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1.  The Health of HIV-exposed Children after Early Weaning 
Maternal & child nutrition  2011;9(2):217-232.
There are potential health risks associated with the use of early weaning to prevent mother-to-child transmission of HIV in resource-poor settings. Our objective was to examine growth and nutrient inadequacies among a cohort of children weaned early. Children participating in the Breastfeeding Antiretrovirals and Nutrition (BAN) Study in Lilongwe, Malawi, had HIV-infected mothers, were weaned at 6 months and fed LNS until 12 months. 40 HIV-negative, BAN-exited children were compared to 40 HIV-negative, community children matched on age, gender and local health clinic. Nutrient intake was calculated from 24-hour dietary recalls collected from BAN-exited children. Anthropometric measurements were collected from BAN-exited and matched community children at 15-16 months, and 2 months later. Longitudinal random effects sex-stratified models were used to evaluate anthropometric differences between the 2 groups. BAN-exited children consumed adequate energy, protein, and carbohydrates but inadequate amounts of fat. The prevalence of inadequate micronutrient intakes were: 46% for vitamin A; 20% for vitamin B6; 69% for folate; 13% for vitamin C; 19% for iron; 23% for zinc. Regarding growth, BAN-exited girls gained weight at a significantly lower rate (0.02g/kg/day [95%CI: 0.01, 0.03] than their matched comparison (0.05g/kg/day [95%CI: 0.03, 0.07]); BAN girls grew significantly slower (0.73cm/month [95%CI: 0.40,1.06]) than their matched comparison (1.55cm/month [95%CI: 0.98, 2.12]). Among this sample of BAN-exited children, early weaning was associated with dietary deficiencies and girls experienced reduced growth velocity. In resource-poor settings, HIV prevention programs must ensure that breastfeeding stop only once a nutritionally adequate and safe diet without breastmilk can be provided.
doi:10.1111/j.1740-8709.2011.00369.x
PMCID: PMC3787136  PMID: 22099216
LNS; early breastfeeding cessation; HIV; Malawi; child growth
2.  Use of Massively Parallel Pyrosequencing to Evaluate the Diversity of and Selection on Plasmodium falciparum csp T-Cell Epitopes in Lilongwe, Malawi 
The Journal of Infectious Diseases  2012;206(4):580-587.
The development of an effective malaria vaccine has been hampered by the genetic diversity of commonly used target antigens. This diversity has led to concerns about allele-specific immunity limiting the effectiveness of vaccines. Despite extensive genetic diversity of circumsporozoite protein (CS), the most successful malaria vaccine is RTS/S, a monovalent CS vaccine. By use of massively parallel pyrosequencing, we evaluated the diversity of CS haplotypes across the T-cell epitopes in parasites from Lilongwe, Malawi. We identified 57 unique parasite haplotypes from 100 participants. By use of ecological and molecular indexes of diversity, we saw no difference in the diversity of CS haplotypes between adults and children. We saw evidence of weak variant-specific selection within this region of CS, suggesting naturally acquired immunity does induce variant-specific selection on CS. Therefore, the impact of CS vaccines on variant frequencies with widespread implementation of vaccination requires further study.
doi:10.1093/infdis/jis329
PMCID: PMC3491736  PMID: 22551816
3.  Predicting Partner HIV Testing and Counseling following a Partner Notification Intervention 
AIDS and behavior  2012;16(5):1148-1155.
