Randomised controlled clinical trial of increased dose and frequency of albendazole and ivermectin on Wuchereria bancrofti microfilarial clearance in northern Malawi.

BACKGROUND: In Africa, albendazole and ivermectin are currently used in combination for annual mass drug administration (MDA) for lymphatic filariasis (LF) elimination. Rapid and sustained clearance is desirable for public health impact and elimination of LF. Increasing the dose and/or frequency of albendazole and ivermectin treatment may be more effective in clearing microfilariae than standard MDA. METHODS: We conducted a randomised controlled open label trial in northern Malawi comparing three modified treatment groups to standard dosage of ivermectin and albendazole in adults with confirmed circulating LF antigen and microfilaria. Participants were followed-up every 6 months for 2 years for repeat microfilarial counts and safety assessments. RESULTS: A total of 1851 adults were screened and 70 with microfilarial counts >80 microfilariae/ml were randomised. All treatment groups achieved a significant reduction of microfilariae levels by 12- and 24-months of follow-up. Doubling the standard dose and administering it twice yearly showed a non-significant tendency towards faster and more complete clearance. There were no serious adverse reactions. CONCLUSIONS: In this small study, all regimens effectively cleared microfilaria. Standard treatment may be adequate in settings like Malawi but not in all endemic settings and larger studies are required to demonstrate benefit of higher dosages. [ClinicalTrials.gov identifier: NCT01213576].

Exploring barriers to the delivery of cervical cancer screening and early treatment services in Malawi: some views from service providers.

BACKGROUND: Cervical cancer is the most common reproductive health cancer in Malawi. In most cases, women report to health facilities when the disease is in its advanced stage. In this study, we investigate service providers' perceptions about barriers for women to access cervical cancer screening and early treatment services in Malawi. METHODS: We conducted in-depth interviews with 13 district coordinators and 40 service providers of cervical cancer screening and early treatment services in 13 districts in Malawi. The study was conducted in 2012. The district coordinators helped the research team identify the health facilities which were providing cervical cancer screening and early treatment services. RESULTS: Almost all informants reported that cervical cancer was a major public health problem in their districts and that prevention efforts for this disease were being implemented. They were aware of the test and treat approach using visual inspection with acetic acid (VIA). They, however, said that the delivery of cervical cancer screening and early treatment services was compromised because of factors such as gross shortage of staff, lack of equipment and supplies, the lack of supportive supervision, and the use of male service providers. Informants added that the lack of awareness about the disease among community members, long distances to health facilities, the lack of involvement of husbands, and prevailing misperceptions about the disease (eg, that it is caused by the exposure to the VIA process) affect the uptake of these services. CONCLUSION: While progress has been made in the provision of cervical cancer screening and early treatment services in Malawi, a number of factors affect service delivery and uptake. There is a need to continue creating awareness among community members including husbands and also addressing identified barriers such as shortage of staff and supplies in order to improve uptake of services.

Zero adjusted models with applications to analysing helminths count data.

BACKGROUND: It is common in public health and epidemiology that the outcome of interest is counts of events occurrence. Analysing these data using classical linear models is mostly inappropriate, even after transformation of outcome variables due to overdispersion. Zero-adjusted mixture count models such as zero-inflated and hurdle count models are applied to count data when over-dispersion and excess zeros exist. Main objective of the current paper is to apply such models to analyse risk factors associated with human helminths (S. haematobium) particularly in a case where there's a high proportion of zero counts. METHODS: The data were collected during a community-based randomised control trial assessing the impact of mass drug administration (MDA) with praziquantel in Malawi, and a school-based cross sectional epidemiology survey in Zambia. Count data models including traditional (Poisson and negative binomial) models, zero modified models (zero inflated Poisson and zero inflated negative binomial) and hurdle models (Poisson logit hurdle and negative binomial logit hurdle) were fitted and compared. RESULTS: Using Akaike information criteria (AIC), the negative binomial logit hurdle (NBLH) and zero inflated negative binomial (ZINB) showed best performance in both datasets. With regards to zero count capturing, these models performed better than other models. CONCLUSION: This paper showed that zero modified NBLH and ZINB models are more appropriate methods for the analysis of data with excess zeros. The choice between the hurdle and zero-inflated models should be based on the aim and endpoints of the study.

Campylobacter infection in children in Malawi is common and is frequently associated with enteric virus co-infections.

