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Background: Cotrimoxazole preventive therapy (CPT) in human immunodeficiency virus (HIV) infection is a World Health Organization-recommended standard of care in resource-limited settings, but the mechanism of CPT's beneficial effects is unclear. The COSTOP trial (ISRCTN44723643) evaluated the noninferiority of discontinuing CPT in stabilized patients on antiretroviral therapy. The COSTOP immunology substudy was conducted on a subset of COSTOP participants randomized to continue CPT (n = 86) or discontinue CPT (placebo, n = 86) as daily treatment for 1 year.Methods: We evaluated whether CPT reduces microbial translocation, indicated by the presence of bacterial lipopolysaccharide (LPS) and LPS control factors such as soluble CD14 (sCD14) and endotoxin core antibody (EndoCAb immunoglobulin M [IgM]) in plasma. Intestinal barrier damage as indicated by plasma intestinal fatty acid binding protein (IFABP), T-cell activation, and the inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were also evaluated.Results: We found no significant change in markers of microbial translocation (LPS, IFABP, sCD14, and T-cell activation), with decreased EndoCAb IgM. There was significant increase in inflammation markers (CRP and IL-6) after stopping CPT compared to those who continued CPT.Conclusions: These results add to the evidence of immunological benefits of CPT among HIV-infected populations in resource-limited settings. However, no evidence of reducing microbial translocation was observed. [ABSTRACT FROM AUTHOR]

A retrospective analysis of the randomized controlled DART (Development of AntiRetroviral Therapy in Africa; ISRCTN13968779) trial in HIV-1-positive adults initiating antiretroviral therapy with co-formulated zidovudine/lamivudine plus either tenofovir, abacavir, or nevirapine was conducted to evaluate the safety of initiating standard lamivudine dosing in patients with impaired creatinine clearance (CLcr). Safety data collected through 96 weeks were analyzed after stratification by baseline CLcr (estimated using Cockcroft-Gault) of 30–49 mL/min (n = 168) versus ≥50 mL/min (n = 3,132) and treatment regimen. The Grade 3–4 adverse events (AEs) and serious AEs (for hematological, hepatic and gastrointestinal events), maximal toxicities for liver enzymes, serum creatinine and bilirubin and maximum treatment-emergent hematology toxicities were comparable for groups with baseline CLcr 30–49 versus CLcr≥50 mL/min. No new risks or trends were identified from this dataset. Substantial and similar increases in the mean creatinine clearance (>25 mL/min) were observed from baseline though Week 96 among participants who entered the trial with CLcr 30–49 mL/min, while no increase or smaller median changes in creatinine clearance (<7 mL/min) were observed for participants who entered the trial with CLcr ≥50 mL/min. Substantial increases (> 150 cells/ mm3) in mean CD4+ cells counts from baseline to Week 96 were also observed for participants who entered the trial with CLcr 30–49 mL/min and those with baseline CLcr ≥50 mL/min. Though these results are descriptive, they suggest that HIV-positive patients with CLcr of 30–49 mL/min would have similar AE risks in comparison to patients with CLcr ≥50 mL/min when initiating antiretroviral therapy delivering doses of 300 mg of lamivudine daily through 96 weeks of treatment. Overall improvements in CLcr were observed for patients with baseline CLcr 30–49 mL/min. [ABSTRACT FROM AUTHOR]

