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author:("kazem, Peter")
1.  Improved identification and enrolment into care of HIV-exposed and -infected infants and children following a community health worker intervention in Lilongwe, Malawi 
Early identification and entry into care is critical to reducing morbidity and mortality in children with HIV. The objective of this report is to describe the impact of the Tingathe programme, which utilizes community health workers (CHWs) to improve identification and enrolment into care of HIV-exposed and -infected infants and children.
Three programme phases are described. During the first phase, Mentorship Only (MO) (March 2007–February 2008) on-site clinical mentorship on paediatric HIV care was provided. In the second phase, Tingathe-Basic (March 2008–February 2009), CHWs provided HIV testing and counselling to improve case finding of HIV-exposed and -infected children. In the final phase, Tingathe-PMTCT (prevention of mother-to-child transmission) (March 2009–February 2011), CHWs were also assigned to HIV-positive pregnant women to improve mother-infant retention in care. We reviewed routinely collected programme data from HIV testing registers, patient mastercards and clinic attendance registers from March 2005 to March 2011.
During MO, 42 children (38 HIV-infected and 4 HIV-exposed) were active in care. During Tingathe-Basic, 238 HIV-infected children (HIC) were newly enrolled, a six-fold increase in rate of enrolment from 3.2 to 19.8 per month. The number of HIV-exposed infants (HEI) increased from 4 to 118. During Tingathe-PMTCT, 526 HIC were newly enrolled over 24 months, at a rate of 21.9 patients per month. There was also a seven-fold increase in the average number of exposed infants enrolled per month (9.5–70 patients per month), resulting in 1667 enrolled with a younger median age at enrolment (5.2 vs. 2.5 months; p<0.001).
During the Tingathe-Basic and Tingathe-PMTCT periods, CHWs conducted 44,388 rapid HIV tests, 7658 (17.3%) in children aged 18 months to 15 years; 351 (4.6%) tested HIV-positive. Over this time, 1781 HEI were enrolled, with 102 (5.7%) found HIV-infected by positive PCR. Additional HIC entered care through various mechanisms (including positive linkage by CHWs and transfer-ins) such that by February 2011, a total of 866 HIC were receiving care, a 23-fold increase from 2008.
A multipronged approach utilizing CHWs to conduct HIV testing, link HIC into care and provide support to PMTCT mothers can dramatically improve the identification and enrolment into care of HIV-exposed and -infected children.
PMCID: PMC4287633  PMID: 25571857
case finding; linkage to care; children; HIV; paediatrics; Africa; community health workers; HIV-exposed infants
2.  Electronic data capture in a rural African setting: evaluating experiences with different systems in Malawi 
Global Health Action  2014;7:10.3402/gha.v7.25878.
As hardware for electronic data capture (EDC), such as smartphones or tablets, becomes cheaper and more widely available, the potential for using such hardware as data capture tools in routine healthcare and research is increasing.
We aim to highlight the advantages and disadvantages of four EDC systems being used simultaneously in rural Malawi: two for Android devices (CommCare and ODK Collect), one for PALM and Windows OS (Pendragon), and a custom-built application for Android (Mobile InterVA – MIVA).
We report on the personal field and development experience of fieldworkers, project managers, and EDC system developers.
Fieldworkers preferred using EDC to paper-based systems, although some struggled with the technology at first. Highlighted features include in-built skip patterns for all systems, and specifically the ‘case’ function that CommCare offers. MIVA as a standalone app required considerably more time and expertise than the other systems to create and could not be customised for our specific research needs; however, it facilitates standardised routine data collection. CommCare and ODK Collect both have user-friendly web-interfaces for form development and good technical support. CommCare requires Internet to build an application and download it to a device, whereas all steps can be done offline with ODK Collect, a desirable feature in low connectivity settings. Pendragon required more complex programming of logic, using a Microsoft Access application, and generally had less technical support. Start-up costs varied between systems, and all were considered more expensive than setting up a paper-based system; however running costs were generally low and therefore thought to be cost-effective over the course of our projects.
EDC offers many opportunities for efficient data collection, but brings some issues requiring consideration when designing a study; the decision of which hardware and software to use should be informed by the aim of data collection, budget, and local circumstances.
PMCID: PMC4216812  PMID: 25363364
mHealth; electronic data capture; Sub-Saharan Africa; MIVA; ODK Collect; CommCare; Pendragon
3.  Routine Inpatient HIV Testing System Increases Access to Pediatric HIV Care in sub-Saharan Africa 
Routine HIV testing, called provider-initiated opt-out HIV testing and counseling (PITC), is recommended in African countries with high HIV prevalence. However, it is unknown whether PITC increases access to pediatric HIV care. In 2008 the Baylor International Pediatric AIDS Initiative implemented PITC (BIPAI-PITC) at a Malawian hospital. We sought to evaluate the influence of BIPAI-PITC, compared to non-routine HIV testing (NRT), on pediatric HIV care access.
Retrospective data from 7,077 pediatric inpatients were collected during sequential four-month periods of NRT and BIPAI-PITC. In-hospital and one-year outcomes for 337 HIV-infected and HIV-exposed uninfected inpatients not previously enrolled in HIV care were analyzed to assess the clinical influence of each testing strategy.
During BIPAI-PITC, a greater proportion of all hospitalized children received HIV testing (81.0% vs 33.3%, p < 0.001), accessed inpatient HIV-trained care (7.5% vs 2.4%, p < 0.001), enrolled into an outpatient HIV clinic after discharge (3.2% vs 1.3%, p < 0.001), and initiated antiretroviral therapy (ART) following hospitalization (1.1% vs 0.6%, p = 0.010) compared to NRT. Additionally, BIPAI-PITC increased the proportion of hospitalized HIV-infected and HIV-exposed uninfected children receiving DNA PCR testing (73.5% vs 35.2%, p < 0.001), but did not improve outpatient enrollment or ART initiation of identified HIV-infected patients.
