On a Darkling Plain -- The Years of Despair
Before the Discovery of HAART
The polymerase chain reaction (PCR) method of measuring DNA or RNA sequences by multiplying their binding to a target genetic sequence was discovered by Kary Mullis and colleagues in 1983. By 1989, early forms of PCR were being applied to HIV research. In January 1995, David Ho and colleagues from New York's Aaron Diamond AIDS Research Center (ADARC) showed in a study of quantitative PCR that unlike the nucleosides, more potent protease inhibitors such as Abbott's ritonavir could reduce HIV levels by 99% (two logs of 10) within two weeks.8 (The weakest nucleoside, ddC, reduced HIV by only one-half log.) However, when protease inhibitors were used alone, drug resistance soon emerged as well.
Now researchers had a tool to measure -- and to try to prevent -- the rebound in viral replication that occurred so quickly after an initial decline on any single drug.
In February 1995, at a hearing of the National Task Force on AIDS Drug Development, TAG and GMHC delivered a series of recommendations to the manufacturers for each protease inhibitor. We recommended that Roche double the size of its pivotal saquinavir efficacy trials. We were scathing about Merck's studies of L-735-524 (MK639, later indinavir), calling them "poorly controlled, badly designed, inadequately powered, and unlikely to provide useful information on the drug's clinical utility."9
However, the activists praised Abbott for adopting a "novel 'standard-of-care' control arm [in its studies of ABT-538 (ritonavir)] ... [allowing p]atients to take any nucleoside analogue they wish, with the possible exception of 3TC ... [and] then be randomized to receive either ABT-538 or a matching placebo."10 This control arm had originally been proposed by Spencer Cox of TAG.
Later in 1995, the first study demonstrating clear clinical benefit to combination therapy was announced. It was a by-now-retrograde comparison of AZT alone, ddI alone, AZT + ddI and AZT + ddC. For once, the researchers studied the regimens in people who were not yet already AZT-resistant. The results of the study, ACTG 175, showed that the combination of AZT and ddI was clearly better than AZT alone. However, ddI alone also appeared to be better than AZT alone, and the study wasn't big enough to conclusively show that two drugs were better than one.
Another study with early results showed something even more promising. Abbott presented some tantalizing early results of ritonavir as monotherapy and in combination. As TAG reported at the time:
We were so used to unsubstantiated or later-to-be-discredited industry -- and, for that matter, academic and NIH -- hype that we were instinctively incredulous at Abbott's claim for the unprecedented ability of a triple combination including two mediocre drugs -- AZT and ddC -- plus the superpotent but also new and untried ritonavir, to render viral cultures negative or viral load in the blood undetectable.
The year ended with a whimper, not a bang. The FDA gave stavudine (d4T) full approval, despite the inadequately powered studies. It approved Glaxo Wellcome's new me-too drug 3TC. And it gave accelerated approval to Roche's saquinavir, the first protease inhibitor approved, and also the weakest.
In the United States, the wave of AIDS-related illness and death crested in 1995.
By 1995, just fourteen years after the disease was identified, the New York Times reported that AIDS had become the leading cause of death among Americans ages 25-44.12 In that year, cumulative U.S. AIDS deaths (311,381)13 as reported by the CDC surpassed the total U.S. battlefield deaths in World War II (291,557).14
It didn't seem like drug development was making a dent in the relentless piling up of bodies.
This article was provided by Treatment Action Group. It is a part of the publication TAGline.
Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read TheBody.com's Comment Policy.)