[Show abstract][Hide abstract] ABSTRACT: Background
Tuberculosis (TB) mortality remains high across sub-Saharan Africa despite integration of TB and HIV/ART programmes. To inform programme design and service delivery, we estimated mortality by time from starting TB treatment.Methods
Routinely collected data on TB treatment, vital status, and the timing and causes of death, were linked to cardio-respiratory autopsy data, from 1995¿2008, from a cohort of male platinum miners in South Africa. Records were expanded into person-months at risk (pm).Results4162 TB episodes were registered; 3170 men were treated for the first time and 833 men underwent retreatment. Overall, 509 men died, with a case fatality of 12.2% and mortality rate of 2.0/100 pm. Mortality was highest in the first month after starting TB treatment for first (2.3/100 pm) and retreatment episodes (4.8/100 pm). When stratified by HIV status, case fatality was higher in HIV positive men not on ART (first episode 14.0%; retreatment episode 26.2%) and those on ART (12.0%; 22.0%) than men of negative or unknown HIV status (2.6%; 3.6%). Mortality was also highest in the first month for each of these groups. Mortality risk factors included older age, previous TB, HIV, pulmonary TB, and diagnostic uncertainty. The proportion of deaths attributable to TB was consistently overestimated in clinical records versus cardio-respiratory autopsy.Conclusions
Programme mortality was highest in those with HIV and during the first month of TB treatment in all groups, and many deaths were not caused by TB. Resource allocation should prioritise TB prevention and accurate earlier diagnosis, recognise the role of HIV, and ensure effective clinical care in the early stages of TB treatment.
[Show abstract][Hide abstract] ABSTRACT: Background. Recurrent tuberculosis is a major health burden and may be due to relapse with the original strain or reinfection with a new strain.Methods. In a population-based study in northern Malawi, tuberculosis patients diagnosed from 1996-2010 were actively followed after the end of treatment. Whole genome sequencing with approximately 100X coverage was carried out on all available cultures. IS6110 RFLP was available on cultures up to 2008.Results. Based on our data, a single nucleotide polymorphism (SNP) difference of ≤10 SNPs was used to define relapse, and >100 SNPs for reinfection. There was no evidence of mixed infections among those classified as reinfections.Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 relapse, 20 reinfection, unclassified for 64. Almost all relapses occurred in the first two years. HIV was associated with reinfection but not relapse. Relapses were associated with isoniazid resistance, treatment before 2007, and lineage-3 strains. We identified several gene variants associated with relapse. Lineage-2 (Beijing) was over-represented and lineage-1 under-represented among the reinfecting strains (p=0.004).Conclusions. While some of the factors determining recurrence depend on the patient and their treatment, differences in the M.tuberculosis genome appear to have a role in both relapse and reinfection.
[Show abstract][Hide abstract] ABSTRACT: Under-five mortality is decreasing but with little change in neonatal mortality rates. We examined the effect of maternal HIV-status on under-five mortality and cause of death since widespread availability of antiretroviral therapy in rural Malawi.
[Show abstract][Hide abstract] ABSTRACT: Strain-specific genomic diversity in the Mycobacterium tuberculosis complex (MTBC) is an important factor in pathogenesis that may affect virulence, transmissibility, host response and emergence of drug resistance. Several systems have been proposed to classify MTBC strains into distinct lineages and families. Here, we investigate single-nucleotide polymorphisms (SNPs) as robust (stable) markers of genetic variation for phylogenetic analysis. We identify B92k SNP across a global collection of 1,601 genomes. The SNP-based phylogeny is consistent with the gold-standard regions of difference (RD) classification system. Of the B7k strain-specific SNPs identified, 62 markers are proposed to discriminate known circulating strains. This SNP-based barcode is the first to cover all main lineages, and classifies a greater number of sublineages than current alternatives. It may be used to classify clinical isolates to evaluate tools to control the disease, including therapeutics and vaccines whose effectiveness may vary by strain type.
[Show abstract][Hide abstract] ABSTRACT: We assessed the impact on measured burden and outcomes of the revised World Health Organization and Malawi guidelines reclassifying people with single (including 'scanty') positive smears as smear-positive pulmonary tuberculosis cases. In a retrospective cohort in rural Malawi, 567 (34%) of 1670 smear-positive episodes were based on single positive smears (including 176 with scanty smears). Mortality rates and the proportion starting treatment were similar in those with two positive smears or single, non-scanty smears. Those with single scanty smears had higher mortality and a lower proportion starting treatment. The reclassification will increase the reported burden substantially, but should improve treatment access.
