Prevalence of renal dysfunction among HIV infected patients receiving Tenofovir at Mulago: a cross-sectional study.

BACKGROUND: There is an increasing burden of non-communicable disease globally. Tenofovir disoproxil fumarate (TDF) is the most commonly prescribed antiretroviral drug globally. Studies show that patients receiving TDF are more prone to renal dysfunction at some point in time during treatment. Evaluation of kidney function is not routinely done in most HIV public clinics. Identification of renal dysfunction is key in resource constrained settings because managing patients with end stage renal disease is costly. METHOD: This was a cross-sectional study conducted at an outpatient clinic in 2018 involving patients on TDF for at least 6 months who were 18 years or older. Patients with documented kidney disease and pregnancy were excluded. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-Epi formula. Renal dysfunction was defined as any of the following; either eGFR< 60 mL/min/1.73m2,or proteinuria of ≥2+ on urine dipstick, glycosuria with normal blood glucose. Electrolyte abnormalities were also documented. RESULTS: We enrolled 278 participants. One hundred sixty nine (60.8%) were females, majority 234(84.2%) were < 50 years old, 205 (73.74%) were in WHO stage 1, most participants 271(97.5%) in addition to TDF were receiving lamivudine/efavirenz. The median age was 37(IQR 29-45) years; median duration on ART was 36 (IQR 24-60) months. The prevalence of renal dysfunction was 2.52% (7/278). Most noted electrolyte abnormality was hypocalcaemia (15.44%). CONCLUSIONS: The prevalence of renal dysfunction was low though some participants had hypocalcaemia. Screening for kidney disease should be done in symptomatic HIV infected patients on TDF

Accuracy of two malaria rapid diagnostic tests (RDTS) for initial diagnosis and treatment monitoring in a high transmission setting in Uganda.

Malaria rapid diagnostic tests (RDTs) may improve fever management in areas without microscopy. We compared the accuracy of histidine-rich protein 2 (HRP2) and Plasmodium lactate dehydrogenase (pLDH)-based RDTs, using expert microscopy as a gold standard, for initial diagnosis, treatment monitoring, and diagnosis of recurrent malaria in a cohort of children followed longitudinally in a high-transmission area in Uganda. For 305 initial fever episodes, sensitivity was 98% for HRP2 and 87% for pLDH, whereas specificity was 55% and 96%, respectively. The HRP2 gave 51% false-positive results on Day 28, whereas pLDH gave no false positives after Day 7. For 59 recurrent fever episodes during follow-up, sensitivity was 100% for HRP2 and 91% for pLDH, whereas specificity was 33% and 100%, respectively. The HRP2-based RDTs are useful for initial diagnosis of malaria caused by superior sensitivity; however, as a result of superior specificity, pLDH-based RDTs are more appropriate to monitor treatment and diagnose recurrent malaria

A situation analysis of competences of research ethics committee members regarding review of research protocols with complex and emerging study designs in Uganda.

BACKGROUND: Over the past two decades, Uganda has experienced a significant increase in clinical research driven by both academia and industry. This has been combined with a broader spectrum of research proposals, with respect to methodologies and types of intervention that need evaluation by Research Ethics Committees (RECs) with associated increased requirement for expertise. We assessed the competencies of REC members regarding review of research protocols with complex and emerging research study designs. The aim was to guide development of a training curriculum to improve the quality of scientific and ethical review. METHODS: This was a cross-sectional study design, with quantitative data collection methods. Research Ethics Committee members completed a structured pre-coded questionnaire on current competence with complex and emerging study design. REC members were asked to outline a list of additional topics for which they needed training. Data from coded questions were entered into Epidata Version 3.1 and then exported to STATA Version14.1 for analysis. Descriptive analysis was performed and findings are presented using percentages and frequencies. RESULTS: We enrolled 55 REC members from 6 RECs who have a total of 97 members. The majority of whom were males (56.4%, n = 31/55). The level of competence for review of selected study design was lowest for Controlled Human Infection Model (10.9%, n = 6) and reverse pharmacology design (10.9%, n = 6), and highest for cluster randomized study design (52.7%, n = 29) and implementation science research (52.7%, n = 29). CONCLUSION: Competence for review of research protocols with complex and emerging study design was low among participating REC members. We recommend prioritising training of REC members on complex and emerging study designs to enhance quality of research protocol review

Update on the efficacy, effectiveness and safety of artemether–lumefantrine combination therapy for treatment of uncomplicated malaria

Artemether–lumefantrine is one of the artemisisnin-based combination therapies recommended for treatment of uncomplicated falciparum malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. It offers the advantage of rapid clearance of parasites by artemether and the slower elimination of residual parasites by lumefantrine. The combination can be used in all populations except pregnant mothers in the first trimester where safety is still uncertain. There are still concerns about safety and pharmacokinetics of the drug combination in children, especially infants, pregnant mothers and drug interactions with mainly non-nucleoside reverse transcriptase inhibitors and protease inhibitors used for HIV therapy

Artemether-Lumefantrine Combination Therapy for Treatment of Uncomplicated Malaria: The Potential for Complex Interactions with Antiretroviral Drugs in HIV-Infected Individuals

Treatment of malaria in HIV-infected individuals receiving antiretroviral therapy (ART) poses significant challenges. Artemether-lumefantrine (AL) is one of the artemisisnin-based combination therapies recommended for treatment of malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. Both artemether and lumefantrine are metabolized by hepatic cytochrome P450 (CYP450) enzymes which metabolize the protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used for HIV treatment. Coadministration of NNRTIs and PIs with AL could potentially cause complex pharmacokinetic drug interactions. NNRTI by inducing CYP450 3A4 enzyme and PIs by inhibiting CYP450 3A4 enzymes could influence both artemether and lumefantrine concentrations and their active metabolites dihydroartemisinin and desbutyl-lumefantrine, predisposing patients to poor treatment response, toxicity, and risk for development of resistance. There are scanty data on these interactions and their consequences. Pharmacokinetic studies to evaluate these interactions in the target populations are urgently needed

Prevalence of microalbuminuria and associated factors among HIV - infected ART naïve patients at Mulago hospital: a cross-sectional study in Uganda.

