Figure 2(a) shows the nonweighted and IPCW-estimated median CD4 cell counts over time by pretreatment CD4 cell category, showing again only small differences between the two analyses. The absolute changes in median CD4 cell count were similar for 3 years irrespective of pretreatment CD4 cell count category; thereafter, the trajectories differed, with an increase in the median CD4 cell count (from 369 to 453 cells/μl) for patients with pretreatment CD4 cell count of 200 cells/μl or less, and declines for patients in the pretreatment CD4 cell count categories of 201–350, 351–500, and more than 500 cells/μl (Table 1). The IPCW-estimated proportion of patients with a CD4 cell count of 350 cells/μl or less at (or dying before) 7 years, by pretreatment CD4 count category, was 33% for pretreatment CD4 cell count of 200 cells/μl or less, 24% for CD4 cell count of 201–350 cells/μl, 16% for CD4 cell count of 351–500 cells/μl, and 8% for CD4 cell count of more than 500 cells/μl (overall 23%). Table 1 also includes these percentages for thresholds of 200 and 500 cells/μl.
Some patients discontinued ART for more than 60 days, and the proportion discontinuing increased with higher pretreatment CD4 cell counts, possibly explaining the decline in median CD4 cell counts in the intent-to-treat analysis for patients in the higher pretreatment CD4 cell count categories. This is addressed in the ‘on-treatment’ analysis, in which it is assumed that patients who discontinued ART might have remained on ART had they known of the potential adverse consequences of discontinuing ART identified in the Strategies for Management of Antiretroviral Therapy (SMART) study . In the models for the on-treatment analysis, older age and vRNA below 400 copies/ml, but not CD4 cell count, significantly increased the probability of staying on treatment, given a patient remained in follow-up.
Figure 2(b) shows the nonweighted and IPCW-estimated median CD4 cell counts over time, had all patients remained on ART throughout the 7 years without interruptions longer than 60 days. As for the intent-to-treat analysis, the differences between results from the two analyses were generally small except for the highest pretreatment CD4 category (>500 cells/μl), for which the difference increased after year 4. In all categories of pretreatment CD4 cell count, the median CD4 cell count either stabilized or continued to rise for 7 years, although more slowly after the first 3 years of ART. Table 2 gives the estimated medians and 25th and 75th percentiles of the distribution of CD4 cell counts during years 3 and 7, had patients remained on ART. As with the intent-to-treat analysis, there were minimal differences in median CD4 cell count according to type of initial ART. The medians and 25th and 75th percentiles typically showed modest increases between years 3 and 7, suggesting a general upward shift in the distribution of CD4 cell counts in the study population, both overall and by pretreatment CD4 cell count category. Had all patients remained on ART, the IPCW-estimated proportion of patients with a CD4 cell count below 350 cells/μl at (or dying before) 7 years after starting ART was 25% for pretreatment CD4 cell count of 200 cells/μl or less, 9% for CD4 cell count of 201–350 cells/μl, 3% for CD4 cell count of 351–500 cells/μl, and 2% for CD4 cell count of more than 500 cells/μl (overall 14%). Table 2 also includes these percentages for thresholds of 200 and 500 cells/μl.
Figure 3 shows the median CD4 cell counts over time in the patients who were followed for 7 years by pretreatment CD4 cell count category, comparing those who did versus did not maintain virologic suppression throughout. In those patients who remained virologically suppressed for 7 years, the median CD4 cell count continued to rise over 7 years in the lower pretreatment CD4 cell count categories, and stabilized in the higher ones. The median CD4 cell count declined in later years among patients who were not virologically suppressed throughout 7 years.
Our study found substantial improvements in median CD4 cell count during 7 years after HIV-infected patients first started ART in the randomized clinical trial ACTG 384, which established the combination of EFV–3TC/ZDV as a standard of care for initial treatment of HIV infection. The largest increases occurred during the first 1–2 years of follow-up and, in the study population as a whole, showed little change between 3 and 7 years. When changes in median CD4 cell count were evaluated by pretreatment CD4 cell count, patients in the lowest category considered, 200 cells/μl or less, experienced a modest gain between 3 and 7 years, whereas patients in the highest category, more than 500 cells/μl, experienced a decline.
