Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 7 July/August, 1993
Gabriel Torres, M.D.

Nevirapine

Dr. Diane Havlir from the University of California at San Diego presented results from ACTG 164, an open-label study of nevirapine monotherapy in 38 HIV-positive patients with CD4 counts less than 400, no previous opportunistic infections, and p24 antigenemia. Participants had taken AZT for an average of 45 weeks, yet all had a 28-day washout period prior to starting 400mg/day of nevirapine. The most common side effect of nevirapine at this dose was a rash involving the trunk and extremities which occurred in 48 percent of patients after a median of thirteen days. Fever and muscle aches also occurred in many patients. The rash could be ameliorated by escalating the dose slowly from 12.5mg/day to 400mg/day over several weeks. Another common toxicity was elevated liver enzymes.

Eight of ten evaluable patients who completed eight weeks of therapy showed a sustained 50 percent reduction in p24 antigenemia as well as a reduction in quantitative HIV RNA after four weeks. The CD4 counts showed a modest rise followed by a decline. There was a demonstrable relationship between higher plasma levels of nevirapine and p24 responses. Although study investigators had hoped that the 400mg dose of nevirapine would delay the onset of resistance to the drug, resistance still developed quickly. However, sustained antiviral activity, measured by p24 antigen suppression, was still demonstrable.

A research group from the Netherlands presented a poster describing a trial which compared alternating and concurrent regimens of AZT and nevirapine.[1] Seventeen p24 antigenemic, AZT-naive patients with CD4 counts less than 500 were treated for a median duration of 50 weeks with combinations of alternating and concurrent nevirapine at 200mg/day and AZT at 600mg/day. After sixteen weeks of treatment, those receiving concurrent treatment had better and more sustained immunologic and virologic responses than those who received the alternating regimen. CD4 counts returned to baseline in both groups after one year of treatment. An Australian study also showed that alternating regimens of AZT and nevirapine were not effective in delaying the emergence of resistance against nevirapine.[2]

Convergent Combination Therapy

Convergent combination therapy, first proposed in February by Yang Kung-Chow, a doctoral student at Harvard Medical School, claimed that three-drug combinations, including AZT and ddI, with either nevirapine, Merck's L-drug, or foscarnet completely stopped HIV replication in test tubes. [See Treatment Issues March/April 1993 for coverage of convergent combination.] A press release issued by the Massachusetts General Hospital which described the discovery as the "Achilles heel of HIV" fueled a media frenzy. However, new information presented in Berlin by several research teams, including Chow's, show that the original report was inaccurate.

Although the original report claimed three drug combinations rendered HIV incapable of replication, with multiple passages in the test tube, resistance developed to all three drugs and the virus remained viable. Despite this setback, convergent combination may still have a role. Firstly, test tube experiments used sequential drug treatment to select for resistance. The clinical study of three-drug combinations, ACTG 241, uses concurrent therapy. Secondly, although three-drug combinations do not eliminate HIV as originally hoped, convergent combination may still delay the onset of resistance or decrease viral burden more than other regimens, possibly extending or improving the clinical effect of the drugs.

3TC: The Next Nucleoside

3TC is a nucleoside analogue similar to AZT which is being developed by Glaxo, Inc. The drug is active against HIV-1, HIV-2, and AZT-resistant viruses. In vitro experiments have shown that 3TC is synergistic with AZT, non-nucleoside reverse transcriptase inhibitors, and with a protease inhibitor. Dr. Mark Wainberg of McGill University presented results from a phase I/II study of 3TC conducted at three sites in the US and Canada. In this open-label, non-randomized, dose-escalation study, 3TC was administered twice daily in escalating doses between 0.5 and 20mg/kg/day. Ninety- seven patients with AIDS or ARC, with a mean CD4 count of 142, and an average of twenty weeks of previous AZT therapy were enrolled. Four clinical events were found to be probably related to 3TC: insomnia, rashes, increased appetite, and increased energy. Three toxicities noted included vasculitis (inflammation of small blood vessels, usually causing a rash), upper extremity paresthesias (the sensation of "pins and needles"), and photophobia. The main laboratory toxicity was neutropenia which was dose-related and occurred more frequently in the 20mg/kg/day group. Weight stabilization or gain was noted at all dose levels.

