High rate of left ventricular hypertrophy on screening echocardiography among adults living with HIV in Malawi.

BACKGROUND: There are limited data on structural heart disease among people living with HIV in southern Africa, where the success of antiretroviral therapy (ART) has drastically improved life expectancy and where risk factors for cardiovascular disease are prevalent. METHODS: We performed a cross-sectional study of screening echocardiography among adults (≥18 years) with HIV in Malawi presenting for routine ART care. We used univariable and multivariable logistic regression to evaluate correlates of abnormal echocardiogram. RESULTS: A total of 202 individuals were enrolled with a median age of 45 years (IQR 39-52); 52% were female, and 27.7% were on antihypertensive medication. The most common clinically significant abnormality was left ventricular hypertrophy (LVH) (12.9%, n=26), and other serious structural heart lesions were rare (<2% with ejection fraction less than 40%, moderate-severe valve lesions or moderate-severe pericardial effusion). Characteristics associated with abnormal echocardiogram included older age (OR 1.04, 95% CI 1.01 to 1.08), higher body mass index (OR 1.09, 95% CI 1.02 to 1.17), higher mean systolic blood pressure (OR 1.03, 95% CI 1.02 to 1.05) and higher mean diastolic blood pressure (OR 1.03, 95% CI 1.01 to 1.05). In a multivariable model including age, duration on ART, body mass index, and systolic and diastolic blood pressure, only mean body mass index (adjusted OR 1.10, 95% CI 1.02 to 1.19), systolic blood pressure (aOR 1.05, 95% CI 1.03 to 1.08) and diastolic blood pressure (aOR 0.96, 95% CI 0.92 to 1.00) remained associated with abnormal echocardiogram. CONCLUSIONS: LVH was common in this population of adults on ART presenting for routine care and was associated with elevated blood pressure. Further research is needed to characterise the relationship between chronic hypertension, LVH and downstream consequences, such as diastolic dysfunction and heart failure in people living with HIV.

Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi.

BACKGROUND: Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. METHODS: From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. RESULTS: Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4(+) cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity +/- standard deviation -0.28 +/- 0.17 log colony-forming units [CFU]/mL per day vs -0.11 +/- 0.09 log CFU/mL per day; P < .001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events. CONCLUSIONS: The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351.

Lessons learned from a paying antiretroviral therapy service in the public health sector at Kamuzu Central Hospital, Malawi: 1-year experience.

BACKGROUND: In October 2001, a paying antiretroviral therapy service was introduced at a Central Hospital in Malawi using stavudine 40 mg/lamivudine 150 mg/nevirapine 200 mg (triomune). The objective of this study was to determine characteristics of patients seeking antiretroviral therapy, retention in care, clinical outcomes, and outlines for program improvement. METHODS: Retrospectively, all patients seeking anti-retroviral therapy initiation (October 2001 to October 2002; follow-up through April 2003) were evaluated for laboratory results, retention in care, toxicity, and mortality. Hazard ratios for factors associated with dropout were determined. RESULTS: Of 757 patients seeking evaluation, 625 began treatment. Documented mortality rate was 61 of 757. Total dropout rate was 50%. Factors associated with dropout include CD4 count <50 cells/mm(3) and Kaposi's sarcoma. Twenty-seven of 625 patients discontinued therapy for toxicity. CONCLUSIONS: The paying antiretroviral therapy program showed an unacceptable dropout rate associated with advanced baseline disease. Severe toxicity rate was low. Areas for improved program performance include lower cost, wide and earlier access to antiretroviral therapy, and targeted retention strategies.

CD4 Variability in Malawi: Implications for Use of a CD4 Threshold of 500 Cells/mm3 Versus Universal Eligibility for Antiretroviral Therapy.

