Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS:We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38­52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63­87), increasing to 89% (80­94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05­3·08) but not after 30 days (1·25, 0·84­2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16­8·84). INTERPRETATION:In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84). INTERPRETATION: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. FUNDING: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.

Priorities, Barriers, and Facilitators towards International Guidelines for the Delivery of Supportive Clinical Care during an Ebola Outbreak: A Cross-Sectional Survey.

During the Ebola outbreak, mortality reduction was attributed to multiple improvements in supportive care delivered in Ebola treatment units (ETUs). We aimed to identify high-priority supportive care measures, as well as perceived barriers and facilitators to their implementation, for patients with Ebola Virus Disease (EVD). We conducted a cross-sectional survey of key stakeholders involved in the response to the 2014⁻2016 West African EVD outbreak. Out of 57 email invitations, 44 responses were received, and 29 respondents completed the survey. The respondents listed insufficient numbers of health workers (23/29, 79%), improper tools for the documentation of clinical data (n = 22/28, 79%), insufficient material resources (n = 22/29, 76%), and unadapted personal protective equipment (n = 20/28, 71%) as the main barriers to the provision of supportive care in ETUs. Facilitators to the provision of supportive care included team camaraderie (n in agreement = 25/28, 89%), ability to speak the local language (22/28, 79%), and having treatment protocols in place (22/28, 79%). This survey highlights a consensus across various stakeholders involved in the response to the 2014⁻2016 EVD outbreak on a limited number of high-priority supportive care interventions for clinical practice guidelines. Identified barriers and facilitators further inform the application of guidelines.

Predictive value of C-reactive protein for tuberculosis, bloodstream infection or death among HIV-infected individuals with chronic, non-specific symptoms and negative sputum smear microscopy.

BACKGROUND: C-reactive protein (CRP) is an inflammatory biomarker that may identify patients at risk of infections or death. Mortality among HIV-infected persons commencing antiretroviral therapy (ART) is often attributed to tuberculosis (TB) or bloodstream infections (BSI). METHODS: In two district hospitals in southern Malawi, we recruited HIV-infected adults with one or more unexplained symptoms present for at least one month (weight loss, fever or diarrhoea) and negative expectorated sputum microscopy for TB. CRP determination for 452 of 469 (96%) participants at study enrolment was analysed for associations with TB, BSI or death to 120 days post-enrolment. RESULTS: Baseline CRP was significantly elevated among patients with confirmed or probable TB (52), BSI (50) or death (60) compared to those with no identified infection who survived at least 120 days (269). A CRP value of >10 mg/L was associated with confirmed or probable TB (adjusted odds ratio 5.7; 95% CI 2.6, 14.3; 87% sensitivity) or death by 30 days (adjusted odds ratio 9.2; 95% CI 2.2, 55.1; 88% sensitivity). CRP was independently associated with TB, BSI or death, but the prediction of these endpoints was enhanced by including haemoglobin (all outcomes), CD4 count (BSI, death) and whether ART was started (death) in logistic regression models. CONCLUSION: High CRP at the time of ART initiation is associated with TB, BSI and early mortality and so has potential utility for stratifying patients for intensified clinical and laboratory investigation and follow-up. They may also be considered for empirical treatment of opportunistic infections including TB.

Trends in ART Initiation among Men and Non-Pregnant/Non-Breastfeeding Women before and after Option B+ in Southern Malawi.

BACKGROUND: Option B+ is promoted as a key component to eliminating vertical transmission of HIV; however, little is known about the policy's impact on non-targeted populations, such as men and non-pregnant/non-breastfeeding women. We compare ART uptake among non-targeted populations during pre/post Option B+ periods in Zomba District, Malawi. METHODS: Individual-level ART registry data from 27 health facilities were digitized and new ART initiates were disaggregated by sex and type of initiate (Option B+ or not). Data were analyzed over the pre- (January 2009-June 2011) and post- (July 2011- December 2013) Option B+ periods. RESULTS: After the implementation of Option B+, the total number of new female initiates increased significantly (quarterly median: 547 vs. 816; P = 0.001) and their median age decreased from 34 to 31 years (P = <0.001). Both changes were the result of the rapid and sustained uptake of ART among Option B+ clients. Post-policy, Option B+ clients represented 48% of all new female initiates while the number of females who initiated through CD4 or WHO staging criteria significantly decreased (quarterly median: 547 vs. 419; P = 0.005). The number and age of male initiates remained stable; however, the proportion of men among new initiates decreased (36% vs. 31%; P = <0.001). CONCLUSIONS: Option B+ shifted the profile of first-time initiates towards younger and fertile women. Declines among non-Option B+ women most likely reflect earlier initiation during pregnancies before deteriorations in health. The decreased proportion of men among first-time initiates represents a growing gender disparity in HIV services that deserves immediate attention.

