39 results on '"Kamwendo, D."'
Search Results
2. Nevirapine Resistance in Human Immunodeficiency Virus Type 1-Positive Infants Determined Using Dried Blood Spots Stored for Up to Six Years at Room Temperature
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Kamwendo, D., Fiscus, S. A., Fawzi, W. W., Nelson, J. A. E., Taha, T. E., Loftis, A. M., and Goldenberg, R. L.
- Abstract
Dried blood spots that had been stored ambiently for 3 to 6 years lost approximately 1 log10 of human immunodeficiency virus type 1 (HIV-1) RNA, but the majority could still be genotyped for resistance. Nevirapine resistance was found in 7/16 (43.5%) HIV-1-positive HIVNET 024 infants at 4 to 6 weeks, but no resistance was found at other time points.
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- 2009
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3. Malaria during pregnancy and foetal haematological status in Blantyre, Malawi
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Abrams, E. T., Kwiek, J. J., Mwapasa, V., Kamwendo, D. D., Tadesse, E., Lema, V. M., Molyneux, Malcolm E, Rogerson, S. J., and Meshnick, S. R.
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parasitic diseases ,wq_200 ,ws_141 ,wq_240 ,wc_750 - Abstract
Background: Although maternal anaemia often stems from malaria infection during pregnancy, its effects on foetal haemoglobin levels are not straightforward. Lower-than-expected cord haemoglobin values in malarious versus non-malarious regions were noted by one review, which hypothesized they resulted from foetal immune activation to maternal malaria. This study addressed this idea by examining cord haemoglobin levels in relation to maternal malaria, anaemia, and markers of foetal immune activation.\ud Methods: Cord haemoglobin levels were examined in 32 malaria-infected and 58 uninfected women in Blantyre, Malawi, in relation to maternal haemoglobin levels, malaria status, and markers of foetal haematological status, hypoxia, and inflammation, including TNF-alpha, TGF-beta, and ferritin. All women were HIV-negative.\ud Results: Although malaria was associated with a reduction in maternal haemoglobin (10.8 g/dL vs. 12.1 g/ dL, p < 0.001), no reduction in cord haemoglobin and no significant relationship between maternal and cord haemoglobin levels were found. Cord blood markers of haematological and hypoxic statuses did not differ between malaria-infected and uninfected women. Maternal malaria was associated with decreased TGF- and increased cord ferritin, the latter of which was positively correlated with parasitaemia (r = 0.474, p = 0.009). Increased cord ferritin was associated with significantly decreased birth weight and gestational length, although maternal and cord haemoglobin levels and malaria status had no effect on birth outcome.\ud Conclusion: In this population, cord haemoglobin levels were protected from the effect of maternal malaria. However, decreased TGF- and elevated ferritin levels in cord blood suggest foetal immune activation to maternal malaria, which may help explain poor birth outcomes.
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- 2005
4. Mutations Associated with Sulfadoxine-Pyrimethamine and Chlorproguanil Resistance in Plasmodium falciparum Isolates from Blantyre, Malawi
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Kamwendo, D. D., Purfield, A., Rogerson, S. J., Molyneux, M. E., Meshnick, S. R., Mwapasa, V., Alker, A. P., Chaluluka, E., and Tadesse, E.
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parasitic diseases ,humanities - Abstract
We conducted a prevalence study of mutations in Plasmodium falciparum that are associated with antifolate resistance in Blantyre, Malawi. The dihydrofolate reductase 164-Leu mutation, which confers resistance to both pyrimethamine and chlorproguanil, was found in 4.7% of the samples. Previously unreported mutations in dihydropteroate synthase were also found.
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- 2005
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5. CCR5 Haplotypes and Mother-to-Child HIV Transmission in Malawi
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Emery, S, Pedersen, BR, Kamwendo, D, Blood, M, Mwapasa, V, Molyneux, M, North, K, Rogerson, SJ, Zimmerman, P, Meshnick, SR, Emery, S, Pedersen, BR, Kamwendo, D, Blood, M, Mwapasa, V, Molyneux, M, North, K, Rogerson, SJ, Zimmerman, P, and Meshnick, SR
- Abstract
BACKGROUND: CCR5 and CCR2 gene polymorphisms (SNPs) have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Delta32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the association between infant CCR2/CCR5 diplotype and HIV mother to child transmission (MTCT) in Malawi. Blood samples from infants (n = 552) of HIV positive women who received nevirapine were genotyped using a post-PCR multiplex ligase detection reaction and haplotypes were identified based on 8 CCR2/CCR5 SNPs and the open reading frame 32 base pair deletion. Following verification of Hardy-Weinberg equilibrium, log linear regression was performed to examine the association between mutations and MTCT. Overall, protection against MTCT was weakly associated with two CCR5 SNPs, -2459G (Risk ratio [RR], 0.78; confidence interval [CI], 0.54-1.12), and the linked CCR5 -2135T (RR, 0.78; CI, 0.54-1.13). No child carried the CCR5 Delta32 SNP. Maternal Viral Load (MVL) was found to be an effect measure modifier. Among mothers with low MVL, statistically significant protection against MTCT was observed for -2459G (RR, 0.50; CI, 0.27-0.91), and -2135T (RR, 0.51; CI, 0.28-0.92). Statistically significant protection was not found at high MVL. CONCLUSIONS/SIGNIFICANCE: Results from this study suggest that CCR5 SNPs -2459G and -2135T associated with reduced receptor expression protect against MTCT of HIV at low MVLs, whereas high MVLs may over-ride differences in coreceptor availability.