BIPAI-PITC increases access to inpatient and outpatient pediatric HIV care for hospitalized children, including DNA PCR testing and ART. Broader implementation of BIPAI-PITC or similar approaches, along with more pediatric HIV-trained clinicians and improved defaulter-tracking methods, would improve pediatric HIV service utilization globally.
PMCID: PMC4157210  PMID: 21297520
Pediatric HIV; Routine HIV Testing; Provider Initiated HIV Testing and Counseling; Early Infant Diagnosis; Africa South of the Sahara
4.  Prevalence of depression and validation of the Beck Depression Inventory-II and the Children's Depression Inventory-Short amongst HIV-positive adolescents in Malawi 
There is a remarkable dearth of evidence on mental illness in adolescents living with HIV/AIDS, particularly in the African setting. Furthermore, there are few studies in sub-Saharan Africa validating the psychometric properties of diagnostic and screening tools for depression amongst adolescents. The primary aim of this cross-sectional study was to estimate the prevalence of depression amongst a sample of HIV-positive adolescents in Malawi. The secondary aim was to develop culturally adapted Chichewa versions of the Beck Depression Inventory-II (BDI-II) and Children's Depression Inventory-II-Short (CDI-II-S) and conduct a psychometric evaluation of these measures by evaluating their performance against a structured depression assessment using the Children's Rating Scale, Revised (CDRS-R).
Study design
Cross-sectional study.
We enrolled 562 adolescents, 12–18 years of age from two large public HIV clinics in central and southern Malawi. Participants completed two self-reports, the BDI-II and CDI-II-S, followed by administration of the CDRS-R by trained clinicians. Sensitivity, specificity and positive and negative predictive values for various BDI-II and CDI-II-S cut-off scores were calculated with receiver operating characteristics analysis. The area under the curve (AUC) was also calculated. Internal consistency was measured by standardized Cronbach's alpha coefficient, and correlation between self-reports and CDRS-R by Spearman's correlation.
Prevalence of depression as measured by the CDRS-R was 18.9%. Suicidal ideation was expressed by 7.1% (40) using the BDI-II. The AUC for the BDI-II was 0.82 (95% CI 0.78–0.89) and for the CDI-II-S was 0.75 (95% CI 0.70–0.80). A score of ≥13 in BDI-II achieved sensitivity of >80%, and a score of ≥17 had a specificity of >80%. The Cronbach's alpha was 0.80 (BDI-II) and 0.66 (CDI-II-S). The correlation between the BDI-II and CDRS-R was 0.42 (p<0.001) and between the CDI-II-S and CDRS-R was 0.37 (p<0.001).
This study demonstrates that the BDI-II has sound psychometric properties in an outpatient setting among HIV-positive adolescents in Malawi. The high prevalence of depression amongst HIV-positive Malawian adolescents noted in this study underscores the need for the development of comprehensive services for HIV-positive adolescents.
PMCID: PMC4119288  PMID: 25085002
HIV; adolescents; depression; prevalence; BDI-II; CDI-II-Short
5.  Changes in HIV-1 Subtypes B and C Genital Tract RNA in Women and Men After Initiation of Antiretroviral Therapy 
Fiscus, Susan A. | Cu-Uvin, Susan | Eshete, Abel Tilahun | Hughes, Michael D. | Bao, Yajing | Hosseinipour, Mina | Grinsztejn, Beatriz | Badal-Faesen, Sharlaa | Dragavon, Joan | Coombs, Robert W. | Braun, Ken | Moran, Laura | Hakim, James | Flanigan, Timothy | Kumarasamy, N. | Campbell, Thomas B. | Klingman, Karin L. | Nair, Apsara | Walawander, Ann | Smeaton, Laura M. | De Gruttola, Victor | Martinez, Ana I. | Swann, Edith | Barnett, Ronald L. | Brizz, Barbara | Delph, Yvette | Gettinger, Nikki | Mitsuyasu, Ronald T. | Eshleman, Susan | Safren, Steven | Andrade, Adriana | Haas, David W. | Amod, Farida | Berthaud, Vladimir | Bollinger, Robert C. | Bryson, Yvonne | Celentano, David | Chilongozi, David | Cohen, Myron | Collier, Ann C. | Currier, Judith Silverstein | Eron, Joseph | Firnhaber, Cynthia | Flexner, Charles | Gallant, Joel E. | Gulick, Roy M. | Hammer, Scott M. | Hoffman, Irving | Kazembe, Peter | Kumwenda, Johnstone | Kumwenda, Newton | Lama, Javier R. | Lawrence, Jody | Maponga, Chiedza | Martinson, Francis | Mayer, Kenneth | Nielsen, Karin | Pendame, Richard B. | Ramratnam, Bharat | Rooney, James F. | Sanchez, Jorge | Sanne, Ian | Schooley, Robert T. | Snowden, Wendy | Solomon, Suniti | Tabet, Steve | Taha, Taha | Uy, Jonathan | van der Horst, Charles | Wanke, Christine | Gormley, Joan | Marcus, Cheryl J. | Putnam, Beverly | Ntshele, Smanga | Loeliger, Edde | Pappa, Keith A. | Webb, Nancy | Shugarts, David L. | Winters, Mark A. | Descallar, Renard S. | Sharma, Jabin | Poongulali, S. | Cardoso, Sandra Wagner | Faria, Deise Lucia | Berendes, Sima | Burke, Kelly | Kanyama, Cecelia | Kayoyo, Virginia | Samaneka, Wadzanai P. | Chisada, Anthony | Santos, Breno | La Rosa, Alberto | Infante, Rosa | Balfour, Henry H. | Mullan, Beth | Kim, Ge-Youl | Klebert, Michael K. | Mildvan, Donna | Revuelta, Manuel | Jan Geiseler, P. | Santos, Bartolo | Daar, Eric S. | Lopez, Ruben | Frarey, Laurie | Currin, David | Haas, David H. | Bailey, Vicki L. | Tebas, Pablo | Zifchak, Larisa | Sha, Beverly E. | Fritsche, Janice M.
