Three seminal studies that compare efficacy of the three leadingdrugs currently prescribed to treat HIV infection show that initiatingtherapy earlier in the course of the disease reduces progression toAIDS and to mortality

Today's New England Journal of Medicine (NEJM) devotes its first25 pages, plus a two-page editorial, to final findings of the studies.The first article, which leads the NEJM issue, bears the self-explanatory title: "A trial comparing nucleoside monotherapy withcombination therapy in HIV-infected adults with CD4 cell countsfrom 200 to 500 per cubic millimeter."

Launched in December 1991, and sponsored by the AIDS Division ofNational Institute of Allergy and Infectious Diseases (NIAID), thefirst treatment study, AIDS Clinical Trials Group (ACTG) 175,enrolled 2,467 early stage HIV patients to measure the relativeclinical benefit of AZT (zidovudine), ddI (didanosine) and ddC(zalcitabine), taken alone or in various combinations. (See BioWorldToday, Feb. 29, 1996, p. 1.)

NIAID's director, Anthony Fauci, acclaimed ACTG 175's results as"noteworthy because it was the first trial to provide conclusiveevidence that antiretroviral therapy could reduce the risk of death inpeople with intermediate-stage HIV and no symptoms."

A second study, Fauci added, of viral replication and immuneresponses in 391 subjects, a subgroup of ACTG 175, "providedimportant information on combination therapy for HIV-infectedpeople with more advanced disease."

Fifty-two AIDS treatment sites throughout the U.S. and Puerto Rico_ 43 of them from the ACTG 175 team, and nine run by theNational Hemophilia Foundation _ took part in the largest-scaleclinical trial. Its 2,467 participants, averaging 40 years of age, weremainly male, white and non-Hispanic. Homosexuals numbered 1,608,injection-drug users, 355, and hemophiliacs, 202. All but 438 weresymptom-free upon enrolling in the study between 1991 and 1992.

Antiviral Combos: Good? Better? Best?

The cohort followed one of four antiviral treatment programs: AZTalone; AZT plus ddI; AZT plus ddC; ddC alone. This meant thatmany of the patients were swallowing 20 pills a day, whichapparently accounted in part for a 19-percent drop-out rate.

During a three-year follow-up period, the investigators measuredthese four courses of reverse-transcriptase-inhibiting chemotherapyagainst three indicative clinical outcomes, namely: significantlydeclining CD4-positive T-cell counts; contracting a new AIDS-defining condition (such as Pneumocystis carinii pneumonia), ordeath. Five-hundred sixty-five participants reached this primaryendpoint.

The study found that ddI taken alone (with 5 percent mortality)scored highest in preventing or postponing these seriousconsequences of HIV infection, whereas AZT alone (at 9 percent)ranked lowest. Another key conclusion: Lowering viral load in apatient's blood, by the antiviral drug treatment, reduced the risk ofprogressing to AIDS or dying.

A smaller, separate study of 1,102 sicker people, with CD4 countsbelow 200, determined that those who had never before receivedantiretroviral therapy (at a time when AZT was the only such game intown) scarcely benefited from the new combination regimens, orfrom AZT by itself.

"[AZT's] beneficial effects," the first paper pointed out, "wane withtime, and a survival advantage is not conferred by prolonged therapyin asymptomatic subjects."

In an editorial accompanying the three reports, Lawrence Corey, whoheads the department of virology at the University of Washington inSeattle, wrote: "Recent results from the European Delta trial confirmthese results. The Delta trial enrolled more than 3,000 symptomaticpatients with CD4 counts between 50 and 350 T cells per cubicmillimeter."

Corey told BioWorld Today: "These NEJM reports are sort ofdefinitive proof of the Delta trial that initiating therapy earlier in thecourse of the disease gives significant benefit with respect toreducing progression to AIDS, and to mortality."

He added: "A major message and implication of the articles is thatthey bring a whole new, large dimension of people under theumbrella of therapy for HIV infections. It shifts the paradigm tomajor benefit for the individual."

Addressing the relevance of these findings to discovery anddevelopment of therapeutic drugs, Corey pointed out: "The more weinhibit the virus, the more likely a better clinical outcome will be.This gives hope with respect to the issue of getting better drugs. Sofrom the biotechnology industry point of view, the outlook is quitebullish. It totally wipes out the "nothing-can-be-done-about-it"nihilism that was around in this area a couple of years ago."

He observed that "measuring plasma HIV-RNA concentration isreally important, to determine who should get therapy, and whether apatient is responding to treatment. Such viral load testing is nowbeing made available to a large number of physicians."

But he sees a continuing role for CD4 counts as "actually needed inclinical care, because they measure overall immunologicalresponsiveness of the patient, and whether they need _ and at whattime they should have initiated _ things like prophylaxis withantibodies."

Corey concluded: "As for my comment on bringing more peopleunder the early-therapy umbrella, I think the [biotechnology]investors will get the point." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.