The International Journal of Tuberculosis and Lung Disease 07/2014; 18(7):843-6. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patient retention in antiretroviral therapy (ART) programs remains a major challenge in sub-Saharan Africa. We examined whether and why retention in ART care has changed with increasing access.
[Show abstract][Hide abstract] ABSTRACT: There are few cohorts of individuals, who have survived infection with HIV-1 for more than 20 years, reported and followed in the literature, and even fewer from Africa. Here we present data on a cohort of subtype C-infected individuals from rural northern Malawi. By sequencing multiple clones from long-term survivors at different time-points, and using multiple genotyping approaches, we show that four of the eleven individuals are predicted as CXCR4-using (by ≥3/5 predictors) but only one individual is predicted as CXCR4-using by all 5 algorithms. Using any one genotyping approach over-estimates the number of predicted CXCR4 sequences. Patterns of diversity and divergence were variable between the HIV-1 long-term survivors with some individuals showing very small amounts of variation and change, while others show a greater amount; both patterns consistent with what has been described in the literature.
AIDS Research and Human Retroviruses 06/2014; · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy.
The Lancet 05/2014; 384(9944). · 39.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background : Verbal autopsy could be more widely used if interpretation by computer algorithm could be relied on. We assessed how InterVA-4 results compared with clinician review in diagnosing HIV/AIDS-related deaths over the period of antiretroviral (ART) roll-out. Design : In the Karonga Prevention Study demographic surveillance site in northern Malawi, all deaths are followed by verbal autopsy using a semi-structured questionnaire. Cause of death is assigned by two clinicians with a third as a tie-breaker. The clinician review diagnosis was compared with the InterVA diagnosis using the same questionnaire data, including all adult deaths from late 2002 to 2012. For both methods data on HIV status were used. ART was first available in the district from 2005, and within the demographic surveillance area from 2006. Results : There were 1,637 adult deaths, with verbal autopsy data for 1,615. Adult mortality and the proportion of deaths attributable to HIV/AIDS fell dramatically following ART introduction, but for each year the proportion attributed to HIV/AIDS by InterVA was lower than that attributed by clinician review. This was partly explained by the handling of TB cases. Using clinician review as the best available 'gold standard', for those aged 15-59, the sensitivity of InterVA for HIV/AIDS deaths was 59% and specificity 88%. Grouping HIV/AIDS/TB sensitivity was 78% and specificity 83%. Sensitivity was lower after widespread ART use. Conclusions : InterVA underestimates the proportion of deaths due to HIV/AIDS. Accepting that it is unrealistic to try and differentiate TB and AIDS deaths would improve the estimates. Caution is needed in interpreting trends in causes of death as ART use may affect the performance of the algorithm.
Global Health Action 04/2014; 7:23621. · 1.65 Impact Factor
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[Show abstract][Hide abstract] ABSTRACT: To identify points of dropout on the pathway from offering HIV testing to maintenance on antiretroviral therapy (ART), following the introduction of the Option B+ policy for pregnant women in Malawi (lifelong ART for HIV-positive mothers and 6 weeks nevirapine for the infants), a retrospective cohort study within a demographic surveillance system in northern Malawi. Women living in the demographic surveillance system who initiated antenatal care (ANC) between July 2011 (date of policy change) and January 2013, were eligible for inclusion. Women who consented were interviewed at home about their health facility attendance and care since pregnancy, including antenatal clinic (ANC) visits, delivery and postpartum care. Women's reports, patient-held health records and clinic health records were manually linked to ascertain service use. Among 395 women, 86% had tested for HIV before the pregnancy, 90% tested or re-tested at the ANC visit, and <1% had never tested. Among 53 mothers known to be HIV-positive before attending ANC, 15 (28%) were already on ART prior to pregnancy. Ten women tested HIV-positive for the first time during pregnancy. Of the 47 HIV-positive mothers not already on ART, 26/47 (55%) started treatment during pregnancy. All but five women who started ART were still on treatment at the time of study interview. HIV testing was almost universal and most women who initiated ART were retained in care. However, nearly half of eligible pregnant women not on ART at the start of ANC had not taken up the invitation to initiate (lifelong) ART by the time of delivery, leaving their infants potentially HIV-exposed.
