Anti-TB drug concentrations and drug-associated toxicities among TB/HIV-coinfected patients.

Background: Toxicities due to anti-TB treatment frequently occur among TB/HIV-coinfected patients. Objectives: To determine the association between anti-TB drug concentrations and the occurrence of hepatotoxicity and peripheral neuropathy among TB/HIV-coinfected patients. Methods: TB/HIV-coinfected patients were started on standard dose anti-TB treatment according to WHO guidelines. Anti-TB drug concentrations were measured using HPLC 1, 2 and 4 h after drug intake at 2, 8 and 24 weeks following initiation of TB treatment. Participants were assessed for hepatotoxicity using Division of AIDS toxicity tables and for peripheral neuropathy using clinical assessment of tendon reflexes, vibration sensation or symptoms. Cox regression was used to determine the association between toxicities and drug concentrations. Results: Of the 268 patients enrolled, 58% were male with a median age of 34 years. Participants with no hepatotoxicity or mild, moderate and severe hepatotoxicity had a median C max of 6.57 (IQR 4.83-9.41) µg/mL, 7.39 (IQR 5.10-10.20) µg/mL, 7.00 (IQR 6.05-10.95) µg/mL and 3.86 (IQR 2.81-14.24) µg/mL, respectively. There was no difference in the median C max of rifampicin among those who had hepatotoxicity and those who did not ( P = 0.322). There was no difference in the isoniazid median C max among those who had peripheral neuropathy 2.34 (1.52-3.23) µg/mL and those who did not 2.21 (1.45-3.11) µg/mL ( P = 0.49). Conclusions: There was no association between rifampicin concentrations and hepatotoxicity or isoniazid concentrations and peripheral neuropathy among TB/HIV-coinfected patients.

The effect of an intervention to promote isoniazid preventive therapy on leadership and management abilities.

BACKGROUND: Across sub-Saharan Africa, mid-level healthcare managers oversee implementation of national guidelines. It remains unclear whether leadership and management training can improve population health outcomes. METHODS: We sought to evaluate leadership/management skills among district-level health managers in Uganda participating in the SEARCH-IPT randomised trial to promote isoniazid preventive therapy (IPT) for persons with HIV (PWH). The intervention, which led to higher IPT rates, included annual leadership/management training of managers. We conducted a cross-sectional survey assessing leadership/management skills among managers at trial completion. The survey evaluated self-reported use of leadership/management tools and general leadership/management. We conducted a survey among a sample of providers to understand the intervention's impact. Targeted minimum loss-based estimation (TMLE) was used to compare responses between trial arms. RESULTS: Of 163 managers participating in the SEARCH-IPT trial, 119 (73%) completed the survey. Intervention managers reported more frequent use of leadership/management tools taught in the intervention curriculum than control managers (+3.64, 95% CI 1.98-5.30, P < 0.001). There were no significant differences in self-reported leadership skills in the intervention as compared to the control group. Among providers, the average reported quality of guidance and supervision was significantly higher in intervention vs control districts (+1.08, 95% CI 0.63-1.53, P = 0.001). CONCLUSIONS: A leadership and management training intervention increased the use of leadership/management tools among mid-level managers and resulted in higher perceived quality of supervision among providers in intervention vs control districts in Uganda. These findings suggest improved leadership/management among managers contributed to increased IPT use among PWH in the intervention districts of the SEARCH-IPT trial.