Background. Given the uncertainty about the ability of a single CD4 count to accurately classify a patient as antiretroviral therapy (ART) eligible, we sought to understand the extent to which CD4 variability results in misclassification at a CD4 threshold of 500 cells/mm3. Methods. We performed a prospective study of CD4 variability in Malawian human immunodeficiency virus-infected, ART-naive, World Health Organization (WHO) stage 1 or 2, nonpregnant adults. CD4 counts were performed daily for 8 days. We fit a Bayesian linear mixed-effects model of log-transformed CD4 cell counts to the data. We used Monte Carlo approximations to estimate misclassification rates for different observed values of CD4. The misclassification rate was calculated based on the conditional probability of true CD4 given the geometric mean of observed CD4 measurements. Results. Fifty patients were enrolled from 2 sites. The median age was 33.5 years (interquartile range, 27.5-40.0) and 34 (68%) were female. Misclassification rates were <1% when the observed CD4 counts were ≤250 or ≥750 cells/mm3. Rates of misclassification were high at observed CD4 counts between 350 and 650 cells/mm3, particularly when a single measurement was used (up to 46.7%). Conclusions. Our data show that ART eligibility based on a single CD4 count results in highest risk of misclassification when observed CD4 counts are in the range of 350-650 cells/mm3. Given the benefits of early ART, countries should weigh the costs and complexity of CD4 testing using a 500 cell/mm3 threshold against the cost savings and public health benefits of universal eligibility.

Feasibility and Acceptability of Cryptococcal Antigen Screening and Prevalence of Cryptocococcemia in Patients Attending a Resource-Limited HIV/AIDS Clinic in Malawi.

BACKGROUND: The World Health Organization (WHO) recommends screening patients living with AIDS to detect and treat early cryptococcal infection. METHODS: The authors evaluated a cryptococcal antigen (CrAg) screening and treatment program at an HIV/AIDS clinic in Malawi. Eligible patients were of age >18 years, had a CD4 count <100 cells/µL or WHO clinical HIV/AIDS stage III or IV. RESULTS: Of 552 patients who presented for care, 113 were eligible, and all (100%) agreed to CrAg screening. Of them, 2 (1.8%; 95% confidence interval [CI]: 0-4.2%) patients were CrAg positive. Among those with CD4 count <100 cells/µL or WHO stage IV, the CrAg prevalence was 3.5% (95% CI: 0-8.4%) and 5.0% (95% CI: 0-15%), respectively. CONCLUSION: A CrAg screening program was acceptable to new patients in a Malawian HIV/AIDS clinic. The CrAg prevalence for patients with CD4 count < 100 cells/µL and WHO stage IV was consistent with cost-effectiveness estimates. CrAg screening and treatment programs for patients living with AIDS should be expanded.

Viral profiling identifies multiple subtypes of Kaposi's sarcoma.

UNLABELLED: Kaposi's sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral therapy (ART). Seventy patients were enrolled. Eighty-one percent had T1 (advanced) KS. Median CD4 and HIV RNA levels were 181 cells/mm(3) and 138,641 copies/ml, respectively. We had complete information and suitable plasma and biopsy samples for 66 patients. For 59/66 (89%) patients, a detectable KSHV load was found in plasma (median, 2,291 copies/ml; interquartile range [IQR], 741 to 5,623). We utilized a novel KSHV real-time quantitative PCR (qPCR) array with multiple primers per open reading frame to examine KSHV transcription. Seventeen samples exhibited only minimal levels of KSHV mRNAs, presumably due to the limited number of infected cells. For all other biopsy samples, the viral latency locus (LANA, vCyc, vFLIP, kaposin, and microRNAs [miRNAs]) was transcribed abundantly, as was K15 mRNA. We could identify two subtypes of treatment-naive KS: lesions that transcribed viral RNAs across the length of the viral genome and lesions that displayed only limited transcription restricted to the latency locus. This finding demonstrates for the first time the existence of multiple subtypes of KS lesions in HIV- and KS-treatment naive patients. IMPORTANCE: KS is the leading cancer in people infected with HIV worldwide and is causally linked to KSHV infection. Using viral transcription profiling, we have demonstrated the existence of multiple subtypes of KS lesions for the first time in HIV- and KS-treatment-naive patients. A substantial number of lesions transcribe mRNAs which encode the viral kinases and hence could be targeted by the antiviral drugs ganciclovir or AZT in addition to chemotherapy.