[Show abstract][Hide abstract] ABSTRACT: Molecular data are now widely used in epidemiological studies to investigate the transmission, distribution, biology, and diversity of pathogens. Our objective was to establish recommendations to support good scientific reporting of molecular epidemiological studies to encourage authors to consider specific threats to valid inference. The statement Strengthening the Reporting of Molecular Epidemiology for Infectious Diseases (STROME-ID) builds upon the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative. The STROME-ID statement was developed by a working group of epidemiologists, statisticians, bioinformaticians, virologists, and microbiologists with expertise in control of infection and communicable diseases. The statement focuses on issues relating to the reporting of epidemiological studies of infectious diseases using molecular data that were not addressed by STROBE. STROME-ID addresses terminology, measures of genetic diversity within pathogen populations, laboratory methods, sample collection, use of molecular markers, molecular clocks, timeframe, multiple-strain infections, non-independence of infectious-disease data, missing data, ascertainment bias, consistency between molecular and epidemiological data, and ethical considerations with respect to infectious-disease research. In total, 20 items were added to the 22 item STROBE checklist. When used, the STROME-ID recommendations should advance the quality and transparency of scientific reporting, with clear benefits for evidence reviews and health-policy decision making.
The Lancet Infectious Diseases 03/2014; · 19.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HIV infection reduces the likelihood that individuals with pulmonary tuberculosis are smear positive and that they have cavitatory disease. Antiretroviral therapy (ART) may shift the pattern of disease to be more similar to that of HIV negative patients. This would aid diagnosis- which often depends on sputum smears - but would also increase infectiousness. We assessed the effect of HIV and ART on smear positivity and cavitatory disease in laboratory-confirmed pulmonary TB patients.
Three sputum samples were collected per pulmonary TB suspect and were examined using microscopy and culture. Chest radiographs were available for a subset of patients as part of another study. The effect of HIV and ART status on sputum smear positivity and lung cavitation were evaluated using multivariable logistic regression.
Of 1024 laboratory-confirmed pulmonary TB patients who were identified between January 2005 and December 2011, 766 had HIV and ART status available. Positive sputum smears were significantly more common among HIV negative individuals than HIV positive individuals (adjusted OR = 2.91, 95% CI 1.53 - 5.55). Compared to those HIV positive but not on ART , patients on ART were more likely to be smear positive (adjusted OR = 2.33, 95% CI 1.01 - 5.39) if they had been on ART <= 6 months, but only slightly more likely to be smear positive (adjusted OR = 1.43, 95% CI 0.68 - 2.99) if they were on ART > 6 months. HIV negative patients were more likely than HIV positive patients to have cavitatory disease (adjusted OR = 1.97, 95% CI 1.20 - 3.23). Patients on ART > 6 months had a slight increase in cavitatory disease compared to HIV positive patients not on ART (adjusted OR = 1.68, CI 0.78 - 3.63).
HIV infection is associated with less smear positivity and cavitation in pulmonary TB patients. Among HIV positive patients, the use of ART shifts the presentation of disease towards that seen in HIV-negative individuals, which facilitates diagnosis but which also could increase infectiousness.
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the second major cause of death from an infectious disease worldwide. Recent advances in DNA sequencing are leading to the ability to generate whole genome information in clinical isolates of M. tuberculosis complex (MTBC). The identification of informative genetic variants such as phylogenetic markers and those associated with drug resistance or virulence will help barcode Mtb in the context of epidemiological, diagnostic and clinical studies. Mtb genomic datasets are increasingly available as raw sequences, which are potentially difficult and computer intensive to process, and compare across studies. Here we have processed the raw sequence data (>1500 isolates, eight studies) to compile a catalogue of SNPs (n = 74,039, 63% non-synonymous, 51.1% in more than one isolate, i.e. non-private), small indels (n = 4810) and larger structural variants (n = 800). We have developed the PolyTB web-based tool (http://pathogenseq.lshtm.ac.uk/polytb) to visualise the resulting variation and important meta-data (e.g. in silico inferred strain-types, location) within geographical map and phylogenetic views. This resource will allow researchers to identify polymorphisms within candidate genes of interest, as well as examine the genomic diversity and distribution of strains. PolyTB source code is freely available to researchers wishing to develop similar tools for their pathogen of interest.