Provider-assisted methods of partner notification increase testing and counseling among sexual partners of patients diagnosed with HIV, however they are resource-intensive. The sexual partners of individuals enrolled in a clinical trial comparing different methods of HIV partner notification were analyzed to identify who was unlikely to seek testing on their own. Unconditional logistic regression was used to identify partnership characteristics, which were assigned a score based on their coefficient in the final model, and a risk score was calculated for each participant. The risk score included male partner sex, relationship duration 6–24 months, and index education > primary. A risk score of ≥ 2 had a sensitivity of 68% and specificity of 78% in identifying partners unlikely to seek testing on their own. A risk score to target partner notification can reduce the resources required to locate all partners in the community while increasing the testing yield compared to patient-referral.
doi:10.1007/s10461-011-0094-9
PMCID: PMC3515685  PMID: 22120879
HIV/AIDS; Partner Notification; Contact Tracing; sub-Saharan Africa
4.  Comparative population structure of Plasmodium falciparum circumsporozoite protein NANP repeat lengths in Lilongwe, Malawi 
Scientific Reports  2013;3:1990.
Humoral immunity to Plasmodium falciparum circumsporozoite protein is partly mediated by a polymorphic NANP tetra-amino acid repeat. Antibody response to these repeats is the best correlate of protective immunity to the RTS,S malaria vaccine, but few descriptions of the natural variation of these repeats exist. Using capillary electrophoresis to determine the distribution of NANP repeat size polymorphisms among 98 isolates from Lilongwe, Malawi, we characterised the diversity of P. falciparum infection by several ecological indices. Infection by multiple distinct variants was common, and 20 distinct repeat sizes were identified. Diversity of P. falciparum appeared greater in children (18 variants) than adults (12 variants). There was evidence of genetic distance between different geographic regions by Nei's Standard Genetic Distance, suggesting parasite populations vary locally. We show that P. falciparum is very diverse with respect to NANP repeat length even on a local level and that diversity appears higher in children.
doi:10.1038/srep01990
PMCID: PMC3683670  PMID: 23771124
5.  Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial 
Lancet  2012;379(9835):2449-2458.
Summary
Background
In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks.
Methods
The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per μL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00164736.
Findings
676 mother–infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5–9) than in the maternal-antiretroviral (4%, 3–6; p=0·0273) or the infant-nevirapine (4%, 2–5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29–48 weeks than during the intervention phase (1·1 [95% CI 1·0–1·2] vs 0·7 [0·7–0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group).
Interpretation
In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity
Funding
US Centers for Disease Control and Prevention.
doi:10.1016/S0140-6736(12)60321-3
PMCID: PMC3661206  PMID: 22541418
6.  Preventive Misconception as a Motivation for Participation and Adherence in Microbicide Trials: Evidence from Female Participants and Male Partners in Malawi and Zimbabwe 
AIDS and behavior  2012;16(3):785-790.
This paper presents empirical data on motivation to join an HIV prevention trial of vaginal microbicide gels in Malawi and Zimbabwe, and participant assumption of a preventive misconception. Interviews were conducted with women participating in the trial and their male partners. Most of the female participants were able to adequately describe basic aspects of the trial design. HIV counseling and testing were primary reasons motivating women’s participation, and male partners’ support of the trial. 29% of women and 20% of men also provided indications of a preventive misconception, attributing gel use and trial participation to avoiding HIV infection.
doi:10.1007/s10461-011-0027-7
PMCID: PMC3658446  PMID: 21863339
Preventive misconception; Microbicide; HIV trials
7.  Prevalence of hepatitis C virus infection among human immunodeficiency virus-1-infected pregnant women in Malawi: The BAN study☆ 
Background
In Sub-Saharan Africa, prevalence estimates of hepatitis C virus (HCV) vary widely.
Objectives
To assess the prevalence of HCV infection among HIV-infected, pregnant women screened for a large clinical trial in Lilongwe, Malawi.
Study design
Plasma from 2041 HIV-infected, pregnant women was screened for anti-HCV IgG using a chemiluminiscent immunometric assay (CIA). Specimens with a signal-cut-off ratio ≥ 1.00 were considered reactive and those with S/Co ratio < 1.00 non-reactive. All CIA-reactive specimens were tested by a recombinant immunoblot assay (RIBA) for anti-HCV and by PCR for HCV RNA.
