abacavir and Kidney-Diseases

The aim of this study was to investigate long-term renal function in HIV-infected adults initiating antiretroviral therapy (ART) with a CD4(+) T-cell count < 200 cells/mm³ in Africa.. This was an observational analysis within the DART trial randomizing 3,316 adults to routine laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). Serum creatinine was measured pre-ART (all ≤ 360 μmol/l), at weeks 4 and 12, then every 12 weeks for 4-5 years; estimated glomerular filtration rate (eGFR) was determined using the Cockcroft-Gault formula. We analysed eGFR changes, and cumulative incidences of eGFR< 30 ml/min/1.73 m² and chronic kidney disease (CKD; <60 ml/min/1.73 m² or 25% decrease if <60 ml/min/1.73 m² pre-ART; confirmed >3 months).. At ART initiation, median CD4(+) T-cell count was 86 cells/mm³; 1,492 (45%) participants had mild (60-< 90 ml/min/1.73 m²), 237 (7%) moderate (30-<60 ml/min/1.73 m² and 7 (0.2%) severe (15-<30 ml/min/1.73 m²) decreases in eGFR. First-line ART was zidovudine/lamivudine plus tenofovir (74%), abacavir (9%) or nevirapine (17%). By 4 years, cumulative incidence of eGFR<30 ml/min/1.73 m² was 2.8% (n=90) and CKD was 5.0% (n=162). Adjusted eGFR increases to 4 years were 1, 9 and 6 ml/min/1.73 m² with tenofovir, abacavir and nevirapine, respectively (P<0.001), and 4 and 2 ml/min/1.73 m² for LCM and CDM, respectively (P=0.005; 2 and 3 ml/min/1.73 m² to 5 years; P=0.81).. On all regimens and monitoring strategies, severe eGFR impairment was infrequent; differences in eGFR changes were small, suggesting that first-line ART, including tenofovir, can be given safely without routine renal function monitoring.

Topics: Adenine; Adult; Africa; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Creatinine; Dideoxynucleosides; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney Diseases; Kidney Glomerulus; Lamivudine; Male; Nevirapine; Organophosphonates; Risk Factors; Tenofovir; Time Factors; Zidovudine

Adolescents with perinatally acquired HIV (PHIV) are at risk of chronic disease due to long-standing immune suppression, HIV disease and antiretroviral therapy (ART) exposure. However, there are few data on multisystem disease in this population. We investigated the overlapping burden of neurocognitive, cardiovascular, respiratory and/or renal impairment among PHIV positive (PHIV+) adolescents.. In this cross-sectional analysis, participants aged 9 to 14 years on ART for >6 months were recruited from seven sites across Cape Town from July 2013 through March 2015, together with age-matched HIV-negative (HIV-) adolescents. Impairment at enrolment was assessed across neurocognitive functioning (using the youth-International HIV Dementia Scale); cardiac function (echocardiogram abnormality); respiratory function (abnormal spirometry) and renal function (abnormal glomerular filtration rate).. Overall, 384 PHIV+ and 95 HIV- adolescents were included (mean age, 11.9 years; 49% female). Median age of ART initiation was 4.2 years (IQR: 1.7 to 7.6) and median CD4 count was 709 (IQR: 556 to 944) with 302 (79%) of PHIV+ adolescents virologically suppressed. Abacavir and Zidovudine were the most commonly used nucleoside reverse transcriptase inhibitors (NRTIs) with 60% of adolescents on non-nucleoside reverse transcriptase inhibitors (NNRTI) and 38% on a protease inhibitor (PI). Among PHIV+ adolescents, 167 (43.5%) had single system impairment only, 110 (28.6%) had two systems involved, and 39 (10.2%) had three or four systems involved. PHIV+ participants had more 2-system and 3-system impairment than HIV-, 110 (28.6%) versus 17 (17.9%), p = 0.03 and 39 (10.2%) versus 3 (4.3%), p = 0.03. PHIV+ participants who had failed a year of school (73.8% vs. 46.4%, p = 0.00) and with a viral load >1000 copies/mL at enrolment (16.8% vs. 8.1%, p = 0.03) were more likely to have dual or multisystem impairment. Of those with cardiac impairment, 86.7% had an additional system impaired. Similarly, in those with neurocognitive impairment, almost 60% had additional systems impaired and of those with respiratory impairment, 74% had additional systems impaired.. Despite relatively early ART initiation, there is a substantial burden of multisystem chronic impairment among PHIV+ adolescents. This phenomenon needs to be further explored as this population ages and begins to engage in adult lifestyle factors that may compound these impairments.

Topics: Adolescent; Anti-Retroviral Agents; Cardiovascular Diseases; CD4 Lymphocyte Count; Child; Cognition Disorders; Cross-Sectional Studies; Dideoxynucleosides; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Kidney Diseases; Male; Respiratory Tract Diseases; South Africa; Viral Load; Zidovudine

Tenofovir disoproxil fumerate (TDF) is an effective nucleoside reverse transcriptase inhibitor for HIV infection but it is potentially nephrotoxic. A selective mithochondrial toxicity has been hypothesized. To assess early markers of renal toxicity, we evaluated a cohort of antiretroviral (ARV)-experienced HIV patients who had been switched from a thymidinic backbone to either a TDF/emtricitabine regimen (TDF; 73 patients) or an abacavir/lamivudine (ABV) regimen (28 patients). Markers of mitochondrial toxicity (cytochrome c, Cyc) or cytosolic (α-glutathione S transferase, α-GST) together with common indicators of renal damage were assessed at baseline (T0) and after 1 (T1), 3 (T2), 6 (T3), and 12 (T4) months of patient exposure to therapy. Clinical features of both groups were comparable at T0. There was no significant variation in estimated glomerular filtration rate (eGRF), median urine protein excretion, or microalbuminuria and serum phosphate levels in both groups during the study period. There was a significant increase in urinary excretion of phosphate in patients on TDF compared to those on ABV at T3 and T4. Fractional excretion of uric acid was also altered in the two treatment groups; there was no change in the ABV (constantly less than 0.10), but a progressive increase in TDF patients. Serum potassium levels were significantly lower in ABV than in TDF treated patients. Urine concentrations of α-GST showed a nonsignificant variation in both groups, while Cyc excretion was significantly higher at T1 and T3 in TDF-treated compared to ABV-treated patients. In conclusion, TDF may be associated with subclinical mitochondrial damage, inducing at a later stage increased urinary excretion of phosphate and uric acid, as markers of incipient tubular injury.

Topics: Adenine; Anti-HIV Agents; Biomarkers; Cohort Studies; Cytochromes c; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Glomerular Filtration Rate; Glutathione Transferase; HIV Infections; Humans; Kidney Diseases; Kidney Tubules, Proximal; Lamivudine; Male; Middle Aged; Mitochondria; Organophosphonates; Tenofovir; Time Factors

Current treatment strategies need to be planned carefully, because there is an inadequate supply of new types of drugs available to treat people who have failed previous therapies. It is important to fully use existing therapies so as not to limit future options. Drugs in development include: ABT-378, a protease inhibitor from Abbott Laboratories; tipranavir (PNU-140690), a protease inhibitor by Pharmacia & Upjohn; and S-1153, a non-nucleoside reverse transcriptase inhibitor from Agouron Pharmaceuticals. All were effective and well-tolerated in recent trials. A warning was issued for adefovir, a nucleoside reverse transcriptase inhibitor, regarding the development of kidney toxicity for people taking the drug more than 20 weeks. Information on expanded access programs for abacavir, adefovir, amprenavir, and efavirenz is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Imidazoles; Kidney Diseases; Lopinavir; Oxazines; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load