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ABSTRACT: BACKGROUND: The role of HIV-1 RNA in the emergence of resistance to antiretroviral therapies (ARTs) is well documented while less is known about the role of historical viruses stored in the proviral DNA. The primary focus of this work was to characterize the genetic diversity and evolution of HIV drug resistant variants in an individual's provirus during antiretroviral therapy using next generation sequencing. METHODS: Blood samples were collected prior to antiretroviral therapy exposure and during the course of treatment from five patients in whom drug resistance mutations had previously been identified using consensus sequencing. The spectrum of viral variants present in the provirus at each sampling time-point were characterized using 454 pyrosequencing from multiple combined PCR products. The prevalence of viral variants containing drug resistant mutations (DRMs) was characterized at each time-point. RESULTS: Low abundance drug resistant viruses were identified in 14 of 15 sampling time-points from the five patients. In all individuals DRMs against current therapy were identified at one or more of the sampling time-points. In two of the five individuals studied these DRMs were present prior to treatment exposure and were present at high prevalence within the amplified and sequenced viral population. DRMs to drugs other than those being currently used were identified in four of the five individuals. CONCLUSION: The presence of DRMs in the provirus, regardless of their observed prevalence did not appear to have an effect on clinical outcomes in the short term suggesting that the drug resistant viral variants present in the proviral DNA do not appear to play a role in the short term in facilitating the emergence of drug resistance.
BMC Infectious Diseases 01/2013; 13(1):52. · 3.12 Impact Factor
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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 01/2013; 8(3):e58192. · 4.09 Impact Factor
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ABSTRACT: BACKGROUND: Decentralised health services form a key part of chronic care strategies in resource-limited settings by reducing the distance between patient and clinic and thereby the time and costs involved in travelling. However, few tools exist to evaluate the impact of decentralisation on patient travel time or what proportion of patients attend their nearest clinic. Here we develop methods to monitor changes in travel time, using data from the antiretroviral therapy (ART) roll-out in a rural district in North Malawi. METHODS: Clinic position was combined with GPS information on the home village of patients accessing ART services in Karonga District (North Malawi) between July 2005 and July 2009. Potential travel time was estimated as the travel time for an individual attending their nearest clinic, and estimated actual travel time as the time to the clinic attended. This allowed us to calculate changes in potential and actual travel time as new clinics opened and track the proportion and origin of patients not accessing their nearest clinic. RESULTS: The model showed how the opening of further ART clinics in Karonga District reduced median potential travel time from 83 to 43 minutes, and median actual travel time fell from 83 to 47 minutes. The proportion of patients not attending their nearest clinic increased from 6% when two clinics were open, to 12% with four open. DISCUSSION: Integrating GPS information with patient data shows the impact of decentralisation on travel time and clinic choice to inform policy and research questions. In our case study, travel time decreased, accompanied by an increased uptake of services. However, the model also identified an increasing proportion of ART patients did not attend their nearest clinic.
International Journal of Health Geographics 11/2012; 11(1):49. · 2.62 Impact Factor
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ABSTRACT: OBJECTIVE:: To estimate the impact of antiretroviral therapy (ART) on the incidence of recurrent tuberculosis in an African population. DESIGN:: A long-term population cohort in Karonga District, northern Malawi. METHODS:: Patients who had completed treatment for laboratory-confirmed TB diagnosed since 1996 were visited annually to record vital status, ART use, and screen for TB. Survival analysis estimated the effect of HIV/ART status at completion of treatment on mortality and recurrence. Analyses were stratified by time since treatment completion to estimate the effects on relapse (predominates during first year) and reinfection disease (predominates later). RESULTS:: Among 1133 index TB cases contributing 4353 person-years of follow-up, there were 307 deaths and 103 laboratory-confirmed recurrences (recurrence rate 4.6/100py). Half the recurrences occurred in the first year since completing treatment. HIV infection increased the recurrence rate (rate ratio [RR] adjusted for age, sex, time period and TB type 2.69, 95%CI 1.69-4.26), but with less effect in the first year (adjusted RR 1.71, 0.87-3.35) than subsequently (adjusted RR 4.2, 2.16-8.15). Recurrence rates on ART were intermediate between those of HIV-negative individuals and HIV-positive individuals without ART. Compared to HIV-positive individuals without ART the adjusted RR was 0.74 (0.27-2.06) in the first year, and 0.43 (0.11-1.73) later. CONCLUSION:: The increased incidence of TB recurrence observed in HIV positive patients appeared to be reduced by ART. The effects are mostly on later (likely reinfection) disease so the impact of ART on reducing recurrence will be highest in high TB incidence settings.