CONTEXTE: Dans toute l'Afrique subsaharienne, les gestionnaires de soins de santé de niveau intermédiaire supervisent la mise en œuvre des directives nationales. Il n'est toujours pas clair si la formation en leadership et en gestion peut améliorer les résultats en matière de santé de la population. MÉTHODES: Nous avons cherché à évaluer les compétences en leadership et en gestion des responsables de la santé au niveau des districts en Ouganda participant à l'essai randomisé SEARCH-IPT visant à promouvoir le traitement préventif à l'isoniazide (TPI) pour les personnes vivant avec le VIH (PWH, pour l'anglais « people living with HIV ¼). L'intervention, qui a permis d'augmenter les taux de TPI, comprenait une formation annuelle en leadership et en gestion des gestionnaires. Nous avons mené une enquête transversale pour évaluer les compétences en leadership et en gestion des gestionnaires à la fin de l'essai. L'enquête a évalué l'utilisation autodéclarée d'outils de leadership et de gestion et de leadership et de gestion en général. Nous avons mené une enquête auprès d'un échantillon de prestataires pour comprendre l'impact de l'intervention. L'estimation ciblée basée sur les pertes minimales (TMLE, « Targeted minimum loss-based estimation ¼) a été utilisée pour comparer les réponses entre les groupes de l'essai. RÉSULTATS: Sur les 163 gestionnaires qui ont participé à l'essai SEARCH-IPT, 119 (73%) ont répondu au sondage. Les gestionnaires d'intervention ont déclaré utiliser plus fréquemment les outils de leadership/gestion enseignés dans le programme d'intervention que les gestionnaires de contrôle (+3,64 ; IC à 95% 1,98­5,30 ; P < 0,001). Il n'y avait pas de différences significatives dans les compétences de leadership autodéclarées dans l'intervention par rapport au groupe témoin. Parmi les prestataires, la qualité moyenne déclarée de l'orientation et de la supervision était significativement plus élevée dans les districts d'intervention que dans les districts témoins (+1,08 ; IC à 95% 0,63­1,53 ; P = 0,001). CONCLUSIONS: Une intervention de formation au leadership et à la gestion a permis d'accroître l'utilisation d'outils de leadership et de gestion parmi les cadres intermédiaires et d'améliorer la perception de la qualité de la supervision parmi les prestataires dans les districts d'intervention par rapport aux districts de contrôle en Ouganda. Ces résultats suggèrent que l'amélioration du leadership et de la gestion chez les gestionnaires a contribué à l'augmentation de l'utilisation du TPI chez les personnes handicapées dans les districts d'intervention de l'essai SEARCH-IPT.

Understanding patient-level costs of weekly isoniazid-rifapentine (3HP) among people living with HIV in Uganda.

BACKGROUND: Twelve weeks of weekly isoniazid and rifapentine (3HP) prevents TB disease among people with HIV (PWH), but the costs to people of taking TB preventive treatment is not well described.METHODS: We surveyed PWH who initiated 3HP at a large urban HIV/AIDS clinic in Kampala, Uganda, as part of a larger trial. We estimated the cost of one 3HP visit from the patient perspective, including both out-of-pocket costs and estimated lost wages. Costs were reported in 2021 Ugandan shillings (UGX) and US dollars (USD; USD1 = UGX3,587)RESULTS: The survey included 1,655 PWH. The median participant cost of one clinic visit was UGX19,200 (USD5.36), or 38.5% of the median weekly income. Per visit, the cost of transportation was the largest component (median: UGX10,000/USD2.79), followed by lost income (median: UGX4,200/USD1.16) and food (median: UGX2,000/USD0.56). Men reported greater income loss than women (median: UGX6,400/USD1.79 vs. UGX3,300/USD0.93), and participants who lived further than a 30-minute drive to the clinic had higher transportation costs than others (median: UGX14,000/USD3.90 vs. UGX8,000/USD2.23).CONCLUSION: Patient-level costs to receive 3HP accounted for over one-third of weekly income. Patient-centered approaches to averting or defraying these costs are needed.

Impact of mycobacterial culture among HIV-infected adults with presumed TB in Uganda: a prospective cohort study.

BACKGROUND: Implementation of new tuberculosis (TB) diagnostic strategies in resource-constrained settings is challenging. We measured the impact of solid and liquid mycobacterial cultures on treatment practices for patients undergoing TB evaluation in Kampala, Uganda. METHODS: We enrolled consecutive smear-negative, human immunodeficiency virus positive adults with cough of ⩾2 weeks from September 2009 to April 2010. Laboratory technicians performed mycobacterial cultures on solid and liquid media. We compared empiric treatment decisions with solid and liquid culture in terms of diagnostic yield and time to results, and assessed impact on patient management. RESULTS: Of 200 patients enrolled, 26 (13%) had culture-confirmed TB: 22 (85%) on solid culture alone, 2 (8%) on liquid culture alone, and 2 (8%) on both solid and liquid culture. Thirty-four patients received empiric anti-tuberculosis treatment, but only 10 (29%) were culture-positive. Median time to a positive result on solid culture was 92 days (interquartile range [IQR] 69-148) compared to 106 days (IQR 66-157) for liquid culture. No patients initiated treatment following a positive result on liquid culture. CONCLUSION: The introduction of mycobacterial culture did not influence care for patients undergoing evaluation for TB in Kampala, Uganda. Attention to contextual factors surrounding implementation is needed to ensure the effective introduction of new testing strategies in low-income countries.

