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On a Darkling Plain -- The Years of Despair

Before the Discovery of HAART

Fall 2012

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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

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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:

D. Norbeck ... described a French triple-combination study. ... Participants were given AZT/ddC/Ritonavir. Their CD4s went up by 110 and their plasma RNA went down by 2.5 logs at 20 weeks. Over the subsequent weeks, he claimed, an increasing proportion of participants became viral culture negative -- which is to say, they could not culture infected cells from the blood. "Some became PCR and culture negative, which suggests that the viral reservoir was empty.11

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

More Americans died of AIDS in 1995 alone (50,798)15 than on the battlefields of Vietnam during the entire course of that war (47,434).16

It didn't seem like drug development was making a dent in the relentless piling up of bodies.


References

  1. Matthew Arnold. "Dover Beach." New Poems. 1867. The Poems of Matthew Arnold 1840-1867. Oxford U. Press (London, New York) 1909.
  2. Harrington M. TAG at 20: Early Campaigns. TAGLine. 2012 Spring.
  3. Barr D. Necessary diversions: The Boston AIDS conference that never was -- and other grim tales. TAGline. 2003 January/February;10(1):1-5.
  4. Harrington M. The crisis in clinical AIDS research. Treatment Action Group. 1993 December 1.
  5. "F.D.A. Panel Recommends AIDS Drug Despite Incomplete Data," New York Times, May 21, 1994.
  6. Wyatt EA. Rushing to judgment. Barron's. 1994;74(33):23.
  7. Cox S, Dennis Davidson, Gregg Gonsalves, Mark Harrington, Carlton Hogan, Rebecca Pringle Smith. Rescuing Accelerated Approval: Moving Beyond the Status Quo. A Report to the FDA Antiviral Drugs Advisory Committee. 12-13 September 1994 Silver Spring, Maryland. Treatment Action Group 1994.
  8. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123-6.
  9. Barr D, Cox S, Gonsalves G, Harrington M, Link D, Ravitch M, et al.; National Task Force on AIDS Drug Development. Problems with protease inhibitor development plans. Treatment Action Group. 1995 February.
  10. Problems with protease.
  11. Harrington M, Marco M, Cox S, Horn T; Antiviral Committee Opportunistic Infections Committee. TAG does ICAAC: AIDS research highlights from the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Treatment Action Group. 1995 September.
  12. Altman, L. "AIDS Is Now the Leading Killer of Americans From 25 to 44," New York Times, 31 January 1995.
  13. CDC MMWR Weekly. First 500,000 AIDS Cases -- United States, 1995. November 24, 1995/44(46);849-853.
  14. Anne Leland, Mari-Jana "M-J" Oboroceanu. American War and Military Operations Casualties: Lists and Statistics. Congressional Research Service. 26 February 2010. Table 1. Principal Wars in Which the United States Participated: U.S. Military Personnel Serving and Casualties. Tables, p. 2.
  15. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report, 2000;12(No. 2): p. 30. Table 21. AIDS cases and deaths, by year and age group, through December 2000, United States.
  16. American War and Military. Tables, p. 3.
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This article was provided by Treatment Action Group. It is a part of the publication TAGline.
 
See Also
Coverage of the 30th Anniversary of AIDS
20 Years of Magic: How One Man's HIV Disclosure Inspired Others
More on the History of the HIV/AIDS Epidemic

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