AIDS (London, England) 08/2012; · 4.91 Impact Factor
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Menard Chihana,
Sian Floyd,
Anna Molesworth, Amelia C Crampin,
Ndoliwe Kayuni,
Alison Price,
Basia Zaba,
Andreas Jahn,
Hazzie Mvula,
Albert Dube,
Bagrey Ngwira,
Judith R Glynn,
Neil French
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ABSTRACT: Developing countries are undergoing demographic transition with a shift from high mortality caused by communicable diseases (CD) to lower mortality rates caused by non-communicable diseases (NCD). HIV/AIDS has disrupted this trend in sub-Saharan Africa. However, in recent years, HIV-associated mortality has been reduced with the introduction of widely available antiretroviral therapy (ART). Side effects of ART may lead to increased risk of cardiovascular diseases, raising the prospects of an accelerated transition towards NCD as the primary cause of death. We report population-based data to investigate changes in cause of death owing to NCD during the first 4 years after introduction of HIV treatment.
We analysed data from a demographic surveillance system in Karonga district, Malawi, from September 2004 to August 2009. ART was introduced in mid-2005. Clinician review of verbal autopsies conducted 2-6 weeks after a death was used to establish a single principal cause of death.
Over the entire period, there were 905 deaths, AIDS death rate fell from 505 to 160/100,000 person-years, and there was no evidence of an increase in NCD rates. The proportion of total deaths attributable to AIDS fell from 42% to 17% and from NCD increased from 37% to 49%.
Our findings show that 4 years after the introduction of ART into HIV care in Karonga district, all-cause mortality has fallen dramatically, with no evidence of an increase in deaths owing to NCD.
Tropical Medicine & International Health 08/2012; 17(8):e74-83. · 2.80 Impact Factor
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Sian Floyd,
Anna Molesworth,
Albert Dube, Amelia C Crampin,
Rein Houben,
Menard Chihana,
Alison Price,
Ndoliwe Kayuni,
Jacqueline Saul,
Neil French,
Judith R Glynn
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ABSTRACT: OBJECTIVE:: To quantify refusal bias due to prior HIV-testing, and its effect on HIV prevalence estimates, in general-population surveys. DESIGN:: Four annual, cross-sectional, house-to-house HIV sero-surveys conducted during 2006-2010 within a demographic surveillance population of 33,000 in northern Malawi. METHODS:: The effect of prior knowledge of HIV status on test acceptance in subsequent surveys was analysed. HIV prevalence was then estimated using ten adjustment methods, including age-standardisation; multiple imputation of missing data; a conditional probability equations approach incorporating refusal bias; using longitudinal data on previous and subsequent HIV results; including self-reported HIV status; and including linked antiretroviral therapy clinic data. RESULTS:: HIV test acceptance was 55-65% in each sero-survey. By 2009/10 79% of men and 85% of women had tested at least once. Known HIV-positive individuals were more likely to be absent, and refuse interviewing and testing. Using longitudinal data, and adjusting for refusal bias, the best estimate of HIV prevalence was 7% in men and 9% in women in 2008/9. Estimates using multiple imputation were 4.8% and 6.4% respectively. Using the conditional probability approach gave good estimates using the refusal risk ratio of HIV-positive to HIV-negative individuals observed in this study, but not when using the only previously published estimate of this ratio, even though this was also from Malawi. CONCLUSION:: As the proportion of the population who know their HIV-status increases, survey-based prevalence estimates become increasingly biased. Since an adjustment method for cross-sectional data remains elusive, sources of data with high coverage, such as ANC surveillance, remain important.
