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

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Prevalence and type of drug-drug interactions involving ART in patients attending a specialist HIV outpatient clinic in Kampala, Uganda.

OBJECTIVES: Scale-up of HIV services in sub-Saharan Africa has rapidly increased, necessitating evaluation of medication safety in these settings. Drug-drug interactions (DDIs) involving antiretrovirals (ARVs) in sub-Saharan Africa are poorly characterized. We evaluated the prevalence and type of ARV DDIs in Ugandan outpatients and identified the patients most at risk. METHODS: A total of 2000 consecutive patients receiving ARVs at the Infectious Diseases Institute, Kampala were studied. The most recent prescription for each patient was screened for clinically significant DDIs using www.hiv-druginteractions.org. Univariable and multivariable logistic regression were used to identify risk factors for DDIs. A screening tool was developed using significant risk factors and tested in a further 500 patients. RESULTS: Clinically significant DDIs were observed in 374 (18.7%) patients, with a total of 514 DDIs observed. Only 0.2% of DDIs involved a contraindicated combination. Comedications commonly associated with DDIs were antibiotics (4.8% of 2000 patients), anthelmintics (2.2%) and antifungals (3.5%). Patient age, gender, CD4 count and weight did not affect risk of DDIs. In multivariable analysis, the patient factors that independently increased risk of DDIs were two or more comedications (P < 0.0001), a PI-containing ARV regimen (P < 0.0001), use of an anti-infective (P < 0.0001) and WHO clinical stage 3-4 (P = 0.04). A scoring system based on having at least two of these risk factors identified between 75% and 90% of DDIs in a validation cohort. CONCLUSIONS: Significant ARV DDIs occur at similar rates in resource-limited settings and developed countries; however, the comedications frequently causing DDIs differ. Development of tools that are relevant to particular settings should be a priority to assist with prevention and management of DDIs

Health care related factors associated with severe malaria in children in Kampala, Uganda

Background: Severe malaria is responsible for the high load of malaria mortality. It is not clearly understood why some malaria episodes progress to severe malaria. Objective: To determine factors associated with severe malaria in children aged 6 months to 5 years living in Kampala. Methods: Over a 6-month period, 100 children with severe malaria were matched by age and place of residence with 100 children with non-severe malaria. We collected health care information from care takers. Results: Mean duration of illness before getting antimalarial treatment was shorter for controls than cases (8hours vs. 20hours, p 0.015). Children with severe malaria were less likely to have been treated with sulphadoxine-pyrimethamine in the preceding 2 weeks (OR 0.2, 95% CI 0.04-0.85, p 0.016). Odds of severe malaria were higher in those who reported lack of protective measures (mosquito coils (OR = 20.63, 95% CI 1.5-283.3, p=0.02 and insecticide sprays OR 10.93, 95% CI 1.13-105.64, p=0.03), although few reported their use. Conclusions: Early anti-malarial treatment and use of barriers against mosquitoes prevent severe malaria in children. There is need to increase the use of barriers against mosquito bites and to scale up prompt treatment and community-based interventions to reduce the incidence of severe malaria in children

Causes and outcome of hospitalization among HIV-infected adults receiving antiretroviral therapy in Mulago hospital, Uganda

BACKGROUND: Cohorts describing cause specific mortality in HIV-infected patients initiating antiretroviral therapy (ART) operate on an outpatient basis. Hospitalized patients represent the spectrum and burden of severe morbidity and mortality in patients on ART. OBJECTIVE: To determine the causes and outcomes of hospitalization among adults receiving ART. METHODS: A prospective cohort study. We enrolled 201 participants (50% female) with median (IQR) age and CD4 count of 34 (28–40) years and 91(29–211) cells/uL respectively. RESULTS: The most frequent causes of hospitalization were tuberculosis (TB) (37, 18%), cryptococcal meningitis (22, 11%), zidovudine (AZT) - associated anemia (19, 10%), sepsis (10, 5%) and Kaposi's sarcoma (10, 5%). Forty two patients (21%) died: 10 (24%) had TB, 8 (19%) had cryptococcal meningitis and 5 (12%) had sepsis, 9 (21%) had undiagnosed neurological syndromes while 10 (24%) had other illnesses. Predictors of death included low Karnofsky performance score of < 40 (OR, 21.1; CI 1.43– 31.6) and age >34 years (OR, 7.65; CI 1.09– 53.8). CONCLUSIONS: Opportunistic infections, malignancy and AZT-associated anemia contributed to most hospitalizations and mortality. It is important to intensify prevention, screening, and treatment for these opportunistic diseases and early ART initiation in HIV-infected patients. Tenofovir-based regimens, unless contraindicated should be scaled up to replace AZT-based regimens as first line ART drugs