However, some patients discontinued ART during follow-up, particularly those with higher pretreatment CD4 cell counts, a practice that is no longer recommended because of the SMART study  results. We, therefore, conducted a novel statistical analysis, IPCW, which estimated CD4 cell count trajectories, had all patients remained on ART. This showed that the median CD4 cell count continued to show a modest increase between 3 and 7 years after starting ART, both in the overall study population and across pretreatment CD4 cell count categories. Of note, this pattern was also seen when considering the 25th and 75th percentiles of the distribution of CD4 cell counts, indicating ongoing peripheral CD4 cell count reconstitution with continued ART in the broad population of patients.
Patients who began ART at lower CD4 cell counts continued to have lower CD4 cell counts than those who began ART at higher CD4 cell counts. We found this not only in the subset of patients for whom virologic suppression was maintained throughout the 7 years of follow-up, as found in other studies [25–27,29,31], but also in our analyses, which evaluated the entire study population who started ART. We estimated that 33% of patients who originally started ART when their CD4 cell counts were 200 cells/μl or less would have had CD4 cell counts 350 cells/μl or less at (or died before) 7 years in the intent-to-treat analysis; the IPCW model suggested that had all patients remained on ART for 7 years, 25% would still have CD4 cell counts below 350 cells/μl after 7 years. In contrast, among patients with pretreatment CD4 cell counts in the 351–500 and more than 500 cells/μl ranges, the latter estimates were 3 and 2%, respectively.
Thus, initiation of ART at higher CD4 cell counts than typically recommended in recent treatment guidelines appears to be associated with maintenance of CD4 cell counts at levels above 350 cells/μl (when the risk of HIV-associated morbidity and mortality is low) for almost all patients for at least 7 years. Postponing ART until the CD4 cell count drops below 350 cells/μl might be too conservative, as patients who are in the pretreatment CD4 cell count category of 201–350 cells/μl have a median 7-year CD4 cell count similar to patients with pretreatment CD4 cell count of 200 cells/μl or less.
In the subgroup of patients who maintained vRNA below 400 copies/ml for 7 years, we observed ongoing improvements in median CD4 cell counts among patients who started ART at CD4 cell counts less than 350 cells/μl. Although this is a selected subgroup, this finding and similar findings in other studies [25,29,31] provide support for treatment management practices that promote sustained virologic suppression. Additionally, individuals without sustained virologic suppression are at risk for acquiring drug resistance mutations. However, it is difficult to distinguish between virologic failure due to drug resistance and virologic failure due to nonadherence or toxicity/intolerance, as it is often due to a combination of these factors.
We found no long-term differences in CD4 cell counts achieved according to initial category of randomized treatment between EFV–3TC/ZDV and the other three and four-drug regimens, a finding made possible by the ALLRT study wherein participants are followed long-term after their participation in randomized ACTG clinical trials and through changes in ART regimens. Like ACTG 384, two other studies [39,40] found no difference between randomized initial ART in short-term CD4 cell count increases (2–3 years). The lack of long-term differences found in our study likely reflects the availability of multiple potent antiretroviral regimens, so that even after 7 years, most patients still have treatment options. In addition, of the six regimens studied in ACTG 384, only the EFV–3TC/ZDV regimen has remained a preferred regimen, and most patients discontinued use of the other regimens; of those randomized to EFV–3TC/ZDV and alive and in follow-up after 7 years, 54% were on their initial regimen as compared with 11% for the other three-drug regimens and 4% for the four-drug regimens.