Contexte : La mise en œuvre de nouvelles stratégies de diagnostic de la tuberculose (TB) dans les contextes de ressources limitées constitue un défi. Nous avons mesuré l'impact des cultures mycobactériennes en milieu solide et liquide sur les pratiques de traitement des patients ayant une évaluation de la TB à Kampala, Ouganda.Méthodes : Nous avons enrôlé des patients adultes consécutifs à frottis négatif, positifs pour le virus de l'immunodéficience humaine avec toux de ⩾2 semaines, de septembre 2009 à avril 2010. Les techniciens de laboratoire ont réalisé des cultures mycobactériennes en milieu solide et liquide. Nous avons comparé les décisions de traitement empirique aux cultures en milieu solide et liquide en termes de rendement diagnostique et de délai d'obtention des résultats et nous avons évalué l'impact sur la gestion des patients.Résultats : Des 200 patients enrôlés, 26 (13%) avaient une TB confirmée par culture, 22 (85%) par culture en milieu solide seule, 2 (8%) par culture en milieu liquide seul et 2 (8%) par culture à la fois en milieu solide et liquide. Trente-quatre patients ont reçu un traitement de TB empirique, mais seulement 10 (29%) ont eu une TB à culture positive. Le délai médian d'obtention d'un résultat de culture positive en milieu solide a été de 92 jours (IQR 69­148). Le délai médian d'obtention d'un résultat de culture positive en milieu liquide a été de 106 jours (IQR 66­157). Aucun patient n'a commencé un traitement à la suite d'un résultat de culture positive en milieu liquide.Conclusion : L'introduction de la culture mycobactérienne n'a pas influencé les soins aux patients bénéficiant d'une évaluation de TB à Kampala, Ouganda. Il est nécessaire d'être attentif aux facteurs contextuels entourant la mise en œuvre afin d'assurer une introduction effective de nouvelles stratégies de tests dans les pays à faible revenu.

Marco de referencia: La ejecución de nuevas estrategias de diagnóstico de la tuberculosis (TB) en los entornos con limitación de recursos es problemática. En el presente estudio se midió la repercusión del uso del cultivo de micobacterias en medio sólido o liquido sobre las prácticas de tratamiento de los pacientes en curso de investigación diagnóstica de la TB en Kampala, Uganda.Métodos: Se incluyeron de manera consecutiva en el estudio los pacientes adultos, seronegativos frente al virus de la inmunodeficiencia humana, que consultaban por tos de ⩾2 semanas de duración y presentaban baciloscopia negativa, de septiembre del 2009 a abril del 2010. Los auxiliares de laboratorio practicaron el cultivo de micobacterias en medio sólido y medio líquido. Se compararon las decisiones empíricas de tratamiento y los tipos de cultivo, con respecto al rendimiento diagnóstico y al lapso hasta obtener los resultados y se evaluó su repercusión en el manejo de los pacientes.Resultados: De los 200 pacientes que participaron en el estudio, 26 obtuvieron confirmación del diagnóstico de TB mediante el cultivo (13%), 22 de ellos con el cultivo en medio sólido únicamente (85%), dos con el cultivo en medio líquido exclusivamente y dos con ambos tipos de cultivo (8%). Treinta y cuatro pacientes recibieron tratamiento antituberculoso empírico, pero solo 10 de ellos obtuvieron un cultivo positivo (29%). La mediana del lapso hasta obtener el resultado del cultivo en medio sólido fue 92 días (IQR 69­148). La mediana de este lapso con los cultivos en medio líquido fue 106 días (IQR 66­157). Ningún paciente inició el tratamiento antituberculoso después de haber obtenido el resultado positivo del cultivo en medio líquido.Conclusión: La introducción del cultivo para micobacterias no tiene ninguna influencia en la atención que reciben los pacientes en quienes se investiga la TB en Kampala, Uganda. Es importante prestar atención a los factores contextuales que rodean la ejecución, a fin de lograr una introducción eficaz de las nuevas estrategias diagnósticas en los países con recursos limitados.

