Combition therapies for HIV infection and genomic durg resistance
Authors: David Katzenstein
Journal: The Lancet (1997)

Drug combinations that reduce HIV plasma RNA and raise CD4 cell numbers are associated with decreased progression to AIDS and increased survival.1Katzenstein DA Hammer SM Hughes M et al.Virologic and immunologic markers and clinical outcomes after nucleoside therapy in adults with 200 to 500 CD4 cells per cubic millimeter: NIAID sponsored AIDS Clinical Trials Group Study 175, a virology substudy.N Eng J Med. 1996; 335: 1091-1098Crossref PubMed Scopus (459) Google Scholar, 2Eron JJ Benoit SL Jemsek J et al.Treatment with lamivudine, zidovudine or both in HIV-positive patients with 200-500 CD4+ cells per cubic millimeter.N Engl J Med. 1995; 333: 1662-1669Crossref PubMed Scopus (497) Google Scholar, 3Hammer SM Squires KE Hughes MD et al.A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less.N Engl J Med. 1997; 337: 725-732Crossref PubMed Scopus (2385) Google Scholar The recent discovery of families of chemokine receptors that are second ligands for CD4 for viral entry4Dean M Carrington M Winkler C et al.Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene.Science. 1996; 273: 1856-1861Crossref PubMed Scopus (2197) Google Scholar provides evidence that host genomic and phenotypic determinants contribute to the pathogenesis of HIV infection. Drug resistance may explain differences in efficacy between the treatment regimens. In today's Lancet the authors of the Delta study describe their investigation of whether specific drug-resistance mutations explain the differences in clinical and virological effects between combination regimens and zidovudine alone. According to the point-mutation assay used in the study, in patients on zidovudine alone resistance to this drug develops rapidly through changes in HIV RNA at multiple loci in the reverse-transcriptase gene in most patients during the first year of treatment. These zidovudine-resistance mutations evolve even earlier in those patients on the two combination treatments given in the Delta trial, but genotypic or phenotypic evidence of resistance to the second drug (didanosine or zalcitabine) in the combination regimens was not found. Although evolution of zidovudine resistance was faster with combination therapy, the combinations produced a clinical benefit compared with zidovudine alone. Thus genomic resistance alone does not account for differences in efficacy of treatment regimens. Despite their superiority over zidovudine monotherapy, the effect of the combinations on viral RNA and CD4 measures waned after a year. Limiting disease progression and drug resistance, through reduction in HIV RNA replication to levels below detection by sensitive assays (itself the subject of heated debate), is increasingly being advocated as the next goal of antiretroviral treatment.5Carpenter CCJ Fischl M Hammer SM et al.Antiretroviral therapy for HIV Infection in 1997: Updated recommendations of an International AIDS Society-USA Panel.JAMA. 1997; 277: 1962-1969Crossref PubMed Google Scholar So long as virus replication remains below the limits of detection, drug resistance is not detected, and disease progression is limited. Conversely, the detection of virus replication in vivo in the presence of drug is evidence of drug failure and, commonly, of drug resistance. Failure to maintain virological suppression or increased CD4 counts in many patients after a year, in the Delta and ACTG 1751 trials for example, shows that combination nucleoside regimens are often inadequate. The Delta and ACTG 175 trials were designed in 1991, when only three reverse-transcriptase inhibitors were used for HIV infection. Another eight drugs have been licensed in the USA for treatment of HIV-two additional reverse-transcriptase inhibitors (lamivudine and stavudine), two non-nucleoside reverse-transcriptase inhibitors (delaviradine and nevaripine), and four protease inhibitors (saquinavir, indinavir, ritonavir, and nelfinavir), with more to come. Wresting the maximum benefit from drug combinations including protease inhibitors and the non-nucleoside reverse-transcriptase inhibitors is the central challenge in the treatment of HIV infection. Partly suppressive therapies combining zidovudine and a second nucleoside drug reduce plasma HIV RNA and provide clinical benefit but, as shown in the Delta patients, rarely reduce virus replication to sufficiently low levels to limit the emergence of zidovudine resistance. This provides clear evidence for the continued adaptive response of virus through selection in the presence of drug. An understanding of drug-resistance mutations in combination therapies and the genetic pathways towards drug resistance has not kept pace with expansion of the therapeutic options. As antiretroviral therapies are applied earlier in the infection, a growing number of patients have been exposed to zidovudine. In zidovudine-experienced patients the addition of a second nucleoside drug after lengthy zidovudine therapy is less effective than starting with the combination straightaway.6 Patients who have received multiple and sequential nucleoside combinations may show high-level multinucleoside resistance.7 Even more alarming is the observation that patients receiving combinations including protease inhibitors can develop virus resistant to all the currently available drugs.8 Strategies for treatment of HIV infection, especially for patients not responding to combination therapies, will need to take account of genetic pathways towards drug resistance. Partly suppressive regimens, while providing clear clinical benefits, limit the options for further treatment and effective long-term therapy. HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trialCombined antiretroviral therapy was more efficient at lowering virus load than monotherapy. Although zidovudine resistance was common in monotherapy and combined-therapy groups, circulating concentrations of resistant virus were substantially lower in the combination groups, which is likely to be a result of the continued antiviral activity of didanosine or zalcitabine. Full-Text PDF DEPARTMENT OF ERRORCombination therapies for HIV infection and genomic drug resistance-In this commentary by David Katzenstein (Oct 4, p 970) the missing references were: Full-Text PDF