Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients

Fätkenheuer, Gerd; Theisen, Albert; Rockstroh, Jürgen K.; Grabow, Tanja; Wicke, Christian; Becker, Katja; Wieland, Ulrike; Pfister, Herbert; Reiser, Marcel; Hegener, P; Franzen, Caspar; Schwenk, Achim; Salzberger, Bernd

doi:10.1097/00002030-199714000-00001

Cited by 255 publications

(109 citation statements)

References 17 publications

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“…Twelve cohorts contributed data: the French Hospital Database on HIV (FHDH) ANRS CO4 [6] and the Aquitaine Cohort ANRS CO3 (France) [7]; the AIDS Therapy Evaluation Project Netherlands (ATHENA) [8]; the Italian Cohort of Antiretroviral-Naive Patients (ICONA) [9]; the Swiss HIV Cohort Study (SHCS) [10]; the Frankfurt HIV Cohort [11] and Köln/Bonn Cohort (Germany) [12]; the EuroSIDA study (20 countries in Europe and Argentina) [13]; the Collaborations in HIV Outcomes Research US (CHORUS; USA) [14]; the Royal Free Hospital Cohort (UK) [15]; and the British Columbia Centre for Excellence in HIV/AIDS [16] and the South Alberta Clinic (Canada) [17]. At all sites, institutional review boards had approved the collection of data.…”

Section: Methodsmentioning

confidence: 99%

“…Age ( (20-27) 21 (18-24) 19 (16-22) 13 (11-15) 8.3 (7.1-9.7) 6.9 (5.9-8.1) Viral load <5 19 (17-22) 17 (14-20) 16 (13-18) 11 (9.3-13) 6.7 (5.8-7.8) 5.6 (4.8-6.5) CDC stage C and no history of IDU Viral load ≥5 42 (37-47) 37 (33-43) 35 (31-40) 25 (22)(23)(24)(25)(26)(27)(28)(29) 16 (14)(15)(16)(17)(18)(19) 14 (11)(12)(13)(14)(15)(16) Viral load <5 35 (31-40) 31 (27-36) 29 (25-34) 21 (18-24) 13 (11)(12)(13)(14)(15)(16) 11 (9.3-13) CDC stage A/B and history of IDU Viral load ≥5 36 (31-41) 31 (27-37) 29 (25-34) 21 (18-24) 13 (11)(12)(13)(14)(15)(16) 11 (9.3-13) Viral load <5 30 (25-35) 26(22-31) 24 …”

Section: Person-years No Of Events Hazard Ratio (95% Ci) Person-yearsmentioning

confidence: 99%

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Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies

