Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients

Objective:To evaluate the effect of drug class-wide resistance (CWR) on survival in HIV-infected individuals who underwent genotypic resistance test after antiretroviral failure. Design:Observational, longitudinal cohort study. Methods:HIV-infected individuals experiencing treatment failure were enrolled at first genotypic resistance test. End-points were death for any cause, AIDS-related death and AIDS-defining event/death. CWR was defined according to the International AIDS Society consensus. Survival analysis was performed with Cox's model. Results:Among 623 patients enrolled and followed for a median of 19 months (interquartile range, 12–29), Kaplan–Meier analyses for end-points at 48 months in patients with no CWR, one CWR, two CWR or three CWR were 8.9, 11.7, 13.4 and 27.1%, respectively, for death; 6.1, 9.9, 13.4 and 21.5%, respectively, for AIDS-related death; and 16.0, 17.7, 19.3 and 35.9%, respectively, for new AIDS event/death. In a multivariate Cox's model, higher HIV RNA level, previous AIDS and detection of three CWR (hazard ratio, 5.34; 95% confidence interval, 1.76–16.24) were all significantly associated with increased risk of death, while higher CD4 cell count and use of a new boosted protease inhibitor drug after identifying genotypic resistance were associated with reduced risk. Detection of three CWR was also significantly associated with higher risk of AIDS-related death and new AIDS event/death. Conclusions:Even in the late era of highly effective antiretroviral treatments, detection of CWR, particularly if extended to all three drug classes is related to poorer clinical outcome and represents a risk-marker of disease progression and death.

[1]  Terri Wrin,et al.  The prevalence of antiretroviral drug resistance in the United States , 2004, AIDS.

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

[3]  Kholoud Porter,et al.  Determinants of survival following HIV-1 seroconversion after the introduction of HAART , 2003, The Lancet.

[4]  S. Hammer,et al.  Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. , 2000, JAMA.

[5]  H. Côté,et al.  Clinical utility of testing human immunodeficiency virus for drug resistance. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  Bruno Ledergerber,et al.  Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes , 2004, The Lancet.

[7]  Julio S. G. Montaner,et al.  Effect of Medication Adherence on Survival of HIV-Infected Adults Who Start Highly Active Antiretroviral Therapy When the CD4+ Cell Count Is 0.200 to 0.350 109 cells/L , 2003, Annals of Internal Medicine.

[8]  M. Wainberg,et al.  Public health implications of antiretroviral therapy and HIV drug resistance. , 1998, JAMA.

[9]  Amalio Telenti,et al.  CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART) , 1998, The Lancet.

[10]  D. Nauwelaers,et al.  Relative Prognostic Value of Self-Reported Adherence and Plasma Nnrti/Pi Concentrations to Predict Virological Rebound in Patients Initially Responding to Haart , 2004, Antiviral therapy.

[11]  T. Merigan,et al.  A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy , 2000 .

[12]  Lidia Ruiz,et al.  Clinical utility of HIV-1 genotyping and expert advice: the Havana trial , 2002, AIDS.

[13]  A. Badley,et al.  Effect of cessation of highly active antiretroviral therapy during a discordant response: implications for scheduled therapeutic interruptions. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  Richard D Moore,et al.  Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing , 2004, AIDS.

[15]  P. Narciso,et al.  Variable prediction of antiretroviral treatment outcome by different systems for interpreting genotypic human immunodeficiency virus type 1 drug resistance. , 2003, Journal of Infectious Diseases.

[16]  R. Chaisson,et al.  Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions , 1999, Annals of Internal Medicine.

[17]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[18]  A. Hsu,et al.  Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. , 2004, The Journal of infectious diseases.

[19]  Gary Collins,et al.  Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. , 2003, The New England journal of medicine.

[20]  Victoria A Johnson,et al.  Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society-USA Panel. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[21]  Richard D Moore,et al.  Survival in an Urban HIV‐1 Clinic in the Era of Highly Active Antiretroviral Therapy: A 5‐Year Cohort Study , 2003, Journal of acquired immune deficiency syndromes.

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

[23]  J. Bartlett.  Decline in the AIDS and Death Rates in the EuroSIDA study: An observational study , 2004 .

[24]  P. Narciso,et al.  The Effect of Number of Mutations and of Drug-Class Sparing on Virological Response to Salvage Genotype-Guided Antiretroviral Therapy , 2002, Antiviral therapy.

[25]  M. Lederman,et al.  Human immunodeficiency virus 1 protease inhibitors in clinical practice: predictors of virological outcome. , 1999, Archives of internal medicine.

[26]  D. Bangsberg,et al.  Paradoxes of adherence and drug resistance to HIV antiretroviral therapy. , 2004, The Journal of antimicrobial chemotherapy.

[27]  P. Kissinger,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. , 1998, The New England journal of medicine.

[28]  K. Hertogs,et al.  Clinical and laboratory guidelines for the use of HIV-1 drug resistance testing as part of treatment management: recommendations for the European setting , 2001 .

[29]  J. Schapiro,et al.  Drug-resistance genotyping in HIV-1 therapy: the VIRAD APT randomi sed controlled trial , 1999, The Lancet.

[30]  D. Costagliola,et al.  Clinical and immunologic outcome in patients with human immunodeficiency virus infection, according to virologic efficacy in the year after virus undetectability, during antiretroviral therapy. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  M. Lederman,et al.  Role of Baseline pol Genotype in HIV-1 Fitness Evolution. , 2003, Journal of acquired immune deficiency syndromes.

[32]  Jonathan AC Sterne,et al.  Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies , 2002, The Lancet.

[33]  A. Antinori,et al.  Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: a randomized study (ARGENTA) , 2002, AIDS.

[34]  V. Vullo,et al.  Time to discontinuation of the first highly active antiretroviral therapy regimen: a comparison between protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-containing regimens. , 2001, AIDS.

[35]  J. Martinez-Picado,et al.  Replicative Fitness of Protease Inhibitor-Resistant Mutants of Human Immunodeficiency Virus Type 1 , 1999, Journal of Virology.

[36]  J. Kilby,et al.  Novel therapies based on mechanisms of HIV-1 cell entry. , 2003, The New England journal of medicine.

[37]  A. Levy,et al.  Antiretroviral resistance among HIV-infected persons who have died in British Columbia, in the era of modern antiretroviral therapy. , 2004, The Journal of infectious diseases.

[38]  A. Phillips,et al.  Immunological, virological and clinical response to highly active antiretroviral therapy treatment regimens in a complete clinic population , 2000, AIDS.

[39]  P. Narciso,et al.  Q151M-mediated multinucleoside resistance: prevalence, risk factors, and response to salvage therapy. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[40]  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.

[41]  D. Katzenstein,et al.  Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy , 2004, AIDS.

[42]  C. Boucher,et al.  Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. , 1999, AIDS.

[43]  D. Bangsberg,et al.  Modeling the HIV protease inhibitor adherence-resistance curve by use of empirically derived estimates. , 2004, The Journal of infectious diseases.

[44]  J. Sterne,et al.  Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies , 2003, The Lancet.