Background: Cotrimoxazole (CTX) preventive therapy (CPT) reduces opportunistic infections and malaria in HIV-infected patients. In Africa, policies on sustained CPT during antiretroviral therapy (ART) differ between countries. We assessed the safety of discontinuing CPT in stable patients on ART in Uganda. Methods: COSTOP was a double-blind placebo-controlled trial. Patients aged ≥18 years, on CPT, and stable on ART (CD4 counts ≥250 cells/μL); were randomised to daily oral placebo (PLC group) or cotrimoxazole 960 mg/tablet (CTX group). Co-primary outcomes were: (i) time to first cotrimoxazole-preventable infection, with non- inferiority of PLC defined as the upper one-sided 95% confidence limit of the adjusted hazard ratio(aHR) ≤1.25; and (ii) time to first grade 3/4 haematological adverse event. Findings: 2180 subjects (1091 PLC; 1089 CTX) were enrolled. 932 PLC and 943 CTX completed the trial after 12 months minimum follow up. Ninety-eight participants (59 PLC; 39 CTX) experienced 120 cotrimoxazole- preventable events, mainly bacterial pneumonia (72 events, 4 deaths PLC); (48 events, 2 deaths CTX). The aHR for time to first event was 1.57 (upper one-sided 95% confidence limit 2.21) in per protocol population (similar results in ITT population). 551 participants (318 CTX; 233 PLC) experienced 1043 haematological adverse events (616 CTX; 427 PLC). Time to the first adverse event, mainly neutropenia, was shorter in the CTX group (aHR 0.70 95%CI 0.59–0.82; log-rank χ2 = 18.08; P<0.0001). 362 (276 PLC, 86 CTX) participants experienced at least one episode of confirmed clinical malaria (P<0.0001). Interpretation: In ART stable patients with CD4 counts ≥250 cells/μL, continued CPT significantly reduces risk of severe bacterial infections and protects against malaria, while discontinuing CPT reduces haematological adverse events. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral therapy (ART) improves the survival and quality of life of HIV-positive individuals, but the effects of long-term ART use do eventually manifest. The Complications of Long-Term Antiretroviral Therapy cohort study in Uganda (CoLTART) was established to investigate the metabolic and renal complications of long-term ART use among Ugandan adults. We describe the CoLTART study set-up, aims, objectives, study methods, and also report some preliminary cross-sectional study enrolment metabolic and renal complications data analysis results. Methods: HIV-positive ART naive and experienced adults (18 years and above) in Uganda were enrolled. Data on demographic, dietary, medical, social economic and behaviour was obtained; and biophysical measurements and a clinical examination were undertaken. We measured: fasting glucose and lipid profiles, renal and liver function tests, full blood counts, immunology, virology and HIV drug resistance testing. Plasma samples were stored for future studies. Results: Between July 2013 and October 2014, we enrolled 1095 individuals, of whom 964 (88.0%) were ART experienced (6 months or more), with a median of 9.4 years (IQR 7.0-9.9) on ART. Overall, 968 (88.4%) were aged 35 years and above, 711 (64.9%) were females, 608 (59.6%) were or had ever been on a Tenofovir ART regimen and 236 (23.1%) on a Protease Inhibitor (PI) regimen. There were no differences in renal dysfunction between patients on Tenofovir and Non-Tenofovir containing ART regimens. Patients on PI regimens had higher total cholesterol, lower high density lipoprotein, higher low density lipoprotein, higher triglycerides, and a high atherogenic index for plasma than the non-PI regimen, p = 0.001 or < 0.001. Patients on Non-PI regimens had higher mean diastolic hypertension than patients on PI regimens, p < 0.001. Conclusions: Our finding of no differences in renal dysfunction between patients on Tenofovir and those on Non-Tenofovir containing ART regimens means that Tenofovir based first line ART can safely be initiated even in settings without routine renal function monitoring. However, integration of cardiovascular risk assessment, preventive and curative measures against cardiovascular disease are required. The CoLTART cohort is a good platform to investigate the complications of long-term ART use in Uganda. [ABSTRACT FROM AUTHOR]