Predictors of chloroquine treatment failure in children and adults with falciparum malaria in Kampala, Uganda.

Chloroquine-resistant falciparum malaria is a serious problem in much of sub-Saharan Africa. However, it is desirable to continue to use chloroquine as first-line therapy for uncomplicated malaria where it remains clinically effective. To identify predictors of chloroquine treatment failure, a 14-day clinical study of chloroquine resistance in patients with uncomplicated falciparum malaria was performed in Kampala, Uganda. Among the 258 patients (88% follow-up), 47% were clinical failures (early or late treatment failure) and 70% had parasitological resistance (RI-RIII). Using multivariate analysis, an age less than five (odds ratio [OR] = 3.4, 95% CI = 1.8-6.3) and a presenting temperature over 38.0 degreesC (OR = 2.0, 95% CI = 1.1-3.7) were independent predictors of treatment failure. In addition, patients who last took chloroquine 3 to 14 days prior to study entry were significantly more likely to be treatment failures compared to patients with very recent (less than 3 days) or no recent chloroquine use. In areas with significant chloroquine resistance, easily identifiable predictors of chloroquine treatment failure might be used to stratify patients into those for whom chloroquine use is acceptable and those for whom alternative treatment should be used.

The comparative efficacy of chloroquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in Kampala, Uganda.

Chloroquine (CQ) remains the first-line treatment for uncomplicated malaria in much of Africa despite the growing problem of resistance to this drug. Sulfadoxine-pyrimethamine (SP) is often used after CQ treatment failure and has replaced CQ as the first-line treatment in parts of Africa. To compare the efficacy of these 2 regimens, we evaluated, in March-August 1999, clinical and parasitological responses over 28 days in 214 children and adults from Kampala, Uganda, with uncomplicated falciparum malaria. Compared to SP, significantly more patients treated with CQ developed early or late clinical failure (54% vs 11%, P < 0.001) and parasitological failure (72% vs 30%, P < 0.001) during 14 days of follow-up. The risk of treatment failure occurring after day 14 was similar between the 2 treatment groups. Among those treated with CQ, children aged < 5 years were at higher risk of clinical failure than older individuals (76% vs 28%, P < 0.001), an association not seen with SP (11% vs 10%, P = 0.91). Although early parasite clearance was significantly better in the SP group (P = 0.001), fever clearance at day 3 was the same (CQ 85%, SP 86%). These and other recent findings suggest that consideration be given to replacing CQ as the first-line therapy for uncomplicated malaria in Uganda, particularly in young children.

Chest X-ray vs. Xpert® MTB/RIF assay for the diagnosis of sputum smear-negative tuberculosis in Uganda.

SETTING: An out-patient clinic in a country with high rates of tuberculosis-human immunodeficiency virus (TB-HIV) co-infection. DESIGN: Cross-sectional analytical study of 123 adults with chronic cough and no previous anti-tuberculosis treatment. Demographic, clinical, chest X-ray (CXR) and GeneXpert® MTB/RIF data were collected. Proportions of TB diagnoses using both tests were calculated and compared using an unpaired t-test. RESULTS: Sixty-six patients (53.7%) were female and 35 (28.5%) tested positive for HIV; 21 (17.1%) were Xpert-positive, while 51 (42.5%) had CXR suggestive of TB (P = 0.0018), of whom only 15 (29.4%) were Xpert-positive. CXR was suggestive of pulmonary TB in 15 (71.4%) of the 21 patients with a positive Xpert test. CONCLUSIONS: The majority of the sputum smear-negative patients did not have TB on single Xpert testing. CXR gave an overestimate of sputum smear-negative TB cases.

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.

Diagnostic accuracy of ultrasensitive heat-denatured HIV-1 p24 antigen in non-B subtypes in Kampala, Uganda.

