AIDS TREATMENT UPDATE, Issue 43, July 1996
Raffi Babakhanian

NNRTIs have been around longer than protease inhibitors, but most researchers, doctors and HIV-positive people have had little interest in them. This was because early clinical trials showed that although NNRTIs, when used alone, caused a sharp drop in viral loads, this effect was very short-lived as resistance developed in a matter of weeks.

On the other hand, NNRTIs have been thought to cause less severe side-effects than nucleoside analogues such as AZT. Probably because of the disappointing early results, the nevirapine hearing in Washington was not nearly as well attended as the recent hearings for the protease inhibitors - saquinavir, ritonavir and indinavir. But many of those attending were pleasantly surprised by the information presented on what was thought to be at best a modest anti-HIV drug.

* Trial results

The FDA heard the results from a recently completed trial (BI 1046) of triple combination therapy with nevirapine plus two nucleoside analogue drugs, in which the effects on viral load were of a similar magnitude to those seen in previous trials of triple combination therapy with two nucleoside analogues plus a protease inhibitor. The study compared three treatment regimens:

- AZT, ddI and nevirapine - AZT and ddI - AZT and nevirapine

The 150 participants were relatively healthy HIV-positive people who had not taken anti-HIV drugs before, and whose average CD4 count was 376 and average viral load about 26,000 copies/ml. After 26 weeks, the viral load had fallen below the lower limit of detection (i.e. under 200 copies/ml) in over 70% of the people taking the triple, but in only 40% of the people taking AZT and ddI and none of the people taking AZT and nevirapine.

Another trial, ACTG 241, enrolled 398 people with extensive prior treatment with nucleoside analogue anti-HIV drugs and an average CD4 count of 153. They were treated with either AZT plus ddI, or AZT, ddI and nevirapine. During 48 weeks of follow-up, the triple combination was associated with larger CD4 count increases and viral load decreases than the double combination.

The FDA committee members were impressed with these results and voted unanimously to recommend the accelerated approval of nevirapine for all HIV-positive people where treatment is indicated (which in the USA usually means anyone with a CD4 count below 500). But because the results of the double combination were not as impressive as the triple combination, the committee recommended that nevirapine should be used in combination with two nucleoside analogues where possible, and that if it is added to existing treatment, at least one nucleoside analogue which the patient has never taken before should also be added at the same time.

Under the US accelerated approval system, the company must conduct further trials to assess the impact of nevirapine on disease progression and death. Last November, a preliminary analysis of ACTG 241 found no significant differences in survival between the double and triple combination arms.

At present, nevirapine shouldn't be taken with protease inhibitors, because drug interaction studies have not been completed. However, preliminary studies show that taking nevirapine with saquinavir lowers the level of saquinavir in the blood by 15 to 17%. It is hard enough to get adequate blood levels of saquinavir, because only 4% of each dose of the current formulation is absorbed from the gut, so combining these two drugs probably won't make much sense. Studies combining nevirapine and other protease inhibitors are ongoing, with results expected by late summer.

Another promising aspect to nevirapine is its ability to penetrate into the brain and spinal fluids. The only licensed anti-HIV drug which penetrates at similar levels is AZT, and studies suggest that people taking AZT are less likely to develop dementia and other neurological symptoms of HIV.

In pregnant women, nevirapine also crosses the placenta into the fetus. A study found that when HIV-positive pregnant women were given nevirapine (in injectable form) during labour, their fetus quickly received a therapeutic dose of nevirapine which lasts through the first week of life. This could be important as doctors now think that up to two thirds of infants born with HIV are infected in the birth canal. This study only focused on drug levels of nevirapine, but Boehringer Ingelheim is now starting a clinical trial to see if giving nevirapine to women during birth does reduce the rate of mother-to-baby transmission of HIV. Treatment with AZT during pregnancy, labour and the child's first weeks of life has also been shown to reduce mother-to-baby transmission. However, a single dose of nevirapine could be affordable even in developing countries where the cost of most anti-HIV drugs makes their use unrealistic.

* Taking it

Nevirapine comes in tablet form. The recommended dose is 200 mg daily for the first two weeks, then increasing to 400 mg daily. By starting at the lower dose, the risk of side-effects is reduced.

Nevertheless, over 20% of people starting nevirapine at this dose get a rash. In most cases the rash goes away after two to four weeks on the drug, and thereafter most people experience very few or no side-effects. However about 7% of people taking nevirapine develop a more serious rash which can require hospitalisation. This rash usually goes away upon discontinuing the drug, but one patient needed a skin graft. The company which produces nevirapine - Boehringer Ingelheim - recommends that people taking nevirapine who develop a rash should contact their doctor immediately.

Nevirapine is not licensed in the UK. The company is planning discussions with the EMEA on whether the available data are sufficient to warrant approval in Europe, and has already filed applications for approval in Canada, Australia and New Zealand. The company is also currently considering whether to make nevirapine available through an expanded access scheme prior to approval in Europe.

In the meantime, people with CD4 counts below 200 who are already taking AZT, plus either ddI or ddC may be eligible to join a clinical trial assessing the clinical benefits of combination therapy with nevirapine. Participants receive an additional nucleoside analogue drug, 3TC, and have a 50% chance of also receiving nevirapine. Six clinics in the UK and one in Brighton are currently recruiting participants; for details, see the listing of centres on page 7 of this issue.

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