[Show abstract][Hide abstract] ABSTRACT: Background: Little is known about the pattern or risk factors for deaths from external causes in sub-Saharan Africa: there is a lack of reliable data, and public health priorities have been focussed on other causes. This study assessed the prevalence and risk factor for deaths from external causes in rural Malawi. Methods: We analysed data from 2002-2012 from the Karonga demographic surveillance site which covers ~35,000 people in rural northern Malawi. Verbal autopsies with clinician coding are used to assign cause of death. Repeated annual surveys capture data on socio-economic factors. Using Poisson regression models we calculated age, sex and cause-specific rates and rate ratios of external deaths. We used a nested case-control study, matched on age, sex and time period, to investigate risk factors for these deaths, using conditional logistic regression. Results: In 315,580 person years at risk (pyar) there were 2673 deaths, including 143 from external causes. The mortality rate from external causes was 47.1/100,000 pyar (95 % CI 32.5-68.2) among under-fives; 20.1/100,000 pyar (95 % CI 13.1-32.2) among 5-14 year olds; 46.3/100,000 pyar (95 % CI 35.8-59.9) among 15-44 year olds; and 98.7/100,000 pyar (95 % CI 71.8-135.7) among those aged ≥45 years. Drowning (including four deaths in people with epilepsy), road injury and suicide were the leading external causes. Adult males had the highest rates (100.7/100,000 pyar), compared to 21.8/100,000pyar in adult females, and the rate continued to increase with increasing age in men. Alcohol contributed to 21 deaths, all in adult males. Children had high rates of drowning (9.2/100,000 pyar, 95 % CI 5.5-15.6) but low rates of road injury (2.6/100,000 pyar, 95 % CI 1.0-7.0). Among 5-14 year olds, attending school was associated with fewer deaths from external causes than among those who had never attended school (adjusted OR 0.15, 95 % CI 0.08-0.81). Fishermen had increased risks of death from drowning and suicide compared to farmers. Discussion: In this population the rate of deaths from external causes was lowest at age 5-14 years. Adult males had the highest rate of death from external causes, 5 times the rate in adult females. Drowning, road injury and suicide were the leading causes of death; alcohol consumption contributed to more than one quarter of the deaths in men Conclusions: The high proportion of alcohol-related deaths in men, the predominance of drowning, deaths linked to uncontrolled epilepsy, and the possible protective effect of school attendance suggest areas for intervention.
BMC Public Health 12/2015; 15(1). DOI:10.1186/s12889-015-2323-z · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The proportion of tuberculosis attributable to transmission from close contacts is not well known. Comparison of the genome of strains from index patients and prior contacts allows transmission to be confirmed or excluded.
In Karonga District, Malawi, all tuberculosis patients are asked about prior contact with others with tuberculosis. All available strains from culture-positive patients were sequenced. Up to 10 single nucleotide polymorphisms between index patients and their prior contacts were allowed for confirmation, and ≥ 100 for exclusion. The population attributable fraction was estimated from the proportion of confirmed transmissions and the proportion of patients with contacts.
From 1997–2010 there were 1907 new culture-confirmed tuberculosis patients, of whom 32% reported at least one family contact and an additional 11% had at least
PLoS ONE 07/2015; 10(7-7):e0132840. DOI:10.1371/journal.pone.0132840 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online ‘TB-Profiler’ tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-015-0164-0) contains supplementary material, which is available to authorized users.
Genome Medicine 05/2015; 7(1). DOI:10.1186/s13073-015-0164-0 · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Phylogenetic-based classification of M. tuberculosis and other bacterial genomes is a core analysis for studying evolutionary hypotheses, disease outbreaks and transmission events. Whole genome sequencing is providing new insights into the genomic variation underlying intra- and inter-strain diversity, thereby assisting with the classification and molecular barcoding of the bacteria. One roadblock to strain investigation is the lack of user-interactive solutions to interrogate and visualise variation within a phylogenetic tree setting.
