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ARVs to prevent sexual transmission of HIV
The case for providing antiviral treatment as 'post-exposure prophylaxis' after sexual exposure is an extension of the case for providing it in occupational settings. Much of the section on needlestick injuries in HIV transmission is relevant here.
The argument is based on a comparison of per-exposure risks, which rates receiving unprotected anal sex or a woman's exposure during rape as comparable to most needle-stick injuries in the level of risk involved (Vittinghof).
It is obviously far more difficult to give prompt access to medical treatment when exposure occurs in the community, than it is when accidents occur in a hospital. The usual occupational exposure target, of starting treatment within four hours of an exposure incident, is unlikely to be achieved.
It has not been possible, and may never be, to organise a randomised controlled trial of antiretroviral treatment to assess its effectiveness. Reasons for this include the rarity of the events where protection is used, so it is hard to predict in advance who will need it. There also has to be a question about the validity of consent to take part in a trial, when someone has just experienced what may have been a traumatic and worrying event.
One precondition for offering PEP is the widespread availability of HIV antibody testing, so that people at risk are aware of their own HIV negative status. This would be especially important if the treatment option provided were inappropriate for treating HIV positive people, for example, single dose nevirapine and/or short course combivir (AZT and 3TC).
There is an unresolved question, whether treatments which are clearly inadequate for treating HIV may be perfectly adequate for preventing infection. Animal studies which used a form of tenofovir, and the mother-to-child prevention with two doses of nevirapine mentioned above, strongly suggest that this is the case. There are precedents from other diseases, such as tuberculosis and malaria, where single agents in relatively low doses are successfully used for prophylaxis whereas treatment requires much higher doses and/or combinations of effective drugs.
It is also argued that when antiviral drugs are given to people who are HIV negative, the level of toxicity that can be tolerated is far lower than when drugs are used to treat a life-threatening illness.
Some occupational guidelines have recommended triple therapy including three-times daily indinavir, which has been rejected as impractical for community use. Similarly, the use of extended courses of nevirapine raises serious safety concerns. (Both issues are discussed in the previous section on occupational PEP).
A San Francisco study group therefore settled on a short course of treatment with a combined AZT/3TC formulation as its preferred option, with nelfinavir added when the source patient was known to have had a high viral load, and d4T/ddI as an alternative when AZT/3TC was intolerable or the virus was thought likely to be resistant to those drugs (Katz).
A survey of occupational antiretroviral post-exposure prophylaxis among health workers in Canada uncovered a major hidden cost. Time off work due to side- effects of the drugs cost the health service as much as providing the drugs for the treatment. This time off work appears to have doubled, from an average of 7.0 days to 15.8 days in the year 2000, when the protease inhibitor nelfinavir was added to the regimen, previously d4T plus 3TC (McLeod).
The challenge of 'pre-exposure prophylaxis'
In some populations, the risk of HIV infection may be so high that even with some of the current ARV drugs, people may choose to take the drug if it can prevent HIV transmission.
In this case, unlike PEP, controlled clinical trials are not only feasible but are being planned and may give conclusive results as early as 2004.
The first feasibility study for this strategy has involved continuous treatment with nevirapine, and is an extension of proposed research to explore the use of nevirapine in HIV-negative babies breast-fed by HIV-positive mothers. 19 individuals completed a Phase I/II trial (HIVHOP 101) of giving a 200 mg tablet of NVP once a week (11 people) or twice a week (9 people) for 12 weeks to HIV uninfected subjects at high HIV risk. The aim was to evaluate the safety, tolerability, and nevirapine trough levels achieved with these regimens. One subject was positive for hepatitis B surface antigen and three were positive for hepatitis C. A CBC (complete blood count test) and levels for liver enzymes, creatinine, and plasma NVP trough levels were carried out on blood samples drawn at entry, 1, 2, 4, 6, 9 and 12 weeks, and a follow-up sample was taken at 16 wks which included an HIV antibody test. Subjects were assessed for signs/symptoms of potential toxicity at the same timepoints and follow-up by phone at 20 weeks. None of the 19 experienced clinical symptoms attributed to drug, including rash. There were no significant changes attributable to study drug in hematology values or in liver enzyme levels (ALT, AST or GGT) from baseline to week 12 in either cohort except for an average 2-fold increase in GGT for cohort B with 2 subjects having a 3-fold increase. Mean and (median) NVP trough levels at weeks 1 and 12 were 119 (108) ng/mL and 206 (135) ng/mL respectively for cohort A, and 820 (569) ng/mL and 952 (430) ng/mL for cohort B. Risk behavior did not increase during the study. No subject became HIV antibody positive. A single dose of NVP taken once or twice/wk for 12 wks was safely tolerated and resulted in nevirapine levels well above the IC50 (10ng/mL) over the 12 week period in nearly all subjects (Jackson).