Women with human immunodeficiency virus (HIV)–1 subtype C had significantly higher genital tract viral loads compared to women with HIV-1 subtype B and men with HIV-1 subtype C or B. Women in general were significantly less likely to have genital tract viral load below the lower limit of quantification compared to men.
Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype.
Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens.
Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected.
Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.
PMCID: PMC3689341  PMID: 23532477
HIV-1 genital tract RNA; HIV-1 subtypes B and C; antiretroviral drugs
6.  Qualitative assessment of attitudes and knowledge on preterm birth in Malawi and within country framework of care 
The overarching goal of this study was to qualitatively assess baseline knowledge and perceptions regarding preterm birth (PTB) and oral health in an at-risk, low resource setting surrounding Lilongwe, Malawi. The aims were to determine what is understood regarding normal length of gestation and how gestational age is estimated, to identify common language for preterm birth, and to assess what is understood as options for PTB management. As prior qualitative research had largely focused on patient or client-based focused groups, we primarily focused on groups comprised of community health workers (CHWs) and providers.
A qualitative study using focus-group discussions, incidence narrative, and informant interviews amongst voluntary participants. Six focus groups were comprised of CHWs, patient couples, midwives, and clinical officers (n = 33) at two rural health centers referring to Kamuzu Central Hospital. Semi-structured questions facilitated discussion of PTB and oral health (inclusive of periodontal disease), including definitions, perception, causation, management, and accepted interventions.
Every participant knew of women who had experienced “a baby born too soon”, or preterm birth. All participants recognized both an etiology conceptualization and disease framework for preterm birth, distinguished PTB from miscarriage and macerated stillbirth, and articulated a willingness to engage in studies aimed at prevention or management. Identified gaps included: (1) discordance in the definition of PTB (i.e., 28–34 weeks or less than the 8th month, but with a corresponding fetal weight ranging 500 to 2300 grams); (2) utility and regional availability of antenatal steroids for prevention of preterm infant morbidity and mortality; (3) need for antenatal referral for at-risk women, or with symptoms of preterm birth. There was no evident preference for route of progesterone for the prevention of recurrent PTB.
Qualitative research was useful in (1) identifying gaps in knowledge in urban and rural Malawi, and (2) informing the development of educational materials and implementation of programs or trials ultimately aimed at reducing PTB. As a result of this qualitative work, implementation planning was focused on the gaps in knowledge, dissemination of knowledge (to both patients and providers), and practical solutions to barriers in known efficacious therapies.
PMCID: PMC3975452  PMID: 24690288
Preterm birth; Qualitative research; Global women’s health; Pregnancy; Periodontal disease
7.  HIV and Childhood Disability: A Case-Controlled Study at a Paediatric Antiretroviral Therapy Centre in Lilongwe, Malawi 
PLoS ONE  2013;8(12):e84024.
As paediatric antiretroviral therapy (ART) is rapidly scaled up in Southern Africa, Human Immunodeficiency Virus (HIV) infection is becoming a chronic illness. Children growing up with HIV may begin to encounter disabilities. The relationship between HIV, disability and the need for rehabilitation has added an additional element that needs to be addressed by paediatric HIV treatment programmes.
Study Objectives
1) Estimate the prevalence of disabilities in HIV-infected and HIV-uninfected children in Lilongwe, Malawi. 2) Examine types of disability and associated clinical and socio-demographic factors. 3) Identify needs, opportunities and barriers for rehabilitation in Malawi.
A case-controlled study of 296 HIV-infected children aged 2–9 years attending an ART centre in Lilongwe (cases) and their uninfected siblings (controls) was conducted. Disability was assessed using the WHO Ten Question Screen (TQS). Socio-demographic and clinical data were collected using a parent-proxy questionnaire and medical records.
Of 296 case and control pairs recruited, 33% (98) versus 7% (20) screened positive for a disability (OR 8.4, 4.4–15.7) respectively. Of these 98 HIV-infected cases, 6%, 36%, 33%, 53%, 46% and 6% had a vision, hearing; physical, learning/comprehension, speech or seizure-related disability respectively and 51% had multiple coexisting disabilities. HIV-infected cases with a disability were more likely to be WHO stage III or IV at enrolment (71% vs. 52%, OR 2.7, 1.5–4.2), to have had TB (58% vs. 39%, OR 2.3, 1.4–3.8) and to have below-average school grades (18% vs. 2%, OR 11.1, 2.2–54.6) than those without. Sixty-seven percent of cases with a disability had never attended any rehabilitative service. Twenty-nine percent of caregivers reported facing stigma and discrimination because of the child’s disability.
This study reveals the magnitude of disability among HIV-infected children and the large unmet need for rehabilitation services. This expanding issue demands further investigation to provide an evidence base for holistic care for disabled children living with HIV.
PMCID: PMC3877142  PMID: 24391869
8.  Effect of women’s groups and volunteer peer counselling on rates of mortality, morbidity, and health behaviours in mothers and children in rural Malawi (MaiMwana): a factorial, cluster-randomised controlled trial 
Lancet  2013;381(9879):1721-1735.
Women’s groups and health education by peer counsellors can improve the health of mothers and children. We assessed their effects on mortality and breastfeeding rates in rural Malawi.
We did a 2×2 factorial, cluster-randomised trial in 185 888 people in Mchinji district. 48 equal-sized clusters were randomly allocated to four groups with a computer-generated number sequence. 24 facilitators guided groups through a community action cycle to tackle maternal and child health problems. 72 trained volunteer peer counsellors made home visits at five timepoints during pregnancy and after birth to support breastfeeding and infant care. Primary outcomes for the women’s group intervention were maternal, perinatal, neonatal, and infant mortality rates (MMR, PMR, NMR, and IMR, respectively); and for the peer counselling were IMR and exclusive breastfeeding (EBF) rates. Analysis was by intention to treat. The trial is registered as ISRCTN06477126.