May

Sterne²,

Sabin³

et al. 2007

Aids

254

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Objective-To estimate the prognosis over 5 years of HIV-1-infected, treatment-naive patients starting HAART, taking into account the immunological and virological response to therapy.Design-A collaborative analysis of data from 12 cohorts in Europe and north America on 20 379 adults who started HAART between 1995 and 2003.Methods-Parametric survival models were used to predict the cumulative incidence at 5 years of a new AIDS-defining event or death, and death alone, first from the start of HAART and second from 6 months after the start of HAART. Data were analysed by intention-to-continuetreatment, ignoring treatment changes and interruptions.Results-During 61 798 person-years of follow-up, 1005 patients died and an additional 1303 developed AIDS. A total of 10 046 (49%) patients started HAART either with a CD4 cell count of less than 200 cells/μl or with a diagnosis of AIDS. The 5-year risk of AIDS or death (death alone) from the start of HAART ranged from 5.6 to 77% (1.8-65%), depending on age, CD4 cell count, HIV-1-RNA level, clinical stage, and history of injection drug use. From 6 months the corresponding figures were 4.1-99% for AIDS or death and 1.3-96% for death alone.Conclusion-On the basis of data collected routinely in HIV care, prognostic models with high discriminatory power over 5 years were developed for patients starting HAART in industrialized countries. A risk calculator that produces estimates for progression rates at years 1 to 5 after starting HAART is available from www.art-cohort-collaboration.org. KeywordsAIDS; antiretroviral therapy; CD4 lymphocyte count; highly active; HIV infections; mortality; prognosis; risk factors; survival analysis; viral load IntroductionEstimates of the probability of progression to AIDS or death are important for HIV-infected patients starting HAART and their treating physicians. Such estimates are also needed for a better understanding of the treated history of HIV infection, to monitor and predict the course of the epidemic, to develop treatment guidelines, and to plan health services.The Antiretroviral Therapy (ART) Cohort Collaboration, an international collaboration between the investigators of cohort studies from Europe and north America, was established in 2000 to monitor disease progression among treatment-naive patients starting HAART [1,2]. Pre-HAART era probabilities of progression by viral load and CD4 cell count were Mellors and colleagues [3] using the Multicenter AIDS Cohort Study (MACS) of homosexual men. In that study, the probability of progression to AIDS within 3 years for those with a high viral load and CD4 cell count between 201 and 350 cells/μl was estimated to be 64%, rising to 89% at 6 years. Since the introduction of HAART, the incidence of AIDS in treated patients has declined markedly. Previous analyses from the ART Cohort Collaboration showed that for those aged under 50 years and starting HAART in the same viral load and CD4 cell count stratum, the 3-year probability of AIDS or death had fallen to 6% [1].As treatment wi...

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Section: Methodsmentioning

confidence: 99%

Section: Person-years No Of Events Hazard Ratio (95% Ci) Person-yearsmentioning

confidence: 99%

Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies

May

Sterne²,

Sabin³

et al. 2007

Aids

254

View full text Add to dashboard Cite

show abstract

“…However, in clinical practice, virologic failure of protease inhibitor-containing therapy occurs in a significant fraction of the treated population (19,22,42,46,52,70). Virologic failure of protease inhibitor treatment is often due to the selection of HIV-1 strains with mutations in the pro gene, which encodes the viral protease (PR), and in specific protease cleavage sites encoded in the gag gene that collectively confer reduced drug susceptibility to the harboring strain (11,12,28,36,43,47,72).…”

mentioning

confidence: 99%

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

Resch¹,

Parkin

Watkins

et al. 2005

J Virol

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We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.Protease inhibitors (PIs) potently inhibit human immunodeficiency virus type 1 (HIV-1) replication, and their initial introduction into combination antiretroviral therapy was associated with a significant decrease of HIV-1-associated mortality and morbidity (41, 45). However, in clinical practice, virologic failure of protease inhibitor-containing therapy occurs in a significant fraction of the treated population (19,22,42,46,52,70). Virologic failure of protease inhibitor treatment is often due to the selection of HIV-1 strains with mutations in the pro gene, which encodes the viral protease (PR), and in specific protease cleavage sites encoded in the gag gene that collectively confer reduced drug susceptibility to the harboring strain (11,12,28,36,43,47,72).The resistance mutations are hypothesized to be largely preexisting, generated by the highly error-prone and rapid replication of HIV-1 in large virus populations (5, 10, 57). However, in PI-naïve subjects, some critical resistance mutations cannot be detected or can only be detected at very low levels, suggesting that these mutations may confer a selective disadvantage relative to wild-type HIV-1 strains (3,18,25,32,34,63). Indeed, it has been shown that the catalytic efficiency of protease is reduced by PI resis...

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“…For many persons, however, this therapy does not provide sustained viral suppression or durable clinical benefit (10,11). Potential reasons for the loss of viral suppression include host immune defects, poor adherence to therapy, pharmacologic factors, and drug resistance (10 -17).…”

mentioning

confidence: 99%

HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir–ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed

et al. 1999

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Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients

Cited by 255 publications

References 17 publications

Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies

Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir–ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed

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