Results of the second clinical trial of AZT were published in 1989, providing evidence that the drug not only benefited those who already had AIDS, but could also slow progression of the disease in people who were HIV-infected. The excitement caused by the results of that trial was overshadowed by the finding, made in the laboratory of Dr. Doug Richman, that HIV became resistant to the drug. Drug resistance quickly became a major challenge in the successful treatment for AIDS. It was likely that combination chemotherapy would be necessary to overcome drug-resistance by HIV. It was only several years later that combination drug cocktails became available that were highly successful in treating AIDS and controlling replication of the virus. Back in those days, however, patients carrying virus resistant to AZT had to switch to a different drug, ddI, which only became available later that year (but in retrospect suffered from cross-resistance to AZT).
HIV with Reduced Sensitivity to Zidovudine (AZT) Isolated During Prolonged Therapy
Science 31 March 1989: Vol. 243 no. 4899 pp. 1731-1734
BA Larder, G Darby and DD Richman
View the rest of the series:
1988 < All years > 1990
Commentary by Dr. Doug Richman
This paper described the progressive development of reduced susceptibility to AZT of isolates of HIV obtained during the course of AZT monotherapy over several months. From this first description of HIV drug resistance, HIV drug resistance testing has become a standard aspect of the clinical management of patients with HIV infection. Phenotypic and genotypic tests for drug resistance and its interpretation are commercially available throughout the developed world. Drug resistance has become a critical driver of new drug design and development. The investigation of the mechanisms, clinical impact and global epidemiology of HIV drug resistance comprise a substantial proportion of research in the field.
As an infectious disease physician, I was aware of the clinical significance of antibiotic resistance in bacteria and as a medical virologist I had closely followed the literature regarding resistance of influenza A virus to amantadine and of herpes simplex virus to acyclovir. Shortly after the announcement of the results of the first phase II trial of AZT of which I was a co-PI (see Fischl, this series
), I arranged in late 1986 with Graham Darby for Brendan Larder, both at the time at Burroughs Wellcome, the company that developed AZT, to come to my lab and help examine isolates from study subjects from San Diego who had participated in this trial. I had worked with Graham and Brendan when I did a sabbatical in Cambridge, UK several years earlier.
I was clearly not surprised by the results. We would not have looked for resistance if we thought we would not find it; however, the field was not completely receptive.
When I submitted my first grant to investigate HIV drug resistance, it was not even scored; it was outright rejected with the comment that it was impossible for reverse transcriptase to tolerate mutations. The reaction to the project and the paper proceeded through the usual 3 stages:
1. Resistance is not possible.
2. The data are real, but probably not clinically significant.
3. Resistance is important, but of course the observations are obvious.
It was clear to the 3 co-authors that our observations were high impact before publication. First my co-authors submitted the draft to Burroughs Wellcome for corporate and regulatory review. The result was some calls to me from incensed corporate directors in the UK in the middle of the night (because of the 8 hour time difference) while I was on a family vacation - their expiring stock options could not be traded until the data were made public. Then my co-authors and I were summoned to a confidential meeting with the FDA, the NIH and some “highly respected senior consultants” to review every detail of the assertions in the paper, consider the broadcast “Dear Doctor letter” to be disseminated by Burroughs Wellcome, and deliberate on the press releases from the government agencies.
I realized from these pre-publication experiences that my training and inclinations as a clinician/investigator had not prepared me for the new intense world of public affairs, regulatory complications and activism in HIV research, a lesson I had to be taught yet again many times subsequently. Nevertheless, the implications and excitement of this important new observation had lasting consequences for the field and myself. HIV drug resistance became and remains a fundamental component of patient management and drug development. For myself the subject represented many years of fascinating research opportunities and channeled my focus into viral dynamics and evolution.
About the author: Dr. Doug Richman is Distinguished Professor of Pathology and Medicine at the University of California, San Diego
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