Important note: Information in this article was accurate in February 2003. The state of the art may have changed since the publication date. A major gap in clinical knowledge about available HIV treatments was "closed" at the 2003 10th National Conference on Retroviruses and Opportunistic Infections (CROI), when the results of the long-awaited "2NN" study demonstrated that nevirapine (Viramune®) is virologically and immunologically equivalent to efavirenz (Sustiva®)!
The study, so-named because it is the first widespread (6 continents, 17 countries, 1,216 patients!) randomized comparison of the 2 most widely used NNRTIs, showed that at 48 weeks, the percentage of people who achieved so-called virologic success in regimens containing either nevirapine or efavirenz was the same. In addition, CD4+ T-cell counts rose comparably in persons on either drug.
In addition, a subset study of cholesterol and triglycerides values validated previous reports by illustrating improved lipid profiles in those on nevirapine compared to those on efavirenz.
More details on the study follow, but first, a bit of HIV treatment history is in order:
Nevirapine was the first FDA-approved NNRTI (non-nucleoside reverse transcriptase inhibitor), and its June 1996 entry onto the market coincided with the onset of the "HAART era,"( i.e. patients were being placed on triple combination regimens, and the first three protease inhibitors (saquinavir, ritonavir, and indinavir) had all been approved within the prior six months. )
The major study which had led to its approval, known as BI-1090 (the "BI" stands for Boehringer-Ingelheim, the pharmaceutical company which then and now is responsible for the development and marketing of Viramune ), had demonstrated that patients on a triple regimen on AZT + ddI + nevirapine fared better than those on AZT + ddI alone.1
By 1998, another NNRTI, efavirenz was approved for use, and the study which led to its rapid approval was the well-known DMP-0062. In this study, efavirenz was shown in combination with AZT and 3TC to be not just as good as, but actually virologically superior to, what was then a "gold standard" triple regimen-AZT + 3TC + indinavir.
Efavirenz's popularity increased as a result of this study, along with several other perceived advantages over a protease inhibitor-containing regimen (fewer pills to take, lower incidence of lipodystrophy, fewer GI side effects, etc.)
Around the same time, the Atlantic Trial was recruiting HIV+ subjects from the U.S. and Europe, and ultimately demonstrated (it was published in 19993) that with a backbone of nucleoside reverse transcriptase inhibitors d4T + ddI, persons receiving nevirapine as the 3rd drug did just as well as those receiving indinavir. (a third arm consisted of those receiving a third NRTI, 3TC, as their third drug.)
Over the last 2-3 years, factors such as those mentioned above (such as pill burden and side effects) have led to an increase in use of NNRTIs as the "third drug" in a HAART regimen.
But the studies noted above all used one NNRTI or the other. While varying successes had been demonstrated for each, a big question remained: How do Viramune and Sustiva compare to each other?
A multicenter team sought to obtain the answer to this increasingly important question, and thus designed the 2NN trial. The International Antiviral Therapy Evaluation Center (IATEC) conducted the trial, which was funded by Boehringer Ingelheim.
The 1,216 patients were all treatment-naïve, and had to have a viral load of greater than 5,000 copies/mL. Any CD4 count was accepted during recruitment-and in reality, the median count of those who came to actually be in the trial was only 190 cells/mm3-thus, rather advanced in the course of their HIV infection.
Subjects who were accepted into the study were each prescribed d4T + 3TC, and then one or two additional medications through a randomization process. The four treatment groups were as follows:
(N=220) received once-daily nevirapine, 400 mg (NVP QD).
(N=387) received the FDA-approved dosing of nevirapine, twice daily, 200 mg each dose (NVP BD)
(N=400) received 600 mg efavirenz administered once daily (EFV QD)
(N=209) was randomized to received both NNRTIs, nevirapine 400 mg + efavirenz 800 mg once daily (NVP + EFV) (Note: larger dose of efavirenz needed in the presence of nevirapine.)
Dr. Joep Lange of the University of Amsterdam, and a lead investigator of the study, presented the results to an audience of several thousand clinicians, researchers, and pharmaceutical company representatives on the final day of the 10th CROI.
The proportion of patients who had an undetectable viral load (less than 50 copies/mL) at the end of the study period was as follows: 70% in the once-daily nevirapine group, 65.4% in those who took the nevirapine twice daily, 70% in the efavirenz arm, and 62.7% for the group who took both nevirapine + efavirenz. Statistically speaking, these results are all comparable, i.e. no one group outperformed the others. Likewise, if we look at the immunological data, the total rise in CD4+ T-cells over the 48 weeks was similar in all groups, ranging from around +150 to +170 cells.
There are, as with any trials, many different ways to look at the data.
Interestingly, if one looks at the proportion of patients in each group who did not have failure (i.e. their viral load was appropriately suppressed, and their disease did not progress clinically, and they did not have to change therapy), there is clear evidence, with statistical significance, that the nevirapine + efavirenz group did not fare as well. Thus, these study results imply that these two NNRTIs should not be used together (which confirms what clinicians have been doing anyway for the past four years).
As with any major study, a careful analysis is done of side effects, both minor as well as serious (sometimes referred to as SAEs, or "serious adverse events").
If we look at actual elevation of liver enzymes, diagnosed via blood tests, the nevirapine once-daily group was statistically significantly higher than the efavirenz only group. (Nevirapine is known to potentially cause liver damage, but monitoring liver enzymes via routine blood tests is able to virtually always eliminate the possibility of this becoming serious.)
Side effects referable to the central nervous system (insomnia, abnormal dreams, anxiety, depression) were all more common, with statistical significance, for those on efavirenz. This, too, confirms what is already known in clinical practice, as the drug is believed to have some CNS effects in at least half of those who take it.
As the possibility of increased rates of cardiovascular disease looms today as one of the major issues in HIV treatment, any maneuver or medication which brings lipids back towards normal is likely to be looked at favorably.
Thus, a sub-study of the larger study looked at patients' lipid levels. In this review, for 833 patients who remained on their regimens for the entire study period, those on nevirapine (either once or twice daily) had a greater rise in the so-called "good cholesterol," or HDL (37% in those who took nevirapine, vs. 24% in those on efavirenz). Similarly, the ratio of total cholesterol to HDL, which is often used to gauge risk of heart attacks, was lowered (improved) in those on nevirapine.
As with any major study release, clinicians and treatment advocates and patients will discuss and sort through results over the next months. However, 2NN appears to confirm that nevirapine has equivalent virological (lowering of viral load) and immunological (raising of T-cells) efficacy as efavirenz.
The NNRTIs overall have been increasingly favored over protease inhibitors, even as first-line therapy, for HIV, due to the ease of administration, lower pill burden, fewer side effects (including lipodystrophy), and cost.
And now using Viramune may not only avoid the potential CNS effects of Sustiva , but could favorably impact lipid levels.
I think back to early 1997, when the most prescribed antiretroviral regimen in much of the U.S. was AZT+ 3TC + nelfinavir (Viracept ). This had to be prescribed, back then, as a total of 17 pills, given out over three dosings across the day.
A regimen today of Combivir + Viramune has 4 pills, 2 given in the morning, and 2 at night, with no food restrictions to speak of. This is certainly progress, and that which drives the search for a cure, drives further progress yet to be made!
1. D'Aquila R et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. Ann Intern Med 1996 Jun 15;124(12):1019-30.
2. 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.
3. 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. Thirteenth International AIDS Conference, Durban, abstract LbPeB7046, 2000.
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