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- 2007
6. On the front line of HIV virological monitoring: barriers and facilitators from a provider perspective in resource-limited settings.
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Rutstein, S.E., Golin, C.E., Wheeler, S.B., Kamwendo, D., Hosseinipour, M.C., Weinberger, M., Miller, W.C., Biddle, A.K., Soko, A., Mkandawire, M., Mwenda, R., Sarr, A., Gupta, S., and Mataya, R.
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ANTIRETROVIRAL agents ,ATTITUDE (Psychology) ,COUNSELING ,DRUGS ,HEALTH services accessibility ,HIV infections ,HIV-positive persons ,INTERVIEWING ,MEDICAL care ,MEDICAL personnel ,PATIENT compliance ,PATIENT monitoring ,RESEARCH funding ,VIROLOGY ,DECISION making in clinical medicine ,VIRAL load ,THEMATIC analysis ,HUMAN services programs ,EVALUATION of human services programs ,DATA analysis software - Abstract
Scale-up of viral load (VL) monitoring for HIV-infected patients on antiretroviral therapy (ART) is a priority in many resource-limited settings, and ART providers are critical to effective program implementation. We explored provider-perceived barriers and facilitators of VL monitoring. We interviewed all providers (n = 17) engaged in a public health evaluation of dried blood spots for VL monitoring at five ART clinics in Malawi. All ART clinics were housed within district hospitals. We grouped themes at patient, provider, facility, system, and policy levels. Providers emphasized their desire for improved ART monitoring strategies, and frustration in response to restrictive policies for determining which patients were eligible to receive VL monitoring. Although many providers pled for expansion of monitoring to include all persons on ART, regardless of time on ART, the most salient provider-perceived barrier to VL monitoring implementation was the pressure of work associated with monitoring activities. The work burden was exacerbated by inefficient data management systems, highlighting a critical interaction between provider-, facility-, and system-level factors. Lack of integration between laboratory and clinical systems complicated the process for alerting providers when results were available, and these communication gaps were intensified by poor facility connectivity. Centralized second-line ART distribution was also noted as a barrier: providers reported that the time and expenses required for patients to collect second-line ART frequently obstructed referral. However, provider empowerment emerged as an unexpected facilitator of VL monitoring. For many providers, this was the first time they used an objective marker of ART response to guide clinical management. Providers’ knowledge of a patient's virological status increased confidence in adherence counseling and clinical decision-making. Results from our study provide unique insight into provider perceptions of VL monitoring and indicate the importance of policies responsive to individual and environmental challenges of VL monitoring program implementation. Findings may inform scale-up by helping policy-makers identify strategies to improve feasibility and sustainability of VL monitoring. [ABSTRACT FROM PUBLISHER]
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- 2016
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7. Point-of-Care Diagnostics for Acute HIV Infection: An Important Public Health Priority
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Rosenberg, N. E., primary, Kamanga, G., additional, Phiri, S., additional, Nsona, D., additional, Pettifor, A., additional, Rutstein, S. E., additional, Kamwendo, D., additional, Hoffman, I. F., additional, Keating, M., additional, Brown, L. B., additional, Ndalama, B., additional, Fiscus, S. A., additional, Congdon, S., additional, Cohen, M. S., additional, and Miller, W. C., additional
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- 2012
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8. Maternal and infant predictors of CRP in exclusively breastfed infants born to HIV‐infected Malawian mothers
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Adair, Linda S, primary, Thompson, A L, additional, Kayira, D, additional, Chasela, C, additional, Kacheche, Z, additional, Kamwendo, D, additional, Bentley, M, additional, Jamieson, D, additional, Allen, L H, additional, and Shahab-Ferdows, S, additional
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- 2012
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9. Impact of aciclovir on ulcer healing, lesional, genital and plasma HIV-1 RNA among patients with genital ulcer disease in Malawi
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Phiri, S., primary, Hoffman, I. F., additional, Weiss, H. A., additional, Martinson, F., additional, Nyirenda, N., additional, Kamwendo, D., additional, Fiscus, S. A., additional, Chen, C.-Y., additional, Miller, W. C., additional, van der Hoeven, L., additional, Chilongozi, D., additional, Cohen, M. S., additional, and Mayaud, P., additional
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- 2010
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10. Detection of acute HIV infection: a field evaluation of the determine® HIV-1/2 Ag/Ab combo test.