AIDS (London, England) 07/2012; · 4.91 Impact Factor
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Amelia C Crampin,
Albert Dube,
Sebastian Mboma,
Alison Price,
Menard Chihana,
Andreas Jahn,
Angela Baschieri,
Anna Molesworth,
Elnaeus Mwaiyeghele,
Keith Branson,
Sian Floyd,
Nuala McGrath,
Paul E M Fine,
Neil French,
Judith R Glynn,
Basia Zaba
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ABSTRACT: The Karonga Health and Demographic Surveillance System (Karonga HDSS) in northern Malawi currently has a population of more than 35 000 individuals under continuous demographic surveillance since completion of a baseline census (2002-2004). The surveillance system collects data on vital events and migration for individuals and for households. It also provides data on cause-specific mortality obtained by verbal autopsy for all age groups, and estimates rates of disease for specific presentations via linkage to clinical facility data. The Karonga HDSS provides a structure for surveys of socio-economic status, HIV sero-prevalence and incidence, sexual behaviour, fertility intentions and a sampling frame for other studies, as well as evaluating the impact of interventions, such as antiretroviral therapy and vaccination programmes. Uniquely, it relies on a network of village informants to report vital events and household moves, and furthermore is linked to an archive of biological samples and data from population surveys and other studies dating back three decades.
International Journal of Epidemiology 06/2012; 41(3):676-85. · 6.41 Impact Factor
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ABSTRACT: Recent UNAIDS guidelines recommend measuring concurrency 6 months before the interview date, based on overlapping partnership dates. This has theoretical advantages, but little is known about how well it can be measured in practice.
The assumptions underlying the UNAIDS measure were tested using data from a sexual behaviour survey conducted in rural northern Malawi. All resident adults aged 15-59 were eligible. Questions included self-reported concurrency and dates for all marital and nonmarital partnerships in the past 12 months.
A total of 6796 women and 5253 men were interviewed, 83 and 72% of those eligible, respectively. Since few women reported multiple partners, detailed analysis was restricted to men. Overall 19.2% [95% confidence interval (CI) 18.1-20.2] of men self-reported concurrent relationships in the past year (almost all of those with more than one partner). Using overlapping dates the estimate was 16.7% (15.7-17.7). Excluding partnerships which tied on dates (making overlap uncertain) or restricting the analysis to the three most recent partners gave similar results. The UNAIDS 6-month measure was 12.0% (11.1-12.9), and current concurrency was 11.5% (10.6-12.4). The difference between dates-based and self-reported 12-month measures was much larger for unmarried men: 11.1% (9.7-12.4) self-reported; 7.1% (6.9-8.2) on dates. Polygyny (15% of married men) and the longer duration of relationships stabilized the estimates for married men. Nonmarital partnerships were under-reported, particularly those starting longer ago.
The difficulties of recall of dates for relationships, and under-reporting of partners lead to underestimation of concurrency using date-based measures. Self-reported concurrency is much easier to measure and appears more complete.
AIDS (London, England) 05/2012; 26(8):977-85. · 4.91 Impact Factor
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David Maman,
Judith R Glynn, Amelia C Crampin,
Katharina Kranzer,
Jacqueline Saul,
Andreas Jahn,
Venance Mwinuka,
Msenga Hc Ngwira,
Hazzie Mvula,
Fipson Munthali,
Nuala McGrath
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ABSTRACT: Antiretroviral (ART) scale-up in Malawi has been achieved on a large scale based mainly on clinical criteria. Simple markers of prognosis are useful, and we investigated the value of very early anthropometric changes in predicting mortality.