Same day HIV diagnosis and antiretroviral therapy initiation affects retention in Option B+ prevention of mother-to-child transmission services at antenatal care in Zomba District, Malawi.

INTRODUCTION: Data from the Option B+ prevention of mother-to-child transmission (PMTCT) program in Malawi show considerable variation between health facilities in retention on antiretroviral therapy (ART). In a programmatic setting, we studied whether the "model of care," based on the degree of integration of antenatal care (ANC), HIV testing and counselling (HTC) and ART service provision-influenced uptake of and retention on ART. METHODS: We conducted a retrospective cohort study of pregnant women seeking ANC at rural primary health facilities in Zomba District, Malawi. Data were extracted from standardized national ANC registers, ART registers and ART master cards. The "model of care" of Option B+ service delivery was determined at each health facility, based on the degree of integration of ANC, HTC and ART. Full integration (Model 1) of HTC and ART initiation at ANC was compared with integration of HTC only into ANC services (Model 2) with subsequent referral to an existing ART clinic for treatment initiation. RESULTS AND DISCUSSION: A total of 10,528 women were newly registered at ANC between October 2011 and March 2012 in 23 rural health facilities (12 were Model 1 and 11 Model 2). HIV status was ascertained in 8,572 (81%) women. Among 914/8,572 (9%) HIV-positive women enrolling at ANC, 101/914 (11%) were already on ART; of those not on treatment, 456/813 (56%) were started on ART. There was significantly higher ART uptake in Model 1 compared with Model 2 sites (63% vs. 51%; p=0.001), but significantly lower ART retention in Model 1 compared with Model 2 sites (79% vs. 87%; p=0.02). Multivariable analysis showed that initiation of ART on the same day as HIV diagnosis, but not model of care, was independently associated with reduced retention in the first six months (adjusted odds ratio 2.27; 95% CI: 1.34-3.85; p=0.002). CONCLUSIONS: HIV diagnosis and treatment on the same day was associated with reduced retention on ART, independent of the level of PMTCT service integration at ANC.

Outcomes and Diagnostic Processes in Outpatients with Presumptive Tuberculosis in Zomba District, Malawi.

BACKGROUND: In Malawi, outpatients who have presumptive tuberculosis (TB), i.e. fever, night sweats, weight loss and/or any-duration cough (HIV-infected) or cough of at least 2 weeks (HIV-uninfected), are registered in chronic cough registers. They should receive a diagnostic work-up with first-step provider-initiated HIV testing and sputum testing which includes XpertMTB/RIF, following a national algorithm introduced in 2012. METHODS: An operational study, in which we prospectively studied 6-month outcomes of adult outpatients who were registered in chronic cough registers in Zomba Central Hospital and Matawale peri-urban Health Center, between February and September 2013. We recorded implementation of the diagnostic protocol and outcomes at 6 months from registration. RESULTS: Of 348 patients enrolled, 165(47%) were male, median age was 40 years, 72(21%) had previous TB. At registration 154(44%) were known HIV-positive, 34(10%) HIV-negative (26 unconfirmed) and 160(46%) had unknown HIV status; 104(56%) patients with unknown/unconfirmed HIV status underwent HIV testing. At 6 months 191(55%) were HIV-positive, 87(25%) HIV-negative (26 unconfirmed) and 70(20%) still had unknown HIV status. Higher age and registration in Matawale were independently associated with remaining unknown HIV status after 6 months. 62% of patients had sputum tested, including XpertMTB/RIF, according to the algorithm. TB was diagnosed in 54(15%) patients. This was based on XpertMTB/RIF results in 8(15%) diagnosed cases. In 26(48%) TB was diagnosed on clinical grounds. Coverage of ART in HIV-positive patients was 89%. At 6 months, 236(68%) were asymptomatic, 48(14%) symptomatic, 25(7%) had been lost-to-follow-up and 39(11%) had died. Mortality among those HIV-positive, HIV-negative and with unknown HIV-status was 15%, 2% and 10%, respectively. Male gender, being HIV-positive-not-on-ART and not receiving antibiotics were independent risk factors for mortality. CONCLUSION: HIV prevalence among patients with presumptive TB was high (55%). One quarter was not HIV tested and mortality in this group was substantial (10%). The impact of XpertMTB/RIF on TB diagnosis was limited.