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Rosenberg NE, Kamanga G, Phiri S, Nsona D, Pettifor A, Rutstein SE, Kamwendo D, Hoffman IF, Keating M, Brown LB, Ndalama B, Fiscus SA, Congdon S, Cohen MS, Miller WC, Rosenberg, Nora E, Kamanga, Gift, Phiri, Sam, Nsona, Dominic, and Pettifor, Audrey
- Abstract
Background: Most human immunodeficiency virus (HIV) point-of-care tests detect antibodies (Ab) but not p24 antigen (Ag) or RNA. In the absence of antibodies, p24 antigen and RNA typically indicate acute HIV infection. We conducted a field evaluation of the Determine® HIV-1/2 Ag/Ab Combo rapid test (Combo RT).Methods: The antigen portion of the Combo RT (for acute HIV infection) was compared with a Roche Monitor HIV RNA polymerase chain reaction assay. The antibody portion of Combo RT (for established HIV infection) was compared with rapid test algorithms. Participants were enrolled at a sexually transmitted infection clinic and HIV testing and counseling center in Lilongwe, Malawi. Rapid testing was conducted with parallel testing in the clinic and serial testing in the center. The Combo RT was performed in clinic participants with negative or discordant antibody results and in all center participants.Results: Of the participants 838 were HIV negative, 163 had established HIV infection, and 8 had acute HIV infection. For detecting acute HIV infection, the antigen portion had a sensitivity of 0.000 and a specificity of 0.983. For detecting established HIV infection, the antibody portion had a sensitivity of 0.994 and a specificity of 0.992.Conclusions: Combo RT displayed excellent performance for detecting established HIV infection and poor performance for detecting acute HIV infection. In this setting, Combo RT is no more useful than current algorithms. [ABSTRACT FROM AUTHOR]- Published
- 2012
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11. Nevirapine Resistance in Human Immunodeficiency Virus Type 1-Positive Infants Determined Using Dried Blood Spots Stored for Up to Six Years at Room Temperature
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Nelson, J. A. E., Loftis, A. M., Kamwendo, D., Fawzi, Wafaie W., Taha, T. E., Goldenberg, R. L., and Fiscus, S. A.
- Abstract
Dried blood spots that had been stored ambiently for 3 to 6 years lost approximately 1 log10 of human immunodeficiency virus type 1 (HIV-1) RNA, but the majority could still be genotyped for resistance. Nevirapine resistance was found in 7/16 (43.5%) HIV-1-positive HIVNET 024 infants at 4 to 6 weeks, but no resistance was found at other time points.
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- 2009
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12. Risk factors and mechanisms of preterm delivery in Malawi
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Abrams, E. T., Milner Jr, D. A., Kwiek, J., Mwapasa, V., Kamwendo, D. D., Zeng, D., Tadasse, E., Lema, V. M., Molyneux, M. E., Stephen Rogerson, and Meshnick, S. R.
13. Viral profiling identifies multiple subtypes of Kaposi's sarcoma
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Mc, Hosseinipour, Km, Sweet, Xiong J, Namarika D, Mwafongo A, Nyirenda M, Chiwoko L, Kamwendo D, Hoffman I, Lee J, Phiri S, Vahrson W, Damania B, and dirk dittmer
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viruses ,virus diseases - Abstract
Kaposi’s sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral therapy (ART). Seventy patients were enrolled. Eighty-one percent had T1 (advanced) KS. Median CD4 and HIV RNA levels were 181cells/mm3 and 138,641 copies/ml, respectively. We had complete information and suitable plasma and biopsy samples for 66 patients. For 59/66 (89%) patients, a detectable KSHV load was found in plasma (median, 2,291 copies/ml; interquartile range [IQR], 741 to 5,623). We utilized a novel KSHV real-time quantitative PCR (qPCR) array with multiple primers per open reading frame to examine KSHV transcription. Seventeen samples exhibited only minimal levels of KSHV mRNAs, presumably due to the limited number of infected cells. For all other biopsy samples, the viral latency locus (LANA, vCyc, vFLIP, kaposin, and microRNAs [miRNAs]) was transcribed abundantly, as was K15 mRNA. We could identify two subtypes of treatment-naive KS: lesions that transcribed viral RNAs across the length of the viral genome and lesions that displayed only limited transcription restricted to the latency locus. This finding demonstrates for the first time the existence of multiple subtypes of KS lesions in HIV- and KS-treatment naive patients.IMPORTANCEKS is the leading cancer in people infected with HIV worldwide and is causally linked to KSHV infection. Using viral transcription profiling, we have demonstrated the existence of multiple subtypes of KS lesions for the first time in HIV- and KS-treatment-naive patients. A substantial number of lesions transcribe mRNAs which encode the viral kinases and hence could be targeted by the antiviral drugs ganciclovir or AZT in addition to chemotherapy.
14. Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without Sexually Transmitted Infection-Associated Urethritis.
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Council OD, Zhou S, McCann CD, Hoffman I, Tegha G, Kamwendo D, Matoga M, Kosakovsky Pond SL, Cohen MS, and Swanstrom R
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- Adult, Base Sequence, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Cohort Studies, Cytokines genetics, Cytokines immunology, HIV Infections epidemiology, HIV Infections immunology, HIV Infections transmission, HIV-1 classification, High-Throughput Nucleotide Sequencing, Humans, Malawi epidemiology, Male, Middle Aged, Phylogeny, Sexually Transmitted Diseases epidemiology, Sexually Transmitted Diseases immunology, Sexually Transmitted Diseases transmission, Urethritis epidemiology, Virus Replication, env Gene Products, Human Immunodeficiency Virus blood, env Gene Products, Human Immunodeficiency Virus classification, HIV Infections virology, HIV-1 genetics, Semen virology, Sexually Transmitted Diseases virology, Urethritis virology, env Gene Products, Human Immunodeficiency Virus genetics
- Abstract
Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from antiretroviral therapy (ART)-naive men living in Malawi with ( n = 19) and without ( n = 5) STI-associated urethritis; for a subset of samples, full-length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of proinflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population, indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified, perhaps initially by cellular proliferation but further by limited viral replication. IMPORTANCE HIV-1 infection is a sexually transmitted infection that coexists with other STI. Here, we examined the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI., (Copyright © 2020 American Society for Microbiology.)
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- 2020
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15. The effects of a lipid-based nutrient supplement and antiretroviral therapy in a randomized controlled trial on iron, copper, and zinc in milk from HIV-infected Malawian mothers and associations with maternal and infant biomarkers.
