AIDS Treatment News #181 - Aug 20 1993
Henry E. Chang

Convergent combination therapy first received widespread publicity in February 1993, after the publication of a major article in Nature (February 18) describing laboratory tests of the concept. (For background, see AIDS TREATMENT NEWS #170, March 5, 1993.) More recently a laboratory error has been found in the work reported in the February paper. The error also received widespread publicity, with a page-one article in The New York Times on July 22.

We believe that both the original work and the error have often been overinterpreted by the public, which underestimates the degree to which laboratory results are only hints or guides to treatment development, and not strong evidence of what will happen in people. Convergent combination therapy never promised more than a limited advance; yet even after the discovery of the highly-publicized error, it is still well worth testing.

The Nature paper reported two different experiments, which people have sometimes confused:

* The Harvard team artificially constructed an HIV provirus (the virus in its DNA form) containing mutations giving resistance to AZT, and to ddI, and also to nevirapine. (Nevirapine, also called BI-RG-587, is an anti-HIV drug being developed by Boehringer Ingelheim Pharmaceuticals, Inc. ; it inhibits reverse transcriptase, an enzyme which is required for HIV to reproduce, but which is not found in uninfected humans. AZT and ddI also inhibit reverse transcriptase. Resistance can develop to each of these drugs, through mutations in the reverse transcriptase, but different mutations are required for each drug.) In separate tests, the researchers also combined AZT, ddI, and pyridinone (also called L-661, a drug being developed by Merck & Co., Inc.).

The Nature paper reported that one such engineered virus, labeled "mutant 4," was dead, and hypothesized that the accumulation of mutations in the reverse transcriptase had weakened the virus to the extent that it was no longer functional. The authors suggested that since one combination of mutations led to a dead virus, it meant that one mutational pathway to the development of multidrug resistance to AZT, ddI, and nevirapine might be blocked.

* In a different experiment, the Harvard team showed that by using a combination of AZT, ddI, and nevirapine (or pyridinone), at concentrations achievable in patients' blood, viral spread in cell cultures was effectively prevented.

Perhaps because of the way the two different experiments were reported in the same paper, many people have misinterpreted the goal of the treatment as using the drug combination to force HIV to mutate into a dead virus. In fact, the construction of mutated viruses in the laboratory only suggested that not every combination of resistance mutations to the different drugs automatically gave rise to multidrug resistance. From that, the researchers theorized that multidrug resistance might be delayed or made more difficult by use of multiple drugs against the same viral target (reverse transcriptase in this case).

The Error

At the Noordwijk Drug Resistance Workshop in the Netherlands, and at the IX International Conference on AIDS in Berlin, both in June of 1993, researchers from other laboratories showed that they could not reproduce the results of a key experiment performed by the Harvard group. The discrepancy between the original report, and the independent findings of two teams, one led by Dr. Brendan Larder at Wellcome Research Laboratories in the UK, and the other led by Dr. Emilio Emini at Merck Research Laboratories in the U. S., centers on the artificially constructed HIV mutants.

In an effort to confirm the original report by the Harvard team, Drs. Larder and Emini constructed HIV mutants with the intended four mutations (at positions 74, 103, 215, and 219 in the genetic code for the reverse-transcriptase enzyme). The result was a virus that could reproduce. Immediately following these reports, the Harvard team went back to their laboratory and discovered that one of their artificially constructed viruses, "mutant 4," had at least one unintended mutation in addition to the intended ones. Additional experiments should have been performed to confirm that all HIV mutants were built as specified and did not have any unwanted mutations. All other data in the original Nature paper have been reviewed and were found to be correct.

According to the Nature paper, HIV did not develop resistance to the triple-drug combination after passing the virus 10 generations in the presence of the drugs in cell cultures. But, using recent data obtained from longer-term cell culture experiments, the Harvard team reported at the Berlin conference that they found multidrug resistance after 20 to 40 generations under different conditions. These new findings are in agreement with those from Dr. Larder's group. They suggest that HIV which is resistant to AZT, ddI, and nevirapine may emerge in treated patients, especially those who started this triple-drug regimen with viruses already resistant to AZT and ddI.

Clinical Trial Continues

A large clinical trial sponsored by the National Institute of Allergy and Infectious Diseases' AIDS Clinical Trials Group (ACTG), designed to evaluate the effectiveness of convergent combination therapy with 400 patients, is currently underway. Despite the announcement of the experimental error, the clinical trial will proceed as originally planned. All study participants will be contacted and will have an opportunity to discuss the information with their investigators. In addition, a "Letter to Patients" has been sent out to all participants in the study.

These recent findings have demonstrated to the research community that the HIV reverse-transcriptase enzyme has more adaptability and ability to evade antiviral treatments than previously believed. And caution must always be used in trying to apply laboratory findings to clinical treatment. Nevertheless, the current trial should determine whether triple-drug combination is a more effective anti-HIV strategy than the more standard combination of only AZT and ddI. In addition, the study should provide a better understanding of the overall biological activity of nevirapine in combination with AZT and ddI, and show whether the three-drug combination will delay the development of resistance in patients.

About the author: Henry E. Chang is an AIDS treatment activist and the director of research and development at Shared Medical Research Foundation in Los Angeles, California. He can be reached at 818/345-2172.

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