A notable strength of our study is the well characterized patient population and the standardized prospective collection of data. The main limitation is that some patients in ACTG 384 did not enroll in the ALLRT study and some patients were lost to follow-up. In addition, some patients discontinued treatment during follow-up, particularly at higher CD4 cell counts, consistent with treatment management practices during the study period. We attempted to address these limitations by using the IPCW method. This method adjusts for factors that are included in the model used to derive weights related to the probability of remaining in follow-up (or on ART), which might also affect a patient's future CD4 cell count trajectory. It is possible, however, that there are other (unmeasured) factors that influenced patient decisions to stay in follow-up or stay on ART that might also have been associated with CD4 cell count outcome. Omitting such factors may lead to bias in our results. For example, among patients with similar covariate histories, if patients who discontinued ART would have had lower CD4 cell counts, had they continued on ART than patients who did actually continue on ART, then the IPCW method might overestimate the subsequent CD4 trajectory that could be achieved in the whole population, had everyone stayed on ART.
This study has other limitations. First, recommended ART regimens have changed during recent years, so CD4 cell count outcomes might be different for patients who are starting ART now. As current regimens tend to be better tolerated and possibly more efficacious, in part because of simpler dosing (e.g. once daily) leading to improved adherence, patients starting ART now might have better CD4 cell count outcomes than in our study. Second, we studied a group of patients who enrolled in a clinical trial, most of whom subsequently participated in a long-term observational study. Outcomes might be different in a more general patient population, although the demographic characteristics of our patients were quite diverse. Third, it is possible that the better outcomes among patients starting ART at higher CD4 cell counts are attributable to differences in other patient characteristics. For example, it is possible that starting ART at higher CD4 cell counts is associated with health-seeking behavior, so patients starting ART at higher CD4 cell counts might be expected to fare better for this reason.
In summary, our study suggests that the median CD4 cell count in this population of patients who initiated NNRTI and protease inhibitor-based regimens increased for 3 years and then stabilized through 7 years of follow-up. However, when adjustment was made for discontinuation of ART, the median CD4 cell count continued to rise in later years. This trend was seen across all categories of pretreatment CD4 cell counts. However, even after 7 years, a significant proportion of patients who initiated ART with CD4 cell counts below 200 cells/μl still had counts below 350 cells/μl. The inability to normalize CD4 cell counts among many patients starting ART at low CD4 cell counts, even after 7 years of treatment, provides additional support to consider initiation of therapy at higher CD4 cell counts, consistent with recent observational studies that suggested benefits in terms of HIV-related morbidity and mortality [9,41,42] and the newly updated treatment guidelines .
We are indebted to the patients who volunteered for ACTG 384 and subsequently to ALLRT, the ACTG sites, and the ACTG 384 and ALLRT study teams. We also want to thank Joe Eron for productive discussions and Andrea Rotnitzky for her valuable insights into inverse probability weighting. This study was supported in part by the ACTG funded by the National Institute of Allergy and Infectious Diseases (NIAID; AI 38858, AI 68636, AI 069434, AI 069472, and AI 062435), the Statistical and Data Management Center (AI 38855 and AI 68634), and the National Institute of Health (NIAID R01 AI 51164, AI 024643, and NIH-R01-GM48704).
R.S. and G.R. were involved in design and conduct of ACTG 384. R.B., C.B., and A.C. were involved in the design and conduct of the ALLRT study. J.L., R.B., and M.H. carried out the analyses. J.L. drafted a first version of the manuscript. All authors contributed to the final manuscript.
ACTG 384: http://clinicaltrials.gov/ct2/show/NCT00000919.
ACTG A5001/ALLRT: http://clinicaltrials.gov/ct2/show/NCT00001137.