BACKGROUND: Campylobacter species are the most common cause of bacterial gastroenteritis in the developed world. However, comparatively few studies have determined the epidemiological features of campylobacteriosis in resource-poor settings. METHODS: A total of 1,941 faecal specimens collected from symptomatic (diarrhoeic) children and 507 specimens from asymptomatic (non-diarrhoeic) children hospitalised in Blantyre, Malawi, between 1997 and 2007, and previously tested for the presence of rotavirus and norovirus, was analysed for C. jejuni and C. coli using a real time PCR assay. RESULTS: Campylobacter species were detected in 415/1,941 (21%) of diarrhoeic children, with C. jejuni accounting for 85% of all cases. The median age of children with Campylobacter infection was 11 months (range 0.1-55 months), and was significantly higher than that for children with rotavirus and norovirus (6 months and 7 months respectively; P<0.001). Co-infection with either rotavirus or norovirus was noted in 41% of all cases in the diarrhoeic group. In contrast, the detection rate of Campylobacter in the non-diarrhoeic group was 14%, with viral co-infection identified in 16% of children with Campylobacter. There was no association between Campylobacter detection rate and season over the 10 year period. DISCUSSION: Using molecular detection methodology in hospitalised Malawian children, we have demonstrated a high prevalence of Campylobacter infection, with frequent viral co-infection. The burden of Campylobacter infection in young African children may be greater than previously recognised.

Efficacy of human rotavirus vaccine against severe gastroenteritis in Malawian children in the first two years of life: a randomized, double-blind, placebo controlled trial.

Rotavirus gastroenteritis is a major cause of morbidity and mortality among African infants and young children. A phase III, placebo-controlled, multi-centre clinical trial of a live, oral G1P[8] human rotavirus vaccine (RIX4414) undertaken in Malawi and South Africa significantly reduced the incidence of severe rotavirus gastroenteritis in the first year of life. We now report on vaccine efficacy in the Malawi cohort of children who were followed into the second year of life. A total of 1773 healthy infants were enrolled in Blantyre, Malawi into three groups. Two groups received three doses of RIX4414 or placebo at age 6, 10, and 14 weeks and the third group received placebo at 6 weeks and RIX4414 at age 10 and 14 weeks. Subjects were followed by weekly home visits for episodes of gastroenteritis until 1 year of age, and were then re-consented for further follow-up to 18-24 months of age. Severity of gastroenteritis episodes was graded according to the Vesikari scoring system. Seroconversion for anti-rotavirus IgA was determined on a subset of children by using ELISA on pre- and post-vaccine blood samples. Rotavirus VP7 (G) and VP4 (P) genotypes were determined by RT-PCR. A total of 70/1030 (6.8%, 95% CI 5.3-8.5) subjects in the pooled (2 dose plus 3 dose) RIX4414 group compared with 53/483 (11.0%, 8.3-14.1) subjects in the placebo group developed severe rotavirus gastroenteritis in the entire follow-up period (vaccine efficacy 38.1% (9.8-57.3)). The point estimate of efficacy in the second year of life (17.6%; -59.2 to 56.0) was lower than in the first year of life (49.4%; 19.2-68.3). There were non-significant trends towards a higher efficacy in the second year of life among children who received the three-dose schedule compared with the two-dose schedule, and a higher anti-rotavirus IgA seroresponse rate in the three-dose RIX4414 group. Rotavirus strains detected included genotype G12 (31%); G9 (23%); and G8 (18%); only 18% of strains belonged to the G1P[8] genotype. While the optimal dosing schedule of RIX4414 in African infants requires further investigation, vaccination with RIX4414 significantly reduced the incidence of severe gastroenteritis caused by diverse rotavirus strains in an impoverished African population with high rotavirus disease burden in the first two years of life.

Epidemiology of rotavirus infection in children in Blantyre, Malawi, 1997-2007.

Acute gastroenteritis caused by rotavirus infection is an important cause of morbidity and mortality among infants and young children in Africa. From 1997 through 2007, we enrolled 3740 children <5 years of age with acute gastroenteritis who received hospital care at the Queen Elizabeth Central Hospital in Blantyre, Malawi. Group A rotavirus was detected in fecal specimens by enzyme immunoassay. Rotavirus strains were characterized for VP7 (G) and VP4 (P) types with use of reverse-transcription polymerase chain reaction. Overall, rotavirus was detected in one-third of children. The median age of children with rotavirus gastroenteritis was 7.8 months, compared with 10.9 months for those without rotavirus in stool specimens (P > .001). Rotavirus circulated throughout the year, with the detection proportion greatest during the dry season (from May through October). A total of 15 single rotavirus strain types were detected during the study period, with genotypes P[8]G1, P[6]G8, P[4]G8, P[6]G1, P[8]G3, and P[6]G9 comprising 83% of all strains characterized. Serotype G12 was detected for the first time in Blantyre during the final 2 years of study. Zoonotic transmission and viral reassortment contributed to the rich diversity of strains identified. Current rotavirus vaccines have the potential to greatly reduce the rotavirus disease burden in Malawi, but they will be required to protect against a broad range of rotavirus serotypes in a young population with year-round rotavirus exposure.

