Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring

BACKGROUND: In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia. DESIGN AND METHODS: Multicohort study of 17 ART programmes. All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored viral load. We compared times to switching, CD4 cell counts at switching and obtained adjusted hazard ratios for switching (aHRs) with 95% confidence intervals (CIs) from random-effects Weibull models. RESULTS: A total of 20 113 patients, including 6369 (31.7%) patients from 10 programmes with access to viral load monitoring, were analysed; 576 patients (2.9%) switched. Low CD4 cell counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months [interquartile range (IQR) 10.1-26.6] in programmes with viral load monitoring and 21.8 months (IQR 14.0-21.8) in programmes without viral load monitoring (P < 0.001). Median CD4 cell counts at switching were 161 cells/microl (IQR 77-265) in programmes with viral load monitoring and 102 cells/microl (44-181) in programmes without viral load monitoring (P < 0.001). Switching was more common in programmes with viral load monitoring during months 7-18 after starting ART (aHR 1.38; 95% CI 0.97-1.98), similar during months 19-30 (aHR 0.97; 95% CI 0.58-1.60) and less common during months 31-42 (aHR 0.29; 95% CI 0.11-0.79). CONCLUSION: In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with viral load monitoring compared with programmes without viral load monitoring.

Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy

OBJECTIVES: To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment. METHODS: Analysis of 10 treatment programmes in Africa and South America that monitor both CD4 cell counts and HIV-1 viral load. Adult patients with at least two CD4 counts and viral load measurements between month 6 and 18 after starting a non-nucleoside reverse transcriptase inhibitor-based regimen were included. WHO immunological criteria include CD4 counts persistently <100 cells/microl, a fall below the baseline CD4 count, or a fall of >50% from the peak value. Virological failure was defined as two measurements > or =10 0000 copies/ml (higher threshold) or > or =500 copies/ml (lower threshold). Measures of accuracy with exact binomial 95% confidence intervals (CI) were calculated. RESULTS: A total of 2009 patients were included. During 1856 person-years of follow up 63 patients met the immunological criteria and 35 patients (higher threshold) and 95 patients (lower threshold) met the virological criteria. Sensitivity [95% confidence interval (CI)] was 17.1% (6.6-33.6%) for the higher and 12.6% (6.7-21.0%) for the lower threshold. Corresponding results for specificity were 97.1% (96.3-97.8%) and 97.3% (96.5-98.0%), for positive predictive value 9.5% (3.6-19.6%) and 19.0% (10.2-30.9%) and for negative predictive value 98.5% (97.9-99.0%) and 95.7% (94.7-96.6%). CONCLUSIONS: The positive predictive value of the WHO immunological criteria for virological failure of antiretroviral treatment in resource-limited settings is poor, but the negative predictive value is high. Immunological criteria are more appropriate for ruling out than for ruling in virological failure in resource-limited settings.

Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

BACKGROUND: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. METHODS: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL. FINDINGS: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL). INTERPRETATION: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.

Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal

BACKGROUND: The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. METHODS: We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together to form a "rare ADEs" category. RESULTS: During a median follow-up period of 43 months (interquartile range, 19-70 months), 2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-Hodgkin's lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84-22.35) and progressive multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70-14.92). Three groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped confidence intervals: severe (non-Hodgkin's lymphoma and progressive multifocal leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55-9.48]), moderate (cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76-3.13]), and mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08-2.00]). CONCLUSIONS: In the combination antiretroviral therapy era, mortality rates subsequent to an ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in clinical end point trials, prognostic studies, and patient management.

Radiation therapy for HIV-associated diffuse large cell non-Hodgkin lymphoma

PURPOSE: To report the clinical experience with external beam radiotherapy (RT) for AIDS-related lymphoma (ARL) with or without the involvement of the central nervous system (CNS) in HIV-infected patients. PATIENTS AND METHODS: Clinical outcome of 24 HIV-seropositive patients with ARL treated with RT from 1995 to 2004 was reviewed, testing factors associated with outcome. RESULTS: After 1 and 5 years, the overall survival was 65% and 35%, respectively. The mean RT dose was 31 Gy after normalization to fractions of daily 2 Gy (range, 7.8-47.2 Gy). Radiotherapy dose was associated with survival in univariate (P = .04) and multivariate analysis (P = .01). Other factors in univariate analysis associated with outcome were viral load (VL), highly active antiretroviral therapy (HAART), ARL stage, and CNS involvement. Patients with CNS involvement achieved complete response in 46% and improved clinical performance was seen in 73%. CONCLUSIONS: After chemotherapy, RT in combination with HAART is highly active, and RT should be encouraged especially after suboptimal responses to induction treatment.

