Robert S. Hogg

Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies.

BACKGROUND Insufficient data are available from single cohort studies to allow estimation of the prognosis of HIV-1 infected, treatment-naive patients who start highly active antiretroviral therapy (HAART). The ART Cohort Collaboration, which includes 13 cohort studies from Europe and North America, was established to fill this knowledge gap. METHODS We analysed data on 12,574 adult patients starting HAART with a combination of at least three drugs. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. We considered progression to a combined endpoint of a new AIDS-defining disease or death, and to death alone. The prognostic model that generalised best was a Weibull model, stratified by baseline CD4 cell count and transmission group. FINDINGS During 24,310 person-years of follow up, 1094 patients developed AIDS or died and 344 patients died. Baseline CD4 cell count was strongly associated with the probability of progression to AIDS or death: compared with patients starting HAART with less than 50 CD4 cells/microL, adjusted hazard ratios were 0.74 (95% CI 0.62-0.89) for 50-99 cells/microL, 0.52 (0.44-0.63) for 100-199 cells/microL, 0.24 (0.20-0.30) for 200-349 cells/microL, and 0.18 (0.14-0.22) for 350 or more CD4 cells/microL. Baseline HIV-1 viral load was associated with a higher probability of progression only if 100,000 copies/microL or above. Other independent predictors of poorer outcome were advanced age, infection through injection-drug use, and a previous diagnosis of AIDS. The probability of progression to AIDS or death at 3 years ranged from 3.4% (2.8-4.1) in patients in the lowest-risk stratum for each prognostic variable, to 50% (43-58) in patients in the highest-risk strata. INTERPRETATION The CD4 cell count at initiation was the dominant prognostic factor in patients starting HAART. Our findings have important implications for clinical management and should be taken into account in future treatment guidelines.

Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies

BACKGROUND Combination antiretroviral therapy has led to significant increases in survival and quality of life, but at a population-level the effect on life expectancy is not well understood. Our objective was to compare changes in mortality and life expectancy among HIV-positive individuals on combination antiretroviral therapy. METHODS The Antiretroviral Therapy Cohort Collaboration is a multinational collaboration of HIV cohort studies in Europe and North America. Patients were included in this analysis if they were aged 16 years or over and antiretroviral-naive when initiating combination therapy. We constructed abridged life tables to estimate life expectancies for individuals on combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, and stratified by sex, baseline CD4 cell count, and history of injecting drug use. The average number of years remaining to be lived by those treated with combination antiretroviral therapy at 20 and 35 years of age was estimated. Potential years of life lost from 20 to 64 years of age and crude mortality rates were also calculated. FINDINGS 18 587, 13 914, and 10 854 eligible patients initiated combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, respectively. 2056 (4.7%) deaths were observed during the study period, with crude mortality rates decreasing from 16.3 deaths per 1000 person-years in 1996-99 to 10.0 deaths per 1000 person-years in 2003-05. Potential years of life lost per 1000 person-years also decreased over the same time, from 366 to 189 years. Life expectancy at age 20 years increased from 36.1 (SE 0.6) years to 49.4 (0.5) years. Women had higher life expectancies than did men. Patients with presumed transmission via injecting drug use had lower life expectancies than did those from other transmission groups (32.6 [1.1] years vs 44.7 [0.3] years in 2003-05). Life expectancy was lower in patients with lower baseline CD4 cell counts than in those with higher baseline counts (32.4 [1.1] years for CD4 cell counts below 100 cells per muL vs 50.4 [0.4] years for counts of 200 cells per muL or more). INTERPRETATION Life expectancy in HIV-infected patients treated with combination antiretroviral therapy increased between 1996 and 2005, although there is considerable variability between subgroups of patients. The average number of years remaining to be lived at age 20 years was about two-thirds of that in the general population in these countries.

