International neurocognitive normative study: neurocognitive comparison data in diverse resource-limited settings: AIDS Clinical Trials Group A5271.

Infrastructure for conducting neurological research in resource-limited settings (RLS) is limited. The lack of neurological and neuropsychological (NP) assessment and normative data needed for clinical interpretation impedes research and clinical care. Here, we report on ACTG 5271, which provided neurological training of clinical site personnel and collected neurocognitive normative comparison data in diverse settings. At ten sites in seven RLS countries, we provided training for NP assessments. We collected normative comparison data on HIV- participants from Brazil (n = 240), India (n = 480), Malawi (n = 481), Peru (n = 239), South Africa (480), Thailand (n = 240), and Zimbabwe (n = 240). Participants had a negative HIV test within 30 days before standardized NP exams were administered at baseline and 770 at 6 months. Participants were enrolled in eight strata, gender (female and male), education (<10 and ≥10 years), and age (<35 and ≥35 years). Of 2400 enrolled, 770 completed the 6-month follow-up. As expected, significant between-country differences were evident in all the neurocognitive test scores (p < 0.0001). There was variation between the age, gender, and education strata on the neurocognitive tests. Age and education were important variables for all tests; older participants had poorer performance, and those with higher education had better performance. Women had better performance on verbal learning/memory and speed of processing tests, while men performed better on motor tests. This study provides the necessary neurocognitive normative data needed to build infrastructure for future neurological and neurocognitive studies in diverse RLS. These normative data are a much-needed resource for both clinicians and researchers.

Improved neuropsychological and neurological functioning across three antiretroviral regimens in diverse resource-limited settings: AIDS Clinical Trials Group study a5199, the International Neurological Study.

BACKGROUND: AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings. METHODS: Participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe were randomized to 3 antiretroviral treatment arms: A (lamivudine-zidovudine plus efavirenz, n = 289), B (atazanavir, emtricitabine, and didanosine-EC, n = 293), and C (emtricitabine-tenofovir-disoproxil fumarate plus efavirenz, n = 278) as part of the ACTG PEARLS study (A5175). Standardized neurological and neuropsychological (NP) screening examinations (grooved pegboard, timed gait, semantic verbal fluency, and finger tapping) were administered every 24 weeks from February 2006 to May 2010. Associations with neurological and neuropsychological function were estimated from linear and logistic regression models using generalized estimating equations. RESULTS: The median weeks on study was 168 (Q1 = 96, Q3 = 192) for the 860 participants. NP test scores improved (P < .05) with the exception of semantic verbal fluency. No differences in neurological and neuropsychological functioning between treatment regimens were detected (P > .10). Significant country effects were noted on all NP tests and neurological outcomes (P < .01). CONCLUSIONS: The study detected no significant differences in neuropsychological and neurological outcomes between randomized ART regimens. Significant improvement occurred in neurocognitive and neurological functioning over time after initiation of ARTs. The etiology of these improvements is likely multifactorial, reflecting reduced central nervous system HIV infection, better general health, and practice effects. This study suggests that treatment with either of the World Health Organization -recommended first-line antiretroviral regimens in resource-limited settings will improve neuropsychological functioning and reduce neurological dysfunction. CLINICAL TRIALS REGISTRATION: NCT00096824.

Second-line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline.