This work was also supported by the NIAID grant numbers AI069474, AI27664, and AI69432. We would like to thank the ACTG 384 and ALLRT participants and acknowledge the following persons and institutions who participated in the conduct of this study: Massachusetts General Hospital, Amy Sbrolla, BSN, RN and Nicole Burgett-Yandow, BSN, RN; Beth Israel Deaconess Medical Center (BIDMC) CRS, Mary Albrecht, MD and Neah Kim, MSN, FNP-C, CTU grant number AI069472, CFAR grant number, P30 AI060354 A0104; Boston Medical Center ACTG CRS, Paul R. Skolnik, MD; Betsy Adams, RN, CTU grant number 5U01AI069472, GCRC grant number M01- RR00533; Brigham and Women's Hospital, Paul Sax, MD and Joanne Delaney RN, CTU grant number AI069472; Johns Hopkins University, Denice Jones and Ilene Wiggins, RN, CTU grant number AI-69465, GCRC grant number RR-00052; NYU/NYC HHC at Bellevue, Janet Forcht, RN and Richardson St. Louis, CTU grant numbers AI27665 and AI69532, GCRC Grant RR00096; Mount Sinai Medical Center; Stanford University, Sandra Valle, PA-C & Jane Norris, PA-C, CTU grant number UOI-A1069556; San Mateo County AIDS Program; Santa Clara Valley Medical Center; Willow Clinic; UCLA School of Medicine, Judith Currier, MD, MSc and Eric Daar, MD, CTU grant number AI069424; Harbor-UCLA Medical Center; University of California, San Diego Antiviral Res, Susan Cahill, RN and Linda Meixner, RN, CTU grant number AI069432; San Francisco General Hospital, C. Bradley Hare, MD and Diane Havlir, MD, CTU grant number AI69502; Marin County Department of Health; University of Miami, Hector H. Bolivar, MD and Margaret A. Fischl, MD, CTU grant numbers AI27675 and AI69477; University of Pittsburgh, Deborah McMahon, MD and Barbara Rutecki, MSN, MPH, CTU grant number AI69494; Georgetown University, Princy Kumar, MD and Karyn Hawkins, RN; University of Rochester Medical Center, Jane Reid, RNc, MS, ANP and Mary Adams, RN, MPH, CTU grant numbers AI27658 and AI69511, GCRC grant number RR00044; SUNY-Buffalo, Erie County Med Ctr, Gene Morse PharmD, CTU: AI069511-02, CRC: 5-MO1 RR00044; McCree McCuller Wellness Center, Nyef El-Daher MD, CTU: AI069511-02, CRC: 5-MO1 RR00044; AIDS Community Health Center, Christine Hurley RN and Roberto Corales DO, CTU: AI069511-02, CRC: 5-MO1 RR00044; University of Southern California, Fred R. Sattler, MD and Frances Marie Canchola, RN, CTU grant numbers AI27673 and AI69428; University of Washington (Seattle), Sheryl S. Storey, PA-C and Shelia Dunaway, MD, CTU grant number AI069434, CTU grant number AI27664; University of Minnesota, Henry H. Balfour, Jr and Christine Fietzer, CTU grant number AI27661; Hennepin County Medical Ctr, Keith Henry, MD and Bette Bordenave, RN; University of Iowa Hospitals and Clinics; University of Nebraska Med. Ctr., Susan Swindells, MBBS and Frances Van Meter, APRN, CTU grant number AI27661; Duke University Medical Center, Gary M. Cox, MD and Martha Silberman, RN, CTU grant number 1U01-AI069484; Washington University (St. Louis), Mark Rodriguez RN BSN and Ge-Youl Kim, RN, BSN, CTU grant UO1 AI069495; St. Louis Connect Care; Ohio State University, Michael F. Para, MD and Diane Gochnour, RN, CTU grant number AI069474; University of Cincinnati, Judith Feinberg, MD and Jenifer Baer, RN, CTU grant number AI-069513; Case Western Reserve University, Benigno Rodriguez, MD, MSc and Barbara Philpotts, RN, BSN, CTU grant numbers AI25879 and AI69501; MetroHealth CRS; Cleveland Clinic; Indiana University, Mitchell Goldman, MD and Beth Zwickl, NP, CTU grant number AI25859-19, GCRC grant number RR000750; Methodist Hospital of Indiana; Wishard Memorial Hospital; Northwestern