Towards elimination of mother-to-child transmission of HIV: performance of different models of care for initiating lifelong antiretroviral therapy for pregnant women in Malawi (Option B+).

INTRODUCTION: Malawi introduced a new strategy to improve the effectiveness of prevention of mother-to-child HIV transmission (PMTCT), the Option B+ strategy. We aimed to (i) describe how Option B+ is provided in health facilities in the South East Zone in Malawi, identifying the diverse approaches to service organization (the "model of care") and (ii) explore associations between the "model of care" and health facility-level uptake and retention rates for pregnant women identified as HIV-positive at antenatal (ANC) clinics. METHODS: A health facility survey was conducted in all facilities providing PMTCT/antiretroviral therapy (ART) services in six of Malawi's 28 districts to describe and compare Option B+ service delivery models. Associations of identified models with program performance were explored using facility cohort reports. RESULTS: Among 141 health facilities, four "models of care" were identified: A) facilities where newly identified HIV-positive women are initiated and followed on ART at the ANC clinic until delivery; B) facilities where newly identified HIV-positive women receive only the first dose of ART at the ANC clinic, and are referred to the ART clinic for follow-up; C) facilities where newly identified HIV-positive women are referred from ANC to the ART clinic for initiation and follow-up of ART; and D) facilities serving as ART referral sites (not providing ANC). The proportion of women tested for HIV during ANC was highest in facilities applying Model A and lowest in facilities applying Model B. The highest retention rates were reported in Model C and D facilities and lowest in Model B facilities. In multivariable analyses, health facility factors independently associated with uptake of HIV testing and counselling (HTC) in ANC were number of women per HTC counsellor, HIV test kit availability, and the "model of care" applied; factors independently associated with ART retention were district location, patient volume and the "model of care" applied. CONCLUSIONS: A large variety exists in the way health facilities have integrated PMTCT Option B+ care into routine service delivery. This study showed that the "model of care" chosen is associated with uptake of HIV testing in ANC and retention in care on ART. Further patient-level research is needed to guide policy recommendations.

Practices and recommendations in infant feeding and HIV prevention: the child's perspective.

Although the attainment of Millennium Development Goal 4 (MDG 4), reducing under-five mortality by two-thirds by the year 2015, depends on optimizing breast-feeding practices in resource-limited settings, there are some conditions in which breast-feeding is impossible, contraindicated, or not recommended. The overall impact of involuntary nonbreast-feeding on the attainment of MDG 4 has not been documented. In industrialized and many middle-income countries replacement feeding is affordable, feasible, acceptable, sustainable, and safe and complete avoidance of breast-feeding is the norm to prevent postnatal transmission of HIV. The situation is very different in many low-income countries affected by the HIV epidemic where infants are exposed to HIV and antiretroviral (ARV) mediation through breast milk for long periods with risk of acquiring HIV infection, development of multidrug resistant HIV and short and long term toxicity associated to ARV medications. Despite the obvious needs, there is no specific research on how to make replacement feeding safer for infants with no access to breast-feeding and for whom replacement feeding is justified. Orphans, abandoned and infants of severely ill mothers unable to breast-feed, won't benefit from the research done on making breast-feeding safer for HIV exposed infants. A child rights perspective illuminates societal obligations to provide replacement feeding with infant formula milk to such infants, and to support research to make it safer at the same time that breast-feeding is promoted and protected for the general population.

Women's choices regarding HIV testing, disclosure and partner involvement in infant feeding and care in a rural district of Malawi with high HIV prevalence.