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Hampel D, Shahab-Ferdows S, Gertz E, Flax VL, Adair LS, Bentley ME, Jamieson DJ, Tegha G, Chasela CS, Kamwendo D, van der Horst CM, and Allen LH
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- Adult, Anti-HIV Agents therapeutic use, Biomarkers blood, Breast Feeding, Dietary Supplements, Female, Hemoglobins metabolism, Humans, Infant, Infant, Newborn, Inflammation blood, Iron blood, Lipids administration & dosage, Malawi, Male, Milk, Human metabolism, Mothers, Young Adult, Anti-HIV Agents pharmacology, Copper metabolism, HIV Infections drug therapy, Iron metabolism, Lipids pharmacology, Milk, Human drug effects, Zinc metabolism
- Abstract
We evaluated effects of antiretroviral (ARV) therapy and lipid-based nutrient supplements (LNSs) on iron, copper, and zinc in milk of exclusively breastfeeding HIV-infected Malawian mothers and their correlations with maternal and infant biomarkers. Human milk and blood at 2, 6, and 24 weeks post-partum and blood during pregnancy (≤30 weeks gestation) were collected from 535 mothers/infant-pairs in the Breastfeeding, Antiretrovirals, and Nutrition study. The participants received ARV, LNS, ARV and LNS, or no intervention from 0 to 28 weeks post-partum. ARVs negatively affected copper and zinc milk concentrations, but only at 2 weeks, whereas LNS had no effect. Among all treatment groups, approximately 80-90% of copper and zinc and <50% of iron concentrations met the current adequate intake for infants at 2 weeks and only 1-19% at 24 weeks. Pregnancy haemoglobin was negatively correlated with milk iron at 2 and 6 weeks (r = -.18, p < .02 for both). The associations of the milk minerals with each other were the strongest correlations observed (r = .11-.47, p < .05 for all); none were found with infant biomarkers. At 2 weeks, moderately anaemic women produced milk higher in iron when ferritin was higher or TfR lower. At 6 weeks, higher maternal α-1-acid glycoprotein and C-reactive protein were associated with higher milk minerals in mildly anaemic women. Infant TfR was lower when milk mineral concentrations were higher at 6 weeks and when mothers were moderately anaemic during pregnancy. ARV affects copper and zinc milk concentrations in early lactation, and maternal haemoglobin during pregnancy and lactation could influence the association between milk minerals and maternal and infant iron status and biomarkers of inflammation., (© 2017 The Authors. Maternal and Child Nutrition Published by John Wiley & Sons, Ltd.)
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- 2018
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16. Effects of concurrent exposure to antiretrovirals and cotrimoxazole prophylaxis among HIV-exposed, uninfected infants.
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Ewing AC, King CC, Wiener JB, Chasela CS, Hudgens MG, Kamwendo D, Tegha G, Hosseinipour MC, Jamieson DJ, Van der Horst C, and Kourtis AP
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- Adolescent, Adult, Alanine Transaminase blood, Anti-Bacterial Agents adverse effects, Anti-Retroviral Agents adverse effects, Antimalarials adverse effects, Bacterial Infections prevention & control, Chemoprevention adverse effects, Female, HIV Infections prevention & control, Hemoglobins analysis, Humans, Infant, Infant, Newborn, Leukocyte Count, Malaria prevention & control, Malawi, Male, Pregnancy, Time Factors, Trimethoprim, Sulfamethoxazole Drug Combination adverse effects, Young Adult, Anti-Bacterial Agents administration & dosage, Anti-Retroviral Agents administration & dosage, Antimalarials administration & dosage, Chemoprevention methods, Drug Interactions, Trimethoprim, Sulfamethoxazole Drug Combination administration & dosage
- Abstract
Background: Given the potential of cotrimoxazole preventive therapy (CPT) to prevent bacterial and malarial infections in HIV-exposed, uninfected (HEU) infants, it is important to evaluate the effects of its concurrent use with antiretroviral agents that have overlapping toxicity profiles., Methods: We used data from the Breastfeeding, Antiretrovirals, and Nutrition study (2004-2010) to evaluate the association of CPT and antiretrovirals with hematologic measures (hemoglobin, neutrophil, and alanine aminotransferase levels) from 6 to 48 weeks of age in 2006 HEU infants in Lilongwe, Malawi. Hazards of severe outcomes (anemia, neutropenia, and elevated alanine aminotransferase), as defined by the National Institutes of Health, were compared using Cox regression models, according to time-varying CPT (implemented June 2006), antiretroviral treatment arm (maternal triple antiretroviral, infant nevirapine, or none during 6 months of breastfeeding), and their interaction. The effects of these treatments on hemoglobin, neutrophil, and alanine aminotransferase levels were assessed using linear mixed models., Results: In Cox models, CPT was associated with an increase in severe neutropenia [hazard ratio 1.97 (1.01, 3.86)] and a decrease in severe anemia (hazard ratio 0.65 (0.48, 0.88)]. Interactions between CPT and antiretroviral treatment were not significant. By 36 weeks, there was a significant association of CPT with increased hemoglobin levels regardless of antiretroviral drug exposure., Conclusions: In addition to expected associations with increased hazard of severe neutropenia and decreased neutrophil count, CPT was associated with reduced hazard of severe anemia and higher infant blood hemoglobin. This provides further support for CPT use in HEU infants in malaria-endemic resource-limited settings where anemia is prevalent.