We monitored outcomes of 26 262 births between 2005 and 2009. In a factorial model adjusted only for clustering and the volunteer peer counselling intervention, in women’s group areas, for years 2 and 3, we noted non-significant decreases in NMR (odds ratio 0·93, 0·64–1·35) and MMR (0·54, 0·28–1·04). After adjustment for parity, socioeconomic quintile, and baseline measures, effects were larger for NMR (0·85, 0·59–1·22) and MMR (0·48, 0·26–0·91). Because of the interaction between the two interventions, a stratified analysis was done. For women’s groups, in adjusted analyses, MMR fell by 74% (0·26, 0·10–0·70), and NMR by 41% (0·59, 0·40–0·86) in areas with no peer counsellors, but there was no effect in areas with counsellors (1·09, 0·40–2·98, and 1·38, 0·75–2·54). Factorial analysis for the peer counselling intervention for years 1–3 showed a fall in IMR of 18% (0·82, 0·67–1·00) and an improvement in EBF rates (2·42, 1·48–3·96). The results of the stratified, adjusted analysis showed a 36% reduction in IMR (0·64, 0·48–0·85) but no effect on EBF (1·18, 0·63–2·25) in areas without women’s groups, and in areas with women’s groups there was no effect on IMR (1·05, 0·82–1·36) and an increase in EBF (5·02, 2·67–9·44) . The cost of women’s groups was US$114 per year of life lost (YLL) averted and that of peer counsellors was $33 per YLL averted, using stratified data from single intervention comparisons.
Community mobilisation through women’s groups and volunteer peer counsellor health education are methods to improve maternal and child health outcomes in poor rural populations in Africa.
Saving Newborn Lives, UK Department for International Development, and Wellcome Trust.
PMCID: PMC3796349  PMID: 23683639
9.  Involving communities in the design of clinical trial protocols: The BAN Study in Lilongwe, Malawi 
Contemporary clinical trials  2006;28(1):59-67.
To learn the attitudes and concerns of the local community on participating in research, infant feeding practices, and maternal nutrition in order to inform the design of a clinical trial in Lilongwe, Malawi on the safety and efficacy of antiretroviral and nutrition interventions to reduce postnatal transmission of HIV.
Formative research methods were used, including semi-structured interviews, focus group discussions, home observations, and taste trials. Data were collected, analyzed, and incorporated into the protocol within three months.
Participants were supportive of the clinical trial, although their overall understanding of research was limited. Mothers agreed that infants’ blood could be drawn by venipuncture, yet concern was raised about the amount of blood proposed to be collected from both infants and mothers. Data demonstrated that rapid breastfeeding cessation would be difficult and malnutrition could be a risk if infants were weaned early. Mothers selected a maternal supplement suitable for use in the clinical trial.
The protocol was rapidly modified to achieve cultural acceptability while maintaining study objectives. Without the formative research, several significant areas would have been undetected and may have jeopardized the implementation of the trial. Additional research was carried out to develop a meaningful informed consent process, the amount of blood collected was reduced to acceptable levels, and the protocol was modified to reduce the risk of malnutrition. Researchers who conduct clinical trials are encouraged to incorporate formative research into their protocol design to ensure participant understanding of the research, to safeguard participants, and to increase feasibility and acceptance of the clinical research in the community.
PMCID: PMC3786401  PMID: 17000137
Qualitative research; ethics; clinical trial; HIV; Africa
10.  Mortality and Clinical Outcomes in HIV-Infected Children on Antiretroviral Therapy in Malawi, Lesotho, and Swaziland 
Pediatrics  2012;130(3):e591-e599.
To determine mortality and immune status improvement in HIV-infected pediatric patients on antiretroviral treatment (ART) in Malawi, Lesotho, and Swaziland.
We conducted a retrospective cohort study of patients aged <12 years at ART initiation at 3 sites in sub-Saharan Africa between 2004 and 2009. Twelve-month and overall mortality were estimated, and factors associated with mortality and immune status improvement were evaluated.
Included in the study were 2306 patients with an average follow-up time on ART of 2.3 years (interquartile range 1.5–3.1 years). One hundred four patients (4.5%) died, 9.0% were lost to follow-up, and 1.3% discontinued ART. Of the 104 deaths, 77.9% occurred in the first year of treatment with a 12-month mortality rate of 3.5%. The overall mortality rate was 2.25 deaths/100 person-years (95% confidence interval [CI] 1.84–2.71). Increased 12-month mortality was associated with younger age; <6 months (hazard ratio [HR] = 8.11, CI 4.51–14.58), 6 to <12 months (HR = 3.43, CI 1.96–6.02), and 12 to <36 months (HR = 1.92, CI 1.16–3.19), and World Health Organization stage IV (HR = 4.35, CI 2.19–8.67). Immune status improvement at 12 months was less likely in patients with advanced disease and age <12 months.
Despite challenges associated with pediatric ART in developing countries, low mortality and good treatment outcomes can be achieved. However, outcomes are worse in younger patients and those with advanced disease at the time of ART initiation, highlighting the importance of early diagnosis and treatment.
PMCID: PMC3962849  PMID: 22891234
HIV; AIDS; pediatric; antiretroviral therapy; mortality; Africa south of the Sahara
11.  Superior Uptake and Outcomes of Early Infant Diagnosis of HIV Services at an Immunization Clinic Versus an “Under-Five” General Pediatric Clinic in Malawi 
Although the Malawian government recommends HIV-exposed infants receive early infant diagnosis of HIV (EID) at “under-five” pediatric clinics (U5Cs), most never enroll. Therefore, we evaluated the integration of EID testing into an immunization clinic (IC) compared to the current standard of EID testing at an U5C.
Prospective observational study.
Using routine provider initiated HIV testing and counseling (PITC) registers, we prospectively studied 1757 children offered PITC at a government IC and U5C. Infants tested by HIV DNA polymerase chain reaction (PCR) were followed until PCR result disclosure or defaulting.
We sampled 877 and 880 consecutive PITC recipients at U5C and IC, respectively. Overall, a 7 fold greater proportion received PITC at IC (84.2% vs 11.4%, p<0.001). PITC recipients at IC were more than 14 months younger (2.6 vs 17.0, p<0.001), with greater proportions HIV-exposed (17.6% vs 5.3%, p<0.001) and PCR eligible (7.9% vs 3.5%, p<0.001).