Results
Of 2041 specimens, 110 (5.3%, 95% CI: 4.5–6.5%) were CIA reactive. Of the 109 CIA reactive specimens available for RIBA testing, 2 (1.8%) were positive, 28 (25.7%) were indeterminate, and 79 (72.5%) were negative. All CIA-reactive specimens were HCV RNA negative (n = 110). The estimated HCV prevalence based on the screening assay alone was 5.3%; based on supplemental RIBA testing, the status of HCV infection remained indeterminate in 1.4% (28/2040, 95% CI: 0.1–2.0) and the prevalence of confirmed HCV infections was 0.1% (2/2040, 95% CI: 0–0.4%).
Conclusions
HCV seroprevalence among HIV-infected, pregnant women in Malawi confirmed by supplemental RIBA HCV 3.0 is low (0.1%); CIA showed a high false-reactivity rate in this population.
doi:10.1016/j.jcv.2012.05.003
PMCID: PMC3652577  PMID: 22658797
HIV; HCV; Pregnant women; Malawi
8.  Diversity of T Cell Epitopes in Plasmodium falciparum Circumsporozoite Protein Likely Due to Protein-Protein Interactions 
PLoS ONE  2013;8(5):e62427.
Circumsporozoite protein (CS) is a leading vaccine antigen for falciparum malaria, but is highly polymorphic in natural parasite populations. The factors driving this diversity are unclear, but non-random assortment of the T cell epitopes TH2 and TH3 has been observed in a Kenyan parasite population. The recent publication of the crystal structure of the variable C terminal region of the protein allows the assessment of the impact of diversity on protein structure and T cell epitope assortment. Using data from the Gambia (55 isolates) and Malawi (235 isolates), we evaluated the patterns of diversity within and between epitopes in these two distantly-separated populations. Only non-synonymous mutations were observed with the vast majority in both populations at similar frequencies suggesting strong selection on this region. A non-random pattern of T cell epitope assortment was seen in Malawi and in the Gambia, but structural analysis indicates no intramolecular spatial interactions. Using the information from these parasite populations, structural analysis reveals that polymorphic amino acids within TH2 and TH3 colocalize to one side of the protein, surround, but do not involve, the hydrophobic pocket in CS, and predominately involve charge switches. In addition, free energy analysis suggests residues forming and behind the novel pocket within CS are tightly constrained and well conserved in all alleles. In addition, free energy analysis shows polymorphic residues tend to be populated by energetically unfavorable amino acids. In combination, these findings suggest the diversity of T cell epitopes in CS may be primarily an evolutionary response to intermolecular interactions at the surface of the protein potentially counteracting antibody-mediated immune recognition or evolving host receptor diversity.
doi:10.1371/journal.pone.0062427
PMCID: PMC3646838  PMID: 23667476
9.  Maternal or Infant Antiretroviral Drugs to Reduce HIV-1 Transmission 
The New England journal of medicine  2010;362(24):2271-2281.
Background
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.
Methods
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.
Results
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.
Conclusions
The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)
doi:10.1056/NEJMoa0911486
PMCID: PMC3440865  PMID: 20554982
10.  Sexual Partnership Patterns in Malawi: Implications for HIV/STI Transmission 
Sexually transmitted diseases  2011;38(7):657-666.
Background
Concurrent sexual partnerships are believed to play an important role in HIV transmission in sub-Saharan Africa, but the contributions of concurrency to HIV and STI spread depend on the details of infectious periods and relationship patterns. To contribute to the understanding of sexual partnership patterns in this region, we estimated partnership lengths, temporal gaps between partners, and periods of overlap across partners at an STI clinic in Lilongwe, Malawi.
Methods
Participants underwent physical examinations and HIV tests, and responded to questionnaires about demographics and risk behaviors, including detailed questions about a maximum of 3 sexual partners in the previous 2 months. We calculated partnership length as the time between the first and most recent sexual contact with a partner, and gap length as the time between the most recent contact with one partner and the first contact with the next. We defined concurrent and consecutive partnerships as gap length≤0 days and gap length>0 days, respectively.
