Extended Triple Antiretroviral Therapy Maintains Superiority

November 1, 1995

SAN FRANCISCO-Two separate clinical trials have demonstrated that triple combination antiretroviral therapy maintains its superiority over double therapy in the extended treatment of HIV infection, although neither study included clinical morbidity as an endpoint.

SAN FRANCISCO-Two separate clinical trials have demonstrated thattriple combination antiretroviral therapy maintains its superiorityover double therapy in the extended treatment of HIV infection,although neither study included clinical morbidity as an endpoint.

In the first multicenter study (AIDS Clinical Trials Group Protocol-ACTGP229), presented at the 35th Interscience Conference on AntimicrobialAgents and Chemotherapy (ICAAC), 302 HIV-infected patients wererandomly assigned to triple or double therapy for an initial periodof 24 weeks.

Triple therapy consisted of the HIV protease inhibitor saquinavir(Hoffman-La Roche) and the two nucleoside analog reverse transcriptaseinhibitors zidovu-dine (AZT, Retrovir) and zalcitabine (ddC, Hivid),while double therapy consisted of saquinavir plus AZT or ddC plusAZT, said Ann C. Collier, MD, associate professor of medicineand head, AIDS Treatment Unit, University of Washington, Seattle.

Doses were as follows: saquinavir, 600 mg three times daily; AZT,200 mg three times daily; and ddC, 0.75 mg three times daily,given orally.

The study included 302 patients, 279 of whom completed 24 weeksof therapy. The results showed that triple therapy raised CD4+cell counts and lowered the level of circulating virus more thandid either of the double therapy combinations, Dr. Collier said.Also, after 24 weeks, CD4+ cell counts had returned to baselinein 37% of those on saquinavir plus AZT and 55% of those on ddCplus AZT, compared with 31% of persons on the triple-drug regimen.

To evaluate the safety, tolerance, and antiviral efficacy of continuedtherapy with saquinavir in combination with one or two of thenucleosides, Dr. Collier said, 244 of the original 302 patientsparticipated in a 24-week extension study.

Of these, 218 individuals were eval-uable at the end of the study.The three treatment regimens were fairly well tolerated, Dr. Colliernoted, with only 19 patients leaving the study for reasons ofdrug-related toxicity.

While the antiviral effect seen with these antiretroviral therapeuticregimens waned with time, triple therapy maintained its antiviralsuperiority over both double combinations, with 54% of patientson triple therapy having CD4+ counts greater than baseline at48 weeks, compared with 36% of patients on saquinavir plus AZT,and 37% of patients on ddC plus AZT.

Furthermore, there was a mean 50-cell maximum increase in CD4+counts with triple therapy, compared with a 30-cell increase withsaquinavir plus AZT, and a 20-cell increase with ddC plus AZT.

Finally, triple therapy resulted in the greatest viral suppression,with a 71% decrease in viral load from baseline with triple therapyvs 30% for saquinavir plus AZT and 43% for ddC plus AZT.

Nevirapine Study

In ACTGP 241, presented at the Infectious Diseases Society ofAmerica's 33rd Annual Meeting given in conjunction with ICAAC,a subgroup analysis showed that the overall benefit of tripletherapy extended across all levels of CD4+ cell counts, said Dr.Maureen Myers, clinical program director, Virology Group, BoehringerIngelheim Pharmaceuticals (Ridgefield, Conn).

This 48-week, randomized, double-blind, placebo-controlled trialcompared triple therapy using the non-nucleoside reverse transcriptaseinhibitor nevirapine (Boehringer Ingelheim Pharmaceuticals) plusdidanosine (ddI, Videx) and AZT, with double therapy consistingof ddI and AZT in 398 HIV-infected patients with significant priorexposure to nucleoside therapy.

Doses were as follows: nevirapine, 200 mg twice daily; ddI, 125or 200 mg twice daily; and AZT, 200 mg three times daily.

The overall analysis pointed out the significant superiority oftriple over double therapy at 48 weeks for CD4+ cell counts, percentof CD4+ T lymphocytes, plasma HIV-RNA, viral infectivity titer,and p24 antigen, Dr. Myers said.

Subgroup Analyses

Further analyses evaluated response to therapy in two subgroupsof patients, the first defined by baseline CD4+ cell counts, andthe second by prior exposure to AZT. This latter factor allowedthe evaluation of the magnitude of response to the addition ofddI alone compared with the addition of ddI plus nevirapine simultaneously.

While the benefit of the triple combination was seen across allCD4+ cell count strata, Dr. Myers said, it was particularly notablein the subgroup of patients with baseline CD4+ counts of 51 to200/mm³. In these patients, the positive effect of tripletherapy was maintained throughout the 48-week study period, whilefading more rapidly in those on double therapy.

Examination of the subgroup that had received only AZT as priortherapy showed that improvement in CD4+ cell count, which occurredwhen ddI was added to AZT, was significantly enhanced when nevirapinewas added to the treatment regimen.

The long-term, 48-week response to triple therapy was improvedby an increase of 22 CD4+ cells and a 0.34 log10 reduction inviral RNA over double therapy. Not unexpectedly, prior exposureto ddI or ddC dampened CD4+ and viral RNA responses in both groups.