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- 2017
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17. Differentiated Care Pathways for Antiretroviral Therapy Monitoring in Malawi: Expanding Viral Load Testing in Setting of Highly Prevalent Resistance.
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Rutstein SE, Compliment K, Nelson JAE, Kamwendo D, Mataya R, Miller WC, and Hosseinipour MC
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We quantified resistance to first-line antiretroviral therapy among previously unmonitored patients in Malawi with viremia (≥1000 copies/mL). Ninety-five percent (n = 57/61) harbored nucleoside/tide reverse transcriptase inhibitor/non-nucleoside reverse transcriptase inhibitor resistance; resistance was more common comparing >2 (97%) versus ≤2 years (87%) on therapy. Immediate switch for persons retained in care may improve monitoring efficiency and maximize clinical outcomes.
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- 2017
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18. Thiamin and Riboflavin in Human Milk: Effects of Lipid-Based Nutrient Supplementation and Stage of Lactation on Vitamer Secretion and Contributions to Total Vitamin Content.
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Hampel D, Shahab-Ferdows S, Adair LS, Bentley ME, Flax VL, Jamieson DJ, Ellington SR, Tegha G, Chasela CS, Kamwendo D, and Allen LH
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- Breast Feeding, Confidence Intervals, Female, Flavin-Adenine Dinucleotide analysis, Humans, Thiamine Monophosphate analysis, Thiamine Pyrophosphate analysis, Vitamins, Dietary Supplements, Lactation, Lipids chemistry, Milk, Human chemistry, Riboflavin analysis, Thiamine analysis
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While thiamin and riboflavin in breast milk have been analyzed for over 50 years, less attention has been given to the different forms of each vitamin. Thiamin-monophosphate (TMP) and free thiamin contribute to total thiamin content; flavin adenine-dinucleotide (FAD) and free riboflavin are the main contributors to total riboflavin. We analyzed milk collected at 2 (n = 258) or 6 (n = 104), and 24 weeks (n = 362) from HIV-infected Malawian mothers within the Breastfeeding, Antiretrovirals and Nutrition (BAN) study, randomly assigned at delivery to lipid-based nutrient supplements (LNS) or a control group, to investigate each vitamer's contribution to total milk vitamin content and the effects of supplementation on the different thiamin and riboflavin vitamers at early and later stages of lactation, and obtain insight into the transport and distribution of these vitamers in human milk. Thiamin vitamers were derivatized into thiochrome-esters and analyzed by high-performance liquid-chromatography-fluorescence-detection (HPLC-FLD). Riboflavin and FAD were analyzed by ultra-performance liquid-chromatography-tandem-mass-spectrometry (ULPC-MS/MS). Thiamin-pyrophosphate (TPP), identified here for the first time in breast milk, contributed 1.9-4.5% to total thiamin. Free thiamin increased significantly from 2/6 to 24 weeks regardless of treatment indicating an active transport of this vitamer in milk. LNS significantly increased TMP and free thiamin only at 2 weeks compared to the control: median 170 versus 151 μg/L (TMP), 13.3 versus 10.5 μg/L (free thiamin, p<0.05 for both, suggesting an up-regulated active mechanism for TMP and free thiamin accumulation at early stages of lactation. Free riboflavin was consistently and significantly increased with LNS (range: 14.8-19.6 μg/L (LNS) versus 5.0-7.4 μg/L (control), p<0.001), shifting FAD:riboflavin relative amounts from 92-94:6-8% to 85:15%, indicating a preferred secretion of the free form into breast milk. The continuous presence of FAD in breast milk suggests an active transport and secretion system for this vitamer or possibly formation of this co-enymatic form in the mammary gland.
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- 2016
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19. Antiretroviral therapy provided to HIV-infected Malawian women in a randomized trial diminishes the positive effects of lipid-based nutrient supplements on breast-milk B vitamins.
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Allen LH, Hampel D, Shahab-Ferdows S, York ER, Adair LS, Flax VL, Tegha G, Chasela CS, Kamwendo D, Jamieson DJ, and Bentley ME
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- Adult, Anti-HIV Agents therapeutic use, Dietary Fats administration & dosage, Dietary Supplements, Drug Therapy, Combination adverse effects, Female, Humans, Malawi, Practice Guidelines as Topic, Pregnancy, Pregnancy Complications chemically induced, Pregnancy Complications prevention & control, Vitamin B Complex antagonists & inhibitors, Vitamin B Complex metabolism, Vitamin B Complex therapeutic use, Vitamin B Deficiency chemically induced, Vitamin B Deficiency prevention & control, World Health Organization, Young Adult, Anti-HIV Agents adverse effects, HIV Infections drug therapy, Lactation drug effects, Maternal Nutritional Physiological Phenomena drug effects, Milk, Human chemistry, Pregnancy Complications, Infectious drug therapy, Vitamin B Complex analysis
- Abstract
Background: Little information is available on B vitamin concentrations in human milk or on how they are affected by maternal B vitamin deficiencies, antiretroviral therapy, or maternal supplementation., Objective: The objective was to evaluate the effects of antiretroviral therapy and/or lipid-based nutrient supplements (LNSs) on B vitamin concentrations in breast milk from HIV-infected women in Malawi., Design: Breast milk was collected from 537 women recruited within the Breastfeeding, Antiretrovirals, and Nutrition study at 2 or 6 wk and 24 wk postpartum. Women were assigned to receive antiretrovirals and LNSs, antiretrovirals only, LNSs only, or a control. Antiretrovirals and LNSs were given to the mothers from weeks 0 to 28. The antiretrovirals were zidovudine/lamivudine and nelfinavir or lopinavir/ritonavir. LNSs provided 93-118% of the Recommended Dietary Allowances of thiamin, riboflavin, niacin, pyridoxine, and vitamin B-12. Infants were exclusively breastfed., Results: LNSs increased milk concentrations of all vitamins except thiamin, whereas antiretrovirals lowered concentrations of nicotinamide, pyridoxal, and vitamin B-12. Although antiretrovirals alone had no significant effect on riboflavin concentrations, they negatively affected the LNS-induced increase in this vitamin. Thiamin was not influenced by the study interventions. Concentrations of all B vitamins were much lower than usually accepted values., Conclusions: All B vitamins were low in milk, and all but thiamin were increased by maternal supplementation with LNSs. Antiretrovirals alone decreased concentrations of some B vitamins in milk. When LNS was given in addition to antiretrovirals, the negative effect of antiretrovirals offset the positive effect of LNSs for all vitamins except thiamin. This trial was registered at clinicaltrials.gov as NCT00164762., (© 2015 American Society for Nutrition.)