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival

BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study

BACKGROUND Results of cohort studies and mathematical models have suggested that increased coverage with highly active antiretroviral therapy (HAART) could reduce HIV transmission. We aimed to estimate the association between plasma HIV-1 viral load, HAART coverage, and number of new cases of HIV in the population of a Canadian province. METHODS We undertook a population-based study of HAART coverage and HIV transmission in British Columbia, Canada. Data for number of HIV tests done and new HIV diagnoses were obtained from the British Columbia Centre for Disease Control. Data for viral load, CD4 cell count, and HAART use were extracted from the British Columbia Centre for Excellence in HIV/AIDS population-based registries. We modelled trends of new HIV-positive tests and number of individuals on HAART using generalised additive models. Poisson log-linear regression models were used to estimate the association between new HIV diagnoses and viral load, year, and number of individuals on HAART. FINDINGS Between 1996 and 2009, the number of individuals actively receiving HAART increased from 837 to 5413 (547% increase; p=0.002), and the number of new HIV diagnoses fell from 702 to 338 per year (52% decrease; p=0.001). The overall correlation between number of individuals on HAART and number of individuals newly testing positive for HIV per year was -0.89 (p<0.0001). For every 100 additional individuals on HAART, the number of new HIV cases decreased by a factor of 0.97 (95% CI 0.96-0.98), and per 1 log(10) decrease in viral load, the number of new HIV cases decreased by a factor of 0.86 (0.75-0.98). INTERPRETATION We have shown a strong population-level association between increasing HAART coverage, decreased viral load, and decreased number of new HIV diagnoses per year. Our results support the proposed secondary benefit of HAART used within existing medical guidelines to reduce HIV transmission. FUNDING Ministry of Health Services and Ministry of Healthy Living and Sport, Province of British Columbia; US National Institute on Drug Abuse; US National Institutes of Health; Canadian Institutes of Health Research.

The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic

examine here the potential role of HAART in HIV prevention and the resulting eff ect this would have on the cost-eff ectiveness of the treatment. We also discuss a theoretical HAART-driven strategy to control the continued expansion of the HIV/AIDS pandemic.

Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies

BACKGROUND We examined specific causes of mortality in human immunodeficiency virus type 1 (HIV-1)-infected patients who initiated antiretroviral therapy (ART) in Europe and North America from 1996 through 2006, and we quantified associations of prognostic factors with cause-specific mortality. METHODS We retrospectively classified all deaths among 39,272 patients enrolled in 13 HIV-1 cohorts (154,667 person years of follow-up) into the categories specified in the Cause of Death (CoDe) project protocol. RESULTS In 1597 (85%) of 1876 deaths, a definitive cause of death could be assigned. Among these, 792 deaths (49.5%) were AIDS related, followed by non-AIDS malignancies (189; 11.8%), non-AIDS infections (131; 8.2%), violence- and/or drug-related causes (124; 7.7%), liver disease (113; 7.0%), and cardiovascular disease (103; 6.5%). Rates of AIDS-related death (hazard ratio [HR] per 100 cell decrease, 1.43; 95% confidence interval [CI], 1.34-1.53) and death from renal failure (HR, 1.73; 95% CI, 1.18-2.55) were strongly inversely related to CD4 count at initiation of ART, whereas rates of death attributable to AIDS (HR for viral load >5 vs 5 log copies/mL, 1.31; 95% CI, 1.12-1.53), infection (HR, 1.85; 95% CI, 1.25-2.73), cardiovascular (HR, 1.54; 95% CI, 1.05-2.27), and respiratory causes (HR, 3.62; 95% CI, 1.30-10.09) were higher in patients with baseline viral load >5 log copies/mL than in other patients. Rates of each cause of death were higher in patients with presumed transmission via injection drug use than in other patients, with marked increases in rates of liver-related (HR for injection drug use vs non-injection drug use, 6.06; 95% CI, 4.03-9.09) and respiratory tract-related (HR, 4.94; 95% CI, 1.96-12.45) mortality. The proportion of deaths classified as AIDS related decreased with increasing duration of ART. CONCLUSIONS Important contributors to non-AIDS mortality in treated HIV-1-infected individuals must be addressed if decreases in mortality rates are to continue.

Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up.

Objective To characterize the impact of intermittent use of triple drug antiretroviral therapy on survival. Design, setting and participants Population-based analysis of 1282 antiretroviral therapy naive HIV-positive individuals aged 18 years and older in British Columbia who started triple-combination therapy between August 1996 and December 1999. Therapy use was estimated by dividing the number of months of medications dispensed by the number of months of follow-up. Intermittent therapy was defined as the participant having obtained less than 75% of their medication in the first 12 months. Main outcome measure Cumulative all-cause mortality rates from the start of triple drug antiretroviral therapy to 30 September 2000. Results As of 30 September 2000, 106 subjects had died. Cumulative mortality was 3.9% (± 0.5%) at 12 months. In a multivariate model, after controlling for other variables that were significant in the univariate analyses each 100 cell decrement in baseline CD4 cell count and the intermittent use of antiretroviral drugs were associated with increased mortality with risk ratios of 1.31 [95% confidence interval (CI), 1.16–1.49;P < 0.001] and 2.90 (95% CI, 1.93–4.36;P < 0.001), respectively. In order to control for downward drift, intermittent use of therapy was measured over the first year whereas other factors were measured at the end of year 1. After adjusting for all other factors, those participants who used antiretroviral drugs intermittently were 2.97 times (95% CI, 1.33–6.62;P = 0.008) more likely to die. Conclusion Our study demonstrates that even after adjusting for other prognostic factors intermittent use of antiretroviral therapy was associated with increased mortality.

Decline in deaths from AIDS due to new antiretrovirals

We determined whether availability of new antiretroviral treatments has had any impact on the rate of death for people with HIV-1 infection. Distribution of antiretroviral drugs in British Columbia, Canada, is free of charge through the Centre for Excellence in HIV/AIDS Treatment Programme. For physicians to prescribe antiretrovirals, they must complete a participant enrolment form that serves as the drug prescription. Individuals infected with HIV-1 are eligible to receive antiretroviral therapy from this programme if they have at least one CD4 cell count less than 0·5 10/L. Until December, 1995, monotherapy was made available to participants with CD4 counts less than 0·5 10/L, while double combination therapy was made available to those with CD4 counts of less than 0·35 10/L. After December, 1995, double combination treatment was made available to everyone with CD4 counts less than 0·5 10/L. Viral-loaddriven antiretroviral treatment and triple combination therapy became available after June, 1996. Of the five new medications introduced in 1996, lamivudine became available in January, saquinavir in June, stavudine in July, and indinavir and ritonavir in September. Patterns of mortality were assessed by comparing changes in death rates for those individuals on antiretroviral therapy by quarter and CD4-count groupings (0·1 10/L, 0·1–0·34 10/L, and 0·35–0·49 10/L). Mortality data were obtained through regular surveillance and computerised record linkages with Division of Vital Statistics of the British Columbia Ministry of Health. Population figures were based on the number of programme participants actively on antiretroviral therapy. Rates were expressed as deaths per 1000 active participants and were calculated over a 3-year period from January, 1994 to December, 1996. There were 604 deaths during this period among individuals ever on antiretroviral therapy; of these, 475 deaths (79%) were attributed to participants with CD4 counts less than 0·1 10/L. There was a significant decline in programme mortality rates since the first quarter of 1994 (trend test p<0·001). On average, the rate of death for those on antiretroviral treatment declined at a rate of 1·7 deaths per 1000 participants per quarter or from 18·9 deaths per 1000 participants in the first quarter of 1994 to 5·7 deaths per 1000 participants in the last quarter of 1996. As shown in the figure, the greatest decline in mortality was experienced in those participants with CD4 counts less than 0·1 10/L (trend test p<0·001). On average, the death rate for participants with CD4 counts of less than 0·1 10/L declined at a rate of 3·5 deaths per 1000 participants per quarter—ie, from 62·0 to 19·8 deaths per 1000 participants from the first quarter of 1994 to the last quarter of 1996. Although there was a decline in the death rates for other two CD4-count groups, the rates were not statistically significant. Delayed reporting was not likely to affect our analysis. The vast majority of deaths were reported through active follow-up. In this analysis, data on 536 (89%) deaths were obtained through physician and hospital reports and data on 68 (11%) were obtained through linkages. Furthermore, in a subanalysis of 179 deaths obtained through physician and hospital reports over a 1-year period ending on June 30, 1996, we found that the median follow-up time between the actual date of death and the date of reporting was 7 days (interquartile range 5–11 days). Our data show a substantial decrease in AIDS-related mortality in the province of British Columbia. The decline in mortality coincides with the availability of lamivudine in the province through open access and with the expanded use of double combination antiretroviral therapy. We believe this mortality trend will likely continue as protease inhibitors and non-nucleoside reverse transcriptase inhibitors are used to greater extent within the treatment programme.