We evaluated the accuracy of heat-denatured, amplification-boosted ultrasensitive p24 assay (Up24) compared with reverse transcriptase polymerase chain reaction (RT-PCR). We tested 394 samples from Ugandans infected with HIV-1 non-B subtypes. We compared Up24 levels (HIV-1 p24 Core Profile enzyme-linked immunosorbent assay (ELISA), NEN Life Science Products) to RNA viral loads (Amplicor HIV-1 Monitor 1.5, Roche) by linear regression, and calculated sensitivity, specificity, positive and negative predictive values. Median viral load was 4.9 log10 copies/mL (interquartile range [IQR], 2.6-5.5); 114 samples (29%) were undetectable (<400 copies/mL). Sensitivity of the Up24 assay to detect viral load ≥400 copies/mL was 69%, specificity was 67%, and positive and negative predictive values were 84% and 47%, respectively. Sensitivity of Up24 was 90%, 80%, 68%, 62% and 45% to detect viral loads of >500,000, 250,000-500,000, 100,000-250,000, 50,000-100,000 and 400-50,000 copies/mL, respectively. In conclusion, when compared with RT-PCR for patients infected with non-B subtypes, the Up24 demonstrated limited sensitivity especially at low viral loads. Moreover, the Up24 was positive in 33% of samples deemed undetectable by RT-PCR, which may limit the use of the Up24 to detect viral suppression.

Low frequency of liver enzyme elevation in HIV-infected patients attending a large urban treatment centre in Uganda.

Liver enzyme elevations among patients on antiretroviral therapy (ART) were determined by prospectively evaluating aspartate aminotransferase (AST) data in a cohort of patients in Kampala over 36 months. A proportion of patients had hepatitis B virus (HBV) status determined. Hepatotoxicity was graded I to IV according to the AIDS Clinical Trial Group criteria. Of 546 patients, 377 (69%) were women; overall median baseline CD4+ T-cell was 97/µL (interquartile range [IQR] 20-164). Hepatitis B surface antigen (HBsAg) was detected in 42 (9%) of 470 persons. ART included lamivudine, with either nevirapine and d4T (74%) or efavirenz and AZT (26%). Median (IQR) AST level at baseline was 35 (27, 53 IU/L). Over 36 months, only eight patients had grade III AST elevation. Neither HBsAg nor ART regimen influenced AST levels. Male gender and CD4+ change from baseline were correlated with AST elevation. Patients with HIV/HBV co-infection were not at an increased risk of AST elevation, which occurred uncommonly in this setting.

Tuberculosis and human immunodeficiency virus co-infections and their predictors at a hospital-based HIV/AIDS clinic in Uganda.

SETTING: Mulago Hospital, Uganda. OBJECTIVE: To evaluate the burden of TB-HIV (tuberculosis-human immunodeficiency virus) co-infections and their predictors in an urban hospital-based HIV programme. DESIGN: Prospective observational study. METHODS: Clinicians screened all patients with HIV/AIDS (acquired immune-deficiency syndrome) for previous and current TB treatment at enrolment and throughout follow-up. RESULTS: Of 10,924 patients enrolled between August 2005 and February 2009, co-prevalent TB was 157/10,924 (1.4%), which included 88/157 (56%) with TB confirmed at enrolment and 65/157 (41%) with TB diagnoses established during follow-up in whom symptoms were present at enrolment. Male sex (adjusted odds ratio [aOR] 2.3, 95%CI 1.6-3.2) and body mass index (BMI) ≤ 20 kg/m(2) (aOR 3.8, 95%CI 2.5-5.4) were associated with co-prevalent TB. Overall, 749/10,767 (7%) were diagnosed with incident TB at a higher rate among antiretroviral treatment (ART) patients (8/100 patient years of observation [PYO]) than non-ART patients (5/100 PYO, log rank P < 0.001). Female sex (adjusted hazard ratio [aHR] 1.4, 95%CI 1.2-1.7) and baseline BMI ≤ 20 (aHR 1.9, 95%CI 1.6-2.2) predicted incident TB. CONCLUSION: Routine TB screening in the HIV/AIDS care programme identified a significant number of TB-HIV co-infections among patients with and without ART, and is therefore a potential strategy to improve HIV treatment outcomes in resource-limited settings.

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 (8 hours vs. 20 hours, 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.

The high prevalence of genital herpes among patients with genital ulcer disease in Uganda.