Results
The study population (n=183) had a mean partnership length of 858 days (median=176 days). Eighty-six percent reported 0 or 1 partner, 5% reported multiple consecutive partnerships, and 9% reported concurrency. Gaps between consecutive partnerships were short (mean=21 days), and overlaps across concurrent partners tended to be long (mean=246 days).
Conclusions
Multiple sexual partnerships were uncommon, and partnerships were long on average. Among those reporting multiple recent partners, both long-term concurrency and narrowly spaced consecutive partnerships could present substantial risk for efficient transmission of HIV and classical STIs.
doi:10.1097/OLQ.0b013e31820cb223
PMCID: PMC3125407  PMID: 21301383
Transmission; concurrency; partnership length; gap length; overlap
11.  HIV partner notification is effective and feasible in sub-Saharan Africa: Opportunities for HIV treatment and prevention 
Background
Sexual partners of persons with newly diagnosed HIV infection require HIV counseling, testing and, if necessary, evaluation for therapy. However, many African countries do not have a standardized protocol for partner notification and the effectiveness of partner notification has not been evaluated in developing countries.
Methods
Individuals with newly diagnosed HIV infection presenting to STI clinics in Lilongwe, Malawi were randomized to one of three methods of partner notification: passive referral, contract referral, or provider referral. The passive referral group was responsible for notifying their partners themselves. The contract referral group was given seven days to notify their partners, after which a health care provider contacted partners who had not reported for counseling and testing. In the provider referral group, a health care provider notified partners directly.
Results
240 index patients named 302 sexual partners and provided locator information for 252. Among locatable partners, 107 returned for HIV counseling and testing; 20/82 (24%; 95% CI 15 – 34%) partners returned in the passive referral arm, 45/88 (51%; 95% CI 41 – 62%) in the contract referral arm, and 42/82 (51%; 95% CI 40 – 62%) in the provider referral arm (p<0·001). Among returning partners (n=107), 67 (64%) of were HIV-infected with 54 (81%) newly diagnosed.
Discussion
This study provides the first evidence of the effectiveness of partner notification in sub-Saharan Africa. Active partner notification was feasible, acceptable, and effective among STI clinic patients. Partner notification will increase early referral to care and facilitate risk reduction among high-risk uninfected partners.
PMCID: PMC3207356  PMID: 22046601
Partner notification; HIV counseling and testing; sub-Saharan Africa
12.  Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance 
Background
Life-threatening infections present major challenges for health systems in Malawi and the developing world because routine microbiologic culture and sensitivity testing are not performed due to lack of capacity. Use of empirical antimicrobial therapy without regular microbiologic surveillance is unable to provide adequate treatment in the face of emerging antimicrobial resistance. This study was conducted to determine antimicrobial susceptibility patterns in order to inform treatment choices and generate hospital-wide baseline data.
Methods
Culture and susceptibility testing was performed on various specimens from patients presenting with possible infectious diseases at Kamuzu Central Hospital, Lilongwe, Malawi.
Results
Between July 2006 and December 2007 3104 specimens from 2458 patients were evaluated, with 60.1% from the adult medical service. Common presentations were sepsis, meningitis, pneumonia and abscess. An etiologic agent was detected in 13% of patients. The most common organisms detected from blood cultures were Staphylococcus aureus, Escherichia coli, Salmonella species and Streptococcus pneumoniae, whereas Streptococcus pneumoniae and Cryptococcus neoformans were most frequently detected from cerebrospinal fluid. Haemophilus influenzae was rarely isolated. Resistance to commonly used antibiotics was observed in up to 80% of the isolates while antibiotics that were not commonly in use maintained susceptibility.