Adult patients who initiated ART in Karonga District, northern Malawi, between September 2005 and August 2006 were included in a prospective cohort study, and followed for up to one year. We used Cox regression to examine the association between anthropometric changes at 2 and 6 weeks and deaths within the first year. 573 patients were included, of whom 59% were women; the median age at initiation was 37 and 64% were in WHO stage 4. Both body mass index (BMI) and mid-upper arm circumference (MUAC) increased linearly with increased time on ART, and were closely correlated with each other. There were 118 deaths. After 2 weeks on ART, a BMI increase of <0.5 kg/m(2) (HR 2.47, 95%CI 1.24-4.94, p=0.005) or a MUAC increase of <0.5cm (HR 2.79, 95%CI 1.19-6.55, p=0.008) were strong predictors of death, and these associations were stronger after adjusting for baseline charactertistics. Similar results were found after 6 weeks on ART.
Very early anthropometric changes, after 2 and 6 weeks on ART, are strong predictors of survival, independent of baseline characteristics. This should help identify patients requiring more detailed assessment where facilities are limited. MUAC is particularly valuable, requiring the simplest equipment and being appropriate for patients who have problems standing.
The Open AIDS Journal 01/2012; 6:36-44.
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Maeve K Lalor,
Sian Floyd,
Patricia Gorak-Stolinska,
Anne Ben-Smith,
Rosemary E Weir,
Steven G Smith,
Melanie J Newport,
Rose Blitz,
Hazzie Mvula,
Keith Branson,
Nuala McGrath, Amelia C Crampin,
Paul E Fine,
Hazel M Dockrell
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ABSTRACT: BCG vaccination of infants is thought to provide good protection in all settings. This study investigated whether Malawian infants made weaker responses across a cytokine panel after BCG vaccination, compared with UK infants.
Diluted whole-blood samples were cultured with Mycobacterium tuberculosis purified protein derivative for 6 days from BCG-vaccinated infants 3 months (n = 40 Malawi, 28 UK) and 12 months (n = 34 Malawi, 26 UK) after vaccination, and also from UK unvaccinated infants (n = 9 at 3 months, n = 10 at 12 months). Forty-two cytokines were measured in supernatants using a multiplex bead array assay. Principal component analysis was used to summarize the overall patterns in cytokine responses.
We found differences in median responses in 27 of the 42 cytokines: 7 higher in the UK and 20 higher in Malawi. The cytokines with higher responses in the UK were all T helper 1 related. The cytokines with higher responses in Malawi included innate proinflammatory cytokines, regulatory cytokines, interleukin 17, T helper 2 cytokines, chemokines, and growth factors. Principal component analysis separated the BCG-vaccinated infants from Malawi from the UK vaccinated infants and from the unvaccinated infants.
Malawian infants make cytokine responses following BCG vaccination, but the cytokine profile is different from that in the UK. The different biosignatures following BCG vaccination in the 2 settings may indicate variability in the protective efficacy of infant BCG vaccination.
The Journal of Infectious Diseases 10/2011; 204(7):1075-85. · 6.41 Impact Factor
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Thorsten Thye,
Fredrik O Vannberg,
Sunny H Wong,
Ellis Owusu-Dabo,
Ivy Osei,
John Gyapong,
Giorgio Sirugo,
Fatou Sisay-Joof,
Anthony Enimil,
Margaret A Chinbuah, [......],
Philip C Hill,
Melanie Newport,
Christian Lienhardt,
Richard A Adegbola,
Tumani Corrah,
Andreas Ziegler,
Andrew P Morris,
Christian G Meyer,
Rolf D Horstmann,
Adrian V S Hill
Nature Genetics 01/2011; 43(10):1040. · 35.53 Impact Factor
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Judith R Glynn,
Ndoliwe Kayuni,
Emmanuel Banda,
Fiona Parrott,
Sian Floyd,
Monica Francis-Chizororo,
Misheck Nkhata,
Clare Tanton,
Joanne Hemmings,
Anna Molesworth, Amelia C Crampin,
Neil French
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ABSTRACT: Sexual behaviour surveys are widely used, but under-reporting of particular risk behaviours is common, especially by women. Surveys in whole populations provide an unusual opportunity to understand the extent and nature of such under-reporting.
All consenting individuals aged between 15 and 59 within a demographic surveillance site in northern Malawi were interviewed about their sexual behaviour. Validity of responses was assessed by analysis of probing questions; by comparison of results with in-depth interviews and with Herpes simplex type-2 (HSV-2) seropositivity; by comparing reports to same sex and opposite sex interviewers; and by quantifying the partnerships within the local community reported by men and by women, adjusted for response rates.