BACKGROUND: HIV infection affects multiple organs and the kidney is a common target making renal disease, one of the recognized complications. Microalbuminuria represents an early, important marker of kidney damage in several populations including HIV-infected antiretroviral therapy (ART) naïve patients. Early detection of microalbuminuria is critical to slowing down progression to chronic kidney disease (CKD) in HIV-infected patients, however, the burden of microalbuminuria in HIV-infected antiretroviral therapy (ART) naïve patients in Uganda is unclear. METHODS: A cross-sectional study was conducted in the Mulago Immune suppression syndrome (ISS) clinic among adult HIV - infected ART naïve outpatients. Data on patient demographics, medical history was collected. Physical examination was performed to assess body mass index (BMI) and hypertension. A single spot morning urine sample from each participant was analysed for microalbuminuria using spectrophotometry and colorimetry. Microalbuminuria was defined by a urine albumin creatinine ratio (UACR) 30-299 mg/g and macroalbuminuria by a UACR > 300 mg/g. To assess the factors associated with microalbuminuria, chi-square, Fisher's exact test, quantile regression and logistic regression were used. RESULTS: A total of 185 adult participants were consecutively enrolled with median age and CD4+ counts of 33(IQR = 28-40) years and 428 (IQR = 145-689) cells/μL respectively. The prevalence of microalbuminuria was 18.9% (95% CI, 14-25%). None of the participants had macroalbuminuria. CD4+ count <350cells/μL was associated with increased risk of microalbuminuria (OR: 0.27, 95% CI: 0.12-0.59), P value = 0.001). Diabetes mellitus, hypertension, smoking, alcohol intake were not found to be significantly associated with microalbuminuria. CONCLUSION: Microalbuminuria was highly prevalent in adult HIV - infected ART naive patients especially those with low CD4+ count. There is need to study the effect of ART on microalbuminuria in adult HIV - infected patients

Steady-state Pharmacokinetic Comparison of Generic and Branded Formulations of Lamivudine, Stavudine, and Nevirapine in HIV-infected Ugandan Adults

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Effect of Food on the Steady-State Pharmacokinetics of Tenofovir and Emtricitabine plus Efavirenz in Ugandan Adults

We investigated the effect of food on the steady-state pharmacokinetics of a proprietary fixed-dose combination (FDC) tablet containing tenofovir disoproxil fumarate (TDF)/emtricitabine/efavirenz. Fifteen Ugandan HIV-1 patients at steady-state dosing with TDF/emtricitabine/efavirenz were admitted for 24-hour intensive pharmacokinetic sampling after dosing in the fasting state. Blood sampling was repeated seven days later with TDF/emtricitabine/efavirenz administered with food (19 g fat). Drug concentrations in plasma were determined by liquid chromatography and tandem mass spectrometry. Geometric mean ratios (GMRs) and confidence intervals (CIs) of parameters were calculated (reference, fasting). For efavirenz, GMRs (90% CIs) for Cmax, AUC0−24, and C24 were 1.47 (1.24–1.75), 1.13 (1.03–1.23), and 1.01 (0.91–1.11), respectively. Corresponding GMRs were 1.04 (0.84–1.27), 1.19 (1.10–1.29), and 0.99 (0.82–1.19) for tenofovir, 0.83 (0.76–0.92), 0.87 (0.78–0.97), and 0.91 (0.73–1.14) for emtricitabine. Stable patients may take the FDC without meal restrictions. The FDC should be taken without food by patients experiencing central nervous system toxicities

Cardiac Conduction Safety during Coadministration of Artemether-Lumefantrine and Lopinavir/Ritonavir in HIV-Infected Ugandan Adults

Background. We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans. Methods. Open-label safety study of HIV-positive adults administered single-dose AL (80/400 mg) alone or with LPV/r (400/100 mg). Cardiac function was monitored using continuous electrocardiograph (ECG). Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naïve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P = .02) and 72 hours (424 versus 408; P = .004) after AL intake. Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated

HIV-positive nigerian adults harbor significantly higher serum lumefantrine levels than HIV-negative individuals seven days after treatment for Plasmodium falciparum infection.

Management of coinfection with malaria and HIV is a major challenge to public health in developing countries, and yet potential drug-drug interactions between antimalarial and antiviral regimens have not been adequately investigated in people with both infections. Each of the constituent components of artemether-lumefantrine, the first-line regimen for malaria treatment in Nigeria, and nevirapine, a major component of highly active antiretroviral therapy, are drugs metabolized by the cytochrome P450 3A4 isoenzyme system, which is also known to be induced by nevirapine. We examined potential interactions between lumefantrine and nevirapine in 68 HIV-positive adults, all of whom were diagnosed with asymptomatic Plasmodium falciparum infections by microscopy. Post hoc PCR analysis confirmed the presence of P. falciparum in only a minority of participants. Day 7 capillary blood levels of lumefantrine were significantly higher in HIV-positive participants than in 99 HIV-negative controls (P = 0.0011). Associations between day 7 levels of lumefantrine and risk of persistent parasitemia could not be evaluated due to inadequate power. Further investigations of the impact of nevirapine on in vivo malaria treatment outcomes in HIV-infected patients are thus needed