Background: Few low-income countries have virological monitoring widely available. We estimated the virological durability of first-line antiretroviral therapy (ART) after five years of follow-up among adult Ugandan and Zimbabwean patients in the DART study, in which virological assays were conducted retrospectively.Methods: DART compared clinically driven monitoring with/without routine CD4 measurement. Annual plasma viral load was measured on 1,762 patients. Analytical weights were calculated based on the inverse probability of sampling. Time to virological failure, defined as the first viral load measurement ≥200 copies/mL after 48 weeks of ART, was analysed using Kaplan-Meier plots and Cox regression models.Results: Overall, 65% of DART trial patients were female. Patients initiated first-line ART at a median (interquartile range; IQR) age of 37 (32-42) and with a median CD4 cell count of 86 (32-140). After 240 weeks of ART, patients initiating dual-class nucleoside reverse-transcriptase inhibitor (NRTI) -non-nucleoside reverse-transcriptase (NNRTI) regimens containing nevirapine + zidovudine + lamivudine had a lower incidence of virological failure than patients on triple-NRTI regimens containing tenofovir + zidovudine + lamivudine (21% vs 40%; hazard ratio (HR) =0.48, 95% CI:0.38-0.62; p < 0.0001). In multivariate analyses, female patients (HR = 0.79, 95% CI: 0.65-0.95; p = 0.02), older patients (HR = 0.73 per 10 years, 95% CI: 0.64-0.84; p < 0.0001) and patients with a higher pre-ART CD4 cell count (HR = 0.64 per 100 cells/mm3, 95% CI: 0.54-0.75; p < 0.0001) had a lower incidence of virological failure after adjusting for adherence to ART. No difference in failure rate between the two randomised monitoring strategies was observed (p= 0.25).Conclusions: The long-term durability of virological suppression on dual-class NRTI-NNRTI first-line ART without virological monitoring is remarkable and is enabled by high-quality clinical management and a consistent drug supply. To achieve higher rates of virological suppression viral-load-informed differentiated care may be required.Trial Registration: Prospectively registered on 18/10/2000 as ISRCTN13968779 . [ABSTRACT FROM AUTHOR]

Background: WHO recommends using Tenofovir containing first line antiretroviral therapy (ART), however, Tenofovir has been reported to be associated with renal impairment and dysfunction. We compared renal function among individuals on Tenofovir and those on non-Tenofovir containing ART. Methods: In a cross-sectional study of HIV-Positive adults on ART, at enrolment into a prospective cohort to study the long-term complications of ART in Uganda, information on biophysical measurements, medical history, clinical examination and renal function tests (RFTs) was collected. Fractional Tubular phosphate reabsorption and estimated glomerular filtration rate (eGFR) were calculated. Mean values of RFTs and proportions with abnormal RFTs were compared between non-Tenofovir containing (Non-TDF) and Tenofovir containing (TDF-ART) ART regimen groups using a general linear regression model. Durations of TDF exposure were also compared. Results: Between July 2013 and October 2014, we enrolled 953 individuals on ART for 6 or more months, median duration on ART was 9.3 years, 385 (40.4 %) were on non-TDF and 568 (59.6 %) on TDF-ART regimens. The proportion of participants with Proteinuria (>30 mg/dl) was higher among the TDF-ART group than the non-TDF ART group. However, in multivariable analysis, there were no significant diferences in the adjusted mean differences of eGFR, serum urea, serum creatinine, fractional tubular reabsorption of phosphate and serum phosphates when patients on TDF-ART were compared with those on non-TDF containing ART. There were no diferences in renal function even when diferent durations on Tenofovir were compared. Conclusions: We found no differences in renal function among patients on Tenofovir and non-Tenofovir containing ART for almost a decade. Tenofovir based first line ART can therefore safely be initiated even in settings without routine renal function monitoring. [ABSTRACT FROM AUTHOR]