OBJECTIVES: The Malawi antiretroviral therapy (ART) programme uses the public health approach to identify ART failure. Advanced disease progression may occur before switching to second-line ART. We report outcomes for patients evaluated and initiated on second-line treatment in Malawi. METHODS: Patients meeting Malawi immunological or clinical criteria for ART failure in two large urban ART clinics were evaluated for virological failure (viral load >400 HIV-1 RNA copies/mL) and, if failure was confirmed, initiated on second-line ART (zidovudine/lamivudine/tenofovir/lopinavir/ritonavir). Patients were seen monthly and laboratory evaluations were performed quarterly and as needed. We performed logistic regression modelling to identify factors associated with mortality, mortality or new HIV illnesses, and virological suppression at 12 months. RESULTS: Of the 109 patients with confirmed virological failure, five patients died prior to initiation, three declined switching and 101 patients initiated second-line treatment. Over 12 months, 10 additional patients died, 34 patients experienced 45 HIV-related events, and 19 patients experienced grade 3 or 4 toxicities. Among survivors, 85.2% had HIV-1 RNA<400 copies/mL at 12 months. While power to distinguish differences was limited, response rates were similar regardless of baseline resistance level. The median CD4 count increase was 142 cells/microL. World Health Organization clinical failure at baseline [odds ratio (OR) 3.47; 95% confidence interval (CI) 1.14-10.59] and body mass index <18.5 (OR 4.43; 95% CI 1.15-17.12) were risk factors for death. Baseline CD4 count <50 cells/microL was associated with increased risk for death or morbidity at 12 months (OR 2.57; 95% CI 1.01-6.52). CONCLUSIONS: Second-line treatment in Malawi was associated with substantial mortality, morbidity and toxicity but, among survivors, virological outcomes were favourable.

The effect of TB treatment on health-related quality of life for people with advanced HIV.

BACKGROUND: Study A5274 was an open-label trial of people with HIV (PLHIV) with CD4 cell count <50 cells/µL who were randomized to empirical TB treatment vs. isoniazid preventive therapy (IPT) in addition to antiretroviral therapy (ART). We evaluated health-related quality of life (HRQoL) by study arm, changes over time, and association with sociodemographic and clinical factors.METHODS: Participants aged >13 years were enrolled from outpatient clinics in 10 countries. HRQoL was assessed at Weeks 0, 8, 24 and 96 with questions about daily activity, hospital or emergency room visits, and general health status. We used logistic regression to examine HRQoL by arm and association with sociodemographic and clinical factors.RESULTS: Among 850 participants (424 empiric arm, 426 IPT arm), HRQoL improved over time with no difference between arms. At baseline and Week 24, participants with WHO Stage 3 or 4 events, or those who had Grade 3 or 4 signs/symptoms, were significantly more likely to report poor HRQoL using the composite of four HRQoL measures.CONCLUSION: HRQoL improved substantially in both arms during the study period. These findings show that ART, TB screening, and IPT can not only reduce mortality, but also improve HRQoL in PLHIV with advanced disease.

HIV-1 incidence among women of reproductive age in Malawi.

The aim of this study was to determine HIV-1 incidence among women of reproductive age in Malawi. A prospective study design was followed. HIV-1 uninfected women were followed up for nine visits during a period of 12 months. At baseline, women received HIV-1 counselling and testing. At each visit, venous blood was collected for HIV-1 testing. Incidence rate for HIV-1 was estimated using person-years of follow up (PYFU). Risk factors for HIV acquisition were assessed using Cox proportional hazard models. A total of 842 HIV-1 negative women were enrolled in the study. Of these, 787 had subsequent HIV testing and 31 were found HIV-1 infected; an overall incidence rate of 4.51 (95% confidence interval: 2.96-6.06) per 100 PYFU was obtained. Young age, using hormonal injectable contraceptives and bacterial vaginosis were the main predictors of HIV acquisition. The incidence of HIV continues to be high among women in Malawi, and young women appear to be at higher risk.

Micronutrient supplements and mortality of HIV-infected adults with pulmonary TB: a controlled clinical trial.

SETTING: Zomba and Blantyre, Malawi, Africa. OBJECTIVES: To determine whether daily micronutrient supplementation reduces the mortality of human immunodeficiency virus (HIV) infected adults with pulmonary tuberculosis (TB). DESIGN: A randomised, controlled clinical trial of micronutrient supplementation for HIV-positive and HIV-negative adults with pulmonary TB. Participants were enrolled at the commencement of chemotherapy for sputum smear-positive pulmonary TB and followed up for 24 months. RESULTS: A total of 829 HIV-positive and 573 HIV-negative adults were enrolled. During follow-up, 328 HIV-positive and 17 HIV-negative participants died. The proportion of HIV-positive participants who died in the micronutrient and placebo groups was 38.7% and 40.4%, respectively (P = 0.49). Micronutrient supplementation did not reduce mortality (hazard ratio [HR] 0.93, 95%CI 0.75-1.15) among HIV-positive adults. CONCLUSIONS: Micronutrient supplementation at the doses used in this study does not reduce mortality in HIV-positive adults with pulmonary TB in Malawi.

