Efavirenz (SUSTIVA [tm]), Formerly DMP-266) 48-Week Data Announced
Efavirenz (brand name SUSTIVA [tm], formerly known as DMP-266) in combination with indinavir (Crixivan(tm)) resulted in an average viral load reduction of 2.38 logs out of a possible 2.49 logs (see "Note on Viral Load," below), after 48 weeks of treatment, in a phase II trial in which 59 patients received this combination. The average CD4 cell count increase was 240. A comparison group, which received indinavir alone for the first 12 weeks and then the combination, at 48 weeks had a 1.89 log average reduction out of a possible 2.42 logs, with an average CD4 increase of 150. The proportion of volunteers whose viral load was reduced to below the limit of quantification (400 copies, in this trial) was 88% in the combination arm, vs. 68% in the arm which started with indinavir alone and later switched to the combination. These results were released September 16 at the Infectious Disease Society of America 35th Annual Meeting in San Francisco (IDSA '97).Efavirenz, being developed by DuPont Merck, in Wilmington, Delaware, is a non-nucleoside reverse transcriptase inhibitor which is effective against many HIV variants which are resistant to other NNRTIs. Resistance to efavirenz does develop slowly in laboratory tests, however, so this drug should only be used in antiretroviral combinations, never alone. A practical advantage of efavirenz over most other antiretroviral treatments is that it needs to be taken only once a day.
Additional data from another study -- not yet unblinded even for the researchers -- will be presented at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection, October 11-15 in Hamburg, Germany.
An expanded access program for patients who have failed other antiretroviral treatments was announced on September 15 (see "Efavirenz (SUSTIVA) Expanded Access Begins October 1," below).
Note on Viral Load
DuPont Merck is reporting its viral load results in a more accurate way than has been customary until now. The AIDS community should have a better understanding of the meaning of low viral load numbers, and should distinguish between "undetectable" and "below the limit of quantification."
The only viral load test approved by the FDA, the Roche Amplicor test, has a limit of quantification of 400 copies. If the viral load is less than that, the test does produce a number; however, that number is not considered reliable. If the viral load is extremely low, the test will find no virus at all and deliver a result of zero. Only zero -- not just any number under 400 -- really means that the viral load is "undetectable"; under 400 but not zero should more correctly be called "below the limit of quantification." There probably is a real difference, with a truly undetectable result meaning that there is less virus present, and probably a better prognosis for the patient, than a test result which did detect virus, but not enough to produce a reliable numerical estimate.
In reporting the results of clinical trials, any number under 400 (including zero) must be taken as 400 for computing the average change in viral load while on a treatment -- since otherwise, inaccurate figures would be used in the averaging. This conservative approach does create a problem, however. For example, if a volunteer has a baseline viral load of 40,000 copies, the maximum possible recorded drop would be two logs (100 fold, from 40,000 copies to 400) -- even if the treatment was able to reduce the viral load by more than two logs. The drug effect will often be underestimated, just because the viral load did not start high enough to show the full antiretroviral suppression.
This is why DuPont Merck is reporting an additional number with its results -- for example, "patients achieved a 2.38 log average reduction in HIV-RNA levels out of a possible 2.49 log" for the combination arm of the trial reported above. The 2.49 log reduction is what would have been achieved if the treatment had worked perfectly and eliminated all of the virus. When the actual average reduction is close to the maximum possible one which could have been seen in the trial (as in this case), that usually means that many of the volunteers went below the level of quantification, and that the treatment actually produced a greater viral decline than this particular trial could measure.
