Effect of HIV infection on plasma exposure to first-line TB drugs and target attainment in children.

BACKGROUND: Whether HIV infection adversely affects exposure to first-line TB drugs in children is debatable. It is also not known whether HIV infection increases the risk of plasma underexposure or overexposure to TB drugs. This study sought to address these questions.DESIGN/METHODS: Children on TB treatment were enrolled. After 4 weeks on therapy, blood samples were collected at pre-dose, 1, 2, 4, 8, and 12 h post-dose for pharmacokinetic analysis. Plasma drug exposure below and above the lower and upper bounds of the 95% confidence intervals of the reference mean for children were considered underexposure and overexposure, respectively. The effect of HIV infection on drugs exposure and risk of underexposure were examined using multivariate analysis.RESULTS: Of 86 participants (median age: 4.9 years), 45 had HIV coinfection. HIV coinfection was associated with lower pyrazinamide (PZA) and ethambutol exposures in adjusted analysis. Patients with TB-HIV coinfection were three times more likely to have PZA underexposure than those with TB only. Underexposure of rifampin was common irrespective of HIV coinfection status.CONCLUSIONS: HIV coinfection was associated with a higher risk for PZA underexposure in children. This effect should be accounted for in models and simulations to determine optimal PZA dose for children.

Adequacy of WHO weight-band dosing and fixed-dose combinations for the treatment of TB in children.

BACKGROUND: We examined whether the updated WHO weight-band dosing recommendations and fixed-dose combination tablets for the treatment of TB in children achieves recommended calculated dosages and adequate drug plasma exposure.DESIGN/METHODS: Children on first-line TB treatment per WHO guidelines were enrolled. Blood sampling at pre-dose, 1, 2, 4, 8, and 12 h post-dose after at least 4 weeks of treatment was performed. Drugs concentrations were measured using validated liquid chromatography tandem with mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Plasma drug exposure below the lower limit of the 95% confidence interval of the mean for children was considered low and above the upper limit was high.RESULTS: Of 71 participants, 34 (47.9%) had HIV coinfection. The median calculated dose for isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) was 10.0 (range 4.3-13.3), 15.0 (range 8.6-20.0), 30.0 (range 21.0-40.0), and 20.4 (range 14.3-26.7) mg/kg, respectively. Overall, most patients had under-exposure for RIF and PZA and over-exposure for INH and EMB. Drug dose and weight-for-age Z-score were associated with area under the curve from time 0-24 h for all drugs.CONCLUSIONS: Despite adherence to WHO dosing guidelines, low PZA and RIF plasma exposures were frequent in our study population. Higher than currently recommended dosages of RIF and PZA may be needed in children.

Effect of malnutrition on the pharmacokinetics of anti-TB drugs in Ghanaian children.

BACKGROUND: Anti-TB drugs dosing based on weight alone may contribute to suboptimal drug concentrations and poor treatment outcomes in malnourished children. We examined the effect of malnutrition on the pharmacokinetics (PK) of first-line anti-TB drugs in children.METHODS: Drug concentrations were measured in Ghanaian children during the intensive phase of TB treatment. Weight-for-age (WFA), height-for-age (HFA), weight-for-height (WFH) and body mass index-for-age (BFA) were calculated and children with Z-scores < -2 SD (standard deviations) were considered as having malnutrition. PK differences of anti-TB drugs were compared by nutritional status.RESULTS: Of 100 participants, 24/48 (50.0%) of those younger than 5 years had wasting, 58/86 (67.4%) were underweight, and 56/99 (56.6%) had stunting; 22/51 (43.1%) children aged ≥5 years had low BFA. Children with stunting were more likely than controls to have lower mean peak concentration (Cmax) and area under the curve (AUC0-8h) of rifampin (RIF) and pyrazinamide (PZA), as well as a higher frequency of Cmax below the normal range. Wasting and underweight were associated with lower mean ethambutol (EMB) Cmax and AUC0-8h.CONCLUSIONS: The current WHO-recommended dosages were associated with lower plasma exposure of RIF, PZA and EMB in children with stunting, wasting and underweight. Anti-TB drugs dosing models for children may need to include height.

The Role of Nutritional Status on Follow-up among HIV-infected Children at a Teaching Hospital Clinic in Ghana.