The influence of HIV-related stigma on women's choices with regard to HIV testing, disclosure and partner involvement in infant feeding and care is not well understood in rural Malawi but may influence the risk of vertical HIV transmission and infant health. In a study of HIV-infected and -uninfected women in 20 rural locations in Zomba District, Malawi, mothers were questioned at 18-20 months post-partum about these issues. Ten per cent of women claimed unknown HIV status in labour so HIV testing should be routinely offered in Labour & Delivery wards. HIV-infected women were somewhat less likely to disclose to their partners than HIV-uninfected women (89 and 97%, respectively; p = 0.007) or to be cohabiting with partners during pregnancy (74 and 86%, respectively; p = 0.03). Partners of women were less inclined to disclose their HIV testing or HIV status (49 and 66% of partners of HIV-infected and -uninfected women, respectively). Greater partner testing and disclosure may improve prevention of mother to child transmission of HIV (PMTCT) in this population. A majority of women were inclined to make feeding decisions on their own, whereas most felt that other health-related decisions should also involve the father. Most mothers believe that exclusive breast feeding (EBF) is the best infant feeding method (for the first six months) but it was actually practiced by a minority of women (20% of HIV-infected and 5% of HIV-uninfected mothers; p = 0.01). EBF needs systematic support in order to be practised.

Building a national direction for research in the prevention of mother to child transmission of HIV: results from a national prioritization initiative in Malawi.

BACKGROUND: In 2011, Malawi initiated an ambitious program for the prevention of maternal to child transmission (PMTCT) of HIV, called 'Option B+,' which employs a universal test and life-long treatment strategy for all pregnant women. Priority setting should take place in defining a national research agenda for evaluating Option B + rollout in Malawi. METHODS: In April 2011, a three-day workshop took place for all major stakeholders in PMTCT aiming to provide an update on current PMTCT operational research in Malawi, find consensus on key questions not yet being addressed, identify opportunities for collaboration, and develop multi-partner research proposals. RESULTS: Overall, 24 participants attended the workshop including representatives from the Ministry of Health, the National AIDS Commission and 12 multilateral, non-governmental organizations and academic partners.Three interrelated clusters emerged as priorities for research: i) pregnancy intentions and family planning needs; ii) evaluation of models of care; and iii) determinants of uptake, adherence, and retention of women for Option B+. In addition, two cross-cutting themes arose: partner involvement in PMTCT services and cost-effectiveness as a guide to priority setting. Within each cluster a coordinator was designated and a proposed plan for research and potential collaborators were discussed. The results of the workshop were presented to the national technical working groups and the National AIDS Commission. Several large-scale, collaborative proposals have been developed and funded to address the research areas defined. CONCLUSIONS: Option B + represents a significant change in PMTCT policy in Malawi and the process for evaluation of the Malawi PMTCT strategy is outlined. This workshop contributed to defining and coordinating the national agenda for research priorities.

Six-month mortality among HIV-infected adults presenting for antiretroviral therapy with unexplained weight loss, chronic fever or chronic diarrhea in Malawi.

BACKGROUND: In sub-Saharan Africa, early mortality is high following initiation of antiretroviral therapy (ART). We investigated 6-month outcomes and factors associated with mortality in HIV-infected adults being assessed for ART initiation and presenting with weight loss, chronic fever or diarrhea, and with negative TB sputum microscopy. METHODS: A prospective cohort study was conducted in Malawi, investigating mortality in relation to ART uptake, microbiological findings and treatment of opportunistic infection (OIs), 6 months after meeting ART eligibility criteria. RESULTS: Of 469 consecutive adults eligible for ART, 74(16%) died within 6 months of enrolment, at a median of 41 days (IQR 20-81). 370(79%) started ART at a median time of 18 days (IQR 7-40) after enrolment. Six-month case-fatality rates were higher in patients with OIs; 25/121(21%) in confirmed/clinical TB and 10/50(20%) with blood stream infection (BSI) compared to 41/308(13%) in patients with no infection identified. Median TB treatment start was 27 days (IQR 17-65) after enrolment and mortality [8 deaths (44%)] was significantly higher among 18 culture-positive patients with delayed TB diagnosis compared to patients diagnosed clinically and treated promptly with subsequent culture confirmation [6/34 (18%);p = 0.04]. Adjusted multivariable analysis, excluding deaths in the first 21 days, showed weight loss >10%, low CD4 count, severe anemia, laboratory-only TB diagnosis, and not initiating ART to be independently associated with increased risk of death. CONCLUSIONS: Mortality remains high among chronically ill patients eligible for ART. Prompt initiation of ART is vital: more than half of deaths were among patients who never started ART. Diagnostic and treatment delay for TB was strongly associated with risk of death. More than half of deaths occurred without identification of a specific infection. ART programmes need access to rapid point-of-care-diagnostic tools for OIs. The role of early empiric OI treatment in this population requires further evaluation in clinical trials.