HIV and the risk of tuberculosis due to recent transmission over 12 years in Karonga District, Malawi.

Tuberculosis (TB) patients with strains common to other recent cases ('clustering') suggest recent transmission. HIV status and age may affect proportions clustered. We investigated TB clustering by HIV and age in a population-based study in Malawi. Among 746 patients, HIV infection increased the proportion clustered. Sex-period-adjusted odds ratios for the association of HIV and clustering were 1.26 (95% CI 0.4-4.1) for ages 15-25 years, 1.40 (0.9-2.3) for 25-50 years and 10.44 (2.3-47.9) for >50 years and remained stable over two periods examined. These results suggest that HIV increases the proportion of TB due to recent transmission in the elderly.

Serotype g12 rotaviruses, Lilongwe, Malawi.

To assess diversity of rotavirus strains in Lilongwe, Malawi, we conducted a cross-sectional study of children with acute gastroenteritis, July 2005-June 2007. Serotype G12 was identified in 30 (5%) of 546 rotavirus-positive fecal specimens. The G12 strain possessed multiple electropherotypes and P-types, but their viral protein 7 sequences were closely related, indicating that reassortment has occurred.

Determinants of cluster size in large, population-based molecular epidemiology study of tuberculosis, northern Malawi.

Tuberculosis patients with identical strains of Mycobacterium tuberculosis are described as clustered. Cluster size may depend on patient or strain characteristics. In a 7-year population-based study of tuberculosis in Karonga District, Malawi, clusters were defined by using IS6110 restriction fragment length polymorphism, excluding patterns with <5 bands. Spoligotyping was used to compare strains with an international database. Among 682 clustered patients, cluster size ranged from 2 to 37. Male patients, young adults, and town residents were over-represented in large clusters. Cluster size was not associated with HIV status or death from tuberculosis. Spoligotypes from 9 (90%) of 10 large cluster strains were identical or very similar (1 spacer different) to common spoligotypes found elsewhere, compared with 37 (66%) of 56 of those from nonclustered patients (p = 0.3). Large clusters were associated with factors likely to be related to social mixing, but spoligotypes of common strains in this setting were also common types elsewhere, consistent with strain differences in transmissibility.

Use of antenatal clinic surveillance to assess the effect of sexual behavior on HIV prevalence in young women in Karonga district, Malawi.

BACKGROUND: Antenatal clinic (ANC) surveillance is the primary source of HIV prevalence estimates in low-resource settings. In younger women, prevalence approximates incidence. Sexual behavior monitoring to explain HIV distribution and trends is seldom attempted in ANC surveys. We explore the use of marital history in ANC surveillance as a proxy for sexual behavior. METHODS: Five ANC clinics in a rural African district participated in surveillance from 1999 to 2004. Unlinked anonymous HIV testing and marital history interviews (including age at first sex and socioeconomic variables) were conducted. Data on women aged <25 years were analyzed. RESULTS: Inferred sexual exposure before marriage and after first marriage increased the adjusted odds of infection with HIV by more than 0.1 for each year of exposure. Increasing years within a first marriage did not increase HIV risk. After adjusting for age, women in more recent birth cohorts were less likely to be infected. CONCLUSIONS: Marital status is useful behavioral information and can be collected in ANC surveys. Exposure in an ongoing first marriage did not increase the odds of infection with HIV in this age group. HIV prevalence decreased over time in young women. ANC surveillance programs should develop proxy sexual behavior questions, particularly in younger women.

The importance of recent infection with Mycobacterium tuberculosis in an area with high HIV prevalence: a long-term molecular epidemiological study in Northern Malawi.

BACKGROUND: The proportion of cases of tuberculosis due to recent infection can be estimated in long-term population-based studies using molecular techniques. Here, we present what is, to our knowledge, the first such study in an area with high human immunodeficiency virus (HIV) prevalence. METHODS: All patients with tuberculosis in Karonga District, Malawi, were interviewed. Isolates were genotyped using restriction-fragment-length polymorphism (RFLP) patterns. Strains were considered to be "clustered" if at least 1 other patient had an isolate with an identical pattern. RESULTS: RFLP results were available from 83% of culture-positive patients from late 1995 to early 2003. When strains with <5 bands were excluded, 72% (682/948) were clustered. Maximum clustering was reached using a 4-year window, with an estimated two-thirds of cases due to recent transmission. The proportion clustered decreased with age and varied by area of residence. In older adults, clustering was less common in men and more common in patients who were HIV positive (adjusted odds ratio, 5.1 [95% confidence interval, 2.1-12.6]). CONCLUSIONS: The proportion clustered found in the present study was among the highest in the world, suggesting high rates of recent transmission. The association with HIV infection in older adults may suggest that HIV has a greater impact on disease caused by recent transmission than on that caused by reactivation.