Contribution of genome-wide significant single-nucleotide polymorphisms and antiretroviral therapy to dyslipidemia in HIV-infected individuals: a longitudinal study

BACKGROUND: HIV-infected individuals have an increased risk of myocardial infarction. Antiretroviral therapy (ART) is regarded as a major determinant of dyslipidemia in HIV-infected individuals. Previous genetic studies have been limited by the validity of the single-nucleotide polymorphisms (SNPs) interrogated and by cross-sectional design. Recent genome-wide association studies have reliably associated common SNPs to dyslipidemia in the general population. METHODS AND RESULTS: We validated the contribution of 42 SNPs (33 identified in genome-wide association studies and 9 previously reported SNPs not included in genome-wide association study chips) and of longitudinally measured key nongenetic variables (ART, underlying conditions, sex, age, ethnicity, and HIV disease parameters) to dyslipidemia in 745 HIV-infected study participants (n=34 565 lipid measurements; median follow-up, 7.6 years). The relative impact of SNPs and ART to lipid variation in the study population and their cumulative influence on sustained dyslipidemia at the level of the individual were calculated. SNPs were associated with lipid changes consistent with genome-wide association study estimates. SNPs explained up to 7.6% (non-high-density lipoprotein cholesterol), 6.2% (high-density lipoprotein cholesterol), and 6.8% (triglycerides) of lipid variation; ART explained 3.9% (non-high-density lipoprotein cholesterol), 1.5% (high-density lipoprotein cholesterol), and 6.2% (triglycerides). An individual with the most dyslipidemic antiretroviral and genetic background had an approximately 3- to 5-fold increased risk of sustained dyslipidemia compared with an individual with the least dyslipidemic therapy and genetic background. CONCLUSIONS: In the HIV-infected population treated with ART, the weight of the contribution of common SNPs and ART to dyslipidemia was similar. When selecting an ART regimen, genetic information should be considered in addition to the dyslipidemic effects of ART agents.

Impact of previous virological treatment failures and adherence on the outcome of antiretroviral therapy in 2007

BACKGROUND: Combination antiretroviral treatment (cART) has been very successful, especially among selected patients in clinical trials. The aim of this study was to describe outcomes of cART on the population level in a large national cohort. METHODS: Characteristics of participants of the Swiss HIV Cohort Study on stable cART at two semiannual visits in 2007 were analyzed with respect to era of treatment initiation, number of previous virologically failed regimens and self reported adherence. Starting ART in the mono/dual era before HIV-1 RNA assays became available was counted as one failed regimen. Logistic regression was used to identify risk factors for virological failure between the two consecutive visits. RESULTS: Of 4541 patients 31.2% and 68.8% had initiated therapy in the mono/dual and cART era, respectively, and been on treatment for a median of 11.7 vs. 5.7 years. At visit 1 in 2007, the mean number of previous failed regimens was 3.2 vs. 0.5 and the viral load was undetectable (<50 copies/ml) in 84.6% vs. 89.1% of the participants, respectively. Adjusted odds ratios of a detectable viral load at visit 2 for participants from the mono/dual era with a history of 2 and 3, 4, >4 previous failures compared to 1 were 0.9 (95% CI 0.4-1.7), 0.8 (0.4-1.6), 1.6 (0.8-3.2), 3.3 (1.7-6.6) respectively, and 2.3 (1.1-4.8) for >2 missed cART doses during the last month, compared to perfect adherence. From the cART era, odds ratios with a history of 1, 2 and >2 previous failures compared to none were 1.8 (95% CI 1.3-2.5), 2.8 (1.7-4.5) and 7.8 (4.5-13.5), respectively, and 2.8 (1.6-4.8) for >2 missed cART doses during the last month, compared to perfect adherence. CONCLUSIONS: A higher number of previous virologically failed regimens, and imperfect adherence to therapy were independent predictors of imminent virological failure.