[Show abstract][Hide abstract] ABSTRACT: To assess the magnitude of loss to follow-up in smear- or culture-positive tuberculosis patients before treatment initiation and outcomes among patients who were traced.
Ovid Medline and Global Health databases were searched for studies published between 1994 and January 2013 that described pre-treatment loss to follow-up in patients with smear- or culture-positive tuberculosis in routine national tuberculosis programmes (NTPs) in low- and lower-middle-income countries and in countries with a high burden of tuberculosis. Data on the proportion of patients who did not initiate treatment after their tuberculosis diagnosis were extracted from studies meeting inclusion criteria. Where available, data on causes and outcomes, including initiation of tuberculosis treatment at another facility, were investigated. Heterogeneity and publication bias were assessed and random-effects meta-analyses by subgroup (region) were performed.
Twenty-three eligible studies were identified, with a total of 34 706 smear- or culture-positive tuberculosis patients from 14 countries (8 in Africa, 5 in Asia and 1 in the western Pacific). Most studies were retrospective and linked laboratory and treatment registers to identify pre-treatment loss to follow-up. Pre-treatment loss to follow-up varied from 4 to 38% and was common in studies from Africa (random-effects weighted proportion, WP: 18%; 95% confidence interval, CI: 13-22) and Asia (WP: 13%; 95% CI: 10-15).
Pre-treatment loss to follow-up, common in most settings, can hinder tuberculosis control efforts. By not counting individuals who are lost to follow-up before treatment when reporting standard programme indicators, NTPs underestimate case detection rates and mortality and overestimate cure rates.
Bulletin of the World Health Organisation 02/2014; 92(2):126-138. · 5.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is increasing interest in social structural interventions for tuberculosis. The association between poverty and tuberculosis is well established in many settings, but less clear in rural Africa. In Karonga District, Malawi, we found an association between higher socioeconomic status and tuberculosis from 1986-1996, independent of HIV status and other factors.
To investigate the relationship in the same area in 1997-2010.
All adults in the district with new laboratory-confirmed tuberculosis were included. They were compared with community controls, selected concurrently and frequency-matched for age, sex and area.
1707 cases and 2678 controls were interviewed (response rates >95%). The odds of TB were increased in those working in the cash compared to subsistence economy (p<0.001), and with better housing (p-trend=0.006), but decreased with increased asset ownership (p-trend=0.003). The associations with occupation and housing were partly mediated by HIV status, but remained significant.
Different socioeconomic measures capture different pathways of the association between socioeconomic status and tuberculosis. Subsistence farmers may be relatively unexposed whereas those in the cash economy travel more, and may be more likely to come forward for diagnosis. In this setting "better houses" may be less well ventilated and residents may spend more time indoors.
PLoS ONE 10/2013; 8(10):e77740. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Remarkably little is known about associations between age at menarche and sexually transmitted infections, although girls with earlier menarche tend to have earlier sexual debut and school drop-out, so an association might be expected. In a population-based survey of >3000 women aged 15-30 in northern Malawi we show that those with earlier menarche had earlier sexual debut, earlier marriage and were more often Herpes simplex type-2 (HSV-2) positive. Compared to those with menarche aged <14, the age-adjusted odds ratios for HSV-2 were 0.89 (95%CI 0.71-1.1), 0.71 (0.57-0.89) and 0.69 (0.54-0.89) for menarche aged 14, 15 and 16+ respectively. This association persisted after adjusting for socio-economic factors, including schooling, and for sexual behaviour. No such association was seen with HIV infection, which is much less common and less uniformly distributed than HSV-2 in this population. The extra vulnerability of girls with earlier menarche needs to be recognised. DOI: http://dx.doi.org/10.7554/eLife.01604.001.