Differential diagnosis of stroke in a setting of high HIV prevalence in Blantyre, Malawi.

BACKGROUND AND PURPOSE: The differential diagnosis of stroke in Africa in areas with high HIV prevalence includes brain infections. We studied causes of stroke in Blantyre, Malawi, where HIV prevalence among medical inpatients is 70%. METHODS: In a descriptive study of 8-month duration, all patients presenting at Queen Elizabeth Central Hospital, Blantyre, with central neurological deficit of acute onset (<24 hours) had baseline investigations, including full blood count, blood glucose, serology for toxoplasmosis, syphilis, and HIV, ECG, echocardiogram, ultrasound of the carotid arteries, and computerized tomography scan of the brain. A lumbar puncture was performed unless contraindicated. RESULTS: Ninety-eight consecutive patients (49 males) were studied. In those who were HIV positive (48%), the mean age was 37.5 years; ischemic stroke was the commonest diagnosis (n=25; 58%), followed by infection (n=11; 23%; including tuberculous [n=4] and cryptococcal [n=2] meningitis; toxoplasmic encephalitis [n=1]; neurocysticercosis [n=1]; brain abscess [n=1]; and progressive multifocal leucoencephalopathy [n=2]). No clinical or laboratory parameters could be identified as predictors for infection, but 3 of 5 patients with fever on admission had tuberculous meningitis. In HIV-negative patients (mean age 58.6 years), 55% had ischemic stroke and 31% had intracerebral hemorrhage; no brain infection was diagnosed. Presence of vascular disease correlated with age but not with HIV status. CONCLUSIONS: Ischemic stroke was found in half of patients irrespective of HIV status. In those who are HIV positive, brain infection should be considered for which the presence of fever and examination of cerebrospinal fluid seem most useful in diagnosis.

Trials of anti-tuberculosis treatment in areas of high human immunodeficiency virus prevalence in sub-Saharan Africa.

Sub-Saharan Africa is bearing the brunt of the human immunodeficiency virus (HIV) pandemic, and HIV-associated tuberculosis (TB) has become a major clinical and public health problem. There is evidence that HIV-infected patients not uncommonly develop disseminated TB, and that this diagnosis is often not made ante mortem because of limited diagnostic facilities and other factors. Where diagnostic facilities are limited, a trial of anti-tuberculosis treatment with drugs specific for Mycobacterium tuberculosis may be a useful way of diagnosing disseminated TB. The case for and against 'a trial of treatment' is presented, and a suggestion is made that 'a trial of treatment' can be incorporated into the case finding package of a National TB Control Programme.

Malnutrition and the severity of lung disease in adults with pulmonary tuberculosis in Malawi.

SETTING: Zomba Central Hospital, Zomba, Malawi. OBJECTIVE: To examine the relationship between malnutrition and the severity of lung disease in human immunodeficiency virus (HIV) positive and negative adults with pulmonary tuberculosis (PTB). DESIGN: Cross-sectional study. METHODS: Chest radiographs and anthropometric measurements were obtained and bioelectrical impedance analysis was conducted in sputum-positive patients with pulmonary tuberculosis. Lung disease in chest radiographs was graded as normal, minimal, moderately advanced and far advanced according to a conventional classification system. RESULTS: Among 319 adults with PTB with or without HIV co-infection, body mass index (BMI), fat mass and phase angle were independently associated with increasing severity of lung disease. Multiple logistic regression analyses showed that BMI, fat mass and phase angle were associated with increasing severity of lung disease among 236 HIV-positive adults, when adjusted for sex, age, and plasma HIV load. CONCLUSION: The severity of lung disease in adults with PTB is associated with the extent of malnutrition, as reflected by BMI and body composition studies using bioelectrical impedance analysis.

Teaching tuberculosis control to medical undergraduates: the Malawi experience.

