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Background: An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics., Methods: We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models., Results: When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm. Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm., Discussion: Starting ART with a CD4 cell count of ≥500 cells/mm makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation.

Objective: Little is known about the impact of acute hepatitis C virus (HCV) co-infection on HIV-1 disease progression. We investigated CD4 cell count and HIV RNA concentration changes after HCV infection in individuals chronically infected with HIV-1., Methods: We selected individuals that had the last negative and first positive HCV RNA test less than 1 year apart. Bivariate linear mixed-effects regression was used to model trends in HIV RNA level and CD4 cell count from 2 years before the last negative HCV RNA test until the first of the following dates: start of anti-HCV medication, change in combination antiretroviral therapy (cART) status, and end of follow-up., Results: At the estimated time of HCV co-infection, of 89 individuals, 63 (71%) were cART-treated and 26 (29%) were not on cART. In persons on cART, median CD4 cell count declined from 587 to 508 cells per cubic millimeter (P < 0.0001) during the first 5 months after HCV infection and returned to 587 cells per cubic millimeter after 2.2 years. Also, the probability of an HIV RNA >50 copies per milliliter peaked to 18.6% at HCV co-infection, with lower probabilities 6 months before (3.5%, P = 0.006 compared with peak probability) and after (2.9%, P = 0.009). In persons not on cART, no significant impact of HCV co-infection on trends in the HIV RNA level or CD4 cell count was observed., Conclusions: Acute HCV infection in cART-treated, chronically HIV-infected patients was associated with a temporary decrease in CD4 cell counts and increased risk of HIV viremia >50 copies per milliliter. This may increase the risk of further HIV transmission.

Background: In HIV-negative patients, radiotherapy (RT) decreases CD4 T-cell counts. We studied the effects of RT in HIV-1 positive patients., Methods: HIV-1 positive patients with a subsequent diagnosis of a solid tumor were selected from the Dutch national observational HIV cohort, Aids Therapy Evaluation in the Netherlands (ATHENA). The patients were grouped according to whether they had received RT or not. Primary endpoint of the study was the time from baseline to reaching CD4 cell counts higher than those at baseline. Kaplan-Meier estimates of the percentage of patients reaching the endpoint were calculated., Results: Ninety patients were included of whom 36 received RT and 54 did not. Median duration of RT was 46 [interquartile range (IQR) 30-63] days. Median first CD4 cell count after stopping RT was 150 (IQR 30-270) × 10/L lower compared with baseline. In 13 of the 36 patients receiving RT, CD4 cell counts recovered to baseline, after a median of 469 (IQR 345-595) days. In 35 of the 54 patients without RT, the CD4 cell count recovered to baseline or higher, after a median of 112 (IQR 42-182) days. After 3 years, in 39% of patients who had RT compared with 71% of patients without RT, CD4 cell counts recovered to baseline or higher (P < 0.0001). In a Cox regression adjusted for potential confounders, RT was associated with a longer (hazard ratio 0.29; 95% confidence interval 0.13 to 0.63) and combination antiretroviral therapy use with a shorter time to return to baseline [hazard ratio 2.46 (95% confidence interval 1.11 to 5.48)]., Conclusions: RT resulted in a significant and prolonged decrease in CD4 cell counts.

Background: Several studies reported an association between immunodeficiency and non-AIDS-defining diseases. We investigated whether nonstructured treatment interruptions and episodes of viremia during suppressive combination antiretroviral therapy were independently associated with non-AIDS diseases., Methods: Six thousand four hundred forty patients with viral suppression (<50 copies/mL) within 48 weeks of starting combination antiretroviral therapy were selected from the Dutch ATHENA cohort. In proportional hazards models, associations between treatment interruptions, viral suppression, low-level (50-400 copies/mL), and high-level viremia (>400), and serious non-AIDS diseases (cardiovascular disease, chronic renal failure, liver fibrosis/cirrhosis) were investigated by including time-updated cumulative exposure to either viremia and interruptions or HIV RNA >400 copies per milliliter., Results: During 24,603 person-years, of which 88.5% occurred during viral suppression, 102 patients developed cardiovascular disease, 54 chronic renal failure, and 70 liver fibrosis/cirrhosis. Overall incidence of non-AIDS diseases ranged from 1.41 (95% confidence interval: 0.73 to 2.46) per 100 person-years for CD4 counts <200 to 0.71 (0.49 to 1.00) for CD4 ≥500 cells per cubic millimeter. Compared with viral suppression, high-level viremia was associated only with cardiovascular disease (relative hazard: 1.37, 1.04 to 1.81 per year longer), whereas interruptions and low-level viremia were not associated with non-AIDS diseases. Relative hazards for cumulative exposure to RNA >400 versus ≤400 copies per milliliter were 1.32 (1.01 to 1.73) for cardiovascular disease, 1.13 (0.66 to 1.92) for renal failure, and 0.86 (0.51 to 1.44) for fibrosis/cirrhosis., Conclusions: Lower CD4 counts are associated with increased risk of non-AIDS diseases, whereas high-level viremia seems to be independently associated with cardiovascular disease. However, the power to detect associations with viremia or interruptions may have been limited as most events occurred during viral suppression.