Mortality and health outcomes of HIV-exposed and unexposed children in a PMTCT cohort in Malawi.

BACKGROUND: Mortality and morbidity among HIV-exposed children are thought to be high in Malawi. We sought to determine mortality and health outcomes of HIV-exposed and unexposed infants within a PMTCT program. METHOD: Data were collected as part of a retrospective cohort study in Zomba District, Malawi. HIV-infected mothers were identified via antenatal, delivery and postpartum records with a delivery date 18-20 months prior; the next registered HIV-uninfected mother was identified as a control. By interview and health record review, data on socio-demographic characteristics, service uptake, and health outcomes were collected. HIV-testing was offered to all exposed children. RESULTS: 173 HIV-infected and 214 uninfected mothers were included. 4 stillbirths (1.0%) occurred; among the 383 livebirths, 41 (10.7%) children died by 20 months (32 (18.7%) HIV-exposed and 9 unexposed children (4.3%; p<0.0001)). Risk factors for child death included: HIV-exposure [adjOR2.9(95%CI 1.1-7.2)], low birthweight [adjOR2.5(1.0-6.3)], previous child death (adjOR25.1(6.5-97.5)] and maternal death [adjOR5.3(11.4-20.5)]. At 20 months, HIV-infected children had significantly poorer health outcomes than HIV-unexposed children and HIV-exposed but uninfected children (HIV-EU), including: hospital admissions, delayed development, undernutrition and restrictions in function (Lansky scale); no significant differences were seen between HIV-EU and HIV-unexposed children. Overall, no difference was seen at 20 months among HIV-infected, HIV-EU and HIV-unexposed groups in Z-scores (%<-2.0) for weight, height and BMI. Risk factors for poor functional health status at 20 months included: HIV-infection [adjOR8.9(2.4-32.6)], maternal illness [adjOR2.8(1.5-5.0)] and low birthweight [adjOR2.0(1.0-4.1)]. CONCLUSION: Child mortality remains high within this context and could be reduced through more effective PMTCT including prioritizing the treatment of maternal HIV infection to address the effect of maternal health and survival on infant health and survival. HIV-infected children demonstrated developmental delays, functional health and nutritional deficits that underscore the need for increased uptake of early infant diagnosis and institution of ART for all infected infants.

Mortality and health outcomes in HIV-infected and HIV-uninfected mothers at 18-20 months postpartum in Zomba District, Malawi.

BACKGROUND: Maternal morbidity and mortality among HIV-infected women is a global concern. This study compared mortality and health outcomes of HIV-infected and HIV-uninfected mothers at 18-20 months postpartum within routine prevention of mother-to-child transmission of HIV (PMTCT) services in a rural district in Malawi. METHODS: A retrospective cohort study of mother-child dyads at 18-20 months postpartum in Zomba District. Data on socio-demographic characteristics, service uptake, maternal health outcomes and biometric parameters were collected. RESULTS: 173 HIV-infected and 214 HIV-uninfected mothers were included. HIV-specific cohort mortality at 18-20 months postpartum was 42.4 deaths/1000 person-years; no deaths occurred among HIV-uninfected women. Median time to death was 11 months post-partum (range 3-19). Women ranked their health on a comparative qualitative scale; HIV-infected women perceived their health to be poorer than did HIV-uninfected women (RR 2.4; 95% CI 1.6-3.7). Perceived maternal health status was well correlated with an objective measure of functional status (Karnofsky scale; p<0.001). HIV-infected women were more likely to report minor (RR 3.8; 95% CI 2.3-6.4) and major (RR 6.2; 95% CI 2.2-17.7) signs or symptoms of disease. In multivariable analysis, HIV-infected women remained twice as likely to report poorer health [adjusted OR (aOR) 2.3; 95% CI 1.4-3.6], as did women with low BMI (aOR 2.1; 95% CI 1.1-4.0) and scoring lowest on the welfare scale (aOR 2.0; 95% CI 1.1-3.8). CONCLUSIONS: HIV-infected women show increased mortality and morbidity at 18-20 months postpartum. In our rural Malawian operational setting, where there is documented under-application of ART and poor adherence to PMTCT services, these results support attention to optimizing maternal participation in PMTCT programs.