As is implied in the elaborate safety monitoring described in this report, there are concerns about liver damage from prolonged use of nevirapine. These may or may not be a problem, when the drug is taken once a week by comparatively healthy adults rather than twice a day, as would be usual for treatment of adults with HIV. There is one other serious concern, which is that nevirapine is vulnerable to a single resistance mutation. If that becomes common among viruses circulating in a community, its value as a preventive drug could quickly diminish.
For these reasons, the search is on for an antiviral drug which has less risk of serious side effects and which it is more difficult for the virus to resist. The two candidate drugs which are being put forwards now for possible use in clinical trials are tenofovir (oral PMPA) and the enteric coated form of ddI (Videx EC).
A double-blinded placebo-controlled trial of one or other of these drugs, recruiting people through clinics treating sexually transmitted infections, could begin during 2003. Potential populations may include sex workers and migrant workers in Southern Africa and gay men who repeatedly test for HIV and have been diagnosed with sexually transmitted infections in Europe and/or North America. The first such trial currently seems most likely to take place in Southern Africa, sponsored by Family Health International with funding from the Bill and Melinda Gates Foundation, using tenofovir in a somewhat larger and lower-risk population than mentioned above, so as to get a more readily generalised result from the trial.
Vaccine trials
As UNAIDS observes in the ethical guidance previously mentioned, and described in detail later in this chapter, there has to be serious consideration of access for vaccine trial participants to post-exposure prophylaxis (PEP) with antiviral drugs. This may or may not be a real obstacle to the evaluation of a preventive vaccine.
With present antiviral drugs, issues around PEP include:
- the reliability with which relevant exposure episodes can be recognised
- the feasibility of delivering the drugs sufficiently rapidly after exposure
- the risks of unwanted effects from the drugs
- ability to adhere to strict regimens and risks of drug-resistance from incorrect use
These issues are sufficiently real and substantial to make it unlikely that PEP will prevent any well-designed vaccine trial from demonstrating the effectiveness or otherwise of a vaccine candidate.
Even if it emerges that continuous treatment with an antiviral drug can prevent HIV with relatively high efficacy, it is likely that there would still be people at risk unable or unwilling to take such a drug, who could be enrolled in vaccine trials.
The use of ARVs for PEP among North American participants in VaxGen’s Phase III efficacy trial of its AIDSVAX gp120 vaccine has been studied in some detail. Overall, 108 (2%) of 5418 participants reported PEP use. These 108 participants were from 36 trial sites (out of 61 in the whole study) in 27 US cities, Puerto Rico, 3 Canadian cities, and the Netherlands. Trial participants were more likely to have used PEP if enrolled in one of seven Californian sites, having a known HIV-positive sex partner, higher education level and greater recreational drug use. (Injecting drug users were excluded from this trial, which is focused on sexual transmission only; 90% gay men, 8% women at heterosexual risk.) Analysis of supplementary PEP survey data from six sites revealed 260 (46%) of 560 participants had heard of PEP. Trial PEP-users were significantly more likely to believe PEP prevents HIV infection than were non-PEP users (81% vs. 59%). The researchers concluded that trial PEP use was limited and ‘did not appear to have an impact on the conduct of this vaccine efficacy trial. As knowledge of and access to PEP expands, its use among trial participants may increase and affect HIV incidence and risk behavior in future HIV vaccine efficacy trials’ (Ackers).
References
Ackers ML et al. Post-exposure prophylaxis among HIV-uninfected participants in a phase III HIV vaccine efficacy trial. XIV International AIDS Conference, Barcelona, abstract WePpD2105, 2002.
Jackson JB et al. Nevirapine prophylaxis for prevention of sexual/blood HIV transmission in HIV uninfected subjects. XIV International AIDS Conference, Barcelona, abstract MoOrD1105, 2002.
Katz M et al. Postexposure treatment of people exposed to the human immunodeficiency virus through sexual contact or injection-drug use. New England Journal of Medicine 336: 1097-1100, 1997.
McLeod A et al. Absenteeism adds significant cost to HIV needlestick prophylaxis. XIV International AIDS Conference, Barcelona, abstract TuPeE5167, 2002.
Tubiana R et al. Warning: Antiretroviral treatment interruption could lead to an increased risk of HIV transmission. AIDS 16(7):1083-1084, 2002.
Vittinghoff E et al. Per-contact risk of human immunodeficiency virus transmission between male sexual partners. American J of Epidemiology 150: 306-311, 1999.