BACKGROUND: Malnutrition and HIV infection in children interact adversely and may have a combined effect on clinical outcomes, including response to antiretroviral treatment (ART). Evidence of the role of malnutrition at the point of registration at HIV clinics is limited. This study sought to determine the role of nutritional status and other clinical factors on loss to follow-up (LTFU) among children at Komfo Anokye Teaching Hospital Pediatric HIV clinic in Kumasi, Ghana. STUDY DESIGN: A total of 324 HIV-positive children aged 1.5 to 10 years old who were registered at the clinic from January 1, 2007 to June 30, 2011 were included in this retrospective study. Weight-for-age z-score (WAZ) was used to classify nutritional status. Characteristics of children who were LTFU and those who remained in care were compared using bivariate analysis and logistic regression. RESULTS: At registration, 116 (35.8%) children were severely underweight (WAZ < -3) and 72 (22.2%) were underweight (WAZ < -2). A total of 163 (50.3%) children were LTFU during the course of one year. Malnourished children compared to normal weight children (WAZ > -2) were more likely to be LTFU (P = 0.003). Initiation of antiretroviral therapy was associated with a lower risk of LTFU. In the multivariate analysis, hospital admission (OR 4.38; 95% CI 2.30, 8.34) and initiation of ART (OR 0.33; CI 0.19, 0.56) were independently associated with LTFU. CONCLUSION: Malnutrition was common among Ghanaian HIV-infected children and appeared to be associated with a higher risk of hospitalization and LTFU. Irrespective of nutritional status, the initiation of ART was associated with better retention in care.

Treatment default among patients initiating HAART at the Korle-Bu Teaching Hospital in Accra, Ghana.

BACKGROUND: Loss-to-follow-up (LTFU) during highly active antiretroviral therapy (HAART) may lead to treatment failure and increased mortality among HIV-infected patients. We investigated LTFU rate among HIV-infected patients at Korle-Bu Teaching Hospital (KBTH), and sought to identify sub-groups at-risk for treatment default in order to improve outcomes among high-risk patients. STUDY DESIGN: We conducted a cross-sectional retrospective chart review of 290 HIV-infected patients who initiated HAART at KBTH between January 1, 2008, and June 31, 2008. Patients were classified as LTFU if they did not return for regularly scheduled care within the study period. Chi-square and t-tests were used to compare demographic and clinical characteristics of patients continuing treatment and those who defaulted. RESULTS: Of the 290 patients who initiated HAART, 41 (14%) defaulted, and 7 (2%) died during the 18-month study period. The mean age was 38.7 ± 9.4 years and 184 (64%) were female. The mean baseline CD4 cell count was 183 ± 144 cells/µl. Age, gender, educational level, marital status, presence of opportunistic infection, body mass index, baseline CD4 cell count, WHO disease stage 3 or 4, HAART initiation while pregnant, incidence of poor adherence, and time to initiating HAART after clinic enrollment were not associated with treatment default (P> 0.05). CONCLUSION: A majority of patients initiating HAART in an urban Ghanaian clinic remained in care through one-year of follow-up. Patients who defaulted therapy were indistinguishable demographically and clinically from those who remained in care. Standardized pre-treatment adherence counseling sessions may have influenced the favorable outcomes.

Outcome of hospital admissions in HIV-infected children at the Korle Bu Teaching Hospital, Accra, Ghana.

BACKGROUND: The burden of paediatric HIV infection remains high in resource-poor settings. Information on morbidity leading to hospitalisation as well as outcome is limited. OBJECTIVE: The objective of this study was to determine the reasons for hospital admissions of HIV-infected paediatric patients to a tertiary teaching hospital and the outcome of these admissions. METHODS: Retrospective chart review of inpatient records of all HIV-infected children aged 0 to 13 years admitted to the paediatric unit at Korle-Bu Teaching Hospital from 30 June 2007 to 30 June 2008 was performed. Abstracted data included age, gender, weight, presenting conditions, diagnosis, duration of hospitalisation, antiretroviral treatment, and outcome. RESULTS: A total of 102 admissions occurred among 76 children. The mean age of the children was 4.5 ± 3.79 years and 42 (55%) were males. HIV diagnosis was made during hospitalisation in 23 (30%) of the 76 patients. Overall, 55 (64%) of the 76 patients had a weight for age less than second percentile and 67% were not on antiretroviral therapy at time of admission. Of the 102 admissions, the predominant diagnosis included pneumonia (40%), gastroenteritis (24%), pulmonary tuberculosis (22%), and/or malaria (19%). Death occurred in 12 of the 102 admissions. Age, gender, and admitting diagnosis were not associated with death. CONCLUSIONS: Failure to thrive and common prevalent infections were the predominant reasons for hospitalisation for paediatric HIV/AIDS patients in Accra. Hospitalisations with these conditions should prompt early HIV testing. Efforts should be intensified to prevent maternal to child transmission of HIV infection.