Background: The effect of CD4 count on malaria incidence in HIV infected adults on antiretroviral therapy (ART) was assessed in the context of a randomized controlled trial on the effect of stopping cotrimoxazole (CTX). Methods: This study presents a sub-analysis of the COSTOP trial (ISRCTN44723643) which was carried out among HIV-infected Ugandan adults stable on ART with CD4 counts ≥250 cells/µl. Participants were randomized (1:1) to continue CTX or stop CTX and receive matching placebo, and were followed up for a minimum of 1 year (median 2.5 years). CD4 counts were measured at baseline, 3 months and then every 6 months. Clinical malaria was defined as fever and a positive blood slide. First, the relationship between current CD4 count during follow-up and malaria among participants on placebo was examined; using random effects Poisson regression to account for repeated episodes. Second, the effect of CD4 count at enrolment, CD4 count at ART initiation, and CD4 count during follow-up on malaria, was assessed within each trial arm; to examine whether the effect of CD4 count differed by CTX use. Results: 2180 participants were enrolled into the COSTOP trial. The incidence of clinical malaria was approximately four episodes/100 person years in the CTX arm and 14 episodes/100 person years in the placebo arm. There was no evidence of an association of current CD4 and clinical malaria incidence (P = 0.56), or parasitaemia levels (P = 0.24), in the placebo arm. Malaria incidence did not differ by CD4 count at ART initiation, enrolment or during follow up, irrespective of CTX use. When compared with participants in the lowest CD4 stratum, rate ratios within each trial arm were all close to 1, and P values were all above P = 0.30. Conclusions: The immune status of HIV infected participants who are stable on ART as measured by CD4 count was not associated with malaria incidence and did not modify the effect of stopping CTX on malaria. The decision of whether to stop or continue CTX prophylaxis for malaria in HIV infected individuals who are stable on ART should not be based on CD4 counts alone. COSTOP trial registration number ISRCTN44723643 [ABSTRACT FROM AUTHOR]

Background: Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)-infected children.Methods: CD4(+) T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART.Results: There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4-11.4 years) and 5.8 years (IQR, 2.3-9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%-9%) and 13% (IQR, 8%-18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4(+) T-cell count ratio (calculated as the ratio of the subject's CD4(+) T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4(+) and CD8(+) T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8(+) T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died).Conclusions: While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes. [ABSTRACT FROM AUTHOR]

Background: There are few data on tuberculosis (TB) incidence in HIV-infected children on antiretroviral therapy (ART). Observational studies suggest co-trimoxazole prophylaxis may prevent TB, but there are no randomized data supporting this. The ARROW trial, which enrolled HIV-infected children initiating ART in Uganda and Zimbabwe and included randomized cessation of co-trimoxazole prophylaxis, provided an opportunity to estimate the incidence of TB over time, to explore potential risk factors for TB, and to evaluate the effect of stopping co-trimoxazole prophylaxis.Methods: Of 1,206 children enrolled in ARROW, there were 969 children with no previous TB history. After 96 weeks on ART, children older than 3 years were randomized to stop or continue co-trimoxazole prophylaxis; 622 were eligible and included in the co-trimoxazole analysis. Endpoints, including TB, were adjudicated blind to randomization by an independent endpoint review committee (ERC). Crude incidence rates of TB were estimated and potential risk factors, including age, sex, center, CD4, weight, height, and initial ART strategy, were explored in multivariable Cox proportional hazards models.Results: After a median of 4 years follow-up (3,632 child-years), 69 children had an ERC-confirmed TB diagnosis. The overall TB incidence was 1.9/100 child-years (95% CI, 1.5-2.4), and was highest in the first 12 weeks following ART initiation (8.8/100 child-years (5.2-13.4) versus 1.2/100 child-years (0.8-1.6) after 52 weeks). A higher TB risk was independently associated with younger age (<3 years), female sex, lower pre-ART weight-for-age Z-score, and current CD4 percent; fewer TB diagnoses were observed in children on maintenance triple nucleoside reverse transcriptase inhibitor (NRTI) ART compared to standard non-NRTI + 2NRTI. Over the median 2 years of follow-up, there were 20 ERC-adjudicated TB cases among 622 children in the co-trimoxazole analysis: 5 in the continue arm and 15 in the stop arm (hazard ratio (stop: continue) = 3.0 (95% CI, 1.1-8.3), P = 0.028). TB risk was also independently associated with lower current CD4 percent (P <0.001).Conclusions: TB incidence varies over time following ART initiation, and is particularly high during the first 3 months post-ART, reinforcing the importance of TB screening prior to starting ART and use of isoniazid preventive therapy once active TB is excluded. HIV-infected children continuing co-trimoxazole prophylaxis after 96 weeks of ART were diagnosed with TB less frequently, highlighting a potentially important role of co-trimoxazole in preventing TB. [ABSTRACT FROM AUTHOR]