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- 2015
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20. Association of HIV-1 Envelope-Specific Breast Milk IgA Responses with Reduced Risk of Postnatal Mother-to-Child Transmission of HIV-1.
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Pollara J, McGuire E, Fouda GG, Rountree W, Eudailey J, Overman RG, Seaton KE, Deal A, Edwards RW, Tegha G, Kamwendo D, Kumwenda J, Nelson JA, Liao HX, Brinkley C, Denny TN, Ochsenbauer C, Ellington S, King CC, Jamieson DJ, van der Horst C, Kourtis AP, Tomaras GD, Ferrari G, and Permar SR
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- Adult, Antibodies, Neutralizing metabolism, Antibody Specificity, Antibody-Dependent Cell Cytotoxicity, Breast Feeding adverse effects, Female, HIV Antibodies blood, HIV Infections complications, Humans, Immunity, Mucosal, Immunoglobulin A blood, Immunoglobulin A, Secretory metabolism, Immunoglobulin G metabolism, Infant, Infant, Newborn, Malawi, Models, Immunological, Pregnancy, Pregnancy Complications, Infectious immunology, Pregnancy Complications, Infectious virology, Risk Factors, Young Adult, env Gene Products, Human Immunodeficiency Virus immunology, HIV Antibodies metabolism, HIV Infections immunology, HIV Infections transmission, HIV-1 immunology, Immunoglobulin A metabolism, Infectious Disease Transmission, Vertical, Milk, Human immunology, Milk, Human virology
- Abstract
Unlabelled: Infants born to HIV-1-infected mothers in resource-limited areas where replacement feeding is unsafe and impractical are repeatedly exposed to HIV-1 throughout breastfeeding. Despite this, the majority of infants do not contract HIV-1 postnatally, even in the absence of maternal antiretroviral therapy. This suggests that immune factors in breast milk of HIV-1-infected mothers help to limit vertical transmission. We compared the HIV-1 envelope-specific breast milk and plasma antibody responses of clade C HIV-1-infected postnatally transmitting and nontransmitting mothers in the control arm of the Malawi-based Breastfeeding Antiretrovirals and Nutrition Study using multivariable logistic regression modeling. We found no association between milk or plasma neutralization activity, antibody-dependent cell-mediated cytotoxicity, or HIV-1 envelope-specific IgG responses and postnatal transmission risk. While the envelope-specific breast milk and plasma IgA responses also did not reach significance in predicting postnatal transmission risk in the primary model after correction for multiple comparisons, subsequent exploratory analysis using two distinct assay methodologies demonstrated that the magnitudes of breast milk total and secretory IgA responses against a consensus HIV-1 envelope gp140 (B.con env03) were associated with reduced postnatal transmission risk. These results suggest a protective role for mucosal HIV-1 envelope-specific IgA responses in the context of postnatal virus transmission. This finding supports further investigations into the mechanisms by which mucosal IgA reduces risk of HIV-1 transmission via breast milk and into immune interventions aimed at enhancing this response., Importance: Infants born to HIV-1-infected mothers are repeatedly exposed to the virus in breast milk. Remarkably, the transmission rate is low, suggesting that immune factors in the breast milk of HIV-1-infected mothers help to limit transmission. We compared the antibody responses in plasma and breast milk of HIV-1-transmitting and -nontransmitting mothers to identify responses that correlated with reduced risk of postnatal HIV-1 transmission. We found that neither plasma nor breast milk IgG antibody responses were associated with risk of HIV-1 transmission. In contrast, the magnitudes of the breast milk IgA and secretory IgA responses against HIV-1 envelope proteins were associated with reduced risk of postnatal HIV-1 transmission. The results of this study support further investigations of the mechanisms by which mucosal IgA may reduce the risk of HIV-1 transmission via breastfeeding and the development of strategies to enhance milk envelope-specific IgA responses to reduce mother-to-child HIV transmission and promote an HIV-free generation., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
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- 2015
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21. Plasma Micronutrient Concentrations Are Altered by Antiretroviral Therapy and Lipid-Based Nutrient Supplements in Lactating HIV-Infected Malawian Women.