SETTING: National Tuberculosis (TB) Control Programme (NTP) and College of Medicine (COM), Malawi. OBJECTIVES: To develop a TB/HIV module, incorporating TB control and the DOTS strategy, for 4th year medical undergraduates. To describe 1) the way in which the module was developed, 2) the contents and structure of the module, 3) the experience of teaching the module from 2000-2002, and d) the financial costs to the NTP. DESIGN: A descriptive study. RESULTS: The TB/HIV module, including the teaching manual, resource materials and undergraduate assessments, was developed between June and December 1999 by NTP, College of Medicine, interested stakeholders and an external consultant. The module was well received by medical undergraduates. Student knowledge, based on pre-module and post-module assessments, increased to satisfactory levels. Novel aspects of teaching, which included reading chapters in class followed by student-led knowledge reviews, modular assessments and using NTP staff as facilitators, were highly rated. The cost of developing the module was 14,070 US dollars, and the recurrent annual cost of teaching the module was 900 US dollars. CONCLUSION: The results show that a national tuberculosis control programme can work effectively with an academic medical institution in teaching medical undergraduates the important principles of country-wide TB control.

Clinical indicators of mycobacteraemia in adults admitted to hospital in Blantyre, Malawi.

SETTING: Adult medical wards of a central hospital in Blantyre, Malawi. OBJECTIVE: To measure the prevalence and outcome of mycobacteraemia in febrile hospitalised adults, and to determine what proportion could be identified using routine methods; to assess clinical indicators of mycobacteraemia, and the usefulness of a diagnostic trial of anti-tuberculosis treatment. DESIGN: We prospectively examined adults admitted with fever or a history of fever. All had blood cultured for bacteria and mycobacteria, chest X-ray and sputum smears. FINDINGS: Mycobacterium tuberculosis was the commonest cause of blood stream infection (BSI), affecting 57 of 344 patients (17%). In 44 (77%) patients with mycobacteraemia, TB was identified using routine investigations; it was not suspected in six (11%). Strong clinical indicators of mycobacteraemia were anaemia, HIV seropositivity, cough, chronic fever and a clinical diagnosis of AIDS on the day of admission. Of nine patients selected for a therapeutic trial of tuberculosis (TB) treatment, six had mycobacteraemia, of whom five died during the trial. Mortality on short-course chemotherapy, on the TB ward after 1 month was similar whether patients had mycobacteremia (21%) or not (32%). CONCLUSION: TB can be identified with routine methods in most patients with mycobacteraemia. If treated, mycobacteraemia has as good an early outcome as TB without mycobacteraemia. Strengthening of basic facilities is likely to improve detection and treatment of mycobacterial disease.

Retinal findings in Malawian patients with AIDS.

The purpose of this study was to determine the prevalence of retinal disease in a group of patients with AIDS in Malawi. Indirect ophthalmoscopy was performed on 99 patients with AIDS who were admitted consecutively to a medical ward at a central hospital. Necrotising retinitis was present in one eye of one patient examined. Non-infectious retinopathy was present in 13%. Retinitis is less common in AIDS patients from Africa compared with those from developed countries; it is believed that most patients die before acquiring it. Non-infectious retinopathy may also be less common.

PIP: Retinal diseases and destructive eye pathology have been recognized in patients with HIV infections and acquired immunodeficiency syndrome (AIDS). Opportunistic viral agents such as herpes simplex virus, cytomegalovirus, and varicella zoster virus have also been described in severe cases of retinitis. Most of these studies have been carried out in developed countries. This article reports the findings of a Malawian study in which 99 AIDS patients (63 men and 36 women) were examined for retinal pathology. A diagnosis of AIDS required a positive enzyme-linked immunosorbent assay (ELISA). 58 patients (58.6%) had pulmonary tuberculosis (TB) and 10 others (10.1%) had extrapulmonary TB. Indirect ophthalmoscopy was performed on all patients. 73 patients (73.7%) had normal eye examinations; 1 patient (1.0%) was found to have necrotizing retinitis; only 13 patients (13.1%) showed noninfectious retinopathy. These studies suggest that retinitis is less common in sub-Saharan Africa than in developed countries. Tuberculosis was the most common opportunistic infection found in this study.

Ocular disease in patients with tuberculosis and HIV presenting with fever in Africa.