A higher percentage of IC infants accepted PCR testing (100.0% vs 90.3%, p=0.03). Additionally, IC PCR recipients were 2.5 months younger (3.1 vs 5.6, p<0.001) with 4 times less testing PCR positive (7.1% vs 32.1%, p<0.001). Importantly, a more than 3 fold greater proportion of HIV-exposed infants at IC returned for their PCR result and enrolled into care (78.6% vs 25.0%, p<0.001).
Compared to an U5C, integrating EID testing into an IC is more acceptable, more feasible, enrolls more infants into EID at younger ages, and would likely strengthen Malawi's EID services if expanded.
PMCID: PMC3412370  PMID: 22614897
Africa; pediatrics; prevention of mother-to-child transmission; early infant diagnosis of HIV; HIV DNA PCR; provider initiated HIV testing and counseling
12.  Low Rates of Mother-to-Child HIV Transmission in a Routine Programmatic Setting in Lilongwe, Malawi 
PLoS ONE  2013;8(5):e64979.
The Tingathe program utilizes community health workers to improve prevention of mother-to-child transmission (PMTCT) service delivery. We evaluated the impact of antiretroviral (ARV) regimen and maternal CD4+ count on HIV transmission within the Tingathe program in Lilongwe, Malawi.
We reviewed clinical records of 1088 mother-infant pairs enrolled from March 2009 to March 2011 who completed follow-up to first DNA PCR. Eligibility for antiretroviral treatment (ART) was determined by CD4+ cell count (CD4+) for women not yet on ART. ART-eligible women initiated stavudine-lamivudine-nevirapine. Early ART was defined as ART for ≥14 weeks prior to delivery. For women ineligible for ART, optimal ARV prophylaxis was maternal AZT ≥6 weeks+sdNVP, and infant sdNVP+AZT for 1 week. HIV transmission rates were determined for ARV regimens, and factors associated with vertical transmission were identified using bivariate logistic regression.
Transmission rate at first PCR was 4.1%. Pairs receiving suboptimal ARV prophylaxis were more likely to transmit HIV (10.3%, 95% CI, 5.5–18.1%). ART was associated with reduced transmission (1.4%, 95% CI, 0.6–3.0%), with early ART associated with decreased transmission (no transmission), compared to all other treatment groups (p = 0.001). No association was detected between transmission and CD4+ categories (p = 0.337), trimester of pregnancy at enrollment (p = 0.100), or maternal age (p = 0.164).
Low rates of MTCT of HIV are possible in resource-constrained settings under routine programmatic conditions. No transmissions were observed among women on ART for more than 14 weeks prior to delivery.
PMCID: PMC3669205  PMID: 23741437
13.  Maternal or Infant Antiretroviral Drugs to Reduce HIV-1 Transmission 
The New England journal of medicine  2010;362(24):2271-2281.
We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.
We randomly assigned 2369 HIV-1–positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan–Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1–negative 2 weeks after birth. Rates were compared with the use of the log-rank test.
Among mother–infant pairs, 5.0% of infants were HIV-1–positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P = 0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P = 0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.
The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. ( number, NCT00164736.)
PMCID: PMC3440865  PMID: 20554982
14.  MaiMwana women’s groups: a community mobilisation intervention to improve mother and child health and reduce mortality in rural Malawi 
This article presents a detailed description of a community mobilization intervention involving women’s groups in Mchinji District, Malawi. The intervention was implemented between 2005 and 2010.
The intervention aims to build the capacities of communities to take control of the mother and child health issues that affect them. To achieve this it comprises trained local female facilitators establishing groups and using a manual, participatory rural appraisal tools and picture cards to guide them through a community action cycle to identify and implement solutions to mother and child health problems. Significant resource inputs include salaries for facilitators and supervisors, and training, equipment and materials to support their work with groups.
It is hypothesized that the groups will catalyse community collective action to address mother and child health issues and improve the health and reduce the mortality of mothers and children. Their impact, implementation and cost-effectiveness have been rigorously evaluated through a randomized controlled trial design. The results of these evaluations will be reported in 2011.
PMCID: PMC3345770  PMID: 21977831
15.  The Tingathe programme: a pilot intervention using community health workers to create a continuum of care in the prevention of mother to child transmission of HIV (PMTCT) cascade of services in Malawi 
Loss to follow-up is a major challenge in the prevention of mother to child transmission of HIV (PMTCT) programme in Malawi with reported loss to follow-up of greater than 70%. Tingathe-PMTCT is a pilot intervention that utilizes dedicated community health workers (CHWs) to create a complete continuum of care within the PMTCT cascade, improving service utilization and retention of mothers and infants. We describe the impact of the intervention on longitudinal care starting with diagnosis of the mother at antenatal care (ANC) through final diagnosis of the infant.
PMTCT service utilization, programme retention and outcomes were evaluated for pregnant women living with HIV and their exposed infants enrolled in the Tingathe-PMTCT programme between March 2009 and March 2011. Multivariate logistic regression was done to evaluate maternal factors associated with failure to complete the cascade.
Over 24 months, 1688 pregnant women living with HIV were enrolled. Median maternal age was 27 years (IQR, 23.8 to 30.8); 333 (19.7%) were already on ART. Among the remaining women, 1328/1355 (98%) received a CD4 test, with 1243/1328 (93.6%) receiving results. Of the 499 eligible for ART, 363 (72.8%) were successfully initiated. Prior to, delivery there were 93 (5.7%) maternal/foetal deaths, 137 (8.1%) women transferred/moved, 51 (3.0%) were lost and 58 (3.4%) refused ongoing PMTCT services. Of the 1318 live births to date, 1264 (95.9%) of the mothers and 1285 (97.5%) of the infants received ARV prophylaxis; 1064 (80.7%) infants were tested for HIV by PCR and started on cotrimoxazole. Median age at PCR was 1.7 months (IQR, 1.5 to 2.5). Overall transmission at first PCR was 43/1047 (4.1%). Of the 43 infants with positive PCR results, 36 (83.7%) were enrolled in ART clinic and 33 (76.7%) were initiated on ART.
