study, a consequence of not being able to control levels of oral drug intake in an animal model was that TDF levels in plasma were often lower than expected.
However, the results of the study by Subbarao et al. [1] may, in reality, be better than the authors claim. Although all monkeys in the treated arms of the study eventually became infected, the results are consistent with previous research that demonstrated that TDF had partial efficacy in the prevention of SHIV infection. Only 3 of 4 of the control animals-but 0 of 8 of the TDF-treated animals-became infected between 2 and 6 weeks after initiation of the study. Statistical analysis indicated a significant delay in the acquisition of infection (P < .05, by exact log-rank test). TDF reduced the chance of being infected from about 50% to about 15% per virus challenge.
Human clinical trials of PrEP have been initiated based on the partial protection observed in nonhuman primate research, as well as the proven concept of chemoprophylaxis for the prevention of tuberculosis pneumonia and malaria. The use of oral contraceptives to prevent unwanted pregnancy is also well established, indicating that use of 1 pill per day for prevention can be acceptable. PrEP trials of TDF are being conducted in the United States, Africa, and Asia, and they are being planned in Latin America. Although some of these studies have now been abandoned because of opposition by a few activists and communities [3, 8, 9], other studies are proceeding successfully [10]. Limited information about safety and acceptability may become available by the end of 2006, whereas information about efficacy is not expected until 2008-2009. Until then, PrEP is not recommended for clinical use. In contrast, guidelines for postexposure prophylaxis have been published elsewhere.
Concerns have been raised about possible TDF toxicity associated with renal function. In fact, TDF use is associated with small subclinical decreases in the glomerular filtration rates in HIV-1-infected persons [11], but clinically important renal insufficiency is rare and has occurred only in persons who are also taking didanosine or ritonavir, who have underlying renal disease, or who have a low body weight. Renal insufficiency may occur even less frequently in HIV-1-uninfected persons and is being evaluated with intensive monitoring in clinical trials. The risk of toxicities that include renal insufficiency, which may be a rare and reversible complication of TDF PrEP, should be weighed against the risk of infection with HIV-1, which develops in 2%-5% of at-risk group members per year despite access to condoms and counseling [12]. Other concerns relate to disinhibition of risky behavior, although this actually decreased during open-label trials that combined postexposure prophylaxis with counseling [13, 14]. Behavioral information is being collected in studies of PrEP, to determine the effects on high-risk behavior.
The potential for the development of HIV-1 resistance to TDF is a more realistic concern, although virtually all clinical studies performed to date have shown that the occurrence of the reverse-transcriptase K65R mutation, which is associated with resistance to TDF, is rare among individuals treated with TDF as part of a triple-combination regimen over long periods [15]. Concern regarding the use of single antiretroviral agents is based on the high proportions of pregnant women in developing countries who developed detectable drug resistance after receiving a single dose of nevirapine for the prevention of mother-to-child transmission of HIV.
However, the situations are very different. Nevirapine prophylaxis for mother-to-child transmission of HIV is given to women with substantial HIV loads, providing an abundance of opportunity for the viral replication that is required for mutation and for selection of drug resistance. TDF PrEP, in contrast, is initiated only after the presence of established HIV infection has been excluded by serological testing. Whether additional nucleic acid testing will be required to screen for seronegative RNA-positive "window-period" infections among persons initiating PrEP is an important aim of existing trials.
Furthermore, resistance to nevirapine does not come with a cost for viral fitness, whereas TDF-resistant HIV-1 typically has a replication capacity that is about 50% of that of drug-susceptible HIV-1. In addition, the best way to prevent drug resistance by HIV is to prevent infection entirely, which is the aim of PrEP.
Of importance, resistance to TDF was not observed by Subbarao et al. [1], although all monkeys eventually become infected despite receiving TDF PrEP, and, after infection, TDF was continued as a single agent for several weeks. This suggests that the levels of TDF PrEP were not sufficient to select for drug resistance, likely because of the unreliability of oral dosing of the monkeys, which may have contributed to the animals becoming infected in the first place.
Another issue relates to viral subtypes. The initial identification of K65R as the mutation in HIV reverse transcriptase associated with resistance to TDF was based on tissue-culture selection protocols using HIV of subtype B origin. The study showed that resistance to TDF could only be selected over multiple passages during many months and that relatively few viral clones from stocks that replicated in the presence of TDF actually contained the K65R substitution [16]. However, the K65R mutation may turn out to be more common in non-subtype B infections [17]. Therefore, attention will need to be paid to the possibility that clinical resistance to TDF may emerge more rapidly after TDF-based treatment of HIV-1 infection in subtype C infections than in subtype B infections. This issue may also have relevance to the potential use of TDF or other single-agent drugs in studies of microbicides.
The limited efficacy of TDF alone in highly stringent monkey models and the concerns about drug resistance raise the possibility that combinations of agents may be more suited for PrEP. Indeed, the combination of emtricitabine and TDF is available as a single tablet that was approved for HIV-1 treatment by the US Food and Drug Administration in 2004. The combination of both drugs provides greater anti-HIV-1 activity, increases the number of mutations required for full drug resistance, and has convenience and tolerability that compares with those associated with TDF alone. On the basis of these reasons and others, investigators funded by the US Centers for Disease Control and Prevention and the National Institutes of Health have recently decided to evaluate the emtricitabine/TDF combination as PrEP in Botswana and Latin America. Trials of TDF PrEP that already have achieved substantial enrollment are planning to continue, which will help address whether TDF monotherapy (plus counseling) will be sufficient for humans, although this approach was only partially effective for animals.
References
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