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| Last updated: 10.07.04 |
If antiretrovirals can be used to prevent HIV infection taking hold after exposure to HIV, then it’s not a giant leap to imagine that taking antiretrovirals prior to HIV exposure might be a good idea for those at high risk.
Pre-exposure Prophylaxis (PREP) has been proven effective in preventing mother-to-infant (vertical) transmission, when expectant HIV-positive mothers are treated with HAART (if their own HIV infection warrants treatment) or AZT or nevirapine (as monotherapy) prior to, during and, if breast-feeding, after birth.
A report on the first feasibility study for this strategy was delivered two years ago at the XVth International AIDS Conference in Barcelona1, and involved the use of the NNRTI nevirapine. This Phase I/II trial (known as HIVHOP 101) provided a 200mg tablet of nevirapine once weekly (n = 12), twice weekly (n = 12), or every other day (n = 9) to a group of men or women in the Baltimore area who were at high risk of contracting HIV. The cohort included gay men, injecting drug users (IDUs) and sex partners of HIV-positive people.
None of the participants experienced physical side-effects associated with the drug, including rash, although increases in GGT (a liver function test) were seen in those receiving higher levels of nevirapine. Additionally, nine of the 33 dropped out of the study before the end of the 12 weeks, most of whom were receiving the higher doses of nevirapine, suggesting a possible toxicity problem.
Although the study did not set out to assess the effectiveness of PREP nor its effect on the risk behaviour of the participants, the authors reported that risk-taking did not increase during the study and that no-one became HIV-positive.
This was a successful “proof of concept” study, even if the drug used was not ideal: there continue to be concerns about nevirapine’s short- and mid-term liver toxicity, particularly in women and those who have more intact immune systems. Last month Boehringer Ingelheim, who market nevirapine as Viramune, issued important new safety information in a letter to US doctors, which cautioned that women with CD4 cell counts above 250 cells/mm3 (including pregnant women) who are taking nevirapine for chronic HIV infection have a twelve-fold greater risk of serious liver side-effects, and that these have sometimes been fatal.
Additionally, a study published last month in the Journal of Acquired Immune Deficiency Syndromes found that HIV-negative people appear to have a higher risk of side-effects when exposed to nevirapine, according to a review of case reports and toxicity reports from people exposed to the drug as a component of PEP after potential exposure to HIV. The authors suggest that autoimmunity may be at the root of these toxicities, since when severe adverse reactions have occurred in HIV-positive people (at a rate of less than 1%), they have tended to be when CD4 counts were high. They conclude that “although precise estimates of the risk for severe hepatotoxicity are not available, the risk appears to be higher than in HIV-infected persons....therefore non-HIV infected individuals should not receive PEP or other prophylaxis regimens that include multiple doses of nevirapine."2
For these reasons, tenofovir (Viread, TDF) has now become the drug of choice for use in PREP studies, the first of which was announced in Barcelona 18 months ago and is currently in the final planning stages.3 The trial will focus on sexually active heterosexual women in resource-poor countries in Africa and Asia with high HIV incidence. Additionally, the US Centers for Disease Control (CDC) are planning a PREP trial in Atlanta and San Francisco which will include 400 men who have sex with men (MSM) for at least 18 months, with a tentative completion date for phase 1 of July 31st 2004.
The CDC explains the rationale behind the use of tenofovir in their PREP study. “TDF has been selected for investigation as chemoprophylaxis against HIV in high-risk individuals because of its unique pharmacologic profile. In addition to the convenience of being a once-daily single tablet with a safety profile comparable to placebo among HIV-infected persons, it has striking anti-HIV potency and a low potential for selection of resistant viruses. Each of these properties is necessary given the realities of the intended target populations.”4
Just as there are concerns that the availability of PEP may increase risky behaviour, particularly amongst gay men, so the CDC are aware that PREP may do the same. “The availability of an oral agent may induce some men to switch from the most effective prevention method (condoms) to one that is less effective (TDF). It is likely that TDF may be highly effective against HIV (i.e. < 80%), but it has no efficacy against other sexually transmitted infections (STIs) such as syphilis and gonorrhoea. Modelling exercises have indicated that the availability of a less-effective method, but one which is used more often, can result in a large decrease in HIV transmission. However, decreases in transmission of HIV would need to be considered in the context of the potential for increased transmission of other serious, although generally non-fatal, STIs.”
A smaller-scale trial, to be led by Dr. Mike Youle at the Royal Free in London, has been planned for some time, but is currently awaiting funding before it can recruit serodiscordant gay couples for his PREP study. Writing about the urgent need for PREP trials in the Journal of the International Association of Physicians in AIDS Care5, Dr Youle wrote that “While barrier methods remain the gold standard for HIV prevention, the use of chemoprophylaxis against HIV infection could benefit those who may be less empowered to insist on condom usage – such as women in commercial sex work, or gay men who choose not to use them....
“HIV serodiscordant couples, commercial sex workers, women wishing to conceive, and individuals unwilling to use condoms are groups that are regularly at significantly higher risk of HIV infection than the general population.
“Could these groups now benefit from HIV pre-exposure chemoprophylaxis with current or soon-to-be available drugs?”
Watch this space.
References
1.Jackson JB et al. XIV Intl. AIDS Conference, Barcelona, abs MoOrD1105, 2002.
2.Patel SM et al. JAIDS 35 (2):120-125, 2004.
3.Bill & Melinda Gates Foundation Press Release. see http://www.gatesfoundation.org/GlobalHealth/HIVAIDSTB/HIVAIDS/Announcements/Announce-021028.htm
4.CDC Solicitation Notice. see http://www.fbodaily.com/archive/2003/05-May/17-May-2003/FBO-00324723.htm
5.Youle et al. JIAPAC 2(3):102-105, 2003