Nonsustained increases in CD4 counts were seen at dose levels of 4 to 20mg/kg/day and significant decreases in p24 antigen levels were seen at the highest dose level. Forty-two patients in the study were included in a resistance analysis. Twelve (25 percent) showed reduced sensitivity to 3TC indicating viral resistance, yet no clinical correlation was observed. Clinical progression of disease occurred in thirteen patients and death in eight patients. In vitro studies have shown that the mutation that causes resistance to 3TC may reverse the resistance to AZT.

Future studies are planned using 3TC alone and in combination with AZT or AZT and DDC. In the United States, two 3TC studies are underway. One study compares 3TC with AZT or the combination of both in AZT-naive patients with CD4 counts between 200 to 500. The other trial includes patients with CD4 counts between 100 and 400 who have received AZT for six months or longer. This trial compares two doses of 3TC and AZT to AZT/ddC combination. In the New York area, the 3TC trials are enrolling at St. Luke's-Roosevelt Hospital (212/523-6743) and the Nassau County Medical Center (516/542- 5707). In the United Kingdom, a phase II study of AZT (200mg tid) versus AZT plus 3TC (300mg bid) in patients with 100 to 400 CD4 cells is ongoing.

Tat Antagonist Disappointment

Dr. Rich Haubrich of the University of California at San Diego presented results from the first human clinical trial of Hoffmann LaRoche's much-publicized tat antagonist.[3] This trial, designated ACTG 213, investigated the safety, tolerance, pharmacokinetics, and activity of oral R0 24-7429, the official name for the Roche drug. Tat, a crucial regulatory gene of HIV, leads to increased viral production. By blocking the function of the tat gene, researchers hoped to reduce HIV replication. The tat antagonist has been shown in test tube experiments to keep the virus in dormancy and to be active in chronically infected cell lines.

In this clinical trial, 96 HIV-infected patients with CD4 cells between 50 and 500 were randomized to receive 75, 150 or 300mg/day of the tat antagonist or nucleoside analogue therapy (AZT or ddI) given orally for twelve weeks. Half of the patients in each group had detectable serum p24 antigen at baseline. Eighty- three percent of the patients completed eight weeks of therapy. The most common side effect was a rash which occurred in 24 percent of patients, usually within two weeks of starting therapy. A few patients also had elevations of liver function tests, headaches, fever, and an increase in the number of KS lesions.

Compared with patients receiving AZT or ddI, those receiving the tat antagonist had declines in CD4 cell counts and rises in p24 antigen levels, indicating poor or no antiviral activity. Quantitative HIV RNA from this study was not available at the time of the presentation. In addition, no data were available on blood levels of the tat antagonist in order to ascertain if the drug was absorbed from the gastrointestinal tract. Needless to say, the data on the tat antagonist were a disappointment for those who hoped that this agent would open the gate to the next generation of antiretroviral agents.

Protease Inhibitors: The Next, Best Hope

Protease inhibitors inactivate protease, a viral enzyme responsible for cutting newly produced viral precursors into mature proteins and enzymes during viral assembly and maturation. Virions produced in vitro in the presence of a protease inhibitor are non-infectious in cultured cells. Protease inhibitors inhibit HIV production in chronically infected cells.

A-77003: The Abbott Protease Inhibitor

The results of the first clinical trial of the Abbott protease inhibitor, A-77003, were presented by a group of investigators from the Netherlands.[4] In this phase I/II trial, A-77003 was administered as an intravenous infusion over 24 hours, followed by a three- to six-day washout period, followed by a 28-day infusion. Patients received the infusions as outpatients through a central venous catheter with a portable infusion pump. Patients enrolled had CD4 counts between 200 and 500 and were asymptomatic or had previous histories of oral thrush, PCP, or limited KS. Women were excluded from the trial because of lack of data on teratogenicity. Twenty two males with an average CD4 count of 308 were enrolled and given infusions at doses of 0.035, 0.07, 0.14 and 0.28mg/kg/hour. The pharmacokinetics of the protease inhibitor showed that the drug is cleared quickly, with an average half-life of 30 minutes. The investigators conclude that A-77003 is metabolized rapidly, explaining the need for a rapid infusion rate.

