An early stage clinical trial suggests that nevirapine could be used as a pre-exposure prophylaxis to prevent transmission of HIV.
In a study published in the March 2003 edition of the journal AIDS, investigators at Johns Hopkins University in the USA found that a single dose of nevirapine taken either weekly, twice weekly or every-other-day was well tolerated and maintained high trough levels. On the basis of these findings the American investigators are calling for a larger study.
"This study wasn't designed to test whether nevirapine could in fact prevent HIV transmission, but it would have been bad for the future of this effort if we'd detected significant side effects or new infection," noted Dr J. Brooks Jackson, lead investigator on the study. "The important thing is that the treatment doses were well tolerated, and now we feel comfortable moving forward."
Nevirapine is already used to prevent mother-to-baby transmission of HIV, and the investigators at Johns Hopkins ultimately wish to see if a low dose of nevirapine is similarly effective at preventing sexual or blood-borne transmission of HIV in high-risk adults. The nucleotide analogue tenofovir is currently being investigated for this use.
Thirty-three HIV-negative people from groups at high risk of HIV (gay men, injecting drug users, and the sexual partners of people already HIV-positive) were recruited to a three arm, phase I/II dose escalation study.
The twelve people randomised to arm A of the trial were given 200 mg of nevirapine weekly. A further twelve patients were given 200mg of nevirapine twice weekly; and nine patients were randomised to receive 200 mg of nevirapine every-other-day.
At baseline, the trial participants were screened for HIV, had liver-function tests performed and were tested for hepatitis B and C. Six people were found to have hepatitis C and one person was positive for hepatitis B.
Counselling about reducing the risks of HIV-transmission and the implications of nevirapine resistance should HIV transmission occur was provided.
Study visits took place at weeks one, two, four, six, nine and twelve and at week 16 a further HIV test was performed.
Nobody in the study developed the rash often seen with nevirapine treatment. Although the trough level of nevirapine required to prevent transmission of HIV is unknown, investigators were eager to see if a level of the drug above 100ng/ml could be maintained. Average trough level of nevirapine in arm A at weeks one and twelve were 119ng/ml (range 25-205ng/ml) and 135ng/ml (range 25-1065ng/ml) respectively; 569ng/ml (range 135-2641ng/ml) and 431ng/ml (range 42-2454ng/ml) in arm B; and, 1942ng/ml (range 1214-2482ng/ml) and 943ng/ml (range 262-5281ng/ml) in arm C.
Although changes in liver function were detected in some patients, none were clinically dangerous and in patients with hepatitis C changes seemed to be associated with heavy alcohol consumption rather than nevirapine therapy.
However, nine patients dropped out from the study, of whom seven were lost to follow-up, leading the investigators to observe that “the toxicity rates may have been higher.”
When asked about their HIV-risk behaviour over the period of the study, 17 people said that they had engaged in a high-risk activity. However, nobody became infected with HIV.
In conclusion the investigators conclude that “a single 200mg dose of nevirapine taken once weekly, twice weekly, or every other day for 12 weeks was well tolerated, resulted in minimal or no hematologic or liver toxicities, and achieved nevirapine trough plasma levels >100ng/ml in most subjects.” Given these results “a larger safety study is warranted, which may be designed to collect preliminary information regarding efficacy using one or more of these low-dose nevirapine regimens.”