6,796 women and 5,253 men (83% and 72% of those eligible) consented and took part in sexual behaviour interviews. Probing questions and HSV-2 antibody tests in those who denied sexual activity identified under-reporting for both men and women. Reports varied little by sex or age of the interviewer. The number of marital partnerships reported was comparable for men and women, but men reported about 4 times as many non-marital partnerships. The discrepancy in reporting of non-marital partnerships was most marked for married women (men reported about 7 times as many non-marital partnerships with married women as were reported by married women themselves), but was only apparent in younger married women.
We have shown that the under-reporting of non-marital partnerships by women was strongly age-dependent. The extent of under-reporting of sexual activity by young men was surprisingly high. The results emphasise the importance of triangulation, including biomarkers, and the advantages of considering a whole population.
PLoS ONE 01/2011; 6(7):e22840. · 4.09 Impact Factor
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ABSTRACT: Treatment seeking delays among people living with HIV have adverse consequences for outcome. Gender differences in treatment outcomes have been observed in sub-Saharan Africa.
To better understand antiretroviral treatment (ART) seeking behaviour in HIV-infected adults in rural Malawi.
Qualitative interviews with male and female participants in an ART cohort study at a treatment site in rural northern Malawi triangulated with analysis of baseline clinical and demographic data for 365 individuals attending sequentially for ART screening between January 2008 and September 2009.
43% of the cohort presented with late stage HIV disease classified as WHO stage 3/4. Respondents reported that women's frequency of testing, health awareness and commitment to children led to earlier ART uptake and that men's commitment to wider social networks of influence, masculine ideals of strength, and success with sexual and marital partners led them to refuse treatment until they were sick. Quantitative analysis of the screening cohort provided supporting evidence for these expressed views. Overall, male gender (adjusted OR 2.3, 95% CI1.3-3.9) and never being married (adjusted OR 4.1, 95% CI1.5-11.5) were risk factors for late presentation, whereas having ≥3 dependent children was associated with earlier presentation (adjusted OR 0.31, 95% CI0.15-0.63), compared to those with no dependent children.
Gender-specific barriers and facilitators operate throughout the whole process of seeking care. Further efforts to enrol men into care earlier should focus on the masculine characteristics that they value, and the risks to these of severe health decline. Our results emphasise the value of exploring as well as identifying behavioural correlates of late presentation.
PLoS ONE 01/2011; 6(11):e27917. · 4.09 Impact Factor
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ABSTRACT: ABSTRACT:
Drug resistance testing before initiation of, or during, antiretroviral therapy (ART) is not routinely performed in resource-limited settings. High levels of viral resistance circulating within the population will have impact on treatment programs by increasing the chances of transmission of resistant strains and treatment failure. Here, we investigate Drug Resistance Mutations (DRMs) from blood samples obtained at regular intervals from patients on ART (Baseline-22 months) in Karonga District, Malawi. One hundred and forty nine reverse transcriptase (RT) consensus sequences were obtained via nested PCR and automated sequencing from blood samples collected at three-month intervals from 75 HIV-1 subtype C infected individuals in the ART programme.
Fifteen individuals showed DRMs, and in ten individuals DRMs were seen from baseline samples (reported to be ART naïve). Three individuals in whom no DRMs were observed at baseline showed the emergence of DRMs during ART exposure. Four individuals who did show DRMs at baseline showed additional DRMs at subsequent time points, while two individuals showed evidence of DRMs at baseline and either no DRMs, or different DRMs, at later timepoints. Three individuals had immune failure but none appeared to be failing clinically.
Despite the presence of DRMs to drugs included in the current regimen in some individuals, and immune failure in three, no signs of clinical failure were seen during this study. This cohort will continue to be monitored as part of the Karonga Prevention Study so that the long-term impact of these mutations can be assessed. Documenting proviral population is also important in monitoring the emergence of drug resistance as selective pressure provided by ART compromises the current plasma population, archived viruses can re-emerge.