The most common adverse effect was phlebitis (inflammation of the vein) which occurred in eight patients receiving the higher dose. The occurrence of phlebitis in most of the patients receiving the higher doses limits continued use of the present formulation. Two patients developed infections related to the catheters and three had elevations in liver function tests. There were no significant changes in CD4 cell counts or p24 antigen levels, though two patients had negative plasma cultures for HIV after the 28-day infusion. However, since the protease inhibitor may lead to the production of inactive virions, the use of p24 antigen levels may not be suitable as a measure of this drug's antiretroviral activity.

R0 31-8059: The Roche Protease Inhibitor

Three trials using the Roche protease inhibitor (R0 31-8959) were presented by investigators from France, the United Kingdom, and Italy. The Roche protease inhibitor is active against HIV at nanomolar concentrations, while toxicity appears only at micromolar concentrations, thus affording a therapeutic index of at least 1000-fold in test tube experiments. In the French double-blind trial, 61 HIV-positive patients who had previously received AZT with CD4 counts between 50 and 250 were randomized to receive one of three doses of the protease inhibitor (75, 200, and 600mg given orally three times daily for sixteen weeks). Sixteen of the 61 participants were women. The drug was well tolerated with few to no adverse effects. A few patients experienced diarrhea, weight loss, and anal sphincter disorders. The highest dose group had the greatest elevations in CD4 counts and decreases in p24 antigen levels, indicating a clear dose response. The maximum increase in CD4 count (56 cells) occurred after four weeks of therapy with a median change of seventeen cells after sixteen weeks of therapy. Plasma levels of the protease inhibitor seemed to correlate with CD4 elevations but the elevations seemed to plateau at a dose of 600mg three times daily, suggesting that increasing the dose beyond this level may not affect CD4 counts. Decreases in plasma viral titers were demonstrated but were not maintained in the majority of patients.

The British study was performed at St. Mary's Hospital in London and examined the effect of the Roche protease inhibitor in asymptomatic or mildly symptomatic HIV-positive patients without prior antiretroviral therapy and CD4 counts less than 500. Four doses were studied (25, 75, 200 and 600mg three times daily). Two patients experienced progression of disease. CD4 count changes tended to be dose-related with the largest increases occurring at the higher dose; the average increase from baseline was 106 cells which occurred after six weeks in the group receiving 600mg thrice daily.

Dr. Stefano Vella from Italy presented the results of a trial comparing the protease inhibitor to AZT alone or the combination of both. Three groups received combination therapy with AZT and either 75, 200, or 600mg thrice daily of the Roche protease. Participants had no previous antiretroviral treatment and had CD4 counts less than 300. The best responses in CD4 counts occurred in the group receiving AZT and the highest dose of the protease inhibitor, with a maximum increase of 147 cells, which was sustained after sixteen weeks. The study concluded that synergy between AZT and the Roche protease inhibitor was present and accounted for the superior effect on the CD4 counts without additive toxicity.

The data on the Roche protease inhibitor, though not spectacular, was perhaps the most encouraging antiretroviral news at the conference. Unfortunately, production of the Roche protease inhibitor requires multiple steps, and drug supply for clinical trials is extremely limited. Finally, ACTG 229, a study of the Roche protease inhibitor in combination with AZT or AZT and DDC, is fully enrolled and is expected to demonstrate whether these drug combinations produce a clinical benefit.

1 Lowenthal M, et al. Abstract PO-B26-2101. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

2 van der Ende ME, et al. Abstract PO-B26-2100. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

3 Haubrich RH, et al. Abstract WS-B26-5. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

4 Danner SA, et al. Abstract WS-B26-6. Ninth International AIDS Conference. Berlin. June 6-11, 1993.

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