Since the discovery of AZT as an antiretroviral agent, NIAID intramural investigators have studied the potential role of combination therapies involving antiretrovirals and immunomodulators in the treatment of HIV-infected people.
While much of their recent work has focused on interleukin-2 in combination with reverse transcriptase or protease inhibitors (see AIDS Agenda, Spring 1995), NIAID researchers also have continued to explore the potential role of interferon-alpha (IFN-alpha) as a component of combination therapy for HIV disease.
A recent report by the NIAID/Clinical Center intramural AIDS program notes that the combination of didanosine (ddI) plus IFN-alpha, at appropriate doses, can be administered safely to HIV-infected people over prolonged periods of time and may benefit selected patients.
The report, in the April Journal of Infectious Diseases, builds on NIAID studies conducted in the late 1980s (see Annals of Internal Medicine 1989; 111:280-287). The early NIAID studies, as well as research from other groups, found that the combination of AZT and IFN-alpha could be safely given to HIV-infected patients and demonstrated evidence of anti-HIV and anti-tumor effects. This research paved the way for subsequent studies of other multi-drug anti-HIV regimens.
Today, a consensus has emerged that combination therapy, rather than treatment with a single anti-HIV agent, offers the best hope of suppressing HIV for long periods of time (see AIDS Agenda 12/95, 3/96). The current NIAID research suggests that IFN-alpha may have a role in anti-HIV treatment regimens.
Inclusion of IFN-alpha in combination therapies may provide important benefits to HIV-infected people, since its probable mechanisms of antiretroviral activity -- blocking viral assembly and/or enhancing HIV-specific host immune responses -- are different from that of ddI and related drugs, which inhibit reverse transcriptase," says Joseph Kovacs, M.D., lead author of the new study. "Targeting separate aspects of the viral life cycle may lead to improved antiviral activity and/or decreased resistance." He notes that test tube studies have shown that IFN-alpha and nucleoside analogues together have a much stronger anti-HIV effect than they do separately.
Long-term utilization of combinations of IFN-alpha and ddI or related drugs may be especially useful for patients with Kaposi's sarcoma, for whom IFN-alpha is an approved drug and often administered chronically," says co-author H. Clifford Lane, M.D., NIAID Clinical Director.
In the current study, 36 asymptomatic patients with CD4+ T cell counts greater than 200/mm3 (mean 448/mm3) were divided into 12 groups (three patients per group) and received sachets of ddI (100 mg, 250 mg, or 375 mg) twice daily for at least six weeks.
After this period, patients received one of four subcutaneous doses of IFN-alpha (1, 5, 10 or 15 MU/day) for an additional 28 weeks.
An additional 14 patients, with a mean CD4+ T cell count of 310/mm3, comprised a 13th group. These individuals had previously received IFN-alpha plus AZT for seven to 45 months. They remained on their previous IFN-alpha dosage (1 to 15 MU/day) and immediately started on the highest dose of ddI.
Of the 36 patients in groups one to 12, 25 completed the initial 34 weeks of the study. In group 13, nine patients completed the study. Pancreatitis, seen in six patients, was the most common dose-limiting toxicity, and occurred only in patients receiving the two higher doses of ddI and at least 5 MU/day of IFN-alpha. Ten other patients, all of whom were receiving the higher doses of ddI and/or IFN-alpha, discontinued therapy prematurely due to events such as flu-like symptoms, peripheral neuropathy and declines in blood cells called neutrophils.
"On the basis of the toxicity profile seen in our study, the maximal tolerated dose for long-term combination therapy is a 250 mg ddI sachet twice daily (equal to 200 mg twice daily in tablets) and 5 MU/day for IFN-alpha," says Dr. Kovacs.
Among most patients in groups one to 12, the investigators noted an increase in CD4+ T cell counts and CD4+ T cell percentages during therapy with ddI alone. Following the addition of IFN-alpha, CD4+ T cell percentages remained elevated while CD4+ T cell counts tended to decrease slightly. Group 13 patients, who previously had received IFN-alpha, showed a trend toward an increase in both CD4+ T cell counts and CD4+ T cell percentages soon after switching to ddI from AZT.
Upon enrollment, 11 patients in groups one through 12 had evidence in their bloodstream of p24 antigen, a protein from the core of HIV. During treatment with ddI alone, seven of these patients had declines in p24 antigen of at least 50 percent, and five had declines after the addition of IFN-alpha. Levels of p24 antigen became undetectable by week 34 in three patients, and no patient who was p24 antigen-negative at enrollment developed antigenemia during the 34 weeks.
Among eight patients in group 13 who were p24 antigen-positive at enrollment, four had at least a 50 percent decrease by week six of ddI therapy; levels declined further in two patients remaining in the study through week 34. No patient in group 13 developed new antigenemia during the study.
In groups one to 12, 17 patients had more than 10,000 copies of HIV RNA per mL of blood at study enrollment. In 13 of these patients with pre-therapy levels of less than 60,000/mL, HIV RNA fell below 10,000 copies/mL by week six. Of the remaining four patients, three had greater than 50 percent decreases in HIV RNA levels after the addition of IFN-alpha.
Thirty patients elected to remain in the study past week 34. Of these individuals, 14 patients have continued in the study 177 to 215 weeks after enrollment, with CD4+ T cell counts that have ranged between 85 percent and 115 percent of baseline.
"Our study has demonstrated that didanosine and IFN-alpha can be safely administered in combination to select patients for over four years," says Dr. Kovacs. "As this was an open-label, non-randomized study, further research is needed to definitively address the role of combination therapy with ddI and IFN-alpha in inhibiting HIV," he emphasizes.
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