Predictors of HIV Drug-Resistance Mutations in a Large Antiretroviral-Naive Cohort Initiating Triple Antiretroviral Therapy

OBJECTIVE The objective of this study was to systematically characterize the incidence and determinants of antiretroviral resistance in the HOMER (Highly Active Antiretroviral Therapy [HAART] Observational Medical Evaluation and Research) cohort of 1191 human immunodeficiency virus-infected, antiretroviral-naive adults initiating HAART in British Columbia, Canada. METHODS All plasma samples with plasma virus loads (pVLs) >1000 copies/mL collected during the first 30 months of follow-up were genotyped for drug resistance. The primary outcome measure was time to the first detection of major drug-resistance mutation(s). Cox proportional hazard regression was used to identify factors significantly associated with the detection of drug-resistance mutations. RESULTS Drug-resistance mutations were detected in 298 subjects (25%). Factors significantly associated with detection of drug-resistance mutations included high baseline pVL (multivariate hazard ratio [HR], 1.59; P<.001) and adherence (estimated using prescription-refill data and/or untimed plasma drug-concentration measurements). When compared with subjects with low (0%-<20%) prescription-refill percentages, subjects at an elevated risk of harboring drug-resistance mutations were those with relatively high but imperfect prescription-refill percentages (80%-<90%; multivariate HR, 4.15; P<.001) and those with essentially perfect (>/=95%) refill percentages but with 2 plasma drug concentrations below the steady-state trough concentration minus 1 standard deviation (multivariate HR, 4.57; P<.001). Initial use of nonnucleoside reverse-transcriptase inhibitor-based HAART was significantly associated with multiclass drug resistance (multivariate HR, 1.84; P=.001). CONCLUSION High baseline pVLs and substantial but imperfect levels of adherence were major predictors of antiretroviral resistance.