Objective: To establish whether efavirenz dose reduction in patients with high plasma concentrations prevents toxicity-induced efavirenz discontinuations., Methods: HIV-infected patients with a high efavirenz plasma concentration (>or=4.0 mg/L) while using efavirenz 600 mg once daily as part of their highly active antiretroviral therapy regimen were selected from the AIDS Therapy Evaluation in The Netherlands cohort study. These patients were classified into 2 groups. The reduced-dose group contained all patients who underwent dose reduction after the high plasma concentration measurement; the standard-dose group consisted of patients who had no dose reduction. Kaplan-Meier and Cox proportional hazards analysis were used to assess the impact of dose reduction on toxicity-induced efavirenz discontinuations., Results: One hundred eighty patients with high plasma efavirenz levels were included, 47 of them subsequently had their efavirenz dose reduced from 600 mg to 400 mg once-daily, which resulted in a 41% decrease in the median efavirenz plasma concentration. At week 48, the Kaplan-Meier estimated cumulative incidence of toxicity-induced efavirenz discontinuations was 11.5% in patients who continued the standard dose versus 2.3% in patients who had a dose reduction; P = 0.066 (log-rank test). Dose reduction was not associated with loss of virological suppression., Conclusions: Dose reduction may prevent toxicity-induced discontinuations in patients with high efavirenz plasma concentrations, whereas not compromising virological efficacy.

Objective: To investigate immunologic, virologic, and clinical consequences of episodes of transient viremia in patients with sustained virologic suppression., Methods: From the AIDS Therapy Evaluation Project, Netherlands cohort, 4447 previously therapy-naive patients were selected who were on continuous combination antiretroviral therapy and had initial success (2 consecutive HIV RNA measurements <50 copies/mL). During episodes of viral suppression (RNA <50 copies/mL), low-level viremia (RNA 50 to 1000 copies/mL), or high-level viremia (RNA >1000 copies/mL) after initial success, the occurrence of therapy changes, drug resistance, and clinical events was assessed., Results: During 11,187 person-years of follow-up, 1281 (28.8%) patients had at least 1 RNA measurement >50 copies/mL. Among 8069 episodes, there were 5989 (74.2%) episodes of suppression, 1711 (21.2%) episodes of low-level viremia, and 369 (4.6%) episodes of high-level viremia. Most episodes of low-level viremia consisted of < or =2 RNA measurements (93.7%), were without clinical events or therapy changes (79.6%), and were without changes in CD4 cell counts. Therapy changes (52.3% of episodes) and resistance (23.3%) were frequently observed during high-level viremia., Conclusions: Episodes of low-level viremia are frequent and short lasting, and the low proportion of episodes with clinical events suggests that leaving therapy unchanged is a clinically acceptable strategy. In contrast, high-level viremia is associated with resistance and is often followed by therapy changes.

Objective: CD4 cell count changes in therapy-naive patients were investigated during 7 years of highly active antiretroviral therapy (HAART) in an observational cohort., Methods: Three endpoints were studied: (1) time to >or=800 CD4 cells/mm in 5299 therapy-naive patients starting HAART, (2) CD4 cell count changes during 7 years of uninterrupted HAART in a subset of 544 patients, and (3) reaching a plateau in CD4 cell restoration after 5 years of HAART in 366 virologically suppressed patients., Results: Among patients with <50, 50 to 200, 200 to 350, 350 to 500, and >or=500 CD4 cells/mm at baseline, respectively, 20%, 26%, 46%, 73%, and 87% reached >or=800 CD4 cells/mm within 7 years of starting HAART. Periods with HIV RNA levels >500 copies/mL and age >or=50 years were associated with lesser increases in CD4 cell counts between 6 months and 7 years. Having reached >or=800 CD4 cells/mm at 5 years, age >or=50 years, and >or=1 HIV RNA measurement >1000 copies/mL between 5 and 7 years were associated with a plateau in CD4 cell restoration., Conclusions: Restoration to CD4 cell counts >or=800 cells/mm is feasible within 7 years of HAART in most HIV-infected patients starting with >or=350 cells/mm and achieving sufficient suppression of viral replication. Particularly in patients >or=50 years of age, it may be beneficial to start earlier than current guidelines recommend.

Mortality in HIV-infected patients has decreased dramatically since the introduction of highly active antiretroviral therapy (HAART). We analyzed progression to death in a population of 3678 antiretroviral treatment-naive patients from the ATHENA national observational cohort from 24 weeks after the start of HAART. Mortality was compared with that in the general population in the Netherlands matched by age and gender. Only log-transformed CD4 cell count (hazard ratio [HR] = 0.50, 95% confidence interval [CI]: 0.40 to 0.61 per unit increase) and plasma viral load (HR = 0.30, 95% CI: 0.15 to 0.60, HIV RNA level <100,000 vs. > or = 100,000 copies/mL) measured at 24 weeks and infection via intravenous drug use (IDU) (HR = 0.16, 95% CI: 0.10 to 0.26, non-IDU vs. IDU) were significantly associated with progression to death. For non-IDU patients with 600 x 10 CD4 cells/L and an HIV RNA level <100,000 copies/mL at 24 weeks, mortality was predicted to be 5.3 (95% CI: 3.5 to 8.4) and 10.4 (95% CI: 6.4 to 17.4) times higher than in the general population for 25-year-old men and women, respectively, and 1.15 (95% CI: 1.08 to 1.25) and 1.29 (95% CI: 1.16 to 1.50) times higher for 65-year-old men and women, respectively. Hence, mortality in HIV-infected patients with a good initial response to HAART is still higher than in the general population.