Transmission of HIV-1 drug-resistant variants: prevalence and effect on treatment outcome.

BACKGROUND Human immunodeficiency virus type 1 (HIV-1) drug resistance is an important threat to the overall success of antiretroviral therapy (ART). Because of the limited sensitivity of commercial assays, transmitted drug resistance (TDR) may be underestimated; thus, the effect that TDR has on treatment outcome needs to be investigated. The objective of this study was to investigate the prevalence of TDR in HIV-infected patients and to evaluate the significance of TDR with respect to treatment outcome by analyzing plasma viral RNA and peripheral blood mononuclear cell proviral DNA for the presence of drug resistance mutations. METHODS In a prospective study, we investigated the level of TDR in 61 patients by comparing the results of a sensitive multiplex-primer-extension approach (termed HIV-SNaPshot) that is capable of screening for 9 common nucleoside reverse-transcriptase inhibitor and nonnucleotide reverse-transcriptase inhibitor mutations with those of a commercial genotyping kit, ViroSeq (Abbott). RESULTS Twenty-two patients were found to carry mutations. More patients with TDR were identified by the HIV-SNaPshot assay than by ViroSeq analysis (33% vs 13%; [P=.015). There was no significant difference in the time from initiation of ART to virological suppression between susceptible patients and those carrying low- or high-level resistance mutations (mean +/- standard deviation, 128 +/- 59.1 vs 164.9 +/- 120.4; P=.147). Furthermore, analyses of CD4 cell counts showed no significant difference between these 2 groups 1 year after the initiation of ART (mean, 184 vs 219 cells/microL; P=.267). CONCLUSION We found the prevalence of TDR in recently infected ART-naive patients to be higher than that estimated by ViroSeq genotyping alone. Follow-up of patients after treatment initiation showed a trend toward there being more clinical complications for patients carrying TDR, although a significant effect on treatment outcome could not be demonstrated. Therefore, the clinical relevance of low-abundance resistant quasispecies in early infection is still in question.

[1]  Gregory S Turenchalk,et al.  Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes. , 2009, The Journal of infectious diseases.

[2]  Matthias Cavassini,et al.  Minority quasispecies of drug-resistant HIV-1 that lead to early therapy failure in treatment-naive and -adherent patients. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  Rodolphe Thiébaut,et al.  Transmission of HIV-1 minority-resistant variants and response to first-line antiretroviral therapy , 2008, AIDS.

[4]  Michael Monsour,et al.  Minority HIV-1 Drug Resistance Mutations Are Present in Antiretroviral Treatment–Naïve Populations and Associate with Reduced Treatment Efficacy , 2008, PLoS medicine.

[5]  D. Richman,et al.  Persistence of Transmitted Drug Resistance among Subjects with Primary Human Immunodeficiency Virus Infection , 2008, Journal of Virology.

[6]  Spread programme,et al.  Transmission of drug-resistant HIV-1 in Europe remains limited to single classes , 2008, AIDS.

[7]  Wei Shao,et al.  Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase , 2008, AIDS.

[8]  H. Jessen,et al.  Impact of transmission of drug‐resistant HIV on the course of infection and the treatment success. Data from the German HIV‐1 Seroconverter Study , 2007, HIV medicine.

[9]  M. Tolstrup,et al.  Dynamics of 103K/N and 184M/V HIV-1 drug resistant populations: relative comparison in plasma virus RNA versus CD45RO+T cell proviral DNA. , 2007, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[10]  A. Geretti,et al.  Prevalence and determinants of transmitted antiretroviral drug resistance in HIV-1 infection. , 2007, The Journal of antimicrobial chemotherapy.

[11]  M. Zazzi,et al.  Both Human Immunodeficiency Virus Cellular DNA Sequencing and Plasma RNA Sequencing Are Useful for Detection of Drug Resistance Mutations in Blood Samples from Antiretroviral-Drug-Naive Patients , 2007, Journal of Clinical Microbiology.

[12]  C. Scagnolari,et al.  Genotypic Resistance of Archived and Circulating Viral Strains in the Blood of Treated HIV-Infected Individuals , 2007, Journal of acquired immune deficiency syndromes.

[13]  M. Re,et al.  Genotypic resistance in plasma and peripheral blood lymphocytes in a group of naive HIV-1 patients. , 2007, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[14]  Allan E. Rodriguez,et al.  Prevalence of Antiretroviral Drug Resistance and Resistance-Associated Mutations in Antiretroviral Therapy-Naïve HIV-Infected Individuals from 40 United States Cities , 2007, HIV clinical trials.

[15]  Gitte Pedersen,et al.  Survival of Persons with and without HIV Infection in Denmark, 19952005 , 2007, Annals of Internal Medicine.

[16]  M. Mcclure,et al.  Prevalence of primary genotypic resistance in a UK centre: comparison of primary HIV-1 and newly diagnosed treatment-naive individuals , 2007, AIDS.

[17]  W. Mcfarland,et al.  Routine surveillance for the detection of acute and recent HIV infections and transmission of antiretroviral resistance , 2006, AIDS.

[18]  John T Brooks,et al.  Mortality in the Highly Active Antiretroviral Therapy Era: Changing Causes of Death and Disease in the HIV Outpatient Study , 2006, Journal of acquired immune deficiency syndromes.

[19]  P. Harrigan,et al.  Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART , 2006, PLoS medicine.

[20]  M. Poljak,et al.  Prevalence of antiretroviral drug resistance mutations and HIV-1 non-B subtypes in newly diagnosed drug-naïve patients in Slovenia, 2000-2004. , 2006, Virus research.

[21]  Klaus Korn,et al.  Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. , 2005, The Journal of infectious diseases.

[22]  R. Shafer,et al.  Detection of Minority Populations of HIV-1 Expressing the K103N Resistance Mutation in Patients Failing Nevirapine , 2005, Journal of acquired immune deficiency syndromes.

[23]  D. Pillay,et al.  Transmission of HIV-1 drug resistance. , 2004, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[24]  K. Metzner,et al.  Emergence of minor populations of human immunodeficiency virus type 1 carrying the M184V and L90M mutations in subjects undergoing structured treatment interruptions. , 2003, The Journal of infectious diseases.

[25]  A. Moorman,et al.  Factors associated with maintenance of long-term plasma human immunodeficiency virus RNA suppression. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  A. Mocroft,et al.  Decline in the AIDS and death rates in the EuroSIDA study: an observational study , 2003, The Lancet.

[27]  Elizabeth Connick,et al.  Antiretroviral-drug resistance among patients recently infected with HIV. , 2002, The New England journal of medicine.

[28]  J. Kahn,et al.  Time trends in primary HIV-1 drug resistance among recently infected persons. , 2002, JAMA.

[29]  Diana D. Huang,et al.  Underestimation of HIV type 1 drug resistance mutations: results from the ENVA-2 genotyping proficiency program. , 2002, AIDS research and human retroviruses.

[30]  C. Boucher,et al.  Worldwide Evaluation of DNA Sequencing Approaches for Identification of Drug Resistance Mutations in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase , 1999, Journal of Clinical Microbiology.