Razing the House of Cards: The Discovery of HAART and the Push for Evidence-Based HIV Treatment
Drug Combinations to the Fore
In September 1995, Spencer Cox, Michael Marco, Tim Horn, and I attended the 35th ICAAC, where the results of AIDS Clinical Trials Group study 175 were presented, along with early phase I viral-load data from Abbott's ritonavir development program.
ACTG 175 was the first study to prove, using clinical endpoints, that ddI alone, AZT plus ddI, or AZT plus ddC were better than AZT alone, in both AZT-naive and -experienced persons, in terms of slowing progression to AIDS or death.
"I mean, it's not like I live for bad news. It looks like we're making some progress," commented Spencer Cox in TAG Does ICAAC.
An early Abbott combination study of ritonavir, AZT, and ddC appeared to show even more arresting data: According to lead author Daniel Norbeck, the regimen yielded a CD4 count increase of 110 cells and an unprecedented 2.5 log decrease in viral RNA lasting for the 20 weeks of the study. Over the subsequent weeks, Norbeck claimed, an increasing proportion of participants became viral culture -- negative -- which is to say they could not culture infected cells from the blood.
The era of monotherapy was on its way out.
In November 1995, the FDA advisory committee met to review Roche's application for accelerated approval of saquinavir, Glaxo Wellcome's for accelerated approval of lamivudine (3TC), and Bristol-Myers's for full approval of stavudine (d4T). The three-day hearing was neither pleasant nor terribly informative. Moving to the combination-therapy era without the proper monitoring tools -- e.g., quantitative viral-load testing, which came of age only the following year -- made it difficult to assess the benefit of the two AZT-like drugs and that of the first PI, saquinavir.
Nonetheless, we believed that Roche had met our demands from the previous year, notably: adequate and well-controlled clinical endpoints studies were under way to show whether the drug could prolong disease-free time or survival; the completion or implementation of studies to demonstrate a favorable combination of changes in CD4 levels and viral load; evidence adequately characterized and acceptable safety evidence; and efforts to enroll an expanded access program.
Therefore, we supported approval of saquinavir, despite its low dose and the lack of definitive clinical endpoint data. The drug was approved in December 1995. Less than two years later, Roche admitted that the licensed dose was suboptimal, though it didn't take responsibility for exposing people to a greater risk of cross-resistance to other, more potent PIs such as ritonavir or indinavir. Ultimately, Roche developed a more bioavailable dose that could have competed with the stronger PIs, but it was too late; the drug was doomed by the company's early mistakes.
Luckily, the FDA had taken proactive steps to expedite its review of the next two PIs in the pipeline, both of them more potent than saquinavir: Abbott's ritonavir and Merck's indinavir.
Abbott had adopted Spencer Cox's recommendation (from the 1994 Rescuing Accelerated Approval: Moving Beyond the Status Quo report):
On February 1, at the 3rd Conference on Retroviruses and Opportunistic Infections in Washington, D.C., Abbott showed the results of the ritonavir study. In just six months, those receiving ritonavir plus standard of care (SOC) had 50% fewer deaths than those receiving placebo plus SOC. Spencer, attending CROI, was in tears: "We're going to live!" (see figure at right).
Evidence of survival with a protease inhibitor. A Kaplan-Meier analysis demonstrating the proportion of subjects who survived and remained free of a new AIDS-defining diagnosis while being treated with either ritonavir or placebo. Exclaimed TAG's first Antivirals Project Director upon seeing these results for the first time in 1996: "We're going to live!" Adapted from Cameron et al. Lancet. 1998 Feb 21;351(9102):543-9.
On February 29, 1996, the FDA advisory committee reviewed ritonavir. Spencer Cox was the ad hoc community representative on the panel. The committee resoundingly recommended approval. On March 1, 1996, the FDA approved ritonavir. Merck's indinavir was approved two weeks later, Roche's Amplicor-brand RT-PCR test for HIV RNA was approved three months later, and on June 21, the FDA granted accelerated approval to the first-ever non-nucleoside reverse transcriptase inhibitor, Boehringer Ingelheim's nevirapine (Viramune).
The media became a bit giddy. At the end of June, the Economist cover story read: "A Solution for AIDS?"
Everything culminated at the 11th International AIDS Conference in Vancouver, British Columbia, in early July 1996. John Mellors presented his famous paper from the Multicenter AIDS Cohort Study (MACS) showing that viral load predicted the rate of CD4 decline. Virologist John Coffin delivered his famous metaphor comparing the HIV-infected patient to a train speeding along a track towards a deadly cliff -- the viral load conveying the speed of the train, with CD4 count measuring the distance to the cliff.
On July 11, 1996, the last day's late-breaker presentations confirmed the overwhelming and unexpected benefit of triple-combination therapy when initiated simultaneously in people who had never received the drugs in question. Six researchers from four teams showed results from six studies of five different regimens that reduced HIV RNA levels to undetectable levels in the plasma.
One of the most dramatic presentations was made by David Ho of the Aaron Diamond AIDS Research Center (ADARC), presenting on 12 antiretroviral-naive individuals receiving AZT, 3TC, and nelfinavir. CD4 counts started at 245 and viral load at 56,000. CD4 counts rose by about 100 cells, while "at twelve weeks, all eleven patients remaining on the study had levels below that threshold [25 HIV RNA copies/ml], and predicted that they were essentially at zero."
As I wrote in Viral Load in Vancouver:
On August 6, I went down to the NIH Clinical Center for my second lymph-node biopsy. My viral load was 76,790 (Chiron bDNA). The next day, I started my first antiretroviral treatment: 3TC, d4T, and indinavir. By August 23, my viral load had dropped to 2,932 (PCR). By December, my CD4 cells had risen from 152 to 597, and my viral load was undetectable.
Not everyone fared as well. Spencer Cox, who was extensively antiretroviral-experienced, mostly with nucleoside analogues, initially responded well to ritonavir but then developed resistance. In midsummer, he switched to indinavir, yet by late September his viral load was virtually back to baseline, at 400,000, just seven months after starting ritonavir. We all feared this trajectory was a harbinger of dangers that might be ahead for everyone who appeared to benefit in the short-term from triple-combination therapy.
On September 21, Tae-Wook Chun, then of Robert Siliciano's lab at Johns Hopkins, later at NIAID, lectured at ADARC on cellular latency of integrated HIV provirus in resting CD4 cells. This prefigured the end of the eradication theory put forth by David Ho and Alan Perelson earlier in the year, by which triple therapy given for a few years might cure HIV.
Two days later, we met Mike Saag from the University of Alabama at Birmingham to talk about his proposed START protocol ("Strategic Timing of ART," ACTG 355). This study would be labeled "overly ambitious" by the ACTG and withdrawn in March 1997. The ACTG would never do a "when to start" study, and 17 years later we still don't know the best time to initiate ART for individual benefit.
That fall, the Department of Health and Human Services convened a Public Health Service panel to develop clinical-practice guidelines for HIV. Both Spencer Cox and I were named to the panel, which was to develop the first guidelines for the use of highly active antiretroviral therapy (HAART).
Laurie Garrett's cover story in Newsday, "The Curse of the Cure," rounded out the year on December 17. Spencer and I were on the cover. Which one had the drug-resistant HIV? And how long would the benefits of HAART last for anyone, drug-experienced or drug-naive?
At the end of that year, I wrote in TAGline:
This article was provided by Treatment Action Group. It is a part of the publication TAGline.
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