[Show abstract][Hide abstract] ABSTRACT: Background
Under-5 child mortality is decreasing, but with little change in neonatal mortality rates. One of the factors associated with improvements in mortality is increasing the availability of antiretroviral therapy (ART) for expectant mothers. We looked at the effect of maternal HIV status on under-5 mortality and cause of death since ART became widely available in rural Malawi.Methods
Children born between September, 2006, and December, 2011, in the Karonga Demographic Surveillance System were included. Maternal HIV status was derived from linked HIV sero-surveys. Age-specific mortality rate ratios of children born to HIV+ and HIV– mothers were obtained by fitting a Poisson random effects model, taking into account child clustering by mother and adjusting for potential confounders. Cause of death was ascertained by verbal autopsy.FindingsThere were 317 deaths among 7054 under-5 singleton children followed for 14 118 person-years. The mortality rate was 22·5 per 1000 person-years (95% CI 20·1–25·1). The neonatal mortality rate was 241 per 1000 person-years, similar in those born to HIV+ and HIV– mothers, rate ratio (RR) 0·7 (95% CI 0·1–3·6), adjusted for child sex and socioeconomic confounders. The mortality rate was 21·6 per 1000 person-years in postneonatal infants, adjusted RR 7·3 (95% CI 4·3–12·4) in those with HIV+ compared with HIV– mothers. In children aged 1–4 years, the mortality rate was 10·9 per 1000 person-years, adjusted RR 3·7 (95% CI 1·9–7·1) in those with HIV+ compared with HIV– mothers. Birth injury/asphyxia, neonatal sepsis, and prematurity contributed over 70% of neonatal deaths, while acute infections, malaria, diarrhoea, and pneumonia accounted for most deaths in older children. Nearly half the deaths in children of HIV+ mothers were attributed to HIV/AIDS.InterpretationMaternal HIV status did not increase neonatal mortality but was still associated with much higher mortality in older children. Greater uptake and retention of ART by pregnant women is needed to help improve child survival, but broader interventions are needed to reduce neonatal mortality.FundingWellcome Trust.
The Lancet 06/2013; 381:S29. · 39.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Screening for tuberculosis (TB) disease aims to improve early TB case detection. The ultimate goal is to improve outcomes for people with TB and to reduce Mycobacterium tuberculosis transmission in the community through improved case detection, reduction in diagnostic delays and early treatment. Before screening programmes are recommended, evidence is needed of individual and/or community-level benefits.
We conducted a systematic review of the literature to assess the evidence that screening for TB disease 1) initially increases the number of TB cases initiated on anti-tuberculosis treatment, 2) identifies cases earlier in the course of disease, 3) reduces mortality and morbidity, and 4) impacts on TB epidemiology.
A total of 28 798 publications were identified by the search strategy: 27 087 were excluded on initial screening and 1749 on full text review, leaving 62 publications that addressed at least one of the study questions. Screening increases the number of cases found in the short term. In many settings, more than half of the prevalent TB cases in the community remain undiagnosed. Screening tends to find cases earlier and with less severe disease, but this may be attributed to case-finding studies using more sensitive diagnostic methods than routine programmes. Treatment outcomes among people identified through screening are similar to outcomes among those identified through passive case finding. Current studies provide insufficient evidence to show that active screening for TB disease impacts on TB epidemiology.
Individual and community-level benefits from active screening for TB disease remain uncertain. So far, the benefits of earlier diagnosis on patient outcomes and transmission have not been established.
The International Journal of Tuberculosis and Lung Disease 04/2013; 17(4):432-46. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The rise in tuberculosis (TB) incidence following generalized HIV epidemics can overwhelm TB control programmes in resource-limited settings, sometimes accompanied by rising rates of drug resistance. This has led to claims that DOTS-based TB control has failed in such settings. However, few studies have described the effect of a sustained and well-supported DOTS programme on TB incidence and drug resistance over a long period. We present long-term trends in incidence and drug resistance in rural Malawi.
Karonga District in northern Malawi has an adult HIV prevalence of ∼10%. A research group, the Karonga Prevention Study, collaborates with the National Tuberculosis Programme to support core TB control activities. Bacteriological, demographic and clinical (including HIV status) information from all patients starting TB treatment in the District have been recorded since 1988. During that period isolates from each culture-positive TB patient were exported for drug sensitivity testing. Antiretroviral therapy (ART) has been widely available since 2005.
Incidence of new smear-positive adult TB peaked at 124/100,000/year in the mid-90s, but has since fallen to 87/100,000/year. Drug sensitivity information was available for 95% (3132/3307) of all culture-positive cases. Initial resistance to isoniazid was around 6% with no evidence of an increase. Fewer than 1% of episodes involved a multi-drug resistant strain.
In this setting with a generalised HIV epidemic and medium TB burden, a well-supported DOTS programme enhanced by routine culture and drug sensitivity testing may well have reduced TB incidence and maintained drug resistance at low levels.
PLoS ONE 03/2013; 8(3):e58192. · 3.53 Impact Factor