Case management and support by dedicated CHWs can create a continuum of longitudinal care in the PMTCT cascade and result in improved outcomes.
PMCID: PMC3499848  PMID: 22789644
prevention of mother to child transmission (PMTCT); early infant diagnosis (EID); paediatric HIV; HIV; task shifting; community engagement; community health workers; retention; loss to follow up
16.  Associations between Peripheral Plasmodium falciparum Malaria Parasitemia, Human Immunodeficiency Virus, and Concurrent Helminthic Infection among Pregnant Women in Malawi 
Approximately 2 billion persons worldwide are infected with schistosomiasis and soil-transmitted helminthes (STH), many in areas where endemic malaria transmission coexists. Few data exist on associations between these infections. Nested within a larger clinical trial, primigravid and secundigravid women provided blood samples for human immunodeficiency virus (HIV) testing and peripheral malaria films and stool and urine for evaluation of STH and Schistosoma spp. during their initial antenatal clinic visit. The most common parasitic infections were malaria (37.6%), S. haematobium (32.3%), and hookworm (14.4%); 14.2% of women were HIV-infected. S. haematobium infection was associated with lower malarial parasite densities (344 versus 557 parasites/μL blood; P < 0.05). In multivariate analysis, HIV and hookworm infection were independently associated with malaria infection (adjusted odds ratio = 1.9 and 95% confidence interval = 1.2–3.0 for HIV; adjusted odds ratio = 1.9 and 95% confidence interval = 1.03–3.5 for hookworm). Concurrent helminthic infection had both positive and negative effects on malaria parasitemia among pregnant women in Malawi.
PMCID: PMC3042811  PMID: 21363973
17.  Adaptation of a probabilistic method (InterVA) of verbal autopsy to improve the interpretation of cause of stillbirth and neonatal death in Malawi, Nepal, and Zimbabwe 
Verbal autopsy (VA) is a widely used method for analyzing cause of death in absence of vital registration systems. We adapted the InterVA method to extrapolate causes of death for stillbirths and neonatal deaths from verbal autopsy questionnaires, using data from Malawi, Zimbabwe, and Nepal.
We obtained 734 stillbirth and neonatal VAs from recent community studies in rural areas: 169 from Malawi, 385 from Nepal, and 180 from Zimbabwe. Initial refinement of the InterVA model was based on 100 physician-reviewed VAs from Malawi. InterVA indicators and matrix probabilities for cause of death were reviewed for clinical and epidemiological coherence by a pediatrician-researcher and an epidemiologist involved in the development of InterVA. The modified InterVA model was evaluated by comparing population-level cause-specific mortality fractions and individual agreement from two methods of interpretation (physician review and InterVA) for a further 69 VAs from Malawi, 385 from Nepal, and 180 from Zimbabwe.
Case-by-case agreement between InterVA and reviewing physician diagnoses for 69 cases from Malawi, 180 cases from Zimbabwe, and 385 cases from Nepal were 83% (kappa 0.76 (0.75 - 0.80)), 71% (kappa 0.41(0.32-0.51)), and 74% (kappa 0.63 (0.60-0.63)), respectively. The proportion of stillbirths identified as fresh or macerated by the different methods of VA interpretation was similar in all three settings. Comparing across countries, the modified InterVA method found that proportions of preterm births and deaths due to infection were higher in Zimbabwe (44%) than in Malawi (28%) or Nepal (20%).
The modified InterVA method provides plausible results for stillbirths and newborn deaths, broadly comparable to physician review but with the advantage of internal consistency. The method allows standardized cross-country comparisons and eliminates the inconsistencies of physician review in such comparisons.
PMCID: PMC3160941  PMID: 21819599
18.  Viral Response to Chemotherapy in Endemic Burkitt Lymphoma 
Some Epstein-Barr virus (EBV)-directed therapies are predicted to be effective only when lytic viral replication occurs. We studied whether cyclophosphamide chemotherapy induces EBV to switch from latent to lytic phases of infection in a series of EBV-associated Burkitt lymphomas.
Experimental Design
Children with first presentation of an expanding, solid maxillary or mandibular mass consistent with Burkitt lymphoma underwent fine needle aspiration just prior to initiation of cyclophosphamide and again 1 to 5 days later. Aspirated cells were examined for latent and lytic EBV infection using in situ hybridization to EBV-encoded RNA (EBER), immunohistochemical analysis of the lytic EBV proteins BZLF1 and BMRF1, reverse transcription PCR targeting BZLF1 transcripts, and EBV viral load measurement by quantitative PCR.
Among 21 lymphomas expressing EBER prior to chemotherapy, 9/10 still expressed EBER on day 1 after therapy while only 2/11 (18%) specimens still expressed EBER at days 3 to 5, implying that chemotherapy was fairly effective at eliminating latently infected cells. Neither of the lytic products, BZLF1 or BMRF1, was significantly upregulated at the post-therapy time-points examined. However, EBV genomic copy number increased in 5/10 samples 1 day after treatment began, suggesting that viral replication occurs within the first 24 hours.
Cyclophosphamide may induce the lytic phase of EBV infection and is fairly effective in diminishing EBER-expressing tumor cells within 5 days. These findings provide the rationale for a trial testing synergistic tumor cell killing using cyclophosphamide with a drug like ganciclovir targeting lytically infected cells.
PMCID: PMC2848899  PMID: 20233888
Epstein-Barr Virus; Burkitt lymphoma; lytic infection; cyclophosphamide; ganciclovir
19.  Reduced risk for placental malaria in iron deficient women 
Malaria Journal  2011;10:47.
Nutritional iron deficiency may limit iron availability to the malaria parasite reducing infection risk, and/or impair host immunity thereby increasing this risk. In pregnant women, there is evidence of an adverse effect with iron supplementation, but the few reported studies are strongly confounded.