BACKGROUND: Genital ulcer disease is a risk factor for transmission of human immunodeficiency virus. One-hundred consecutive Ugandan patients (median age, 25 years) with genital ulcer disease were examined to determine the prevalence of genital herpes and its relationship to human immunodeficiency virus seropositivity. GOAL OF THIS STUDY: To improve management, prevention, and control of genital ulcer disease, thus reducing human immunodeficiency virus infections attributable to genital ulcer disease. STUDY DESIGN: This was a prevalence study of genital herpes in a consecutive sample of an urban sexually transmitted disease clinic population. RESULTS: Forty-nine percent (48/98) of the patients had genital herpes (36% by direct fluorescent antigen and 13% by history of recurrent vesicles). There was a trend toward larger lesions in patients who were human immunodeficiency virus seropositive. Twelve percent (11/89) of patients had syphilis, and 30% (30/100) remained sexually active, despite the presence of active genital ulcer disease. Sixty-five percent of 89 patients tested had antibodies to human immunodeficiency virus. CONCLUSIONS: Genital herpes is a common cause of genital ulcer disease in patients attending sexually transmitted disease clinics in Uganda, and herpes ulcers may be more extensive among those who are infected with human immunodeficiency virus.

Polymorphisms in the Plasmodium falciparum pfcrt and pfmdr-1 genes and clinical response to chloroquine in Kampala, Uganda.

The molecular mechanism of chloroquine resistance in Plasmodium falciparum remains uncertain. Polymorphisms in the pfcrt and pfmdr-1 genes have been associated with chloroquine resistance in vitro, although field studies are limited. In evaluations of known polymorphisms in parasites from patients with uncomplicated malaria in Kampala, Uganda, the presence of 8 pfcrt mutations and 2 pfmdr-1 mutations did not correlate with clinical response to therapy with chloroquine. Most notably, the pfcrt lysine-->threonine mutation at position 76, which recently correlated fully with chloroquine resistance in vitro, was present in 100% of 114 isolates, of which about half were from patients who recovered clinically after chloroquine therapy. These results suggest that, although key pfcrt polymorphisms may be necessary for the elaboration of resistance to chloroquine in areas with high levels of chloroquine resistance, other factors, such as host immunity, may contribute to clinical outcomes.

Amodiaquine, sulfadoxine/pyrimethamine, and combination therapy for treatment of uncomplicated falciparum malaria in Kampala, Uganda: a randomised trial.

BACKGROUND: Increasing Plasmodium falciparum resistance to chloroquine in sub-Saharan Africa necessitates use of alternative antimalarial agents. Affordable alternative treatments include sulfadoxine/pyrimethamine and amodiaquine. Combination of antimalarial agents can increase therapeutic efficacy and delay emergence of drug resistance. We compared the efficacy of sulfadoxine/pyrimethamine, amodiaquine, and an amodiaquine/sulfadoxine/pyrimethamine combination for treatment of uncomplicated malaria in a region of high chloroquine resistance. METHODS: Patients with symptoms of uncomplicated falciparum malaria and confirmed disease in Kampala, Uganda, were randomly assigned to receive sulfadoxine/pyrimethamine (25 mg/kg sulfadoxine, and 1.25 mg/kg pyrimethamine) plus placebo; amodiaquine (25 mg/kg) plus placebo; or amodiaquine plus sulfadoxine/pyrimethamine. Patients were followed up for 14 days, and clinical and parasitological outcomes were assessed. FINDINGS: 90% (400/445) of patients enrolled in the study successfully completed 14 days of follow-up. Treatment failure based on clinical criteria occurred in 13 of 131 (10%) patients on sulfadoxine/ pyrimethamine, nine of 131 (7%) on amodiaquine, and four of 138 (3%) on amodiaquine/sulfadoxine/pyrimethamine. Based on parasitological criteria, treatment failed in 26%, 16%, and 10% of these patients, respectively. Amodiaquine/sulfadoxine/pyrimethamine was significantly more effective than sulfadoxine/pyrimethamine alone in children aged younger than 5 years (clinical failure in 3.5% vs 13.9%, respectively, risk difference 10.4% [95% CI, 1.6-19.3] p=0.021; parasitological failure in 12.8% vs 26.4%, risk difference 13.6% [1.2-26.0] p=0.041). INTERPRETATION: Sulfadoxine/pyrimethamine, amodiaquine, and amodiaquine/sulfadoxine/pyrimethamine were all effective for treatment of uncomplicated falciparum malaria in Uganda. The amodiaquine/sulfadoxine/pyrimethamine combination was the most effective, and could be the optimum low-cost alternative to chloroquine in Africa.