Uptake of and virological response to antiretroviral therapy among HIV-infected former and current injecting drug users and persons in an opiate substitution treatment programme: the Swiss HIV Cohort Study

OBJECTIVES: The aim of the study was to investigate the influence of continued injecting drug use, enrolment in an opiate substitution treatment programme (OSTP), or cessation of injecting drug use on the uptake and course of antiretroviral therapy (ART). Design A prospective observational study of all participants in the Swiss HIV Cohort Study followed between 1997 and 2006 was carried out. METHODS: We distinguished four groups of former or current injecting drug users (IDUs): (i) abstinent former IDUs; (ii) persons in OSTPs without concomitant injecting drug use; (iii) persons in OSTPs with concomitant injecting drug use; (vi) current IDUs. These groups were compared with a group of patients who had never been IDUs. Factors related to ART uptake and virological endpoints were analysed using logistic generalized estimating equations. RESULTS: We followed 8660 participants for 48 477 person-years; 29.7% were in the IDU HIV transmission group. The likelihood of being on ART at biannual visits was lower among individuals in OSTPs with concomitant injecting drug use [odds ratio (OR) 0.79; 95% confidence interval (CI) 0.71-0.89] and current IDUs (OR 0.80; 95% CI 0.67-0.96), compared with those who had never been IDUs (reference), abstinent former IDUs (OR 1.13; 95% CI 1.02-1.25) and individuals in OSTPs without injecting drug use (OR 1.18; 95% CI 1.06-1.31). The likelihood of suppressed viral replication on ART was similar among those who had never been IDUs, abstinent former IDUs and individuals in an OSTP without injecting drug use, and lower among those in OSTPs with concomitant drug use (OR 0.82; 95% CI 0.72-0.93) and current IDUs (OR 0.81; 0.65-1.00). Adherence to ART was decreased among persons with continued injecting drug use, and correlated with virological outcome. CONCLUSIONS: Uptake of and virological response to ART were improved among abstinent former IDUs and persons in OSTPs without concomitant injecting drug use, compared with persons with continued injecting drug use.

Self-reported alcohol consumption and its association with adherence and outcome of antiretroviral therapy in the Swiss HIV Cohort Study

BACKGROUND: Alcohol consumption leading to morbidity and mortality affects HIV-infected individuals. Here, we aimed to study self-reported alcohol consumption and to determine its association with adherence to antiretroviral therapy (ART) and HIV surrogate markers. METHODS: Cross-sectional data on daily alcohol consumption from August 2005 to August 2007 were analysed and categorized according to the World Health Organization definition (light, moderate or severe health risk). Multivariate logistic regression models and Pearson's chi(2) statistics were used to test the influence of alcohol use on endpoints. RESULTS: Of 6,323 individuals, 52.3% consumed alcohol less than once a week in the past 6 months. Alcohol intake was deemed light in 39.9%, moderate in 5.0% and severe in 2.8%. Higher alcohol consumption was significantly associated with older age, less education, injection drug use, being in a drug maintenance programme, psychiatric treatment, hepatitis C virus coinfection and with a longer time since diagnosis of HIV. Lower alcohol consumption was found in males, non-Caucasians, individuals currently on ART and those with more ART experience. In patients on ART (n=4,519), missed doses and alcohol consumption were positively correlated (P<0.001). Severe alcohol consumers, who were pretreated with ART, were more often off treatment despite having CD4+ T-cell count <200 cells/microl; however, severe alcohol consumption per se did not delay starting ART. In treated individuals, alcohol consumption was not associated with worse HIV surrogate markers. CONCLUSIONS: Higher alcohol consumption in HIV-infected individuals was associated with several psychosocial and demographic factors, non-adherence to ART and, in pretreated individuals, being off treatment despite low CD4+ T-cell counts.

Hierarchical modeling gave plausible estimates of associations between metabolic syndrome and components of antiretroviral therapy

OBJECTIVE: Hierarchical modeling has been proposed as a solution to the multiple exposure problem. We estimate associations between metabolic syndrome and different components of antiretroviral therapy using both conventional and hierarchical models. STUDY DESIGN AND SETTING: We use discrete time survival analysis to estimate the association between metabolic syndrome and cumulative exposure to 16 antiretrovirals from four drug classes. We fit a hierarchical model where the drug class provides a prior model of the association between metabolic syndrome and exposure to each antiretroviral. RESULTS: One thousand two hundred and eighteen patients were followed for a median of 27 months, with 242 cases of metabolic syndrome (20%) at a rate of 7.5 cases per 100 patient years. Metabolic syndrome was more likely to develop in patients exposed to stavudine, but was less likely to develop in those exposed to atazanavir. The estimate for exposure to atazanavir increased from hazard ratio of 0.06 per 6 months' use in the conventional model to 0.37 in the hierarchical model (or from 0.57 to 0.81 when using spline-based covariate adjustment). CONCLUSION: These results are consistent with trials that show the disadvantage of stavudine and advantage of atazanavir relative to other drugs in their respective classes. The hierarchical model gave more plausible results than the equivalent conventional model.

Risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy

BACKGROUND: This collaboration of seven observational clinical cohorts investigated risk factors for treatment-limiting toxicities in both antiretroviral-naive and experienced patients starting nevirapine-based combination antiretroviral therapy (NVPc). METHODS: Patients starting NVPc after 1 January 1998 were included. CD4 cell count at starting NVPc was classified as high (>400/microl/>250/microl for men/women, respectively) or low. Cox models were used to investigate risk factors for discontinuations due to hypersensitivity reactions (HSR, n = 6547) and discontinuation of NVPc due to treatment-limiting toxicities and/or patient/physician choice (TOXPC, n = 10,186). Patients were classified according to prior antiretroviral treatment experience and CD4 cell count/viral load at start NVPc. Models were stratified by cohort and adjusted for age, sex, nadir CD4 cell count, calendar year of starting NVPc and mode of transmission. RESULTS: Median time from starting NVPc to TOXPC and HSR were 162 days [interquartile range (IQR) 31-737] and 30 days (IQR 17-60), respectively. In adjusted Cox analyses, compared to naive patients with a low CD4 cell count, treatment-experienced patients with high CD4 cell count and viral load more than 400 had a significantly increased risk for HSR [hazard ratio 1.45, confidence interval (CI) 1.03-2.03] and TOXPC within 18 weeks (hazard ratio 1.34, CI 1.08-1.67). In contrast, treatment-experienced patients with high CD4 cell count and viral load less than 400 had no increased risk for HSR 1.10 (0.82-1.46) or TOXPC within 18 weeks (hazard ratio 0.94, CI 0.78-1.13). CONCLUSION: Our results suggest it may be relatively well tolerated to initiate NVPc in antiretroviral-experienced patients with high CD4 cell counts provided there is no detectable viremia.

Treatment response and mortality among patients starting antiretroviral therapy with and without Kaposi sarcoma: a cohort study

BACKGROUND Improved survival among HIV-infected individuals on antiretroviral therapy (ART) has focused attention on AIDS-related cancers including Kaposi sarcoma (KS). However, the effect of KS on response to ART is not well-described in Southern Africa. We assessed the effect of KS on survival and immunologic and virologic treatment responses at 6- and 12-months after initiation of ART. METHODS We analyzed prospectively collected data from a cohort of HIV-infected adults initiating ART in South Africa. Differences in mortality between those with and without KS at ART initiation were estimated with Cox proportional hazard models. Log-binomial models were used to assess differences in CD4 count response and HIV virologic suppression within a year of initiating treatment. RESULTS Between January 2001-January 2008, 13,847 HIV-infected adults initiated ART at the study clinics. Those with KS at ART initiation (n = 247, 2%) were similar to those without KS (n = 13600,98%) with respect to age (35 vs. 35yrs), presenting CD4 count (74 vs. 85cells/mm³) and proportion on TB treatment (37% vs. 30%). In models adjusted for sex, baseline CD4 count, age, treatment site, tuberculosis and year of ART initiation, KS patients were over three times more likely to have died at any time after ART initiation (hazard ratio[HR]: 3.62; 95% CI: 2.71-4.84) than those without KS. The increased risk was highest within the first year on ART (HR: 4.05; 95% CI: 2.95-5.55) and attenuated thereafter (HR: 2.30; 95% CI: 1.08-4.89). Those with KS also gained, on average, 29 fewer CD4 cells (95% CI: 7-52cells/mm³) and were less likely to increase their CD4 count by 50 cells from baseline (RR: 1.43; 95% CI: 0.99-2.06) within the first 6-months of treatment. CONCLUSIONS HIV-infected adults presenting with KS have increased risk of mortality even after initiation of ART with the greatest risk in the first year. Among those who survive the first year on therapy, subjects with KS demonstrated a poorer immunologic response to ART than those without KS.