Conclusions
There is widespread resistance to almost all of the antibiotics that are empirically used in Malawi. Antibiotics that have not been widely introduced in Malawi show better laboratory performance. Choices for empirical therapy in Malawi should be revised accordingly. A microbiologic surveillance system should be established and prudent use of antimicrobials promoted to improve patient care.
doi:10.1186/1471-2334-12-67
PMCID: PMC3342226  PMID: 22436174
13.  The Role of Acute and Early HIV Infection in the Spread of HIV-1 in Lilongwe, Malawi: Implications for “Test and Treat” and Other Transmission Prevention Strategies 
Lancet  2011;378(9787):256-268.
Background
HIV transmission risk during acute and early HIV infection (EHI) is sharply elevated, but the contribution of EHI to ongoing HIV transmission is controversial. However, in settings where EHI contributes substantially to secondary transmissions, early diagnosis and intervention may be critical for HIV prevention. We estimated the contribution of EHI to HIV incidence in Lilongwe, Malawi and predicted the future impact of hypothetical prevention interventions affecting EHI only, chronic HIV infection (CHI) only, or both stages.
Methods
We developed a deterministic mathematical model describing heterosexual HIV transmission, informed by detailed behavioural and viral load data collected in Lilongwe. We included sexual contact within and outside steady pairs and divided the infectious period into multiple intervals to allow for changes in transmissibility by infection stage. We used a Bayesian melding approach to fit the model to HIV prevalence data collected over time at Lilongwe antenatal clinics. We evaluated interventions that reduced the per-contact transmission probability to 0·00003 in those receiving them and varied the proportion of individuals receiving the intervention in each stage.
Findings
We estimated that 38·4% (95% credible interval: 18·6%-52·3%) of ongoing HIV transmissions in Lilongwe are attributable to sexual contact with EHI index cases. Interventions acting only during EHI substantially reduced HIV prevalence, but did not lead to elimination, even with 100% coverage. Interventions acting only during CHI also reduced HIV prevalence, but coverage levels of 95%-99% were required to move the epidemic toward elimination. In scenarios with <95% CHI coverage, additional interventions reaching 25%-75% of EHI cases reduced HIV prevalence substantially.
Interpretation
Our results suggest that EHI plays an important role in HIV transmission in this sub-Saharan African setting. Without near-perfect coverage, interventions during CHI will likely have incomplete effectiveness unless complemented by strategies targeting the heightened transmission risk of EHI.
doi:10.1016/S0140-6736(11)60842-8
PMCID: PMC3274419  PMID: 21684591
14.  The acceptance and feasibility of replacement feeding at 6 months as an HIV prevention method in Lilongwe, Malawi: Results from the BAN Study 
International guidelines recommend exclusive breastfeeding to 6 months among HIV-infected mothers choosing to breastfeed and cessation thereafter if replacement feeding is acceptable, feasible, affordable, sustainable and safe. When mothers wean they are challenged to provide an adequate replacement diet. This study investigates the use and acceptability of a lipid-based nutrient supplement (LNS) as a breastmilk substitute when provided to infants (6-12mo) of HIV-positive mothers, as part of the Breastfeeding, Antiretroviral, and Nutrition (BAN) Study. A sub-sample of mothers (n=45) participated in interviews that explored exclusive breastfeeding, weaning, and strategies to feed LNS. Mothers reported several weaning strategies, including gradual reduction of breastfeeding, expressing breastmilk into a cup, and separation of mother and child. LNS, a peanut-based micronutrient fortified paste, was highly accepted and incorporated into the traditional diet. Weaning is a feasible HIV prevention method among this population in Malawi when supported by the provision of LNS as a breastmilk substitute.
doi:10.1521/aeap.2011.23.3.281
PMCID: PMC3197736  PMID: 21696245
HIV; infant feeding; breastfeeding; weaning; LNS
15.  Viral Response to Chemotherapy in Endemic Burkitt Lymphoma 
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1158/1078-0432.CCR-09-2424
PMCID: PMC2848899  PMID: 20233888
Epstein-Barr Virus; Burkitt lymphoma; lytic infection; cyclophosphamide; ganciclovir
16.  Effect of prenatal and perinatal antibiotics on maternal health in Malawi, Tanzania, and Zambia 
Objective
We assessed the effect of prenatal and peripartum antibiotics on maternal morbidity and mortality among HIV-infected and uninfected women.