High Frequency of First-Line Anti-Tuberculosis Drug Resistance among Persons with Chronic Pulmonary Tuberculosis at a Teaching Hospital Chest Clinic.

INTRODUCTION: The burden of MDR-TB is unknown in areas that do not have drug susceptibility testing (DST), but its frequency is expected to be higher in previously treated cases. Where DST is not available the WHO recommended standardized retreatment (Category II) regimen is given to previously treated TB patients OBJECTIVE: To evaluate the frequency and pattern of drug resistance of Mycobacterium tuberculosis isolated from patients with chronic smear positive pulmonary tuberculosis. METHOD: We conducted a retrospective review of mycobacterial cultures and drug susceptibility testing (DST) performed on sputum samples collected, between January 2005 and September 2006, from 40 patients with pulmonary TB who had failed at least one standard retreatment regimen. Clinical data was extracted from patients' case notes. RESULTS: M. tuberculosis was recovered from 28 (70%) of the 40 patients. Of the 28 culture positive cases, 10 (36%) had resistance to at least rifampicin and isoniazid (multi-drug resistant TB), 22 (79%) isolates had resistance to streptomycin and 13 (46%) to ethambutol. Of the patients with a positive culture, only one (3.6%) had a fully susceptible organism. Of the 10 patients with MDR TB, 7 had received two or more retreatment courses. CONCLUSION: The frequency of drug resistant TB was high among patients who failed at least one course of category II therapy. Effective combination regimens based on DST is necessary in patients who remain smear positive on the standardized retreatment regimen.

Highly active antiretroviral therapy and employment status in accra, ghana.

OBJECTIVES: This study investigated the immunologic responses and employment history of highly-active antiretroviral therapy (HAART) patients. DESIGN: We interviewed patients and reviewed medical records to collect demographic, clinical, and employment history while on HAART. Demographic characteristics were tested as predictors of immunological response while on HAART using hierarchical linear models. SETTING: Fevers Unit, Korle-Bu Teaching Hospital, Accra, Ghana PARTICIPANTS: Subjects comprised a convenience sample of adult HAART patients receiving therapy for at least 9 months. 270 patients were interviewed. 38 were excluded due to inadequate time on HAART or inability to locate all necessary patient information. INTERVENTION: This was an observational study. MAIN OUTCOME MEASURES: We investigated the change in CD4 cell count and weight since the initiation of therapy, and their ability to maintain or regain employment as well as the reasons for this. RESULTS: The estimated mean ± standard error increase in CD4 cell count from baseline at 6, 12, and 18 months were 102 ± 5, 204 ± 11, and 236 ± 10 cells/µL, respectively. Overall, 147 patients (63.4%) reported remaining employed or obtaining new employment while on HAART. Patients who were asymptomatic at initial presentation were more likely to remain employed or returned to work while on HAART than those who were symptomatic (66.4% vs. 48.8%, P = 0.009). Most patients were employed in the informal sector, which made their economic situation particularly vulnerable to HIV-associated illness. CONCLUSION: The findings suggest that patients receiving HAART experience good clinical and immunological responses as well as improvement in employment status.

Manifestations and outcome of extra-pulmonary tuberculosis: impact of human immunodeficiency virus co-infection.