Kaposi sarcoma-associated herpes virus and response to antiretroviral therapy: a prospective study of HIV-infected adults

BACKGROUND The possible impact of coinfection with the Kaposi sarcoma-associated herpes virus (KSHV) on the response to antiretroviral therapy (ART) is unknown. Prospective studies are rare, particularly in Africa. METHODS We enrolled a prospective cohort of HIV-infected adults initiating ART in Johannesburg, South Africa. The subjects were defined as seropositive to KSHV if they were reactive to either KSHV lytic K8.1 or latent Orf73 antigen or to both. The subjects were followed from ART initiation until 18 months of treatment. HIV viral load and CD4 counts were tested 6 monthly. Linear generalized estimating and log-binomial regression models were used to estimate the effect of KSHV infection on immunologic recovery and response and HIV viral load suppression within 18 months after ART initiation. RESULTS Three hundred eighty-five subjects initiating ART from November 2008 to March 2009 were considered to be eligible including 184 (48%) KSHV+. The KSHV+ group was similar to the KSHV- in terms of age, gender, initiating CD4 count, body mass index, tuberculosis, and hemoglobin levels. The KSHV+ group gained a similar number of cells at 6 [difference of 10 cells per cubic millimeter, 95% confidence interval (CI): -11 to 31], 12 (3 cells per cubic millimeter, 95% CI: -19 to 25), and 18 months (24 cells per cubic millimeter, 95% CI: -13 to 61) compared with that gained by the KSHV- group. Adjusted relative risk of failure to suppress viral load to <400 copies per milliliter (1.03; 95% CI: 0.90 to 1.17) were similar for KSHV+ and KSHV- by 6 months on treatment. CONCLUSIONS In a population with a high KSHV prevalence, HIV-positive adults coinfected with KSHV achieved similar immunologic and virologic responses to ART early after treatment initiation compared with those with KSHV-.

Impact of definitions of loss to follow-up (LTFU) in antiretroviral therapy program evaluation: variation in the definition can have an appreciable impact on estimated proportions of LTFU

OBJECTIVE To examine the impact of different definitions of loss to follow-up (LTFU) on estimates of program outcomes in cohort studies of patients on antiretroviral therapy (ART). STUDY DESIGN AND SETTING We examined the impact of different definitions of LTFU using data from the International Epidemiological Databases to Evaluate AIDS-Southern Africa. The reference approach, Definition A, was compared with five alternative scenarios that differed in eligibility for analysis and the date assigned to the LTFU outcome. Kaplan-Meier estimates of LTFU were calculated up to 2 years after starting ART. RESULTS Estimated cumulative LTFU were 14% and 22% at 12 and 24 months, respectively, using the reference approach. Differences in the proportion LTFU were reported in the alternative scenarios with 12-month estimates of LTFU varying by up to 39% compared with Definition A. Differences were largest when the date assigned to the LTFU outcome was 6 months after the date of last contact and when the site-specific definition of LTFU was used. CONCLUSION Variation in the definitions of LTFU within cohort analyses can have an appreciable impact on estimated proportions of LTFU over 2 years of follow-up. Use of a standardized definition of LTFU is needed to accurately measure program effectiveness and comparability between programs.

CD4 count slope and mortality in HIV-infected patients on antiretroviral therapy: multicohort analysis from South Africa

BACKGROUND In many resource-limited settings monitoring of combination antiretroviral therapy (cART) is based on the current CD4 count, with limited access to HIV RNA tests or laboratory diagnostics. We examined whether the CD4 count slope over 6 months could provide additional prognostic information. METHODS We analyzed data from a large multicohort study in South Africa, where HIV RNA is routinely monitored. Adult HIV-positive patients initiating cART between 2003 and 2010 were included. Mortality was analyzed in Cox models; CD4 count slope by HIV RNA level was assessed using linear mixed models. RESULTS About 44,829 patients (median age: 35 years, 58% female, median CD4 count at cART initiation: 116 cells/mm) were followed up for a median of 1.9 years, with 3706 deaths. Mean CD4 count slopes per week ranged from 1.4 [95% confidence interval (CI): 1.2 to 1.6] cells per cubic millimeter when HIV RNA was <400 copies per milliliter to -0.32 (95% CI: -0.47 to -0.18) cells per cubic millimeter with >100,000 copies per milliliter. The association of CD4 slope with mortality depended on current CD4 count: the adjusted hazard ratio (aHRs) comparing a >25% increase over 6 months with a >25% decrease was 0.68 (95% CI: 0.58 to 0.79) at <100 cells per cubic millimeter but 1.11 (95% CI: 0.78 to 1.58) at 201-350 cells per cubic millimeter. In contrast, the aHR for current CD4 count, comparing >350 with <100 cells per cubic millimeter, was 0.10 (95% CI: 0.05 to 0.20). CONCLUSIONS Absolute CD4 count remains a strong risk for mortality with a stable effect size over the first 4 years of cART. However, CD4 count slope and HIV RNA provide independently added to the model.