High prevalence of tuberculosis and serious bloodstream infections in ambulatory individuals presenting for antiretroviral therapy in Malawi.

BACKGROUND: Tuberculosis (TB) and serious bloodstream infections (BSI) may contribute to the high early mortality observed among patients qualifying for antiretroviral therapy (ART) with unexplained weight loss, chronic fever or chronic diarrhea. METHODS AND FINDINGS: A prospective cohort study determined the prevalence of undiagnosed TB or BSI among ambulatory HIV-infected adults with unexplained weight loss and/or chronic fever, or diarrhea in two routine program settings in Malawi. Subjects with positive expectorated sputum smears for AFB were excluded. Investigations Bacterial and mycobacterial blood cultures, cryptococcal antigen test (CrAg), induced sputum (IS) for TB microscopy and solid culture, full blood count and CD4 lymphocyte count. Among 469 subjects, 52 (11%) had microbiological evidence of TB; 50 (11%) had a positive (non-TB) blood culture and/or positive CrAg. Sixty-five additional TB cases were diagnosed on clinical and radiological grounds. Nontyphoidal Salmonellae (NTS) were the most common blood culture pathogens (29 cases; 6% of participants and 52% of bloodstream isolates). Multivariate analysis of baseline clinical and hematological characteristics found significant independent associations between oral candidiasis or lymphadenopathy and TB, marked CD4 lymphopenia and NTS infection, and severe anemia and either infection, but low positive likelihood ratios (<2 for all combinations). CONCLUSIONS: We observed a high prevalence of TB and serious BSI, particularly NTS, in a program cohort of chronically ill HIV-infected outpatients. Baseline clinical and hematological characteristics were inadequate predictors of infection. HIV clinics need better rapid screening tools for TB and BSI. Clinical trials to evaluate empiric TB or NTS treatment are required in similar populations.

Involving expert patients in antiretroviral treatment provision in a tertiary referral hospital HIV clinic in Malawi.

BACKGROUND: Current antiretroviral treatment (ART) models in Africa are labour intensive and require a high number of skilled staff. In the context of constraints in human resources for health, task shifting is considered a feasible alternative for ART service delivery. In 2006, Dignitas International in partnership with the Malawi Ministry of Health trained a cadre of expert patients at the HIV Clinic at a tertiary referral hospital in Zomba, Malawi. Expert patients were trained to assist with clinic tasks including measurement of vital signs, anthropometry and counseling. METHODS: A descriptive observational study using mixed methods was conducted two years after the start of program implementation. Semi-structured interviews were conducted with 20 patients, seven expert patients and six formal health care providers to explore perceptions towards the expert patients' contributions in the clinic. Structured exit interviews with 81 patients, assessed whether essential ART information was conveyed during counseling sessions. Vital signs and anthropometry measurements performed by expert patients were repeated by a nurse to assess accuracy of measurements. Direct observations quantified the time spent with each patient. RESULTS: There were minor differences in measurement of patients' weight, height and temperature between the expert patients and the nurse. The majority of patients exiting a counseling session reported, without prompting, at least three side effects of ART, correct actions to be taken on observing a side-effect, and correct consequences of non-adherence to ART. Expert patients carried out 368 hours of nurse tasks each month, saving two and a half full-time nurse equivalents per month. Formal health care workers and patients accept and value expert patients' involvement in ART provision and care. Expert patients felt valued by patients for being a 'role model', or a 'model of hope', promoting positive living and adherence to ART. CONCLUSIONS: Expert patients add value to the ART services at a tertiary referral HIV clinic in Malawi. Expert patients carry out shifted tasks acceptably, saving formal health staff time, and also act as 'living testimonies' of the benefits of ART and can be a means of achieving greater involvement of People Living with HIV in HIV treatment programs.

Mapping alteration minerals at prospect, outcrop and drill core scales using imaging spectrometry.

