Quadruple Therapy With a Protease Inhibitor and NNRTI Achieves Highest Rate of Viral Suppression in Nucleoside Analogue-Experienced Patients

Quadruple therapy consisting of two nucleoside reverse transcriptase inhibitors (one of which is new), a protease inhibitor and a non-nucleoside reverse transcriptase inhibitor achieves a higher rate of viral suppression in patients who have already been treated with NRTIs than treatment regimens consisting of NRTIs and either a NNRTI or a protease inhibitor, according to a study published in the Aug. 9 edition of the New England Journal of Medicine. Dr. Mary Albrecht and colleagues of the AIDS Clinical Trials Group monitored 195 patients with initial HIV RNA levels of >= 500 copies per milliliter to determine which of three randomly assigned combinations -- two NRTIs plus the NNRTI efavirenz, two NRTIs plus the protease inhibitor nelfinavir or two NRTIs plus both efavirenz and nelfinavir -- was most successful at suppressing the viral load level below 500 copies per milliliter. All of the patients had undergone therapy with at least one NRTI before, but none had used an NNRTI or a protease inhibitor. Viral suppression was achieved in 81% of the quadruple therapy group at 16 weeks and in an average of 74% of the group at weeks 40 and 48. Sixty-nine percent of the patients in the efavirenz-only group achieved viral suppression at 16 weeks, with an average of 60% maintaining suppressed levels at 40 and 48 weeks. Of the group that received nelfinavir only, 64% had viral suppression at 16 weeks, but that number dropped to an average of 35% for weeks 40 and 48.

Implications
According to the study's authors, the findings indicate that quadruple therapy offers "significantly more durable suppression" than either version of triple therapy. "Extensive previous treatment" with NRTIs that has led to zidovudine resistance "may result in hypersusceptibility to NNRTIs" and the continued use of NRTIs to "maintain hypersusceptibility in salvage regimens ... warrants further evaluation," they state. "Although conserving some classes of treatment for later use is an important consideration ... [t]he benefits of using additional classes of potent agents, as we did in the nelfinavir-plus-efavirenz group, with the goal of suppressing viral replication to below the limit of detection and of restoring the immune response must be weighed against the potential risks of incurring new or long term toxic effects and limiting future treatment options," the researchers conclude (Albrecht et al., NEJM, 8/9).

Options Needed
In an accompanying commentary, Drs. Julio Montaner of the University of British Columbia and John Mellors of the University of Pittsburgh School of Medicine write that the study "confirm[s] the importance of prescribing, whenever possible, at least two drugs of new classes for patients who have already received treatment, so as to increase the likelihood of a sustained virologic response." However, when patients have already been exposed to two or three classes of drugs, very few effective treatment options remain, with the "likelihood of achieving [viral] suppression ... decreas[ing] with each subsequent treatment regimen." Some physicians, they note, "abandon the goal of viral suppression" in treatment-experienced patients. This "nonaggressive approach," however, may lead to an "inability to identify and correct reversible causes of treatment failure," the "continued evolution of resistance and cross-resistance" to antiretrovirals, "continued transmission of drug-resistant HIV" and impediments to "efforts to develop better suppressive treatments that involve the use of several investigational agents." Several drugs currently in development "offer some promise" for patients who have already been treated, Montaner and Mellors note. However, the "staggered release" of new drugs "through uncoordinated programs of expanded access" often results in the "addition of only one new drug at a time to a failing treatment regimen," they state. Coordinating expanded-access programs should enable doctors to "gain access to more than one investigational agent at a time," Montaner and Mellors continue. "We need greater cooperation among academia, industry and regulatory agencies to improve outlook for the patients for whom effective treatment options are currently lacking," they conclude (Montaner/Mellors, NEJM, 8/9).