Causes and outcome of hospitalization among HIV-infected adults receiving antiretroviral therapy in Mulago hospital, Uganda

Background: Cohorts describing cause specific mortality in HIV-infected patients initiating antiretroviral therapy (ART) operate on an outpatient basis. Hospitalized patients represent the spectrum and burden of severe morbidity and mortality in patients on ART. Objective: To determine the causes and outcomes of hospitalization among adults receiving ART. Methods: A prospective cohort study. We enrolled 201 participants (50% female) with median (IQR) age and CD4 count of 34 (28-40) years and 91(29-211) cells/uL respectively. Results: The most frequent causes of hospitalization were tuberculosis (TB) (37, 18%), cryptococcal meningitis (22, 11%),zidovudine (AZT)- associated anemia (19, 10%), sepsis (10, 5%) and Kaposi’s sarcoma (10, 5%). Forty two patients (21%) died: 10 (24%) had TB, 8 (19%) had cryptococcal meningitis and 5 (12%) had sepsis, 9 (21%) had undiagnosed neurological syndromes while 10 (24%) had other illnesses. Predictors of death included low Karnofsky performance score of < 40 (OR, 21.1; CI 1.43- 31.6) and age >34 years (OR, 7.65; CI 1.09- 53.8). Conclusions: Opportunistic infections, malignancy and AZT-associated anemia contributed to most hospitalizations and mortality. It is important to intensify prevention, screening, and treatment for these opportunistic diseases and early ART initiation in HIV-infected patients. Tenofovir-based regimens, unless contraindicated should be scaled up to replace AZT based regimens as first line ART drugs

Piperaquine concentration and malaria treatment outcomes in Ugandan children treated for severe malaria with intravenous Artesunate or quinine plus Dihydroartemisinin-Piperaquine

Background: Treatment for severe malaria must be prompt with effective parenteral antimalarial drugs for at least 24 h to achieve fast parasite clearance, and when the patient can tolerate oral therapy, treatment should be completed with effective artemisinin based combination therapy (ACT) for complete parasite clearance and to prevent recrudescence. We evaluated piperaquine concentration and malaria treatment outcomes among Ugandan children treated for severe malaria with intravenous artesunate (AS) or quinine (QN) plus dihydroartemisininpiperaquine (DP), in Tororo District Hospital in Eastern Uganda. Methods: Capillary blood piperaquine concentration data were obtained from a randomized clinical trial whose objective was to evaluate parasite clearance, 42-day parasitological treatment outcomes and safety, following treatment of severe malaria with intravenous AS or QN, plus artemether-lumefantrine or DP among children in Tororo District Hospital, in Eastern Uganda. Results: Piperaquine concentration data from 150 participants who received DP were analyzed. Participants with unadjusted treatment failure had lower median day 7 capillary piperaquine concentration than those with treatment success (34.7 (IQR) (17.9–49.1) vs 66.7 (IQR) (41.8–81.9), p < 0.001), and lower than the recommended day 7 cut off level of 57 ng/mL. There was no difference in median capillary piperaquine concentrations among participants with re-infection and recrudescence (35.3 (IQR) (17.9–55.2) vs 34.8 (IQR) (18.1–45.1), p = 0.847). The risk of treatment failure was two times higher among children with low (< 57 ng/mL) day 7 capillary piperaquine concentration (relative risk: 2.1 CI 1.4–3.1), p < 0.001) compared to children with high day 7 capillary piperaquine concentrations (> 57 ng/mL). Conclusion: Considering the low day 7 concentrations of piperaquine reported in the patients studied here, we suggest to adopt the recently recommended higher dose of DP in young children or a prolonged 5-day dosing in children living in malaria endemic areas who have suffered an initial episode of severe malaria in order to achieve adequate drug exposures for effective post-treatment prophylactic effects