Background: Community-drug distribution point is a care model for stable patients in the community designed to make ART delivery more efficient for the health system and provide appropriate support to encourage long-term retention of patients. We examined program retention among ART program participants in rural Uganda, which has used a community-based distribution model of ART delivery since 2004. Methods: We analyzed data of all patients >18 years who initiated ART in Jinja, Ugandan site of The AIDS Support Organization between January 1, 2004 and July 31, 2009. Participants attended clinic or outreach visits every 2-3 months and had CD4 cell counts measured every 6 months. Retention to care was defined as any patient with at least one visit in the 6 months before June 1, 2013. We then identified participants with at least one visit in the 6 months before June 1, 2013 and examined associations with mortality and lost-to-follow-up (LTFU). Participants with >4 years of follow up during August, 2012 to May, 2013 had viral load conducted, since no routine viral load testing was available. Results: A total of 3345 participants began ART during 2004-2009. The median time on ART in June 2013 was 5.69 years. A total of 1335 (40 %) were residents of Jinja district and 2005 (60 %) resided in outlying districts. Of these, 2322 (69 %) were retained in care, 577 (17 %) died, 161 (5 %) transferred out and 285 (9 %) were LTFU. Factors associated with mortality or LTFU included male gender, [Adjusted Hazard Ratio (AHR) = 1.56; 95 % CI 1.28-1.9], CD4 cell count <50 cells/μL (AHR = 4.09; 95 % CI 3.13-5.36) or 50-199 cells/μL (AHR = 1.86; 95 % CI 1.46-2.37); ART initiation and WHO stages 3 (AHR = 1.35; 95 % CI 1.1-1.66) or 4 (AHR = 1.74; 95 % CI 1.23-2.45). Residence outside of Jinja district was not associated with mortality/LTFU (p value = 0.562). Of 870 participants who had VL tests, 756 (87 %) had VLs <50 copies/mL. Conclusion: Community-based ART distribution systems can effectively mitigate the barriers to program retention and result in good rates of virologic suppression. [ABSTRACT FROM AUTHOR]

Background Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%–10% of patients. In the most serious cases (1.3%) this can manifest as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Methods DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivity (57 from a prospective cohort and 152 routine clinic patients) and compared with 463 control patients on nevirapine without any hypersensitivity. The case group included 70 patients with SJS/TEN. All individuals were genotyped for two SNPs in the CYP2B6 gene [c.516G>T (CYP2B6*9) and c.983T>C (CYP2B6*18)] using the TaqMan real-time genotyping platform. The replication cohort comprised 29 controls and 55 nevirapine hypersensitive patients, including 8 SJS/TEN cases. Results An association between the CYP2B6 c.983T>C polymorphism and nevirapine-induced SJS/TEN was observed. In the SJS/TEN group, 30% of individuals possessed at least one c.983T>C versus 16% in the tolerant group [P = 0.006; OR (95% CI) 2.24 (1.27–3.94)]. This association was not significant in the replication cohort [P = 0.075; OR (95% CI) 4.33 (0.80–23.57)]. Combined analysis resulted in an OR of 2.52 (95% CI 1.48–4.20; P = 0.0005) for the association of c.983T>C with SJS/TEN. No association was observed for c.983T>C with other hypersensitivity phenotypes and for CYP2B6 c.516G>T with any hypersensitivity phenotypes. Conclusions Our data show an association between the c.983T>C polymorphism and nevirapine-induced SJS/TEN. CYP2B6 c.983T>C has a frequency of 5%–10% in a variety of African populations, but is not observed in Caucasians, thus representing an ethnic-specific predisposing factor. [ABSTRACT FROM PUBLISHER]

