Relative to EFV, hazards of AIDS events (adjusted hazard ratio = 0.98, 95% CI = 0.79–1.21), death (0.89, 95% CI = 0.63–1.28), and the combined clinical endpoint (0.92, 95% CI = 0.76–1.11) were slightly lower for NFV (Table 4). In adjusted analyses, hazards of death (adjusted hazard ratio = 1.41, 95% CI = 1.01–1.99) and the combined clinical endpoint (1.22, 95% CI = 1.00–1.48) appeared higher for ABC than for EFV. Such differences were not apparent in unadjusted analyses, in part because the median baseline CD4 cell count was higher for patients on ABC (median 251 cells/μl) than for those on EFV (median 207 cells/μl).
In general, sensitivity analyses of the combined clinical outcome measure (incident AIDS event or death) restricted to patients with baseline CD4 cell counts 200 cells/μl or less when initiating ART yielded parameter estimates of similar magnitude for each third drug relative to the primary analyses, although CIs were wider (Table 5). However, larger shifts in hazards ratios relative to primary analyses were observed when AIDS events and death were modelled separately, relative to models of the composite clinical outcome measure. On the whole, sensitivity analyses of clinical outcomes restricted to non-IDU patients yielded similar findings to primary analyses (Table 6). Evaluation of longer-term clinical events by initial ART regimen removing 2-year censoring yielded similar results to primary analyses, although, as expected, hazard ratios were attenuated towards one (Table 7).
Among antiretroviral-naïve patients initiating ART in clinical practice settings, short-term (24-week) virologic failure was more common for all third drugs evaluated (NVP, LPV/r, NFV, and ABC) relative to EFV when given in combination with ZDV and 3TC. However, compared with EFV, estimated rates of AIDS and death appeared higher only with NVP and ABC. For LPV/r and NFV, we found little evidence that rates of AIDS and death differed from those on EFV. Taken together, these findings suggest that, between ART regimen, differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes.
Although suppression of plasma HIV RNA is an important goal of treatment to avoid the emergence of viral resistance among other reasons, the ultimate aim of antiretroviral therapy is to prevent clinical progression and death. Preferred initial ART regimens change frequently, based on differential rates of virologic suppression observed in clinical trials. Our study suggests that such differences in virologic suppression between ART regimens may not translate to differences in clinical events among patients receiving treatment in a clinical practice setting. This observation may relate, in part, to the many available antiretroviral treatment options: patients failing treatment at 24-weeks may subsequently switch to other effective ART regimens. A recent study recognized the association of longitudinal CD4 cell count and plasma HIV RNA responses in contributing to long-term clinical outcomes in patients initiating modern ART, regardless of specific initial regimen .
Most previous observational studies (like RCTs) have lacked statistical power to analyse between-regimen differences in clinical events among patients initiating ART [9–20]. The ART-CC makes such comparisons possible through the collaborative efforts of multiple observational HIV cohort studies. The current study advances the findings of an earlier report from the ART-CC , by focusing on more recent ART regimens at the level of the third drug among patients receiving the same NRTI backbone (ZDV and 3TC). Importantly, the current study allowed for the evaluation of LPV/r individually, and not grouped with other RTV-boosted protease inhibitors (amprenavir, saquinavir, and indinavir) as done in the earlier analysis due to the relatively small frequency of LPV/r use during the earlier evaluation period (1996–2002).
In contrast with our earlier study, in which RTV-boosted protease inhibitors were associated with increased rates of both short-term virologic failure and clinical outcomes compared with EFV , LPV/r was associated only with 24-week virologic failure in the current study. The AIDS Clinical Trial Group (ACTG) 5142 study found a higher frequency of virologic failure among ARV-naïve patients treated with two NRTIs and LPV/r compared with those treated with two NRTIs and EFV . Although EFV outperformed LPV/r in achieving plasma HIV RNA levels of less than 50 copies/ml and showed a trend for superiority at less than 200 copies/ml, increases in CD4 cell counts were greater for patients receiving LPV/r than for those receiving EFV in that randomized clinical trial. In the current study, similar 24-week CD4 responses were observed for patients treated with LPV/r and EFV (median CD4 cell count increase 110 vs. 100 cells/μl, respectively). These similar CD4 responses among ART-CC patients treated with LPV/r and EFV may have contributed to comparable hazards of clinical outcomes, despite a higher frequency of 24-week virologic failure in patients treated with LPV/r.