We have developed a web-based tool called PhyTB (http://pathogenseq.lshtm.ac.uk/phytblive/index.php) to assist phylogenetic tree visualisation and identification of M. tuberculosis clade-informative polymorphism. Variant Call Format files can be uploaded to determine a sample position within the tree. A map view summarises the geographical distribution of alleles and strain-types. The utility of the PhyTB is demonstrated on sequence data from 1,601 M. tuberculosis isolates.
PhyTB contextualises M. tuberculosis genomic variation within epidemiological, geographical and phylogenic settings. Further tool utility is possible by incorporating large variants and phenotypic data (e.g. drug-resistance profiles), and an assessment of genotype-phenotype associations. Source code is available to develop similar websites for other organisms (http://sourceforge.net/projects/phylotrack).
[Show abstract][Hide abstract] ABSTRACT: People have argued that the benefits of human immunodefi-ciency virus (HIV) testing and counselling are so important that participants in HIV surveys must be given their HIV test results and that individuals who decline to receive their test results should be excluded from participation in such surveys. 1–3 In early attempts at HIV surveillance, there were many logistical issues that complicated the return of test results and few advantages to infected individuals in receiving their test results. 4 Now the situation has changed radically with the widespread roll-out of HIV treatment and care – which not only prolongs life but also reduces sexual and vertical transmission of HIV. 2 We agree that researchers now have an obligation to offer and encourage post-test counselling as part of a research encounter but argue that there are both practical and ethical reasons to allow study participants to opt out of post-test counselling. In African populations with HIV prevalence above 4%, between 30% and 81% of infected men and women have ever been tested for HIV. 5 Those who know they are HIV-positive may be willing to donate blood samples for research purposes but may not want to repeat pre-and post-test counselling. The same may be true of those who feel certain that they are uninfected. Sexually active men and women are encouraged to be tested regularly. Research studies should provide the option for those who arrange to be frequently retested – so-called repeat testers – to be given their test results in a short format and be allowed to opt out of post-test counselling. They should also be prepared for participants who do not wish to collect their test results in any format. All participants – including those who provide blood samples for research but opt out of post-test counselling – can be asked to report their testing histories and testing motives. Importantly, the opt-out provisions we discuss here align with the general principles of research ethics. We agree that there is public health utility in informing people of their HIV status but we think that this should not override the ethics of respect for individual autonomy. Informed consent procedures typically tell willing subjects that they have a right not to answer questions that make them uncomfortable and a right to withdraw from the study at any time without completing all the activities and procedures. Declining to receive a test result is an example of the right of participants to opt out of part of a study. Whether in research or clinical practice, public health utility would be better served through understanding peoples' reasons for not wanting to receive an HIV test result – while informing individuals about all of the available testing and counselling options. Rather than excluding those who decline post-test counselling , we have the obligation to understand the reasons for research participation – and non-participation – better, including attitudes to learning or confirming one's HIV status. Longitudinal studies with repeated HIV testing are particularly well placed to investigate decision-making around HIV testing. The results of such studies could demonstrate whether refusal to participate or receive test results lead to biased estimates of HIV prevalence that weaken the public health utility of the data. 6,7 They could also teach us about why and how people become motivated to be tested 8 and that knowledge could lead to improvements in the design of programmes of HIV testing. ■
Bulletin of the World Health Organisation 05/2015; 93(5):356-357. DOI:10.2471/BLT.14.135756 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To improve understanding of the factors influencing tuberculosis transmission and the role of pathogen variation, we sequenced all available specimens from patients diagnosed over 15 years in a whole district in Malawi. Mycobacterium tuberculosis lineages were assigned and transmission networks constructed, allowing ≤10 single nucleotide polymorphisms (SNPs) difference. We defined disease as due to recent infection if the network-determined source was within 5 years, and assessed transmissibility from forward transmissions resulting in disease. High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient. The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21-0.31). We showed striking differences by lineage in the proportion of disease due to recent transmission and in transmissibility (highest for lineage-2 and lowest for lineage-1) that were not confounded by immigration, HIV status or drug resistance. Transmissions resulting in disease decreased markedly over time.