University, Robert L. Murphy, MD and Baiba Berzins, MPH, CTU grant number AI69471; Rush University Medical Center in Chicago, Beverly E. Sha, MD and Janice Fritsche, MS, APRN, CTU grant number U01 AI069471; Cook County Hospital Core Center, Oluwatoyin Adeyemi, MD and Joanne Despotes, RN, MPH; Beth Israel Medical Center, Donna Mildvan, MD and Gwendolyn Costantini, FNP, CTU grant number AI46370; The Miriam Hospital, Karen T. Tashima, MD, Pamela Poethke, RN, BSN, and Katherine Wright and Kim Raposa, CTU grant numbers AI46381 and AI69472; University of North Carolina, David Ragan, RN and Joseph J. Eron Jr, MD, CTU grant number U01 AI069423, CFAR grant number P30AI050410(-11), GCRC grant number M01 RR000046-48; Moses H. Cone Hospital, Kim Epperson, RN and Timothy Lane, MD; Carolinas Medical Center; Wake County Human Services, David Currin, RN and Kristine Patterson, MD; Vanderbilt University, Michael Morgan, FNP, Brenda Jackson, RN, Vicki Bailey, RN and Janet Nicotera, RN, BSN, CTU grant number AI069439; University of Texas, Southwestern Medical Center, Philip Keiser, MD and Tianna Petersen, MS, CTU grant number AI46376; University of California, Davis Medical Center, Melissa Schreiber, PA and Abby Olusanya, NP, CTU grant number AI38858-09S1; UC Davis Medical Center; University of Maryland, Institute of Human Virology, Charles Davis, MD and Onyinye Erondu, RN, CTU grant number AI69447; University of Hawaii, Nancy Hanks, RN and Lorna Nagamine, RN, CTU grant number AI34853; Puerto Rico-AIDS Clinical Trial Unit (PR-ACTU), Jorge L Santana, MD and Santiago Marrero, MD, CTU grant number Al69415; University of Alabama at Birmingham, Michael Saag, MD and Kerry Upton, RN, CTU grant number AI069452, GCRC grant number M01-RR00032; Emory University, The Ponce de Leon Center, Jeffrey Lennox, MD and Carlos del Rio, MD, CTU grant number AI69418, CFAR grant number AI50409; University of Colorado Health Sciences Center, Denver, Beverly Putnam, MSN and Cathi Basler, MSN, CTU grant number AI069450, GCRC grant number RR00051, CFAR grant number AI054907; University of Pennsylvania, Philadelphia, Harvey Friedman, MD and Rosemarie Kappes, MPH, UO1-AI 032783-14 and AI69467, CFAR grant number 5-P30-AI-045008-09; Presbyterian Medical Center; University of Texas, Galveston, William A. O'Brien, MD and Gerianne Casey, RN, CTU grant number AI32782; Aaron Diamond AIDS Research Center; Columbia University, Jolene Noel Connor, RN, RNC and Madeline Torres, RN, RNC, CTU grant number AI069470, GCRC grant number RR024156; Weill Medical College, Valery Hughes, FNP and Todd Stroberg, RN, GCRC grant number RR00047; Cornell University CRS; Emory University Comprehensive Hemophilia Program, James Paul Steinberg, MD; Tulane University, Cindy Leissinger, MD.
M.D.H. is a paid member of Data and Safety Monitoring Boards for Boehringer-Ingelheim, Medicines Development Ltd., Pfizer, and Tibotec. These companies are all manufacturers or developers of ART or other therapy for HIV infection. In the last year and currently, C.A.B. has served on advisory boards for GlaxoSmithKline and Merck, and served on a Data and Safety Monitoring Board for Achillion, A.C.C. receives research support from Merck & Co. and Schering-Plough, has served on advisory boards for GlaxoSmithKline and Pfizer, is a member of a Data and Safety Monitoring Board for Merck & Co., and owns stock in Abbott Laboratories and Bristol Myers Squibb. In the last year, G.K.R. was a consultant for Johnson and Johnson.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; HIV/AIDS; long-term CD4+ T-cell count; loss to follow-up; observational data