AIDS Research and Therapy 01/2011; 8(1):38. · 2.54 Impact Factor
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ABSTRACT: To assess the performance of rapid HIV antibody tests when used as part of a home-based community wide counseling and testing strategy in northern Malawi.
A cross-sectional population survey of HIV infection, 2007 to 2008.
Adults aged 15 years or older in a demographic surveillance area were counseled and then offered an HIV test at their home by government-certified counselors. Two initial rapid tests (Determine and Uni-Gold) were performed on all samples and a third, tie-breaker test (SD Bioline) used to resolve discordant results. All people who wanted to know were posttest-counseled and informed of their results with referral to local clinical services if found to be HIV-positive. Laboratory quality control comprised retesting all positive and every tenth negative venous blood sample collected.
A total of 10,819 adults provided venous blood samples for HIV testing, of whom 7.5% (813) were HIV-positive. The accuracy of the parallel testing strategy used was high with 99.6% sensitivity, 100.0% specificity, 99.9% positive predictive value, and 99.9% negative predictive value.
Face-to-face rapid testing by health personnel with minimum training at the client's home performs well when used on a wide scale in the community setting.
JAIDS Journal of Acquired Immune Deficiency Syndromes 12/2010; 55(5):625-30. · 4.43 Impact Factor
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ABSTRACT: The occurrence of mixed infections of Mycobacterium tuberculosis is no longer disputed. However, their frequency, and the impact they may have on our understanding of tuberculosis (TB) pathogenesis and epidemiology, remains undetermined. Most previous studies of frequency applied genotyping techniques to cultured M. tuberculosis isolates and found mixed infections to be rare. PCR-based techniques may be more sensitive for detecting multiple M. tuberculosis strains and can be applied to sputum. To date, one study in South Africa has used a PCR approach and suggested that mixed infection could be common. We investigated mixed infections in northern Malawi using two lineage-specific PCR assays targeting the Latin American-Mediterranean (LAM) and Beijing lineages. Compared with spoligotyping, the specificity and sensitivity of both assays was 100%. From 160 culture-positive sputa, mixed LAM and non-LAM strains were detected in 4 sputa belonging to 2 (2.8%) patients. Both patients were HIV positive, with no history of TB. Cultured isolates from both patients showed only LAM by PCR and spoligotyping. In a set of 377 cultured isolates, 4 were mixed LAM and non-LAM. Only one showed evidence of more than one M. tuberculosis strain using IS6110-based restriction fragment length polymorphism (IS6110-RFLP) and spoligotyping analyses. Corresponding sputa for the 4 isolates were unavailable. Mixed Beijing and non-Beijing strains were not detected in this study. Mixed infections appear to be rare in our setting and are unlikely to affect findings based on DNA fingerprinting data. Molecular methods, which avoid the selective nature of culture and target distinct strains, are well suited to detection of mixed infections.
Journal of clinical microbiology 10/2010; 48(12):4512-8. · 4.16 Impact Factor
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Nuala McGrath,
Judith R Glynn,
Jacqueline Saul,
Katharina Kranzer,
Andreas Jahn,
Frank Mwaungulu,
Msenga H C Ngwira,
Hazzie Mvula,
Fipson Munthali,
Venance Mwinuka,
Lorren Mwaungulu,
Paul E M Fine, Amelia C Crampin
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ABSTRACT: Routine ART programme statistics generally only provide information about individuals who start treatment. We aimed to investigate the outcome of those who are eligible but do not start ART in the Malawi programme, factors associated with this dropout, and reasons for not starting treatment, in a prospective cohort study.
Individuals having a first screening visit at the ART clinic at Karonga District Hospital, northern Malawi, between September 2005 and July 2006 were interviewed. Study follow-up to identify treatment outcomes was conducted at the clinic and in the community. Logistic regression models were used to identify factors associated with dropout before ART initiation among participants identified as clinically eligible for ART.
