A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086.

BACKGROUND The role of structured treatment interruption (STI) before optimized antiretroviral therapy (ART) in patients with drug-resistant human immunodeficiency virus type 1 (HIV-1) is uncertain. METHODS AIDS Clinical Trial Group protocol A5086 was a prospective trial of 41 patients with multiple drug class-resistant HIV who were randomized to undergo a 16-week STI followed by optimized ART (STI) or immediate optimized ART (no STI). The primary end point was the proportion of subjects with HIV-1 RNA loads <400 copies/mL 48 weeks after randomization. RESULTS Of 39 evaluable patients, 4 (19%) in the STI arm and 6 (33%) in the no STI arm had HIV-1 RNA loads <400 copies/mL at 48 weeks (P=.44). Median changes from baseline in CD4+ cell counts and HIV-1 RNA loads were similar for both arms. Standard genotypes at the end of STI showed nearly complete reversion to wild-type virus in a minority of patients (n=5; 28%). Virus with 3-drug class resistance reemerged even when ART included only 1 or 2 drug classes. Single-genome sequencing showed that each genome encoded resistance mutations for 3 drug classes. CONCLUSIONS A 16-week STI before optimized ART did not improve virologic response. Genetic analyses strongly suggest that virologic failure resulted from the reemergence of virus present before STI that encoded 3-drug class resistance on the same genome.

[1]  K. Hertogs,et al.  HIV Drug Susceptibility and Treatment Response to Mega-Haart Regimen in Patients from the Frankfurt HIV Cohort , 2000, Antiviral therapy.

[2]  R. Grant,et al.  Activity of a ritonavir plus saquinavir‐containing regimen in patients with virologic evidence of indinavir or ritonavir failure , 1998, AIDS.

[3]  Jacques Izopet,et al.  Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy , 2001, Journal of Virology.

[4]  T. Perneger,et al.  Impact of drug resistance mutations on virologic response to salvage therapy. Swiss HIV Cohort Study. , 1999, AIDS.

[5]  P. Harrigan,et al.  Multiple drug rescue therapy for HIV-infected individuals with prior virologic failure to multiple regimens , 2001, AIDS.

[6]  S. Hammer,et al.  The Relation between Baseline HIV Drug Resistance and Response to Antiretroviral Therapy: Re-Analysis of Retrospective and Prospective Studies Using a Standardized Data Analysis Plan , 2000, Antiviral therapy.

[7]  Victor DeGruttola,et al.  Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. , 2002, JAMA.

[8]  D. Richman,et al.  2022 update of the drug resistance mutations in HIV-1. , 2022, Topics in antiviral medicine.

[9]  S. Hammer,et al.  HIV-1 genotype and phenotype correlate with virological response to abacavir, amprenavir and efavirenz in treatment-experienced patients , 2002, AIDS.

[10]  P. Tebas,et al.  Virologic responses to a ritonavir--saquinavir-containing regimen in patients who had previously failed nelfinavir. , 1999, AIDS.

[11]  Amalio Telenti,et al.  Update of the Drug Resistance Mutations in HIV-1: 2005. , 2005, Topics in HIV medicine : a publication of the International AIDS Society, USA.

[12]  M. Zhang,et al.  Predictors of Virological Response in HIV-Infected Patients to Salvage Antiretroviral Therapy that Includes Nelfinavir , 2001, Antiviral therapy.

[13]  R. Grant,et al.  Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. , 2000, The Journal of infectious diseases.

[14]  R. Paredes,et al.  Role of structured treatment interruption before a 5-drug salvage antiretroviral regimen: the Retrogene Study. , 2003, The Journal of infectious diseases.

[15]  Terri Wrin,et al.  Persistence of drug-resistant HIV-1 after a structured treatment interruption and its impact on treatment response , 2003, AIDS.

[16]  K. Hertogs,et al.  Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure , 2000, AIDS.

[17]  Vincent Calvez,et al.  No benefit of a structured treatment interruption based on genotypic resistance in heavily pretreated HIV-infected patients , 2005, AIDS.

[18]  M. P. Cummings.  PHYLIP (Phylogeny Inference Package) , 2004 .

[19]  J. Bartlett.  Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus , 2004 .

[20]  S. Hammer,et al.  A Randomized Trial of Nelfinavir and Abacavir in Combination with Efavirenz and Adefovir Dipivoxil in HIV-1-Infected Persons with Virological Failure Receiving Indinavir , 2002, Antiviral therapy.

[21]  John W. Mellors,et al.  Multiple, Linked Human Immunodeficiency Virus Type 1 Drug Resistance Mutations in Treatment-Experienced Patients Are Missed by Standard Genotype Analysis , 2005, Journal of Clinical Microbiology.

[22]  R Hoh,et al.  Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. , 2001, The New England journal of medicine.

[23]  Roland Tubiana,et al.  Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097) , 2004, AIDS.

[24]  D. Katzenstein,et al.  Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. , 2000, The Journal of infectious diseases.