Tuberculosis drug resistance and outcomes among tuberculosis inpatients in Lilongwe, Malawi.

UNLABELLED: SETTING/OBJECTIVE: We evaluated clinical characteristics, yield of solid vs. liquid culture, polymerase chain reaction (PCR)-based drug-resistance profiles, and clinical outcomes of tuberculosis (TB) inpatients in Lilongwe, Malawi. DESIGN: We enrolled adult patients admitted to the Bwaila TB Ward from Jan-Aug/2010. Evaluations included questionnaires, clinical exam, chest radiograph, HIV status, CD4 lymphocyte count, plasma HIVRNA and sputum analysis including Auramine-O stain, Lowenstein-Jensen (LJ) and Mycobacterial Growth Indicator Tube (MGIT) culture, and susceptibility testing using the HAIN GenoType® MTBDRplus. RESULTS: Eighty-eight patients were enrolled (88% re-treatment, 42% smear positive, 93% pulmonary TB, 74% HIV co-infected). At baseline, 44/88 (50%) MGIT and 28 (32%) LJ cultures were positive with a mean time to positivity of 12.1 (Range 1-42) and 21.5 (Range 7-58) days, respectively. Four percent (3/77) of retreatment patients or 8% of the 38 MGIT+ PCR-confirmed retreatment cases had multi-drug resistant tuberculosis (MDR TB). One MDR TB patient was smear negative and only one MDR patient was identified with LJ. Lower mean hemoglobin at admission was associated with mortality (10.5 vs. 7.5; p<0.01; CI 101 9.8-11.0). CONCLUSIONS: The MDR TB burden among the retreatment population in Lilongwe, Malawi is similar to regional estimates by the WHO (7.7% 95% CI 0-18.1). MDR TB patients are not routinely identified with sputum smear or LJ, suggesting more efficient technology should be adopted.

A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis in Africa is associated with up to 70% mortality at 3 months and 500 000 deaths annually. We examined strategies to improve on fluconazole (FLU) monotherapy: addition of flucytosine (5-FC) and/or addition of short-course amphotericin B (AmB). METHODS: In step 1, previously reported, patients were randomized to receive FLU 1200 mg per day with or without 5-FC 100 mg/kg per day for 14 days. In step 2, 43 patients were similarly randomized, with addition of AmB 1 mg/kg per day for 7 days to both arms. After 2 weeks, patients received FLU monotherapy and were followed to 10 weeks. The primary endpoint was rate of clearance of infection (early fungicidal activity, EFA). Secondary endpoints related to safety and mortality. RESULTS: Forty patients (25% with Glasgow Coma Scale <15) were analyzed. EFA for the triple combination arm was greater than that for AmB-FLU: -0.50 ±â€Š0.15 log CFU/day vs. -0.38 ±â€Š0.19 log colony forming units per day (P=0.03); and greater than that for step 1 with FLU-5-FC (-0.28 ±â€Š0.17) or FLU alone (-0.11 ±â€Š0.09). Combined analysis across steps revealed that addition of 5-FC and AmB had significant, independent additive effects on EFA, with trends toward fewer early deaths with addition of 5-FC (4/41 vs. 11/39, P = 0.05) and fewer deaths overall with addition of AmB (13/39 vs. 20/40, P = 0.1). CONCLUSION: Addition of 5-FC and short-course AmB to high-dose FLU significantly enhanced EFA and may be associated with favorable trends in survival. Both these strategies should be tested in a larger phase III study.

Chronic symptomatic hypocalcaemia - difficulties in diagnosis and treatment in rural Africa.

We describe a case of an African woman who had been misdiagnosed with peripheral neuropathy secondary to antiretroviral therapy. After clinical examination and laboratory investigation, an alternative diagnosis was made - chronic symptomatic hypocalcaemia secondary to hypoparathyroidism as a consequence of thyroid surgery approximately 30 years previously. We discuss the challenges faced by patients in areas with limited resources for the diagnosis and/or treatment of metabolic conditions such as this.