88 participants eligible for ART at their first screening visit (out of 633, 13.9%) defaulted before starting ART. Participants with less education, difficulties in dressing, a more delayed ART initiation appointment, and mid-upper arm circumference (MUAC) < 22 cm were significantly less likely to have visited the clinic subsequently. Thirty-five (58%) of the 60 participants who defaulted and were tracked at home had died, 21 before their ART initiation appointment.
MUAC and reported difficulties in dressing may provide useful screening indicators to identify sicker ART-eligible individuals at high risk of dropping out of the programme who might benefit from being brought back quickly or admitted to hospital for observation. Individuals with less education may need adapted health information at screening. Deaths of ART-eligible individuals occurring prior to ART initiation are not included in routine programme statistics. Considering all those who are eligible for ART as a denominator for programme indicators would help to highlight this vulnerable group, in order to identify new opportunities for further improving ART programmes.
BMC Public Health 10/2010; 10:601. · 2.00 Impact Factor
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Thorsten Thye,
Fredrik O Vannberg,
Sunny H Wong,
Ellis Owusu-Dabo,
Ivy Osei,
John Gyapong,
Giorgio Sirugo,
Fatou Sisay-Joof,
Anthony Enimil,
Margaret A Chinbuah, [......],
Philip C Hill,
Melanie Newport,
Christian Lienhardt,
Richard A Adegbola,
Tumani Corrah,
Andreas Ziegler,
Andrew P Morris,
Christian G Meyer,
Rolf D Horstmann,
Adrian V S Hill
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ABSTRACT: We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.8 x 10(-9), odds ratio = 1.19, 95% CI = 1.13-1.27). Our study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.
Nature Genetics 09/2010; 42(9):739-41. · 35.53 Impact Factor
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Chiea C Khor,
Fredrik O Vannberg,
Stephen J Chapman,
Haiyan Guo,
Sunny H Wong,
Andrew J Walley,
Damjan Vukcevic,
Anna Rautanen,
Tara C Mills,
Kwok-Chiu Chang, [......],
Kevin Marsh,
Kathryn Maitland,
J Anthony Scott,
Thomas N Williams,
James A Berkley,
Sian Floyd,
Nelson L S Tang,
Paul E M Fine,
Denise L M Goh,
Adrian V S Hill
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ABSTRACT: The interleukin-2-mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling.
Using a case-control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections.
We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P=3.8x10(-11) for all comparisons), with -292 accounting for most of the association signal (P=4.58x10(-7)). Peripheral-blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production--that is, 25 to 40% less CISH expression.
Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.
New England Journal of Medicine 06/2010; 362(22):2092-101. · 53.30 Impact Factor
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ABSTRACT: To estimate rates of recurrent tuberculosis due to reinfection and relapse, by HIV status, in a general population.
Long-term cohort study in Karonga district, rural Malawi.
All tuberculosis patients with culture-proven disease in Karonga district were followed up after treatment. HIV testing was offered and all Mycobacterium tuberculosis isolates were fingerprinted using IS6110 RFLP. Fingerprints from initial and recurrent disease episodes were compared to distinguish relapse and reinfection: a second episode was considered a relapse if the fingerprint was identical or differed by only 1-4 bands and was the first occurrence of that pattern in the population. Rates of and risk factors for recurrence, reinfection disease, and relapse were estimated using survival analysis and Poisson regression.
Five hundred and eighty-four culture-positive episodes of tuberculosis were diagnosed and treatment was completed during 1995-2003 in patients with known HIV status; 53 culture-positive recurrences occurred by May 2005. Paired fingerprints were available for 39 of these. Reinfections accounted for 1/16 recurrences in HIV-negative and 12/23 in HIV-positive individuals. Rates of relapse were similar in HIV-positive and HIV-negative individuals. Using multiple imputation to allow for missing fingerprint information, the rate of reinfection disease in HIV-positive individuals was 2.2/100 person-years, and in HIV-negative individuals 0.4/100 person-years.
HIV increases the rate of recurrent tuberculosis in this setting by increasing the rate of reinfection disease, not relapse.
AIDS (London, England) 01/2010; 24(3):417-26. · 4.91 Impact Factor