Increasing antimalarial drug resistance in Uganda and revision of the national drug policy.

Chloroquine (CQ) resistance was first documented in Uganda in 1988. Subsequent surveillance of antimalarial drug resistance, conducted by the Ugandan Ministry of Health and several research organizations, suggests that resistance to CQ is now widespread, reaching critical levels in many areas of the country. In June 2000, the Ministry of Health held a National Consensus Meeting to evaluate the available drug efficacy data and review the national antimalarial drug policy. After extensive debate, the combination of CQ + sulfadoxine-pyrimethamine (SP) was chosen to replace CQ as the first-line treatment of uncomplicated malaria as an interim policy. This review evaluates the in vivo drug efficacy studies conducted in Uganda since 1988 and issues confronted in revision of the drug policy. The Ugandan experience illustrates the challenges faced by sub-Saharan African countries confronted with rising CQ resistance but limited data on potential alternative options. The choice of CQ + SP as a provisional policy in the absence of prerequisite efficacy, safety and cost-effectiveness data reflects the urgency of the malaria treatment problem, and growing pressure to adopt combination therapies. Surveillance of CQ + SP treatment efficacy, collection of additional data on alternative regimens and active consensus building among key partners in the malaria community will be necessary to develop a rational long-term antimalarial treatment policy in Uganda.

A prospective study of community-acquired bloodstream infections among febrile adults admitted to Mulago Hospital in Kampala, Uganda.

Septicemia is a frequent cause of death in HIV-infected adults in developing countries. Additional prospective studies are needed to determine the etiology of bloodstream infections (BSI) in febrile HIV-infected adults and guide initial evaluation and treatment in this setting. We assessed the prevalence and etiology of community-acquired BSI among 299 consecutive febrile adult medical admissions to Mulago Hospital, Kampala, Uganda, over a 4-month period in 1997. The median age of our patients was 30 years, 159 (53%) were male, and 227 (76%) HIV-1-seropositive. Overall, prevalence of bacteremia or fungemia (1 patient) was 24%. Bacteremia was more frequent in HIV-infected than in uninfected patients (27% versus 15%, respectively; p = .04). Mycobacterium tuberculosis (n = 28), Streptococcus pneumoniae (n = 15) and Salmonella species (n = 13) were the most frequent isolates. All Salmonella and mycobacterial isolates were recovered from HIV-infected patients. Pneumococcal bacteremia was not associated with HIV seropositivity. M. avium complex and M. simiae were isolated from two HIV-infected patients. The rate of mycobacteremia among febrile HIV-infected adults presenting for hospitalization was 13%. Bacteremia and disseminated tuberculosis are frequent causes of morbidity in febrile HIV-infected Ugandan adults. Initial empiric antibiotic coverage in this setting should be targeted toward the pneumococcus and gram-negative enteric bacilli, especially nontyphi Salmonella species. All patients presenting with chronic cough should be evaluated for tuberculosis.

PIP: Septicemia often causes death in HIV-infected adults in developing countries. The prevalence and etiology of community-acquired bloodstream infections (BSI) were measured among 299 consecutive febrile adult medical admissions to Mulago Hospital, Kampala, Uganda, during 4 months in 1997. The 299 patients in the final study sample were of median age 30 years, of whom 159 (53%) were male and 227 (76%) were HIV-1-seropositive. The overall prevalence of bacteremia or fungemia was 24%, with 27% of HIV-infected patients and 15% of uninfected patients being bacteremic. 28 people were infected with Mycobacterium tuberculosis, 15 with Streptococcus pneumoniae, and 13 with Salmonella species; these were the most frequent isolates. All Salmonella and mycobacterial isolates were recovered from HIV-infected patients. Pneumococcal bacteremia was not associated with HIV seropositivity. M. avium complex and M. simiae were isolated from 2 patients infected with HIV. 13% of febrile HIV-infected adults who presented for hospitalization were mycobacteremic. These findings suggest that bacteremia and disseminated tuberculosis (TB) are frequent causes of morbidity in febrile HIV-infected Ugandan adults. Initial empiric antibiotic coverage in this setting should target pneumococcus and gram-negative enteric bacilli, while patients presenting with chronic cough should be evaluated for TB.