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

Context Highly active antiretroviral therapy (HAART) improves outcomes in HIV-infected patients. When is the best time to start this therapy? Contribution 1422 HIV-infected adults were followed for 2 to 6 years after starting HAART. Adherent patients who started treatment with lower (0.200 to 0.349 109 cells/L) and higher ( 0.350 109 cells/L) CD4+ cell counts had statistically similar mortality rates. Nonadherent patients had higher mortality rates than adherent patients, regardless of baseline CD4+ cell count of 0.200 to 0.349 109 cells/L or 0.350 109 cells/L or greater. Implications In HIV-infected patients, adherence, rather than when therapy is initiated before a CD4+ cell count of 0.200 109 cells/L, may be the most important determinant of survival. The Editors The benefits of highly active antiretroviral therapy (HAART) in the management of HIV disease are well established. By suppressing plasma HIV-1 RNA, HAART decreases morbidity and mortality in HIV-infected patients (1, 2). However, the optimal time to initiate HAART is uncertain. As a result, expert recommendations on the optimal time to initiate antiretroviral therapy widely differ (3-6). Several studies have suggested that only patients who initiated therapy when the CD4+ cell count had declined below 0.200 109 cells/L were at increased risk for disease progression, regardless of the baseline HIV RNA level (7-9). In 1 of these studies, further examination with additional duration of follow-up suggested that mortality may be elevated in patients who initiated therapy after the CD4+ cell count declined below 0.350 109 cells/L (10). In fact, a growing number of studies have suggested that delaying HAART after the CD4+ cell count declines below 0.350 109 cells/L may be unsafe (11-14). However, previous studies (7, 9, 11-14) did not adjust for patient adherence. This limitation is critically important because incomplete adherence is associated with increased mortality (15-17). Therefore, we sought to evaluate the effect of baseline CD4+ cell count and adherence on survival rates after the initiation of HAART. Methods The HAART Observational Medical Evaluation and Research (HOMER) study, conducted through the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program, has been described in detail elsewhere (7, 17). Briefly, the Centre is the only free source of antiretroviral medications in British Columbia, Canada; pharmaceutical sales suggest that less than 1% of HIV-infected patients in this province obtain antiretroviral agents outside the program (18). For all participants, the program maintains a complete prospective profile of antiretroviral therapy. In the present study, we restricted analyses to HIV-infected men and women who had been antiretroviral naive until triple-drug antiretroviral therapy was prescribed between 1 August 1996 and 31 July 2000 and were followed through 31 March 2002. Study participants were initially prescribed HAART regimens that included 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor (the enrolling physician, in consultation with the patient, chose the regimen). End Points The primary end point in this analysis was time to death. Deaths occurring during the follow-up period were continuously identified from physician reports and through record linkages with the British Columbia Division of Vital Statistics. In the primary analysis, we evaluated all-cause mortality; in subanalyses, we censored deaths from accidental causes at the time of death and classified them as nonevents (7). Statistical Analysis KaplanMeier Analyses For the KaplanMeier analyses, we stratified patients into 5 baseline CD4+ cell count strata on the basis of previous studies and the recommendations of therapeutic guidelines: less than 0.200, 0.200 to 0.249, 0.250 to 0.299, 0.300 to 0.349, and greater than or equal to 0.350 109 cells/L (3-5, 7-9). We further stratified patients into adherent and nonadherent categories according to adherence to prescription refills (19). The definition of adherence was based on the ratio of time that medication dispensed would last as a proportion of follow-up time. This calculation was restricted to each patients first year of therapy in order to limit the potential for reverse causation in patients who ceased antiretroviral therapy after they became too sick to take medication (15, 20). We have previously demonstrated that adherence defined in this way strongly predicts virologic response and mortality and that it can be used to adjust for the potentially confounding effect of treatment interruption (15, 17, 21, 22). In the primary analysis, we wanted to evaluate how moderate adherence to HAART affected survival. Therefore, to estimate the effect of moderate adherence, a priori we categorized patients as nonadherent only if they received antiretroviral medications less than 75% of the time during the first year of therapy (15, 17). In