In low-income countries, children ≥4 years and adults with low CD4 count have equally high mortality risk in the 3 months after initiation of antiretroviral therapy, similar to that of untreated individuals. Bacterial infections play a major role; targeted interventions could have important benefits.Background. Adult mortality in the first 3 months on antiretroviral therapy (ART) is higher in low-income than in high-income countries, with more similar mortality after 6 months. However, the specific patterns of changing risk and causes of death have rarely been investigated in adults, nor compared with children in low-income countries.Methods. We used flexible parametric hazard models to investigate how mortality risks varied over the first year on ART in human immunodeficiency virus–infected adults (aged 18–73 years) and children (aged 4 months to 15 years) in 2 trials in Zimbabwe and Uganda.Results. One hundred seventy-nine of 3316 (5.4%) adults and 39 of 1199 (3.3%) children died; half of adult/pediatric deaths occurred in the first 3 months. Mortality variation over year 1 was similar; at all CD4 counts/CD4%, mortality risk was greatest between days 30 and 50, declined rapidly to day 180, then declined more slowly. One-year mortality after initiating ART with 0–49, 50–99 or ≥100 CD4 cells/μL was 9.4%, 4.5%, and 2.9%, respectively, in adults, and 10.1%, 4.4%, and 1.3%, respectively, in children aged 4–15 years. Mortality in children aged 4 months to 3 years initiating ART in equivalent CD4% strata was also similar (0%–4%: 9.1%; 5%–9%: 4.5%; ≥10%: 2.8%). Only 10 of 179 (6%) adult deaths and 1 of 39 (3%) child deaths were probably medication-related. The most common cause of death was septicemia/meningitis in adults (20%, median 76 days) and children (36%, median 79 days); pneumonia also commonly caused child deaths (28%, median 41 days).Conclusions. Children ≥4 years and adults with low CD4 values have remarkably similar, and high, mortality risks in the first 3 months after ART initiation in low-income countries, similar to cohorts of untreated individuals. Bacterial infections are a major cause of death in both adults and children; targeted interventions could have important benefits. [ABSTRACT FROM AUTHOR]

Background: Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)-recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. Methods and Findings: Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0-4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12-38) months. From mothers' ART, 62/9/111 infants had no/20%-89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75-212) days. Overall, 14 infants died at median (IQR) age 9 (3-23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens. Conclusions: Overall 1-year 5% infant mortality was similar to the 2%-4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children. [ABSTRACT FROM AUTHOR]

Background: Despite funding constraints for treatment programmes in Africa, the costs and economic consequences of routine laboratory monitoring for efficacy and toxicity of antiretroviral therapy (ART) have rarely been evaluated. Methods: Cost-effectiveness analysis was conducted in the DART trial (ISRCTN13968779). Adults in Uganda/Zimbabwe starting ART were randomised to clinically-driven monitoring (CDM) or laboratory and clinical monitoring (LCM); individual patient data on healthcare resource utilisation and outcomes were valued with primary economic costs and utilities. Total costs of first/second-line ART, routine 12-weekly CD4 and biochemistry/haematology tests, additional diagnostic investigations, clinic visits, concomitant medications and hospitalisations were considered from the public healthcare sector perspective. A Markov model was used to extrapolate costs and benefits 20 years beyond the trial. Results: 3316 (1660LCM;1656CDM) symptomatic, immunosuppressed ART-naive adults (median (IQR) age 37 (32,42); CD4 86 (31,139) cells/mm3) were followed for median 4.9 years. LCM had a mean 0.112 year (41 days) survival benefit at an additional mean cost of $765 [95%CI:685,845], translating into an adjusted incremental cost of $7386 [3277,dominated] per life-year gained and $7793 [4442,39179] per quality-adjusted life year gained. Routine toxicity tests were prominent costdrivers and had no benefit. With 12-weekly CD4 monitoring from year 2 on ART, low-cost second-line ART, but without toxicity monitoring, CD4 test costs need to fall below $3.78 to become cost-effective (<3xper-capita GDP, following WHO benchmarks). CD4 monitoring at current costs as undertaken in DART was not cost-effective in the long-term. Conclusions: There is no rationale for routine toxicity monitoring, which did not affect outcomes and was costly. Even though beneficial, there is little justification for routine 12-weekly CD4 monitoring of ART at current test costs in low-income African countries. CD4 monitoring, restricted to the second year on ART onwards, could be cost-effective with lower cost second-line therapy and development of a cheaper, ideally point-of-care, CD4 test. [ABSTRACT FROM AUTHOR]