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Flax VL, Adair LS, Allen LH, Shahab-Ferdows S, Hampel D, Chasela CS, Tegha G, Daza EJ, Corbett A, Davis NL, Kamwendo D, Kourtis AP, van der Horst CM, Jamieson DJ, and Bentley ME
- Subjects
- Adult, Anti-Retroviral Agents administration & dosage, Antiretroviral Therapy, Highly Active, Female, HIV Infections epidemiology, Humans, Malawi epidemiology, Male, Young Adult, Anti-Retroviral Agents therapeutic use, Dietary Supplements, HIV Infections blood, HIV Infections drug therapy, Lipids chemistry, Micronutrients blood
- Abstract
Background: Little is known about the influence of antiretroviral therapy with or without micronutrient supplementation on the micronutrient concentrations of HIV-infected lactating women in resource-constrained settings., Objective: We examined associations of highly active antiretroviral therapy (HAART) and lipid-based nutrient supplements (LNS) with concentrations of selected micronutrients in HIV-infected Malawian women at 24 wk postpartum., Methods: Plasma micronutrient concentrations were measured in a subsample (n = 690) of Breastfeeding, Antiretrovirals, and Nutrition (BAN) study participants who were randomly assigned at delivery to receive HAART, LNS, HAART+LNS, or no HAART/no LNS (control). HAART consisted of protease inhibitor-based triple therapy. LNS (140 g/d) met energy and micronutrient requirements of lactation. Multivariable linear regression tested the association of HAART and LNS, plus their interaction, with micronutrient concentrations, controlling for season, baseline viral load, and baseline CD4 count., Results: We found significant HAART by LNS interactions for folate (P = 0.051), vitamin B-12 (P < 0.001), and transferrin receptors (TfRs) (P = 0.085). HAART was associated with lower folate (with LNS: -27%, P < 0.001; without LNS: -12%, P = 0.040) and higher TfR concentrations (with LNS: +14%, P = 0.004; without LNS: +28%, P < 0.001), indicating iron deficiency. LNS increased folate (with HAART: +17%, P = 0.037; without HAART: +39%, P < 0.001) and decreased TfR concentrations (with HAART only: -12%, P = 0.023). HAART was associated with lower vitamin B-12 concentrations only when LNS was present (-18%, P = 0.001), whereas LNS increased vitamin B-12 only when no HAART was present (+27%, P < 0.001). HAART, but not LNS, was associated with higher retinol-binding protein (RBP; +10%, P = 0.007). We detected no association of HAART or LNS with selenium, ferritin, or hemoglobin., Conclusion: The association of HAART with lower folate, iron deficiency, and higher RBP plus the attenuation of LNS effects on folate and vitamin B-12 when combined with HAART has implications for the health of lactating HIV-infected women taking HAART in prevention of mother-to-child transmission programs. This trial was registered at clinicaltrials.gov as NCT00164736., (© 2015 American Society for Nutrition.)
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- 2015
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22. Effect of cytomegalovirus infection on breastfeeding transmission of HIV and on the health of infants born to HIV-infected mothers.
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Chang TS, Wiener J, Dollard SC, Amin MM, Ellington S, Chasela C, Kayira D, Tegha G, Kamwendo D, Jamieson DJ, van der Horst C, and Kourtis AP
- Subjects
- Cytomegalovirus isolation & purification, DNA, Viral blood, DNA, Viral genetics, Female, Humans, Incidence, Infant, Infant, Newborn, Leukocytes, Mononuclear virology, Malawi, Male, Plasma virology, Polymerase Chain Reaction, Pregnancy, Breast Feeding, Cytomegalovirus Infections complications, Disease Transmission, Infectious, HIV Infections complications, HIV Infections transmission
- Abstract
Background: Cytomegalovirus (CMV) infection can be acquired in utero or postnatally through horizontal transmission and breastfeeding. The effect of postnatal CMV infection on postnatal HIV transmission is unknown., Methods: The Breastfeeding, Antiretrovirals and Nutrition study, conducted in Malawi, randomized 2369 mothers and their infants to three antiretroviral prophylaxis arms - mother (triple regimen), infant (nevirapine), or neither - for 28 weeks of breastfeeding, followed by weaning. Stored plasma and peripheral blood mononuclear cell specimens were available for 492 infants at 24 weeks and were tested with CMV PCR. Available samples from infants who were CMV PCR-positive at 24 weeks were also tested at birth (N = 242), and from infants PCR-negative at 24 weeks were tested at 48 weeks (N = 96). Cox proportional-hazards models were used to determine if CMV infection was associated with infant morbidity, mortality, or postnatal HIV acquisition., Results: At 24 weeks of age, CMV DNA was detected in 345/492 infants (70.1%); the estimated congenital CMV infection rate was 2.3%, and the estimated rate of CMV infection at 48 weeks was 78.5%. CMV infection at 24 weeks was associated with subsequent HIV acquisition through breastfeeding or infant death between 24 and 48 weeks of age (hazard ratio 4.27, P = 0.05)., Conclusion: Most breastfed infants of HIV-infected mothers in this resource-limited setting are infected with CMV by 24 weeks of age. Early CMV infection may be a risk factor for subsequent infant HIV infection through breastfeeding, pointing to the need for comprehensive approaches in order to achieve elimination of breastfeeding transmission of HIV.
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- 2015
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23. Dried blood spots for viral load monitoring in Malawi: feasible and effective.
