The Hopkins HIV Report A bimonthly newsletter for healthcare providers Volume 8, Number 4, November 1996

News From ICAAC: Antiretroviral Therapy

Joel E. Gallant, M.D., M.P.H.

With the International AIDS Conference in Vancouver only a recent memory, it was no surprise that there wasn't a great deal of news on antiretroviral therapy at ICAAC in New Orleans. Nevertheless, a number of important studies were presented at Monday's Late-Breaker session, including the CAESAR study, which demonstrated a clinical and survival benefit of 3TC, as well as a study confirming the safety and efficacy of combination therapy with ritonavir and saquinavir, and early studies of two promising new antiretroviral agents: 141W94, an investigational protease inhibitor, and DMP-266, a new non-nucleoside reverse transcriptase inhibitor.

The CAESAR Study

Dr. Julio Montaner presented preliminary results from the CAESAR study, a multinational trial in which participants were randomized in a 2:1:1 fashion to receive either 3TC, 3TC plus loviride (a non-nucleoside reverse transcriptase inhibitor), or placebo, in addition to an AZT-containing regimen (AZT monotherapy, AZT/ddI, or AZT/ddC) [Abstract LB-6*]. After 52 weeks on blinded therapy, all participants were offered open-label 3TC and loviride. Primary endpoints were progression to new AIDS events or death. Entry criteria included a CD4 count between 25 and 250 cells/mm3.

The study was unblinded early after an interim analysis revealed that 3TC was superior to placebo. Progression or death occurred in 17% of those taking placebo compared to 9% and 8% in those taking 3TC or 3TC/loviride, respectively (p=.0001 for 3TC vs. placebo). Death occurred in 4.6%, 2.4%, and 2.7%, respectively (p=.012 for 3TC vs. placebo).

Thus, the CAESAR study confirmed the clinical benefit of adding 3TC to AZT-containing regimens, and this benefit included a reduction in mortality. There was no additional benefit to the addition of loviride, although the study was not powered to detect a difference between the 3TC arm and the 3TC/loviride arms. The data have not yet been analyzed to look for differences based on the AZT-containing arm.

More on the Ritonavir/Saquinavir Combination

It has been known for some time that ritonavir increases the bioavailability of saquinavir, but concerns over additive hepatotoxicity have kept this com-bination from being used clinically. Data presented at the international conference in Vancouver suggested that the combination was safe and effective. In New Orleans, Dr. Cal Cohen from the Community Research Initiative of New England presented results of a trial of combination therapy with ritonavir (RTV) and saquinavir (SQV) in patients with CD4 counts between 100 and 500 cells/mm3 who had no prior exposure to protease inhibitors [Abstract LB-7b]. After discontinuing nucleoside reverse transcriptase inhibitors, participants were assigned to receive one of four regimens:

A. RTV 400 bid + SQV 400 bid
B. RTV 600 bid + SQV 400 bid
C. RTV 400 tid + SQV 400 tid
D. RTV 600 bid + SQV 600 bid

Thirty patients were assigned to each group. Complete data were available for groups A and B, while data for groups C and D were preliminary. Viral load at baseline was approximately 4.5 logs.

Groups A and B experienced profound antiviral effects at 12 weeks, with a median RNA decrease of over 3 logs and a median increase in CD4 cell count of over 100 cells/mm3 in group B. Viral load was undetectable (< 200 copies/ml) in approximately 75% at two weeks. Groups C and D appear to be behaving similarly so far, although data are only available to 6 weeks. There was more intolerance of the tid regimens than the bid regimens.

While it is not clear that the combination of ritonavir and saquinavir is superior to combinations of indinavir or ritonavir with one or two nucleosides, it offers a safe and attractive option for patients who have been heavily pre-treated with nucleoside analogs. Such patients may have extensive nucleoside resistance and cross-resistance, and therefore, may not experience sustained benefit when a single protease inhibitor is used with nucleoside analogs.

141W94, a New Protease Inhibitor

Dr. Robert T. Schooley, from the University of Colorado Health Sciences Center, presented data from a multicenter, open-label phase I/II dose escalation trial examining the safety and efficacy of the investigational protease inhibitor, 141W94 (Vertex GlaxoWellcome) [Abstract LB-7a]. The drug is felt to have good bioavailability and a unique resistance profile, and it exhibits synergy with nucleoside analog reverse transcriptase inhibitors.

In this trial, 42 patients with CD4 counts between 150 and 400 cells/mm3 and no prior exposure to protease inhibitors received monotherapy with 141W94 for four weeks at doses of 300 mg bid (600 mg), 300 mg tid (900 mg), 900 mg bid (1800 mg) and 1200 mg bid (2400 mg). A dose-response effect was seen in this trial with respect to reduction of viral RNA, with a median maximum decline of 1.95 logs and a median maximum increase in CD4 count of 110 cells/mm3 at the highest dose. 141W94 was well-tolerated, although three patients discontinued the drug because of adverse events.

It is hoped that 141W94 will penetrate the CNS more effectively than currently-available protease inhibitors. Thus far, however, data on CSF drug levels are available only for a small number of patients, and levels varied widely.

DMP-266: A New NNRTI

Dr. Douglas Mayers presented data from a small trial examining the safety and efficacy of DMP-266 (Dupont Merck), a new non-nucleoside reverse transcriptase inhibitor (NNRTI) [Abstract LB8a]. Sixteen patients with CD4 counts between 200 and 500 cells/mm3 and HIV RNA > 20,000 copies/ml were random-ized to receive either DMP-266 monotherapy (200 mg qd) or placebo. Thirteen patients (81%) had received antiretrovirals previously, including one who had received a protease inhibitor. After a period of two weeks, open-label indinavir was added to both regimens.

Patients receiving DMP-266 mono-therapy had an average viral load reduction of 1.68 logs at two weeks, with a CD4 increase of 96 cells/mm3. After the addition of indinavir, viral load in patients taking DMP-266 plus indinavir dropped to 3.2 logs below baseline, compared to 2 logs in those taking indinavir monotherapy. Viral load was suppressed below 400 copies/ml in 80% of those on combination therapy, compared to 20% on indinavir monotherapy. However, patients taking indinavir alone had greater average increases in CD4 cell counts than those on combination therapy, possibly because DMP-266 lowers indinavir levels.

*Abstract numbers refer to Abstracts of the 26th ICAAC, New Orleans, LA. Washington: American Society for Microbiology, 1996.