Background. We investigated virological response and the emergence of resistance in the Nevirapine or Abacavir (NORA) substudy of the Development of Antiretroviral Treatment in Africa (DART) trial. Methods. Six hundred symptomatic antiretroviral-naive human immunodeficiency virus (HIV)-infected adults (CD4 cell count, <200 cells/mm3) from 2 Ugandan centers were randomized to receive zidovudine-lamivudine plus abacavir or nevirapine. Virology was performed retrospectively on stored plasma samples at selected time points. In patients with HIV RNA levels >1000 copies/mL, the residual activity of therapy was calculated as the reduction in HIV RNA level, compared with baseline. Results. Overall, HIV RNA levels were lower in the nevirapine group than in the abacavir group at 24 and 48 weeks (P<.001), although no differences were observed at weeks 4 and 12. Virological responses were similar in the 2 treatment groups for baseline HIV RNA level <100,000 copies/mL. The mean residual activity at week 48 was higher for abacavir in the presence of the typically observed resistance pattern of thymidine analogue mutations (TAMs) and M184V (1.47 log10 copies/mL) than for nevirapine with M184V and nonnucleoside reverse-transcriptase inhibitor mutations, whether accompanied by TAMs (0.96 log10 copies/mL) or not (1.18 log10 copies/mL). Conclusions. There was more extensive genotypic resistance in both treatment groups than is generally seen in resource-rich settings. However, significant residual activity was observed among patients with virological failure, particularly those receiving zidovudine-lamivudine plus abacavir. [ABSTRACT FROM AUTHOR]

HIV/AIDS has had a devastating impact at individual, household and community levels. This qualitative research investigates the role of HIV voluntary counselling and testing (VCT) and treatment in enabling HIV-positive Ugandans to cope with this disease. Twelve predetermined focus group discussions (FGDs) were conducted; six with men and six with women. Half of the men and women's groups were receiving antiretroviral therapy (ART) and half were not. An FGD was held with the health care providers administering ART. Testing for HIV was perceived as soliciting a death warrant. Participants affirmed that the incentive for testing was the possibility of accessing free ART. They described experiencing gender-variant stigma and depression on confirming their HIV status and commended the role of counselling in supporting them to adopt positive living. For those receiving ART, counselling reinforced treatment adherence. The findings also revealed gender differences in treatment adherence strategies. ART was described to reduce disease symptoms and restore physical health allowing them to resume their daily activities. Additionally, ART was preferred over traditional herbal treatment because it had clear dosages, expiry dates and was scientifically manufactured. Those that were not receiving ART bore myths and misconceptions about the effectiveness and side effects of ART, delaying the decision to seek treatment. Stigma and the attached concern of HIV/AIDS-related swift death, is a major barrier for VCT. Based on this study's findings, ensuring the provision of quality assured and gender conscious VCT and ART delivery services will enhance positive living and enforce compliance to ART programmes. [ABSTRACT FROM AUTHOR]