AIMS: To investigate ocular disease in patients with tuberculosis (TB) and HIV in Africa presenting with fever, and to determine if indirect ophthalmoscopy is useful in the diagnosis of mycobacteraemia. METHODS: A prospective study of all adult patients admitted with fever to a large central hospital in Malawi, Africa. All recruited patients had an ophthalmic examination, HIV tests, chest x ray, sputum examinations, bacterial and mycobacterial blood cultures, and malaria slide to observe the presence of parasites. RESULTS: 307 patients were recruited; 109 (36%) had TB, including 53 (17%) with mycobacteraemia; 255 (83%) had HIV and 191 (62%) had AIDS. Of the patients with TB 102 (94%) had HIV. Choroidal granulomas were found in four patients, all of whom had AIDS; three (2.8% of those with TB) had disseminated TB with mycobacteraemia, and one had persistent fever but no other evidence of TB. Among the patients with AIDS, 32 (17%) had microangiopathy manifest by cotton wool spots; one (0.5%) had signs of active cytomegalovirus (CMV) retinitis. The presence of microangiopathy was not related to TB. CONCLUSIONS: In Malawian patients with TB presenting acutely with fever, choroidal granulomas were found in 2.8%, and were concurrent with mycobacteraemia and AIDS. Ophthalmoscopy was not a useful aid in the diagnosis of mycobacteraemia. Cytomegalovirus (CMV) retinitis is rarely seen in African AIDS patients. This may be the result of mortality early in the disease course, or differences in race, HIV subtype, or comorbidity.

Use and costs of antimicrobial drugs in medical wards of a central hospital in Malawi.

Economic constraints experienced by many African countries make it vital that reliable information is collected about the cost of patient care in health institutions. Case files and treatment charts of 509 patients admitted to non-fee paying medical wards of Queen Elizabeth Central Hospital, Blantyre, Malawi for the month of September 1992 were analysed in order to determine the amount and costs of drugs and antimicrobial agents given to inpatients. Infectious diseases accounted for 76% of all admissions. A total of 59 different drug items were used (cost U.S. $732). In all, 18 antimicrobial agents were given (31% of all drug items) at a cost of U.S. $615 (84% of all drug costs). Calculated costs of antimicrobial agents for each patient and for annual admissions (10325 in 1992) were U.S. $1.21 and U.S. $12,558 respectively. Although the present study has its limitations, it provides a rational basis for planning departmental drug budgets.

Coverage of highly active antiretroviral therapy among postpartum women in Malawi.

The expanding services of antiretroviral treatment (ART) in sub-Saharan Africa provide unique opportunities to reduce HIV/AIDS-related morbidity and mortality. In these settings, HIV prevalence among antenatal women remains high and treating eligible pregnant or breastfeeding women with antiretrovirals can substantially reduce transmission of HIV from the mother to her infant. However, identification of women eligible for treatment and ensuring access to ART services is challenging. In this analysis, we used data from a large clinical trial (the PEPI-Malawi study, 2004-09) to prevent mother-to-child transmission of HIV through extended antiretroviral prophylaxis of infants to examine barriers for wider coverage with highly active antiretroviral treatment (HAART) of postpartum women. Maternal HAART was not part of the original PEPI-Malawi clinical trial but became available through a government programme during the course of the study. Therefore, eligible women (CD4 cell count <250) who participated in the PEPI-Malawi trial were counselled and referred to the government ART clinics to initiate HAART. Of 3335 women who enrolled in the PEPI-Malawi study, 803 (24%) were eligible for HAART based on CD4 cell count. The proportion of women newly initiating HAART at the ART clinic remained low and constant (<20%) throughout the study period. However, the cumulative proportion of women receiving HAART increased substantially over time (29% in 2005 to 69% in 2009). Similarly, counselling and referral of eligible women substantially increased and became 100% during the last two years. There were no statistically significant differences in characteristics of eligible women who received or did not receive HAART postpartum. Despite limitations of not being able to obtain detailed data, the main barriers appeared to be related to the health-care system delivery of ART services. Issues of physical space, more personnel and better delivery need to be addressed to increase access to HAART in these settings.