Episodes of HIV viremia and the risk of non-AIDS diseases in patients on suppressive antiretroviral therapy.

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.

Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort.

OBJECTIVE: We investigated the risk of AIDS and serious non-AIDS-defining diseases (non-ADDs) according to the degree of immunological recovery after 2 years of virological successful antiretroviral therapy (HAART). DESIGN: Retrospective observational cohort study including HIV-infected patients treated with HAART resulting in viral suppression (<500 copies/ml). METHODS: Patients were grouped according to their CD4 cell count after 2 years of HAART: CD4 cell count less than 200 cells/µl (group A), 200-350 cells/µl (group B), 351-500 cells/µl (group C) or more than 500 cells/µl (group D). Analysis was done to assess predictors for poor immunological recovery and the occurrence of a composite endpoint [death, AIDS, malignancies, liver cirrhosis and cardiovascular events (CVEs)], non-ADDs, CVEs and non-AIDS-defining malignancies (non-ADMs). RESULTS: Three thousand and sixty-eight patients were included. Older age, lower CD4 cell nadir and lower plasma HIV-RNA at the start of HAART were independent predictors for a poor immunological recovery. The composite endpoint, non-ADDs and CVE were observed most frequently in group A (overall log rank, P < 0.0001, P = 0.002 and P = 0.01). In adjusted analyses, age was a strong independent predictor for all endpoints. Compared with group A, patients in group D had a lower risk for the composite endpoint [hazard ratio 0.54 (95% confidence interval [CI] 0.33-0.87]; patients in group B had a lower risk for CVEs [hazard ratio 0.34 (95% CI 0.14-0.86)]. CONCLUSION: Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients.

Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy.

BACKGROUND: The aim of this study was to investigate the association between immunodeficiency, viremia, and non-AIDS-defining malignancies (NADM). METHODS: Patients starting combination antiretroviral therapy (cART) as of 1 January 1996 were selected from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. In Cox models, risk factors for NADM were investigated. These included age, sex, transmission route, smoking, alcohol abuse, prior AIDS diagnosis, duration of exposure to cART, and estimated duration of human immunodeficiency virus infection. CD4+ cell count and viral load (VL) were considered as time-updated variables and as measures of cumulative exposure to CD4+ cell counts of < 200, < 350, or < 500 cells/mm³ and detectable VL >50, >400, and >1000 copies/mL, respectively. RESULTS: In a cohort of 11,459 patients, 236 NADMs were diagnosed; 102 were caused by infection, and 134 were attributable to other causes. Median CD4+ cell count at NADM diagnosis was 340 cells/mm³ (range, 210-540 cells/mm³). Median time to first NADM after starting cART was 5.0 years (range, 2.2-8.2 years). In multivariate models, cumulative exposure to CD4+ cell counts < 200 cells/mm³ remained significant (hazard ratio [HR], 1.12; range, 1.03-1.22) for each additional year of exposure. In stratified analyses, cumulative exposure to CD4+ cell counts < 200 cells/mm³ was associated with malignancies possibly caused by infection (HR, 1.16; range, 1.03-1.31]) but was not associated with other types of cancers. No significant effect of viremia was seen in either type of cancer. CONCLUSIONS: Cumulative exposure to CD4+ cell counts < 200 cells/mm³ during cART was associated with an increased risk of infection-related non-AIDS-defining malignancies.

Immune restoration and onset of new AIDS-defining events with combination antiretroviral therapy in HIV type-1-infected immigrants in the Netherlands.

BACKGROUND: We investigated differences in immune restoration and onset of new AIDS-defining events on combination antiretroviral therapy (cART) among HIV type-1 (HIV-1)-infected patients of different regional origin now living in the Netherlands. METHODS: Treatment-naive adults reaching plasma viral load (pVL)<400 copies/ml within 9 months of starting cART were selected from the Netherlands ATHENA cohort. CD4(+) T-cell response on cART was determined over 7 years using mixed models. CD4(+) T-cell counts were excluded from the analyses at the first of two consecutive measurements of pVL≥400 copies/ml following prior suppression to <400 copies/ml. Multivariate analyses included gender, age, CD4(+) T-cell count and pVL prior to cART, hepatitis coinfection, HIV-1 transmission and region of origin (Western Europe/North America [WN], sub-Saharan Africa [SSA], Southeast Asia [SEA], Latin America/Caribbean [LAC] or other). RESULTS: For 6,057 selected patients (WN 3,947, SSA 989, SEA 237, LAC 695 and other 189), median follow-up was 3.2 years (WN 3.3, SSA 2.9, SEA 3.2, LAC 2.7 and other 2.7). CD4(+) T-cell increase in the first 6 months of cART was lower in males than females (-26 cells/mm(3); P<0.0001) and in patients from SSA compared with WN (-36 cells/mm(3); P<0.0001). Because men from SSA started with lower CD4(+) T-cell counts than men from WN, they continued to lag behind and had lower absolute CD4(+) T-cell counts after 7 years of cART. Furthermore, cumulative tuberculosis incidence after 7 years of cART was higher in SSA compared with WN (4.5% versus 0.5%, hazard ratio 5.08, 95% confidence interval 2.22-11.60). CONCLUSIONS: HIV-1-infected immigrants from SSA have blunted immune restoration on fully suppressive cART and should be identified at an earlier disease stage. Our results call for more intensive screening for both latent and active tuberculosis in these patients.

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.

Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study.

BACKGROUND: Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell counts >250 cells/microL and in male individuals with CD4 cell counts >400 cells/microL are based on findings in treatment-naive patients. It is unclear whether these guidelines also apply to treatment-experienced patients switching to NVP-based combination therapy. METHODS: Patients in the ATHENA cohort study who had used NVP-based combination therapy were included. We identified patients who discontinued NVP-based combination therapy because of hypersensitivity reactions (HSRs; rash and/or hepatotoxicity) within 18 weeks after starting such therapy. We grouped patients according to their CD4 cell count at the start of NVP-based combination therapy (current CD4 cell count) as having a high CD4 cell count (for female patients, >250 cells/microL; for male patients, >400 cells/microL) or a low CD4 cell count. Treatment-experienced patients were further subdivided according to the last available CD4 cell count before first receipt of antiretroviral therapy (ART; pre-ART CD4 cell count) using the same criteria. Risk factors for HSR were assessed using multivariate logistic regression. RESULTS: Of 3752 patients receiving NVP-based combination therapy, 231 patients (6.2%) discontinued NVP therapy because of HSRs. Independent risk factors included female sex and Asian ethnicity. Having an undetectable viral load (VL) at the start of NVP therapy was associated with reduced risk of developing an HSR (adjusted odds ratio [OR], 0.52; 95% confidence interval [CI], 0.38-0.71). Pretreated patients with low pre-ART and high current CD4 cell counts and a detectable VL when switching to NVP-based combination therapy had a significantly higher risk of developing an HSR, compared with treatment-naive patients who started NVP therapy with low CD4 cell counts (adjusted OR, 1.87; 95% CI, 1.11-3.12); pretreated patients with low pre-ART CD4 cell counts who switched to NVP therapy with a high current CD4 cell count and an undetectable VL did not have an increased risk of developing an HSR (adjusted OR, 1.03; 95% CI, 0.66-1.61). CONCLUSIONS: Treatment-experienced patients who start NVP-based combination therapy with low pre-ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of HSRs, compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds.

CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater.

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.