Another possible explanation for the apparent lack of difference in clinical endpoints between EFV and LPV/r may relate to varying resistance patterns emerging upon treatment failure between different initial ART regimens. Recently, it was shown that patients failing a first-line nonnucleoside reverse transcriptase inhibitor (NNRTI) containing regimen harboured viruses with higher numbers of IAS-USA drug resistance mutations and resistance to more antiretroviral drug classes when compared with patients initiating therapy with ritonavir-boosted protease inhibitor containing regimens . Thus, EFV-based regimens, although more virologically effective as shown in this study, may result in more HIV resistance upon failure making it more difficult to generate potent successive ART regimens. In contrast, it might be easier to find effective salvage regimens for patients failing an initial boosted protease inhibitor regimen due to the lower number of drug resistance mutations observed. Furthermore, another study found the emergence of resistance to NNRTIs was associated with a greater risk of subsequent death than was the emergence of protease inhibitor resistance .
This updated analysis of the ART-CC found higher odds of 24-week virologic failure and hazards of clinical endpoints with NVP compared with EFV in analyses adjusted for covariates (Table 4). The findings regarding virologic failure are in contrast to the 2NN clinical trial , but consistent with other observational studies comparing these NNRTIs [18–20]. Although we are not able to determine the reasons for the observed inferior virologic and clinical outcomes associated with NVP use in the current study, it is possible that EFV outperformed NVP in a clinical practice setting. It is also possible that unmeasured confounders associated with NVP selection in clinical practice, confounding by indication, contributed to the inferior outcomes for NVP in the current study. Notably, shifts in parameter estimates for both NVP (increased) and LPV/r (decreased) for clinical outcome measures were observed between unadjusted and adjusted analyses attributable to differential patient profiles (e.g., baseline CD4 cell count and plasma HIV viral load) among patients stratified by third drug receipt (Table 1).
The impact of confounding by indication in the selection of third drugs was more apparent in the evaluation of clinical outcomes than observed in analyses of short-term virologic failure; more marked shifts in parameter estimates between crude and adjusted analyses were observed for the clinical outcomes models (Tables 2 and 4). Prior studies have shown the importance of baseline CD4 cell counts at the time of ART initiation on subsequent clinical events [24,48]. Taking into account the drastically different median CD4 cell counts among patients initiating ART observed in this study (e.g., LPV/r 150 cells/μl, NVP 260 cells/μl, and ABC 251 cells/μl), it would be expected that multivariable models controlling for these differences would lead to shifts in estimates observed for crude analyses, as was seen. Although the impact of confounding by indication is observed across analyses in this study, it is notable that sensitivity analyses of adjusted models largely yielded consistent findings to those observed in primary analyses.
The findings of our study must be interpreted with regard to the study limitations. The potential for confounding is inherent to all observational studies. The impact of confounding by indication is demonstrated and discussed in this study, but it is possible that other unmeasured confounders not included in adjusted statistical models may have contributed to observed study findings. As with prior studies of the ART-CC, we have adjusted for factors associated with clinical events (e.g., baseline CD4 cell count), but cannot rule out the possibility of unmeasured confounding. For example, it is possible that a provider's selection of initial ART regimen was influenced by their expectations of a patient's adherence to their antiretroviral medications. Such prescribing bias may represent unmeasured confounding that contributed to the between-regimen differences in outcomes observed in this study. Furthermore, between-provider differences (e.g., experience) may also have contributed to differential outcomes. Finally, although the ART-CC has broad geographic representation from Europe and North America, findings of this study may not apply to other geographic settings.
In summary, among patients initiating ART from 2000 to 2005 in clinical practice settings with a ZDV and 3TC backbone, those receiving third drugs other than EFV (NVP, LPV/r, NFV, and ABC) were more likely to experience short-term (24-week) virologic failure. However, such differences were not as prominent in the evaluation of clinical events, which were more common (relative to EFV) in patients receiving NVP and ABC as the third drug of their initial ART regimen, but with little evidence of such differences for those receiving NFV and LPV/r. This study clearly demonstrates the impact of confounding by indication: such confounding, as well as the potential for unmeasured confounding should be taken into account when conducting, evaluating, and reviewing studies utilizing this methodology [6,49]. Because of the limited available evidence from randomized trials on the impact of initial ART regimens on rates of clinical events, findings from well designed observational cohort studies may serve a complementary role to findings from clinical trials in informing clinical practice.
We are grateful to all patients, doctors, nurses, and other persons who were involved with the participating cohort studies. We would like to thank participating cohort members who provided thoughtful review and feedback on the content of this manuscript, particularly Colette Smith, Bruno Ledergerber, Peter Reiss, and Caroline Sabin.
The ART Cohort Collaboration is supported by the UK Medical Research Council grant RD1564. Sources of funding of individual cohorts include the Agence Nationale de Recherche contre le SIDA (ANRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the French, Italian, Spanish and Swiss Ministries of Health, The Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant no. 33CSC0-108787), the Stichting HIV Monitoring, the European Commission, the British Columbia and Alberta Governments, the Michael Smith Foundation for Health Research, the Canadian Institutes of Health Research, the VHA Office of Research and Development and unrestricted grants from GlaxoSmithKline, Roche and Boehringer-Ingelheim. Supported in part by the Spanish Network for AIDS Research (RIS; ISCIII-RETIC RD06/006).