Background. We sought to investigate renal function in previously untreated symptomatic human immunodeficiency virus (HIV)-infected adults with CD4+ cell counts of !200 cells/mm3 who were undergoing antiretroviral therapy (ART) in Africa. Methods. The study was an observational analysis within a randomized trial of ART management strategies that included 3316 participants with baseline serum creatinine levels of ⩽360 mmol/L. Creatinine levels were measured before ART initiation, at weeks 4 and 12 of therapy, and every 12 weeks thereafter. We calculated estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault formula. We analyzed the incidence of severely decreased eGFR (<30 mL/min/1.73 m2) and changes in eGFR to 96 weeks, considering demographic data, type of ART, and baseline biochemical and hematological characteristics as predictors, using random-effects models. Results. Sixty-five percent of the participants were women. Median values at baseline were as follows: age, 37 years; weight, 57 kg; CD4+ cell count, 86 cells/mm3; and eGFR, 89 mL/min/1.73 m2. Of the participants, 1492 (45%) had mild (⩾60 but <90 mL/min/1.73 m2) and 237 (7%) had moderate (⩾30 but ⩾60 mL/min/1.73 m2) impairments in eGFR. First-line ART regimens included zidovudine-lamivudine plus tenofovir disoproxil fumarate (for 74% of patients), nevirapine (16%), and abacavir (9%) (mostly nonrandomized allocation). After ART initiation, the median eGFR was 89-91 mL/min/1.73 m2 for the period from week 4 through week 96. Fifty-two participants (1.6%) developed severe reductions in eGFR by week 96; there was no statistically significant difference between these patients and others with respect to first-line ART regimen received (Pp.94). Lower baseline eGFR or hemoglobin level, lower body mass index, younger age, higher baseline CD4+ cell count, and female sex were associated with greater increases in eGFR over baseline, with small but statistically significant differences between regimens (P < .001 for all). Conclusions. Despite screening, mild-to-moderate baseline renal impairment was relatively common, but these participants had greatest increases in eGFR after starting ART. Severe eGFR impairment was infrequent regardless of ART regimen and was generally related to intercurrent disease. Differences between ART regimens with respect to changes in GFR through 96 weeks were of marginal clinical relevance, but investigating longer-term nephrotoxicity remains important. [ABSTRACT FROM AUTHOR]

The article discusses the adherence of Africans to antiretroviral therapy (ART). It states that there has been an increase in the usage of ART in Africa than in any developed countries in 2008, where mortality rates of African patients have fallen compared to the pre-ART period. However, it mentions that there is low retention of patients in ART programs, and suggests that further research is needed to identify the reasons why patients do not continue the treatment.

Introduction Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organisation for HIV infected persons. However, once HIV infected patients have commenced ART in resource limited settings, the benefits of continued CTX prophylaxis are not known. The few studies that investigated the safety of discontinuing CTX prophylaxis in these settings had limitations due to their design. Materials and methods COSTOP is a randomised double blind placebo controlled non-inferiority trial among HIV infected Ugandan adults stabilised on anti-retroviral treatment (ART). Participants with CD4 count of 250 or more cells/mm 3 are randomised to two arms: the intervention arm in which CTX is discontinued and the control arm in which CTX prophylaxis is continued. The study aims to assess whether the intervention regimen is not inferior, with respect to the incidence of pre-defined CTX-preventable events, to the control regimen and superior with respect to the incidence of haematological adverse events. Discussion Studies that have previously evaluated the safety of discontinuing CTX prophylaxis among HIV infected adults in resource limited settings have provided moderate to low quality evidence owing in part to methodological limitations. COSTOP is designed and conducted with sufficient rigour to answer this question. The results of the trial will assist in guiding policy recommendations. Conclusion This paper describes the design and methodological considerations important for the conduct of CTX cessation studies. [ABSTRACT FROM AUTHOR]

The article compared the cessation of co-trimoxazole prophylaxis with continued prophylaxis in HIV-infected children and adolescents treated with antiretroviral therapy (ART) in sub-Saharan Africa. The study found benefits in continuing co-trimoxazole prophylaxis after 96 weeks of ART, with fewer hospitalizations for both malaria and infection not related to malaria. No evidence of variation in the benefits of co-trimoxazole prophylaxis across ages or CD4 T-cell values was found.

The article offers information on the individual and population-level adherence to antiretroviral therapy (ART) provision. A study was conducted in Africa to determine the risk factors for poor adherence to ART. The result of the study revealed that population level adherence to ART improve over time due to continuing association with clinical experience.