SETTING: Metropolitan New Orleans. OBJECTIVE: To determine the impact of human immunodeficiency virus (HIV) co-infection on the manifestations and outcome of extra-pulmonary tuberculosis (EPTB). DESIGN: Retrospective analysis of 136 patients diagnosed with EPTB between 1 January 1993 to 31 December 2001. Characteristics of EPTB were compared by HIV serostatus. RESULTS: Of those tested for HIV (n = 87), 42.5% were seropositive. Except for a higher frequency of disseminated TB among co-infected persons, the manifestations, laboratory diagnostic yield and outcome of EPTB were similar between HIV-infected and non-infected persons. The overall fatality rate was 20%; HIV-infected patients had a three-fold higher mortality compared to non-infected persons. In multivariate logistic regression analysis, factors associated with death were: HIV-seropositive (adjusted odds ratio [aOR] 5.2, 95% CI 1.1-24.65) compared to HIV-seronegative, disseminated and meningeal compared to lymphatic disease (aOR 16.87, 95% CI 12.31-123.34), and lack of TB treatment compared to receipt of TB treatment (aOR 29.23, 95% CI 14.47-191.23). CONCLUSION: Manifestations of EPTB were non-specific and did not differ between HIV-infected and non-infected persons. Severe disease, lack of TB treatment and HIV co-infection were associated withdeath. Approaches are needed to reduce EPTB morbidity and mortality, especially among HIV-infected persons.

Highly active antiretroviral therapy (HAART) in adults with tuberculosis: current status.

The overlapping epidemiology of human immunodeficiency virus (HIV) infection and tuberculosis (TB) and the catastrophic consequences of the interactions between the two epidemics have led to increased morbidity and mortality due to HIV-associated TB. While effective therapy is available for both conditions, there are major challenges in the concurrent treatment of HIV and TB co-infection. This review examines the interactions between HIV and TB infections and reviews the current status of highly active antiretroviral therapy (HAART) in patients with co-infection. Specific questions relating to optimal timing of concurrent HAART, challenges to concurrent HAART, optimal regimens and future considerations are discussed.

Respiratory illness after severe respiratory syncytial virus disease in infancy in The Gambia.

OBJECTIVE: To determine the frequency of later respiratory tract morbidity after respiratory syncytial virus (RSV) disease in infancy. DESIGN: Cohort study with passive, clinic-based surveillance. SETTING: Outpatient department in The Gambia. SUBJECTS: One hundred five children admitted to the hospital with severe RSV disease (case cohort), 105 control children matched for age not admitted to the hospital during the previous RSV season (control cohort 1), and 102 control children born after the RSV season (control cohort 2). MAIN OUTCOME MEASURES: Frequencies of pneumonia, wheezing, and hospital admission with acute lower respiratory tract infection. RESULTS: Pneumonia was more common in case children than in both control groups (adjusted incidence rate ratio [IRR, 95% CI]: 3.80 [2.73, 6. 10]), as was wheezing (IRR 7.33 [3.10,17.54]), pneumonia or wheezing (IRR 3.96 [2.60, 6.04]), and admission with pneumonia or wheezing (IRR 3.40 [1.87, 6.15]). The incidence rate per 100 child-years for pneumonia in the dry season for 12-month-old children was 27 for case patients, 8.1 for control cohort 1, and 6.51 for control cohort 2. By 3 years of age, the rates had fallen to low levels in all groups. CONCLUSIONS: Pneumonia and wheezing are significantly more common in children after RSV-associated lower respiratory tract disease than in control subjects, but the incidence declines rapidly with increasing age.

Meningitis caused by a serogroup W135 clone of the ET-37 complex of Neisseria meningitidis in West Africa.

Meningococci belonging to serogroup W135 caused several cases of meningococcal meningitis in The Gambia in 1995 and were isolated during a serogroup A epidemic in Mali in 1994. The eight isolates tested belonged to the same clone of the ET-37 complex and differed in several bands from the pulsed-field gel electrophoresis restriction pattern of serogroup C meningococci of the ET-37 complex isolated in Mali. Three of 6 patients infected in The Gambia died, indicating that this W135 clone is virulent. Vaccines that protect only against infections with meningococci belonging to serogroups A and C are usually used to control outbreaks in Africa, although vaccines containing the W135 polysaccharide are available. The findings of this study indicate that outbreaks of meningococcal meningitis in Africa can be associated with serogroup W135 infections and that serogrouping is essential before vaccination campaigns are started.