AIDS TREATMENT NEWS Issue #299, July 17, 1998
John S. James

Of course much remains to be learned about the benefits and drawbacks of each antiretroviral treatment, but a widespread consensus at the conference seemed to accept efavirenz combinations as now "on the table" for consideration among other major treatment options, which until now have mostly been built around protease inhibitors. Efavirenz is a non- nucleoside reverse transcriptase inhibitor (NNRTI), like nevirapine or delavirdine.

The following research reports were presented at Geneva:

* The most noteworthy result was a comparison of viral load reduction with efavirenz plus AZT plus 3TC, vs. a standard- of-care control group treated with indinavir plus AZT plus 3TC; data were available for up to 24 weeks of treatment. This study assigned 150 patients to each arm, all of them treatment naive to NNRTIs, protease inhibitors, and 3TC. Volunteers had to have viral load over 10,000 copies, and CD4 count over 50.

The efavirenz combination suppressed viral load to below 400 copies in a significantly higher proportion of the volunteers than the control arm, at all time points between week 2 and week 24. And fewer patients dropped out of the efavirenz study arm due to adverse events, suggesting that the side effects may have been less of a problem than with the standard-of-care treatment.

* While longer-term followup is not yet available from this study, there are 72-week results from a different trial, which tested efavirenz in combination with indinavir. The proportion of volunteers with viral load below 400 copies peaked at week 16 but was still very good at week 72 (the exact percentages depend greatly on how one accounts for missing data--an issue we will cover separately in AIDS TREATMENT NEWS). These volunteers were also NNRTI and protease inhibitor naive when they started the trial; their baseline viral load was over 20,000 copies, and their baseline CD4 count was 100 to 500. This 72-week report was based on over 40 study volunteers who have been on the treatment that long.

* Much less information is available for patients who are more heavily pre-treated. But in two studies presented at Geneva, either efavirenz plus indinavir, or efavirenz plus nelfinavir, vs. the protease inhibitor alone, was added to ongoing antiretroviral therapy with two nucleoside analogs. All these volunteers had received the nucleoside analogs for at least eight weeks before they added the new drugs. An analysis of the first 184 patients in this trial showed a statistically significant advantage of the four drugs over the three drugs, in the proportion of persons whose viral load was suppressed to below 50 copies, the cutoff for the test which was used.

* Several other efavirenz studies were presented in Geneva-- including combinations with other drugs, and also including a small study showing that efavirenz plus other antiretrovirals successfully reduced HIV levels in cerebrospinal fluid to below 400 copies, the limit of quantification of the test used, in all eight patients tested.

* According to DuPont Pharmaceuticals, common side effects of efavirenz include rash, nausea, dizziness, diarrhea, headache, and insomnia--with the incidence of severe skin rash under one percent. Due to birth defects in an animal study, the drug should only be used in pregnancy if the benefit to the mother outweighs the risk to the fetus. In the trial comparing efavirenz plus AZT plus 3TC, vs. indinavir plus AZT plus 3TC, dizziness was significantly more common in the efavirenz arm (9% vs. 1%); significantly less common were nausea (10% vs. 22%) and vomiting. Most side effects were moderate and lasted less than two weeks.

Comment

One concern about efavirenz is that it may be unlikely to work in patients who have already developed resistance to either nevirapine or delavirdine, the two NNRTI drugs currently approved in the U.S. The three drugs of this class appear to be cross resistant, due to a few mutations, especially K103N. It is particularly important to use any NNRTI correctly, and in a maximally suppressive regimen, to minimize the chance of developing resistant HIV. (In the future it might be possible to extend the usefulness of this class of drugs, by developing an antiretroviral which is particularly effective against virus with the K103N mutation. But no such drug is available yet.)

With the protease-inhibitor-containing regimens which are now in common use, physicians have noticed that even when patients "fail" virologically, they often continue to do well clinically; virological failure (rebound of viral load, although usually not all the way to baseline) has not necessarily caused clinical failure. But no one knows if this will also happen with efavirenz. Each different class of drugs forces HIV to develop very different mutations. It is possible that some of the mutations causing viral resistance to protease inhibitors might also cause the virus to become less harmful; but even if this does turn out to be true for protease inhibitors, it might not apply to other drugs.

With protease inhibitors, the first hint of this effect was seen in an early indinavir trial, where patients were given that protease inhibitor alone at a dose which is now known to be too low. At first the median viral load went down, and the median CD4 count rose, as expected. Then resistance developed, and the viral load came back up. However, the CD4 count did not go back down, but remained up. It may be worth asking whether or not CD4 count increases are similarly sustained when HIV develops resistance to efavirenz.

Meanwhile, this question does not argue against efavirenz, since patients who start that drug would presumably switch to a protease-inhibitor regimen anyway if the first treatment failed. They would not be left on a failing efavirenz regimen.

For More Information

Efavirenz is currently available through expanded access programs; for more information, call the Sustiva Expanded Access Program, 800-998-6854 (8 a.m. to 6 p.m. Monday through Friday, from the U.S. or Canada) or in Europe call +44 (0) 1462 488263.

Additional information about the Geneva efavirenz presentations is available on the World Wide Web. See "Geneva Conference: Finding Information on the Web and Elsewhere," in this issue of AIDS TREATMENT NEWS.

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