A case control study in pregnant Malawian women was undertaken in Chikhwawa southern Malawi in order to describe iron status in relation to placental malaria controlling for several confounding factors. Pregnancy characteristics were obtained and a blood sample at delivery. A full blood count was performed and serum ferritin and transferrin receptor quantified by enzyme-linked immunoassay. DNA analysis was used to identify genetic polymorphisms for ABO phenotype, hemoglobin HbS, and glucose -6 phosphate dehydrogenase deficiency. Placental tissue was obtained and malaria histology classified as active, past or no malaria infection.
112 cases with placental malaria were identified and 110 women with no evidence of placental infection. Iron deficiency was less frequent in women with placental Plasmodium falciparum infection. In those with acute, chronic or past placental infections the odds ratio for iron deficiency was 0.4, 95% CI 0.2-0.8, p = 0.01; for acute and chronic infections 0.4, 0.2-0.8, p = 0.006; for acute infection 0.3, 0.1-0.7, p = 0.001. The association was greater in multigravidae.
Women with either acute, or acute and chronic placental malaria were less likely to have iron deficiency than women without placental malaria infection There is a priority to establish if reversing iron deficiency through iron supplementation programs either prior to or during pregnancy enhances malaria risk.
PMCID: PMC3050778  PMID: 21345193
20.  A cluster randomised controlled trial of the community effectiveness of two interventions in rural Malawi to improve health care and to reduce maternal, newborn and infant mortality 
Trials  2010;11:88.
The UN Millennium Development Goals call for substantial reductions in maternal and child mortality, to be achieved through reductions in morbidity and mortality during pregnancy, delivery, postpartum and early childhood. The MaiMwana Project aims to test community-based interventions that tackle maternal and child health problems through increasing awareness and local action.
This study uses a two-by-two factorial cluster-randomised controlled trial design to test the impact of two interventions. The impact of a community mobilisation intervention run through women's groups, on home care, health care-seeking behaviours and maternal and infant mortality, will be tested. The impact of a volunteer-led infant feeding and care support intervention, on rates of exclusive breastfeeding, uptake of HIV-prevention services and infant mortality, will also be tested. The women's group intervention will employ local female facilitators to guide women's groups through a four-phase cycle of problem identification and prioritisation, strategy identification, implementation and evaluation. Meetings will be held monthly at village level. The infant feeding intervention will select local volunteers to provide advice and support for breastfeeding, birth preparedness, newborn care and immunisation. They will visit pregnant and new mothers in their homes five times during and after pregnancy.
The unit of intervention allocation will be clusters of rural villages of 2500-4000 population. 48 clusters have been defined and randomly allocated to either women's groups only, infant feeding support only, both interventions, or no intervention. Study villages are surrounded by 'buffer areas' of non-study villages to reduce contamination between intervention and control areas. Outcome indicators will be measured through a demographic surveillance system. Primary outcomes will be maternal, infant, neonatal and perinatal mortality for the women's group intervention, and exclusive breastfeeding rates and infant mortality for the infant feeding intervention.
Structured interviews will be conducted with mothers one-month and six-months after birth to collect detailed quantitative data on care practices and health-care-seeking. Further qualitative, quantitative and economic data will be collected for process and economic evaluations.
Trial registration
PMCID: PMC2949851  PMID: 20849613
21.  HIV-1 Populations in Semen Arise through Multiple Mechanisms 
PLoS Pathogens  2010;6(8):e1001053.
HIV-1 is present in anatomical compartments and bodily fluids. Most transmissions occur through sexual acts, making virus in semen the proximal source in male donors. We find three distinct relationships in comparing viral RNA populations between blood and semen in men with chronic HIV-1 infection, and we propose that the viral populations in semen arise by multiple mechanisms including: direct import of virus, oligoclonal amplification within the seminal tract, or compartmentalization. In addition, we find significant enrichment of six out of nineteen cytokines and chemokines in semen of both HIV-infected and uninfected men, and another seven further enriched in infected individuals. The enrichment of cytokines involved in innate immunity in the seminal tract, complemented with chemokines in infected men, creates an environment conducive to T cell activation and viral replication. These studies define different relationships between virus in blood and semen that can significantly alter the composition of the viral population at the source that is most proximal to the transmitted virus.
Author Summary
The work described in this report is directed at how HIV-1 viral RNA populations differ between the blood plasma and male genital tract in established infection. This site is of special interest since it is the proximal source of most transmissions of HIV-1. Thus, lessons learned about HIV-1 in the seminal tract are directly relevant to the mechanism of HIV-1 transmission. We have used single genome amplification to generate viral sequences from paired blood and semen samples in men with chronic HIV-1 infection. When compared to viral populations in blood plasma, we observe that virus in the seminal plasma can be equilibrated, clonally-amplified, or compartmentalized. We have also performed a characterization of the cytokine and chemokine milieu in these two compartments. We report a dramatic concentration of immune modulators in the seminal plasma relative to the blood, and these likely enhance the potential for viral replication in this compartment by creating an environment where target cells are kept in an activated state. These data define new and distinct features of virus:host interactions and represent a significant advance in our understanding of HIV-1 replication in the male genital tract.
PMCID: PMC2924360  PMID: 20808902
22.  Discontinuation of standard first-line antiretroviral therapy in a cohort of 1434 Malawian children 
The standard first-line antiretroviral (ART) regimen in Malawi for both adults and children is a fixed-dose combination tablet containing stavudine (d4T), lamivudine (3TC) and nevirapine (NVP). This regimen has been shown to yield satisfactory virologic and immunologic outcomes in children. Published studies have described insights into discontinuation of first-line regimen and toxicities of ART in adults, but similar studies in paediatric populations are lacking.