Methods
A multicenter trial was conducted at clinical sites in 4 Sub-Saharan African cities: Blantyre and Lilongwe, Malawi; Dar es Salaam, Tanzania; and Lusaka, Zambia. A total of 1558 HIV-infected and 271 uninfected pregnant women who were eligible to receive both the prenatal and peripartum antibiotic/placebo regimens were enrolled. Pregnant women were interviewed at 20–24 weeks of gestation and a physical examination was performed. Women were randomized to receive either antibiotics or placebo. At the 26–30 week visit, participants were given antibiotics or placebo to be taken every 4 hours beginning at the onset of labor and continuing after delivery 3 times a day until a 1-week course was completed. Logistic regression and Cox proportional hazards models were used.
Results
There were no significant differences between the antibiotic and placebo groups for medical conditions, obstetric complications, physical examination findings, puerperal sepsis, and death in either the HIV-infected or the uninfected cohort.
Conclusion
Administration of study antibiotics during pregnancy had no effect on maternal morbidity and mortality among HIV-infected and uninfected pregnant women.
doi:10.1016/j.ijgo.2009.07.037
PMCID: PMC2783250  PMID: 19716560
Antibiotics; HIV; Maternal morbidity; Maternal mortality; Pregnancy
17.  EVALUATING NURSES’ IMPLEMENTATION OF AN INFANT-FEEDING COUNSELING PROTOCOL FOR HIV-INFECTED MOTHERS: THE BAN STUDY IN LILONGWE, MALAWI 
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.
doi:10.1521/aeap.2009.21.2.141
PMCID: PMC2903193  PMID: 19397436
18.  Modifications of a large HIV prevention clinical trial to fit changing realities: A case study of the Breastfeeding, Antiretroviral, and Nutrition (BAN) Protocol in Lilongwe, Malawi 
Contemporary clinical trials  2008;30(1):24-33.
In order to evaluate strategies to reduce HIV transmission through breast milk and optimize both maternal and infant health among HIV-infected women and their infants, we designed and implemented a large, randomized clinical trial in Lilongwe, Malawi. The development of protocols for large, randomized clinical trials is a complicated and lengthy process often requiring alterations to the original research design. Many factors lead to delays and changes, including study site-specific priorities, new scientific information becoming available, the involvement of national and international human subject committees and monitoring boards, and alterations in medical practice and guidance at local, national, and international levels. When planning and implementing a clinical study in a resource-limited setting, additional factors must be taken into account, including local customs and program needs, language and socio-cultural barriers, high background rates of malnutrition and endemic diseases, extreme poverty, lack of personnel, and limited infrastructure. Investigators must be prepared to modify the protocol as necessary in order to ensure participant safety and successful implementation of study procedures. This paper describes the process of designing, implementing, and subsequently modifying the Breastfeeding, Antiretrovirals, and Nutrition, (BAN) study, a large, ongoing, randomized breastfeeding intervention trial of HIV-infected women and their infants conducted at a single site in Lilongwe, Malawi. We highlight some of the successes, challenges, and lessons learned at different stages during the conduct of the trial.
doi:10.1016/j.cct.2008.09.001
PMCID: PMC2790186  PMID: 18805510
Mother-to-child transmission of HIV; breastfeeding; HIV/AIDS; nutrition; study design and management; antiretroviral drugs
19.  Intrapartum Antibiotic Exposure and Early Neonatal Morbidity and Mortality in Africa 
Pediatrics  2009;124(1):e137-e144.
Background
Infants born to women who receive intrapartum antibiotics may have higher rates of infectious morbidity and mortality than unexposed infants.