a subanalysis, we estimated the risk for death from HIV disease among patients who were highly adherent to HAART. We defined adherence more rigorously for this analysis; patients were considered nonadherent only if they received antiretroviral medications less than 95% of the time during the first year of therapy (21, 23). We also censored deaths from accidental causes at the time of death and classified them as nonevents (7). For both analyses, we evaluated the cumulative mortality rates among the predefined baseline CD4+ cell count strata using KaplanMeier methods. Survival curves were compared by using the log-rank test. Cox Regression Analyses We were aware that additional confounding may persist if the distribution of baseline AIDS diagnoses or baseline HIV RNA levels differed between patients with various baseline CD4+ cell counts (9). Therefore, we performed Cox proportional-hazards regression analyses to calculate the adjusted relative hazards of mortality (24). In these analyses, we stratified patients into combined low (<0.200 109 cells/L), medium (0.200 to 0.349 109 cells/L), and high ( 0.350 109 cells/L) CD4+ cell count strata (3-5, 7-9). To derive adjusted relative hazards of mortality among adherent and nonadherent patients in the various CD4+ cell count strata, we built fixed models with indicator variables for each adherence and CD4+ cell count strata while adjusting for baseline HIV RNA level and other relevant covariates. Variables examined in these analyses included protease inhibitor use in the initial regimen (yes or no), a previous clinical diagnosis of AIDS (yes or no), age, sex, physician experience ( 6 patients previously enrolled in the program) (17), date of therapy initiation (before or after July 1997) (25), and baseline HIV RNA levels (log10-transformed). The assumption of proportional hazards was validated by inspection of log (log [survival function]) estimates against log time plots. We fit all multivariate models by adjusting for all variables that were statistically significant (P < 0.05) in univariate analyses. Role of the Funding Sources The funding sources had no role in the design, conduct, or reporting of the study or the decision to submit the manuscript for publication. Results Between 1 August 1996 and 31 July 2000, 1583 antiretroviral-naive participants 18 years of age and older began triple-drug therapy. Of these, 161 (10%) were excluded from this analysis because baseline CD4+ cell count and plasma HIV-1 RNA levels were not available within 6 months before the start of antiretroviral therapy. Therefore, the study sample was based on 1422 (90%) participants (1198 men [84%] and 224 women [15%]). Sex, presence of AIDS at baseline, and subsequent mortality did not differ between the study sample and the persons excluded. However, excluded persons were more likely to be younger (P = 0.04) and to be taking protease inhibitors (P = 0.02). The overall median follow-up time was 40.1 months (interquartile range, 27.7 to 52.9 months). At baseline, the median patient age was 37 years (interquartile range, 32 to 44 years), the median CD4+ cell count was 0.270 109 cells/L (interquartile range, 0.130 to 0.420 109 cells/L), and the median plasma HIV RNA level was 120 000 copies/mL (interquartile range, 38 000 to 300 000 copies/mL). Initial therapy was a protease inhibitor in 983 (69.1%) patients and a nonnucleoside reverse transcriptase inhibitor in 439 (31%) patients. During the study period, 193 patients died: 25 (13%) as a result of an accident or suicide and 14 (7%) as a result of an illicit drug overdose. Compared with patients who were less than 75% adherent, patients who were at least 75% adherent were more likely to be male (78.0% vs. 59.4%) and older (37.9 years vs. 35.4 years) and were less likely to have a history of injection drug use (78.3% vs. 65.5%) (P < 0.05 for all comparisons). In the primary analysis that considered all-cause mortality and 75% adherence, 45 of the 632 patients with at least 75% adherence who initiated HAART before the CD4+ cell count reached 0.200 109 cells/L had died by 31 March 2002; the crude mortality rate was 7.1% (Figure 1, left). Conversely, among the 264 patients who started HAART when the CD4+ cell count was 0.200 109 cells/L or greater and who were less than 75% adherent, 40 had died (crude mortality rate, 15.2%) (Figure 1, right). The absolute difference in crude mortality between adherent and nonadherent patients with a baseline CD4+ cell count of 0.200 109 cells/L or greater was 8.1 percentage points (Table 1). In KaplanMeier analyses, when patients were considered according to the CD4+ cell count strata (<0.200, 0.200 to 0.249, 0.250 to 0.299, 0.300 to 0.349, and 0.350 109 cells/L), starting HAART at a CD4+ count of 0.200 109 cells/L or greater had no survival benefit in the 632 patients who were at least 75% adherent (Figure 1, left). Table 2 shows the log-rank P values and estimated CIs comparing patients with