A retrospective cohort study was undertaken to assess reasons for discontinuation of the standard first-line ART regimen (d4T/3TC/NVP) in a paediatric population. In total, 1434 patients met eligibility criteria and were included. The cohort had mean and median age at ART initiation of 4.7 years and 2.9 years, respectively (range: 0.1 months-18.7 years). The gender distribution was 47% female and 53% male. Median follow-up time on ART was 1.8 years (range: 2 weeks-3.9 years). A majority (96.2%) of patients were on the standard first-line ART regimen, while 3.8% (54) were on a different regimen. Twenty-eight patients (2.0%) were on an alternative first-line regimen due to toxicities, 22 patients (1.5%) were on a second-line regimen due to ART failure, and four patients (0.3%) were on a non-standard regimen for other clinical reasons.
Of the 28 patients who experienced toxicities requiring ART regimen change, 60.7% (17) were caused by NVP, 39.3% (11) by d4T, and none by 3TC. The median time from first-line ART initiation to alternative first-line ART was two months (range: 10 days-28.1 months); 60.7% of patients on alternative first-line ART were male. Average time on ART until switch to second-line ART regimen was 16.3 months (SD: 9.3 months). The probability of failure after one year on first-line regimen was 1.6% (95% CI: 0.9-2.6).
There was no compelling evidence in this cohort, representing approximately 10% of all children on ART in Malawi, to support changing the standard paediatric first-line regimen based on early toxicities or failure. However, experience from the national adult cohort, longer term follow up of the paediatric cohort in this study, emerging data on resistance after single-dose NVP containing mother to child transmission antiretroviral prophylaxis, and new 2009 World Health Organization ART recommendations may influence national policy change to a different first-line regimen.
PMCID: PMC2923102  PMID: 20691049
23.  Predictors for mortality and loss to follow-up among children receiving anti-retroviral therapy in Lilongwe, Malawi 
To determine predictors of mortality in children on anti-retroviral therapy (ART) who attended the Paediatric HIV Clinic at Kamuzu Central Hospital in Lilongwe, Malawi.
Retrospective case cohort study by chart review of children who had started ART between October 2004 and May 2006. Bivariable and multivariable analysis were performed with and without defaulters to evaluate associations according to vital status and to identify independent predictors of mortality.
Forty-one of 258 children (15.9%) were deceased, 185 (71.7%) were alive, and 32 (12.4%) had defaulted: 51% were female, 7% were under 18 months, 26% were 18 months to 5 years, and 54% were >5 years of age. Most were WHO stage III or IV (56% and 37%, respectively). On multivariate analysis, factors most strongly associated with mortality and defaulting were age <18 months [hazards ratio (HR) 2.11 (95% CI 1.0–4.51)] and WHO stage IV [HR 2.00 (95% CI 1.07–3.76)].
To improve outcomes of HIV-positive children, they must be identified and treated early, specifically children under 18 months of age. Access to infant diagnostic procedures must be improved to allow effective initiation of ART in infants at higher risk of death.
PMCID: PMC2892779  PMID: 19563431
Malawi; HIV/AIDS; paediatrics; mortality; anti-retroviral therapy
A process evaluation of nurses’ implementation of an infant-feeding counseling protocol was conducted for the Breastfeeding, Antiretroviral and Nutrition (BAN) Study, a prevention of mother-to-child transmission of HIV clinical trial in Lilongwe, Malawi. Six trained nurses counseled HIV-infected mothers to exclusively breastfeed for 24 weeks postpartum and to stop breastfeeding within an additional four weeks. Implementation data were collected via direct observations of 123 infant feeding counseling sessions (30 antenatal and 93 postnatal) and interviews with each nurse. Analysis included calculating a percent adherence to checklists and conducting a content analysis for the observation and interview data. Nurses were implementing the protocol at an average adherence level of 90% or above. Although not detailed in the protocol, nurses appropriately counseled mothers on their actual or intended formula milk usage after weaning. Results indicate that nurses implemented the protocol as designed. Results will help to interpret the BAN Study’s outcomes.
PMCID: PMC2903193  PMID: 19397436
25.  Task Shifting Routine Inpatient Pediatric HIV Testing Improves Program Outcomes in Urban Malawi: A Retrospective Observational Study 
PLoS ONE  2010;5(3):e9626.
This study evaluated two models of routine HIV testing of hospitalized children in a high HIV-prevalence resource-constrained African setting. Both models incorporated “task shifting,” or the allocation of tasks to the least-costly, capable health worker.
Methods and Findings
Two models were piloted for three months each within the pediatric department of a referral hospital in Lilongwe, Malawi between January 1 and June 30, 2008. Model 1 utilized lay counselors for HIV testing instead of nurses and clinicians. Model 2 further shifted program flow and advocacy responsibilities from counselors to volunteer parents of HIV-infected children, called “patient escorts.” A retrospective review of data from 6318 hospitalized children offered HIV testing between January-December 2008 was conducted. The pilot quarters of Model 1 and Model 2 were compared, with Model 2 selected to continue after the pilot period. There was a 2-fold increase in patients offered HIV testing with Model 2 compared with Model 1 (43.1% vs 19.9%, p<0.001). Furthermore, patients in Model 2 were younger (17.3 vs 26.7 months, p<0.001) and tested sooner after admission (1.77 vs 2.44 days, p<0.001). There were no differences in test acceptance or enrollment rates into HIV care, and the program trends continued 6 months after the pilot period. Overall, 10244 HIV antibody tests (4779 maternal; 5465 child) and 453 DNA-PCR tests were completed, with 97.8% accepting testing. 19.6% of all mothers (n = 1112) and 8.5% of all children (n = 525) were HIV-infected. Furthermore, 6.5% of children were HIV-exposed (n = 405). Cumulatively, 72.9% (n = 678) of eligible children were evaluated in the hospital by a HIV-trained clinician, and 68.3% (n = 387) successfully enrolled into outpatient HIV care.
The strategy presented here, task shifting from lay counselors alone to lay counselors and patient escorts, greatly improved program outcomes while only marginally increasing operational costs. The wider implementation of this strategy could accelerate pediatric HIV care access in high-prevalence settings.
PMCID: PMC2835755  PMID: 20224782

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