Objective
To determine the association of maternal intrapartum antibiotics and early neonatal morbidity and mortality.
Methods
Secondary analysis of data from a multi-site randomized placebo-controlled clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV-1 and preterm birth in sub-Saharan Africa. Early neonatal morbidity and mortality were analyzed. In an intent-to-treat (ITT) analysis, infants born to women randomized to antibiotics or placebo were compared. Additionally, non-ITT analysis was performed because some women received non-study antibiotics for various clinical indications.
Results
Overall, 2659 pregnant women were randomized. Of these, 2466 HIV-1-infected and -uninfected women delivered 2413 live born and 84 stillborn infants. In the ITT analysis, there were no significant associations between exposure to antibiotics and early neonatal outcomes. Non-ITT analyses showed more illness at birth (11.2% vs. 8.6%, p=0.03) and more admissions to the Special Care Baby Unit (12.6% vs. 9.8%, p = 0.04) among infants exposed to maternal intrapartum antibiotics than among unexposed infants. Further analyses revealed greater early neonatal morbidity and mortality among infants of mothers who received non-study antibiotics than of mothers who received study antibiotics.
Conclusion
There is no association between intrapartum exposure to antibiotics and early neonatal morbidity or mortality. The associations observed in non-ITT analyses are most likely the result of women with peripartum illnesses being more likely to receive non-study antibiotics.
doi:10.1542/peds.2008-1873
PMCID: PMC2764263  PMID: 19564260
Antibiotic resistance; Antibiotics; Neonatal morbidity; Neonatal mortality; Neonatal sepsis
20.  Correlates of Syphilis Seroreactivity Among Pregnant Women: The HIVNET 024 Trial in Malawi, Tanzania, and Zambia 
Sexually transmitted diseases  2006;33(10):604-609.
Objective
The objectives of this cross-sectional study were to determine correlates of syphilis seroprevalence among HIV-infected and -uninfected antenatal attendees in an African multisite clinical trial, and to improve strategies for maternal syphilis prevention.
Results
A total of 2270 (86%) women were HIV-infected and 366 (14%) were HIV-uninfected. One hundred seventy-five (6.6%) were syphilis-seropositive (7.3% among HIV-infected and 2.6% HIV-uninfected women). Statistically significant correlates included geographic site (odds ratio [OR] = 4.5, Blantyre; OR = 3.2, Lilongwe; OR = 9.0, Lusaka vs. Dar es Salaam referent); HIV infection (OR = 3.3); age 20 to 24 years (OR = 2.5); being divorced, widowed, or separated (OR = 2.9); genital ulcer treatment in the last year (OR = 2.9); history of stillbirth (OR = 2.8, one stillbirth; OR = 4.3, 2–5 stillbirths); and history of preterm delivery (OR = 2.7, one preterm delivery).
Conclusion
Many women without identified risk factors were syphilis-seropositive. Younger HIV-infected women were at highest risk. Universal integrated antenatal HIV and syphilis screening and treatment is essential in sub-Saharan African settings.
doi:10.1097/01.olq.0000216029.00424.ae
PMCID: PMC2743105  PMID: 16601659
21.  Improved detection of acute HIV-1 infection in sub-Saharan Africa: development of a risk score algorithm 
AIDS (London, England)  2007;21(16):2237-2242.
Objective
Individuals with acute (preseroconversion) HIV infection (AHI) are important in the spread of HIV. The identification of AHI requires the detection of viral proteins or nucleic acids with techniques that are often unaffordable for routine use. To facilitate the efficient use of these tests, we sought to develop a risk score algorithm for identifying likely AHI cases and targeting the tests towards those individuals.
Design
A cross-sectional study of 1448 adults attending a sexually transmitted infections (STI) clinic in Malawi.
Methods
Using logistic regression, we identified risk behaviors, symptoms, HIV rapid test results, and STI syndromes that were predictive of AHI. We assigned a model-based score to each predictor and calculated a risk score for each participant.