Mycobacterium tuberculosis Beijing genotype, northern Malawi.

In a 7-year population-based study in Malawi, we showed that Beijing genotype tuberculosis (TB) increased as a proportion of TB cases. All the Beijing genotype strains were fully drug sensitive. Contact histories, TB type, and case-fatality rates were similar for Beijing and non-Beijing genotype TB.

DNA fingerprint changes in tuberculosis: reinfection, evolution, or laboratory error?

BACKGROUND: DNA fingerprint patterns of Mycobacterium tuberculosis strains vary within individuals and between epidemiologically linked individuals because of pattern evolution, new infections, and laboratory error. We explored the importance of these factors. METHODS: Cultures from individuals in northern Malawi who had been diagnosed with tuberculosis (TB) during 1996-2001 were fingerprinted with restriction fragment-length polymorphism (RFLP). Probable laboratory error was inferred by use of dates or isolated positive cultures. Pattern evolution was explored within and between individuals, and the relative importance of relapse and reinfection was estimated in individuals with recurrent TB. RESULTS: RFLP results were available for 930 isolates from 806 individuals. The maximum laboratory-error rate was 3.9%. Pattern evolution was more common in linked individuals (17%) than on relapse (11%) or during treatment (3%). Twenty individuals had recurrent TB after completing treatment: in human immunodeficiency virus (HIV)-positive individuals, 7 of 12 recurrences were due to reinfection, compared with 0 of 8 in HIV-negative individuals (P=.01). CONCLUSIONS: The rate of DNA fingerprint-pattern evolution is not linear, and rates of change calculated from repeat cultures within individuals may not be applicable to transmission between individuals. The high proportion of recurrence due to reinfection found in HIV-positive individuals suggests that secondary prophylaxis and/or antiretroviral treatments are needed for such individuals.

Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988-2001.

OBJECTIVE: To document the changing incidence and patterns of tuberculosis (TB) in rural Africa and the extent to which they are influenced by HIV. METHODS: As part of longstanding epidemiological studies in Karonga District, Malawi, a series of case control studies of TB and HIV were conducted from 1988 onwards. Data from these studies, from a total population survey, and from the Malawi national census have been used to reconstruct the changes in the TB epidemic in the area from 1988 to 2001, examining the role of HIV. RESULTS: The incidence of all confirmed TB, and of new smear-positive TB, in adults increased to peak in the late 1990s but appears to have decreased since. Two-thirds of cases are now HIV positive. The rise in incidence was greatest in the 30-44-year-old age group and was particularly marked for women, leading to a decrease in the male : female ratio for TB incidence from 1.3 to 0.8. The proportion of new smear-positive TB cases attributable to HIV increased from 17% in 1988-1990 to 57% in 2000-2001, but the estimated rate of smear-positive TB in the absence of HIV decreased from 0.78/1000 to 0.45/1000. CONCLUSIONS: Without HIV the incidence of smear-positive TB would have fallen in this population. Instead it has risen and is predominantly affecting young adults and women. There is some evidence that the HIV-associated TB epidemic may have passed its peak.

Trends and measurement of HIV prevalence in northern Malawi.

BACKGROUND: Most data on HIV prevalence in Malawi come from antenatal clinic (ANC) surveillance and are, therefore, subject to bias. OBJECTIVES: HIV prevalence and risk factors were measured using population-based data to assess the accuracy of ANC surveillance and changes in prevalence and risk factors for HIV over time. METHODS: HIV prevalence was measured in 1988-1993 and 1998-2001 in community controls from case-control studies of mycobacterial disease in Karonga District, Malawi. ANC surveillance studies in the district began in 1999. RESULTS: Age and area-standardized HIV prevalence in women aged 15-49 years in the community was 3.9% in 1988-1990, 12.5% in 1991-1993 and 13.9% in 1998-2001. For men, HIV prevalence was 3.7%, 9.2% and 11.4% in the same periods. In 1988-1993, HIV positivity was associated with occupations other than farming, with increased schooling and being born outside Karonga District. In 1998-2001, non-farmers were still at higher risk but the other associations were not seen. The age- and area-adjusted HIV prevalence in the ANC in 1999-2001 was 9.2%. The underestimate can be explained largely by marriage and mobility. Reduced fertility in HIV-positive individuals was demonstrated in both ANC and community populations. A previously recommended parity-based adjustment gave an estimated female HIV prevalence of 15.0%. CONCLUSIONS: HIV prevalence has increased and continues to be higher in non-farmers. The increase is particularly marked in those with no education. ANC surveillance underestimated HIV prevalence in the female population in all but the youngest age group. Although there were differences in sociodemographic factors, a parity-based adjustment gave a reasonable estimate of female HIV prevalence.