In recent years, one of the pressing clinical questions facing treaters and patients alike is whether or not a regimen which does not contain a protease inhibitor (PI) is comparable in potency to one which does not. The quest for such regimens comes out of numerous reports of the possibility that lipodystrophy, cardiovascular and bone disease occur more frequently with PIs, as well as the fact that alternatives to PI-containing regimens are generally simpler in terms of pill burden and dosing.

Following the release of data of the worldwide 2NN study in early 2003-which demonstrated equivalent virologic potency between the two most commonly prescribed non-nucleoside reverse transcriptase inhibitors, nevirapine (Viramune®) and efavirenz (Sustiva®)—two more studies have been presented which further our knowledge of the clinical usefulness of Viramune®.

The NEFA study (nevirapine, efavirenz, abacavir), published in the world-prestigious New England Journal of Medicine on September 11, 2003, involved the substitution of one of these three drugs for a protease inhibitor (PI) in a HAART-regimen in which undetectable viral load had been achieved. The study subjects were 460 patients in Barcelona, Spain, and the results once again affirmed essential equivalence between Viramune® and Sustiva®—this time in a group of pre-treated patients. (The 2NN study had involved patients who had never been treated with antiretrovirals, so called "naïve.")

The NEFA study was conducted prospectively, in the same manner of the 2NN study, which is thought to be more scientifically rigorous than studies which look at data already gathered (so-called retrospective). Subjects all had been on a HAART regimen, with undetectable viral load, and agreed to be randomized to one of the three new drugs in place of the PI. (They remained on the same nucleoside reverse transcriptase inhibitors [NARTIs] as before.)

The Results

After a year of therapy, there was no statistical difference between the three regimens in terms of patients that had disease progression, detectable viral load, or death. In addition, there was no difference between the number of patients on Viramune and the patients on Sustiva that needed to discontinue due to drug side effect. Treatment discontinuations for both arms was 17%: Neuropsychiatric side effects were the most common type of side effect seen in Sustiva-treated patients, and this occurred in 48 of the 156 patients on this drug (not all of whom had to stop the drug for this reason).

For Viramune®, the most common side effect was rash, in 20 of 155 patients (and, again, many of these patients did not need to stop the regimen). The abacavir (Ziagen®) group had a statistically significant lower percentage of discontinuations (6%), but there was a trend towards a greater incidence of virological failure in such patients. However, a majority of the patients who did have virological failure were shown to have had already-existing resistance mutations to one or both of the NARTIs they were on. Thus, the lack of success of the regimen can in part be interpreted by the fact that there were fewer than three "active" drugs being used.

Three-Year Switch Data from Gil et al

Another study, entitled, "Efficacy and Safety of Protease Inhibitor (PI) Switching to Nevirapine (NVP) in HIV Patients with Undetectable Viral Load: Results after 3 Years," was presented at the July 2003 International AIDS Society meeting in Paris, and subsequently at the September national meeting of the Interscience College of Antimicrobial and Chemotherapuetic Agents (ICAAC). Similar to the NEFA study, all subjects had been on a PI and had achieved an undetectable viral load.

This study involved a smaller number of patients, 143, and the patients were followed for three years. The average CD4 count at the time of the switch to Viramune® was 608. This data supports that Viramune® can maintain an undetectable viral load for a long period of time (durable response) when switching to it from a PI.

Ninety-six of the 143 patients had finished three years on Viramune® at the time of the presentation of the results: 97% of those who remained on it for this entire period maintained undetectable viral loads!

In addition, a continued rise in CD4 counts were seen each year on Viramune® when compared to the baseline--8.5% the first year, up to 12.6% in year two, and 17.7% the third year! (The latter two years' rises achieved statistical significance, meaning that such a difference could not have happened through chance alone-it was "real"!) Although this study did not have a control group of people who stayed on their PIs to compare, a continuing rise of this magnitude further illustrates that drugs such as Viramune® not only achieve comparable viral suppression, but also strengthen the body's immune response.

The authors here also logged the reasons for the patients switching off their PIs. The most common reason was simplification of regimen (45%), followed by lipodystrophy (23%) and kidney problems (20%).

Also examined were the lipid levels, and here a segment of the cohort who had had elevated cholesterol at baseline had a decline of around 20% within the first year, which stayed level through year three. Likewise, there was a greater decline, more than 70%, in a subpopulation who had had elevated triglycerides at baseline, which also occurred in the first year and remained stable.

Both these studies provide additional evidence that Viramune® is a potent and durable antiretroviral drug and is an effective agent when switching off a PI-based regimen. These studies also suggest that nevirapine has the potential to improve the body's lipid levels, and this in turn may reduce the risk of cardiovascular complications.

References:

1. Staszewski S et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999 Dec 16;341(25):1865-73. [Abstract] [Full-text] [Related articles]

2. Squires K et al. The Atlantic Study: a randomized, open-labeled trial comparing two protease inhibitor (PI)-sparing anti-retroviral strategies versus a standard PI-containing regimen, final 48 week data. Int Conf AIDS. 2000 Jul 9-14;13:Abstract No. LbPeB7046.

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