Results
Twenty-one participants (1.45%) had AHI, 588 had established HIV infection, and 839 were HIV-negative. AHI was strongly associated with discordant rapid HIV tests and genital ulcer disease (GUD). The algorithm also included diarrhea, more than one sexual partner in 2 months, body ache, and fever. Corresponding predictor scores were 1 for fever, body ache, and more than one partner; 2 for diarrhea and GUD; and 4 for discordant rapid tests. A risk score of 2 or greater was 95.2% sensitive and 60.5% specific in detecting AHI.
Conclusion
Using this algorithm, we could identify 95% of AHI cases by performing nucleic acid or protein tests in only 40% of patients. Risk score algorithms could enable rapid, reliable AHI detection in resource-limited settings.
doi:10.1097/QAD.0b013e3282f08b4d
PMCID: PMC2673577  PMID: 18090052
acute HIV infection; detection; diagnosis; risk score algorithm; screening
22.  Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection 
AIDS (London, England)  2007;21(13):1723-1730.
Objectives
This study was conducted to compare viral dynamics in blood and semen between subjects with antibody negative, acute HIV-1 infection and other subjects with later stages of infection.
Design
A prospective cohort study was embedded within a cross-sectional study of HIV screening in a Lilongwe, Malawi STD clinic.
Methods
Blood samples from HIV antibody negative or indeterminate volunteers were used to detect HIV RNA in plasma using a pooling strategy. Blood and seminal plasma HIV-1 RNA concentrations were measured over 16 weeks.
Results
Sixteen men with acute HIV infection and 25 men with chronic HIV infection were studied. Blood viral load in subjects with acute HIV infection was highest about 17 days after infection (mean ± SE, 6.9 ± 0.5 log10 copies/ml), while semen viral load peaked about 30 days after infection (4.5 ± 0.4 log10 copies/ml). Semen viral load declined by 1.7 log10 to a nadir by week 10 of HIV infection. Semen and blood viral loads were more stable in chronically infected subjects over 16 weeks. Higher semen levels of HIV RNA were noted in subjects with low CD4 cell counts.
Conclusions
These results provide a biological explanation for reported increases in HIV transmission during the very early (acute) and late stages of infection. Recognizing temporal differences in HIV shedding in the genital tract is important in the development of effective HIV prevention strategies.
doi:10.1097/QAD.0b013e3281532c82
PMCID: PMC2673564  PMID: 17690570
semen; HIV transmission; acute HIV infection; peak viral load
23.  Validation of a Urine-Based PCR-Enzyme-Linked Immunosorbent Assay for Use in Clinical Research Settings To Detect Trichomonas vaginalis in Men 
Journal of Clinical Microbiology  2003;41(1):318-323.
Trichomonas vaginalis infection is highly prevalent worldwide and is associated with urethritis, prostatitis, and urethral strictures in men. However, the natural history and importance of T. vaginalis in men are poorly understood, in part because of difficulties in diagnosing infection. Traditional detection methods rely on culture and wet-mount microscopy, which can be insensitive and time consuming. Urethral swabs are commonly used to detect T. vaginalis in men, but discomfort from specimen collection is a barrier to large studies. One thousand two hundred twenty-five Malawian men attending sexually transmitted disease and dermatology clinics were enrolled in this cross-sectional study to validate detection by urine-based PCR-enzyme-linked immunosorbent assay (ELISA) with urine and urethral swab culture as the reference standard. This assay for detection of amplified T. vaginalis DNA in first-catch urine (≤30 ml) performed with a sensitivity of 92.7%, a specificity of 88.6%, and an adjusted specificity of 95.2% compared to culture of urethral swabs or urine sediment. For clinical research settings in which urethral swabs are not available and culture is not feasible, the urine-based PCR-ELISA may be useful for detection of trichomoniasis in men.
doi:10.1128/JCM.41.1.318-323.2003
PMCID: PMC149613  PMID: 12517867

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