Imaging spectrometer data (also known as 'hyperspectral imagery' or HSI) are well established for detailed mineral mapping from airborne and satellite systems. Overhead data, however, have substantial additional potential when used together with ground-based measurements. An imaging spectrometer system was used to acquire airborne measurements and to image in-place outcrops (mine walls) and boxed drill core and rock chips using modified sensor-mounting configurations. Data were acquired at 5 nm nominal spectral resolution in 360 channels from 0.4 to 2.45 µm. Analysis results using standardized hyperspectral methodologies demonstrate rapid extraction of representative mineral spectra and mapping of mineral distributions and abundances in map-plan, with core depth, and on the mine walls. The examples shown highlight the capabilities of these data for mineral mapping. Integration of these approaches promotes improved understanding of relations between geology, alteration and spectral signatures in three dimensions and should lead to improved efficiency of mine development, operations and ultimately effective mine closure.

Uptake and outcomes of a prevention-of mother-to-child transmission (PMTCT) program in Zomba district, Malawi.

BACKGROUND: HIV prevalence among pregnant women in Malawi is 12.6%, and mother-to-child transmission is a major route of transmission. As PMTCT services have expanded in Malawi in recent years, we sought to determine uptake of services, HIV-relevant infant feeding practices and mother-child health outcomes. METHODS: A matched-cohort study of HIV-infected and HIV-uninfected mothers and their infants at 18-20 months post-partum in Zomba District, Malawi. 360 HIV-infected and 360 HIV-uninfected mothers were identified through registers. 387 mother-child pairs were included in the study. RESULTS: 10% of HIV-infected mothers were on HAART before delivery, 27% by 18-20 months post-partum. sd-NVP was taken by 75% of HIV-infected mothers not on HAART, and given to 66% of infants. 18% of HIV-infected mothers followed all current recommended PMTCT options. HIV-infected mothers breastfed fewer months than HIV-uninfected mothers (12 vs.18, respectively; p < 0.01). 19% of exposed versus 5% of unexposed children had died by 18-20 months; p < 0.01. 28% of exposed children had been tested for HIV prior to the study, 76% were tested as part of the study and 11% were found HIV-positive. HIV-free survival by 18-20 months was 66% (95%CI 58-74). There were 11(6%) maternal deaths among HIV-infected mothers only. CONCLUSION: This study shows low PMTCT program efficiency and effectiveness under routine program conditions in Malawi. HIV-free infant survival may have been influenced by key factors, including underuse of HAART, underuse of sd-NVP, and suboptimal infant feeding practices. Maternal mortality among HIV-infected women demands attention; improved maternal survival is a means to improve infant survival.

Total lymphocyte count as a possible surrogate of CD4 cell count to prioritize eligibility for antiretroviral therapy among HIV-infected individuals in resource-limited settings.

OBJECTIVE: To characterize the value of total lymphocyte counts in predicting risk of death among patients initiating triple combination antiretroviral therapy. METHODS: Study subjects included antiretroviral-naive persons aged 18 years or older who initiated treatment with triple combination therapy between August 1 1996 and September 30 1999 in a population-based observational cohort of HIV-infected individuals. Total lymphocyte counts as well as CD4 count and plasma viral load were assessed at baseline. Separate Cox proportional hazards models were devised to evaluate the effect on survival of total lymphocyte count in lieu of or with CD4 count after adjustment for other prognostic factors including plasma viral load. RESULTS: A total of 733 antiretroviral-naive persons initiated triple drug combination antiretroviral therapy over the study period with a median follow-up of 29.5 months. In the first analysis, only baseline CD4 cell counts of 50-199 cells/microl or less than 50 microl were associated with an increased risk of mortality [adjusted relative risk (ARR) 2.90; 95% CI: 1.40, 5.98] and (ARR 6.30; 95% CI: 2.93, 13.54), respectively. When CD4 counts were excluded from the analysis as if unavailable, total lymphocyte count of between 0.8 and 1.4 G/I, and less than 0.8 G/I were both significantly associated with an increased risk of mortality (ARR 2.36; 95% CI: 1.16, 4.78) and (ARR 6.17; 95% CI: 2.93, 13.01), respectively. CONCLUSION: Total lymphocyte count may provide a simple and cost-effective alternative for prioritizing therapy initiation in resource-limited settings. Our results suggest that, if appropriately validated, judicious application of total lymphocyte counts could overcome one of the practical obstacles to more widespread provision of antiretroviral therapy in resource-poor settings.