Author contributions: Study conception and design: Robert Hogg, Michael J. Mugavero, Margaret May, Michael S. Saag, Matthias Egger, Jonathan A.C. Sterne.
Data analysis: Margaret May, Ross Harris.
Acquisition of data and/or interpretation of data: Dominique Costagliola, Frank de Wolf, Amy Justice, Matthias Egger, Huldrych F. Günthard, Antonella D'Arminio Monforte, Jose M. Miró, Schlomo Staszewski, Andrew Phillips, Robert Hogg, Francois Dabis, Fiona Lampe, Gerd Fatkenheuer, M. John Gill, Michael J. Mugavero, Michael S. Saag, Margaret May, Ross Harris, Jonathan A.C. Sterne.
Drafting the manuscript: Michael J. Mugavero, Margaret May, Michael S. Saag, Jonathan A. C. Sterne.
Critical revision of the manuscript for important intellectual content: Ross Harris, Dominique Costagliola, Matthias Egger, Andrew Phillips, Huldrych F. Günthard, Francois Dabis, Robert Hogg, Frank de Wolf, Gerd Fatkenheuer, M. John Gill, Amy Justice, Antonella D'Arminio Monforte, Fiona Lampe, Jose M. Miró, Schlomo Staszewski.
Final manuscript approval: Michael J. Mugavero, Margaret May, Ross Harris, Michael S. Saag, Dominique Costagliola, Matthias Egger, Andrew Phillips, Huldrych F. Günthard, Francois Dabis, Robert Hogg, Frank de Wolf, Gerd Fatkenheuer, M. John Gill, Amy Justice, Antonella D'Arminio Monforte, Fiona Lampe, Jose M. Miró, Schlomo Staszewski, Jonathan A.C. Sterne.
The antiretroviral therapy cohort collaboration (ART-CC) study group.
Steering committee: Jordi Casabona (PISCIS), Geneviève Chêne (Aquitaine), Dominique Costagliola (FHDH), François Dabis (Aquitaine), Antonella D'Arminio Monforte (ICONA), Julia del Amo (CoRIS-MD), Frank de Wolf (ATHENA), Matthias Egger (SHCS), Gerd Fätkenheuer (Koln/Bonn), John Gill (South Alberta Clinic), Jodie Guest (HAVACS), Robert Hogg (BCCfE-HIV), Amy Justice (VACS), Mari Kitahata (Washington), Fiona Lampe (Royal Free), Bruno Ledergerber (SHCS), Amanda Mocroft (EuroSIDA), Peter Reiss (ATHENA), Michael Saag (Alabama), Schlomo Staszewski (Frankfurt).
Coordinating team: Matthias Egger, Margaret May, Ross Harris, Jonathan Sterne (Principal Investigator).
Writing committee: Michael J. Mugavero, Division of Infectious Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, USA; Margaret May, Department of Social Medicine, University of Bristol, Bristol, UK; Ross Harris, Department of Social Medicine, University of Bristol, Bristol, UK; Michael S. Saag, Division of Infectious Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, USA; Dominique Costagliola, INSERM U720, UPMC Paris 06, Paris, France; Matthias Egger, Department of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Andrew Phillips, Department of Primary Care and Population Sciences Royal Free and University College Medical School, London, UK; Huldrych F. Günthard, Divison of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland; Francois Dabis, INSERM U593, Université Victor Segalen Bordeaux, France; Robert Hogg, Division of Epidemiology and Population Health, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada; Frank de Wolf, Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam. The Netherlands; Gerd Fatkenheuer, Department of Internal Medicine, University of Cologne, Germany; M. John Gill, Division of Infectious Diseases, University of Calgary, Calgary, Canada; Amy Justice, Yale University School of Medicine, New Haven, CT, USA and VA Connecticut Healthcare System, West Haven, CT, USA; Antonella D'Arminio Monforte, Clinic of Infectious Diseases & Tropical Medicine, ‘San Paolo’ Hospital, University of Milan, Italy; Fiona Lampe, Department of Primary Care and Population Sciences Royal Free and University College Medical School, London, UK; Jose M. Miró, Hospital Clinic – IDIBAPS. University of Barcelona, Barcelona, Spain; Schlomo Staszewski, Zentrum der Inneren Medizin, J.W. Goethe Universität, Frankfurt, Germany; Jonathan A.C. Sterne, Department of Social Medicine, University of Bristol, Bristol, UK.
Presented in part at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA; February 2007, abstract 527.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
AIDS; AIDS-related opportunistic infections; antiretroviral therapy; cohort analysis; highly active; HIV; mortality; viral load