[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, patients with tuberculosis diagnosed from 1996 to 2010 were actively followed after the end of treatment. Whole-genome sequencing with approximately 100-fold coverage was performed on all available cultures. Results of IS6110 restriction fragment-length polymorphism analyses were available for cultures performed up to 2008.
Results. Based on our data, a difference of ≤10 single-nucleotide polymorphisms (SNPs) was used to define relapse, and a difference of >100 SNPs was used to define reinfection. There was no evidence of mixed infections among those classified as reinfections. Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 had relapse, and 20 had reinfection; for 64 type of recurrence was unclassified. Almost all relapses occurred in the first 2 years. Human immunodeficiency virus infection 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 overrepresented and lineage-1 underrepresented among the reinfecting strains (P = .004).
Conclusions. While some of the factors determining recurrence depend on the patient and their treatment, differences in the Mycobacterium tuberculosis genome appear to have a role in both relapse and reinfection.
The Journal of Infectious Diseases 10/2014; 211(7):1154-1163. DOI:10.1093/infdis/jiu574 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
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.
Children born in 2006-2011 in the Karonga demographic surveillance area were included. Maternal HIV status was available from HIV serosurveys. Age-specific mortality rate ratios for children born to HIV-positive and HIV-negative mothers were obtained by fitting a Poisson model accounting for child clustering by mother and adjusting for potential confounders. Cause of death was ascertained by verbal autopsy.
There were 352 deaths among 6913 under-five singleton children followed for 20,754 person-years (py), giving a mortality rate of 17.0/1000 py overall, 218/1000 py (16.5/1000 live births) in neonates, 20/1000 py (17.4/1000 live births) in postneonatal infants, and 8/1000 py in 1-4 years old. Comparing those born to HIV-positive and HIV-negative mothers, the rate ratio adjusted for child age, sex, maternal age, parity, and drinking water source was 1.5 (95% confidence interval [CI]: 0.6 to 3.7) in neonates, 11.5 (95% CI: 7.2 to 18.5) in postneonatal infants, and 4.6 (95% CI: 2.7 to 7.9) in 1-4 years old. Birth injury/asphyxia, neonatal sepsis, and prematurity contributed >70% of neonatal deaths, whereas acute infections, malaria, diarrhea, and pneumonia accounted for most deaths in older children.
Maternal HIV status had little effect on neonatal mortality but was associated with much higher mortality in the postneonatal period and among older children. Greater attention to HIV care in pregnant women and mothers should help improve child survival, but broader interventions are needed to reduce neonatal mortality.
[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. DOI:10.5588/ijtld.13.0811 · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
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.
Retrospective cohort study combining individual data from ART registers and interview data, enabling us to link patients across different ART clinics in Karonga District, Malawi. We recorded information on all adults (≥15 years) starting ART between July 2005 and August 2012, including those initiating due to pregnancy and breastfeeding (Option B+). Retention in care was defined as being alive and receiving ART at the end of study. Predictors of attrition were assessed using a multivariable Cox proportional hazards model.
The number of clinics providing ART increased from 1 in 2005 to 16 in 2012. Six-month retention increased from 73% [95% confidence interval (CI): 71 to 76] to 93% (95% CI: 92 to 94) when comparing the 2005-2006 and 2011-2012 cohorts, and 12-month retention increased from 70% (95% CI: 67 to 73) to 92% (95% CI: 90 to 93). Over the study period, the proportion of patients starting ART at World Health Organization stage 4 declined from 62% to 10%. Being a man, younger than 35 years, having a more advanced World Health Organization stage and being part of an earlier cohort were all independently associated with attrition. Women starting ART for Option B+ experienced higher attrition than women of childbearing age starting for other reasons.
In this area, retention in care has increased dramatically. Improved health in patients starting ART and decentralization of ART care to peripheral health centers seem to be the major drivers for this change.
[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; 30(10). DOI:10.1089/AID.2013.0240 · 2.33 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). DOI:10.1016/S0140-6736(14)60162-8 · 45.22 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.
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.
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.
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. DOI:10.3402/gha.v7.23621 · 1.93 Impact Factor
[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.
[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.