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Rutstein SE, Hosseinipour MC, Kamwendo D, Soko A, Mkandawire M, Biddle AK, Miller WC, Weinberger M, Wheeler SB, Sarr A, Gupta S, Chimbwandira F, Mwenda R, Kamiza S, Hoffman I, and Mataya R
- Subjects
- Adolescent, Adult, Antiretroviral Therapy, Highly Active, CD4 Lymphocyte Count, Female, HIV Infections virology, HIV-1 isolation & purification, Humans, Malawi, Male, Middle Aged, Prospective Studies, RNA, Viral isolation & purification, Time Factors, Treatment Outcome, Viral Load drug effects, Anti-HIV Agents therapeutic use, Dried Blood Spot Testing, Drug Monitoring, HIV Infections diagnosis, HIV-1 genetics, RNA, Viral genetics
- Abstract
Objectives: To evaluate the feasibility and effectiveness of dried blood spots (DBS) use for viral load (VL) monitoring, describing patient outcomes and programmatic challenges that are relevant for DBS implementation in sub-Saharan Africa., Methods: We recruited adult antiretroviral therapy (ART) patients from five district hospitals in Malawi. Eligibility reflected anticipated Ministry of Health VL monitoring criteria. Testing was conducted at a central laboratory. Virological failure was defined as >5000 copies/ml. Primary outcomes were program feasibility (timely result availability and patient receipt) and effectiveness (second-line therapy initiation)., Results: We enrolled 1,498 participants; 5.9% were failing at baseline. Median time from enrollment to receipt of results was 42 days; 79.6% of participants received results within 3 months. Among participants with confirmed elevated VL, 92.6% initiated second-line therapy; 90.7% were switched within 365 days of VL testing. Nearly one-third (30.8%) of participants with elevated baseline VL had suppressed (<5,000 copies/ml) on confirmatory testing. Median period between enrollment and specimen testing was 23 days. Adjusting for relevant covariates, participants on ART >4 years were more likely to be failing than participants on therapy 1-4 years (RR 1.7, 95% CI 1.0-2.8); older participants were less likely to be failing (RR 0.95, 95% CI 0.92-0.98). There was no difference in likelihood of failure based on clinical symptoms (RR 1.17, 95% CI 0.65-2.11)., Conclusions: DBS for VL monitoring is feasible and effective in real-world clinical settings. Centralized DBS testing may increase access to VL monitoring in remote settings. Programmatic outcomes are encouraging, especially proportion of eligible participants switched to second-line therapy.
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- 2015
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24. Viral profiling identifies multiple subtypes of Kaposi's sarcoma.
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Hosseinipour MC, Sweet KM, Xiong J, Namarika D, Mwafongo A, Nyirenda M, Chiwoko L, Kamwendo D, Hoffman I, Lee J, Phiri S, Vahrson W, Damania B, and Dittmer DP
- Subjects
- Adult, Body Mass Index, CD4 Lymphocyte Count, Cross-Sectional Studies, DNA, Viral genetics, Female, HIV Infections complications, HIV Infections epidemiology, Herpesvirus 8, Human isolation & purification, Humans, Malawi epidemiology, Male, Polymerase Chain Reaction, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Viral genetics, Sarcoma, Kaposi complications, Sarcoma, Kaposi epidemiology, Viral Load, HIV Infections virology, Herpesvirus 8, Human classification, Sarcoma, Kaposi virology
- Abstract
Unlabelled: Kaposi's sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral therapy (ART). Seventy patients were enrolled. Eighty-one percent had T1 (advanced) KS. Median CD4 and HIV RNA levels were 181 cells/mm(3) and 138,641 copies/ml, respectively. We had complete information and suitable plasma and biopsy samples for 66 patients. For 59/66 (89%) patients, a detectable KSHV load was found in plasma (median, 2,291 copies/ml; interquartile range [IQR], 741 to 5,623). We utilized a novel KSHV real-time quantitative PCR (qPCR) array with multiple primers per open reading frame to examine KSHV transcription. Seventeen samples exhibited only minimal levels of KSHV mRNAs, presumably due to the limited number of infected cells. For all other biopsy samples, the viral latency locus (LANA, vCyc, vFLIP, kaposin, and microRNAs [miRNAs]) was transcribed abundantly, as was K15 mRNA. We could identify two subtypes of treatment-naive KS: lesions that transcribed viral RNAs across the length of the viral genome and lesions that displayed only limited transcription restricted to the latency locus. This finding demonstrates for the first time the existence of multiple subtypes of KS lesions in HIV- and KS-treatment naive patients., Importance: KS is the leading cancer in people infected with HIV worldwide and is causally linked to KSHV infection. Using viral transcription profiling, we have demonstrated the existence of multiple subtypes of KS lesions for the first time in HIV- and KS-treatment-naive patients. A substantial number of lesions transcribe mRNAs which encode the viral kinases and hence could be targeted by the antiviral drugs ganciclovir or AZT in addition to chemotherapy., (Copyright © 2014 Hosseinipour et al.)
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- 2014
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25. Measures of viral load using Abbott RealTime HIV-1 Assay on venous and fingerstick dried blood spots from provider-collected specimens in Malawian District Hospitals.
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Rutstein SE, Kamwendo D, Lugali L, Thengolose I, Tegha G, Fiscus SA, Nelson JA, Hosseinipour MC, Sarr A, Gupta S, Chimbwandira F, Mwenda R, and Mataya R
- Subjects
- Adult, Anti-HIV Agents therapeutic use, Antiretroviral Therapy, Highly Active, Blood Specimen Collection, Female, HIV Infections drug therapy, HIV Infections virology, HIV-1 genetics, Hospitals, Humans, Malawi, Male, Phlebotomy methods, RNA, Viral blood, Sensitivity and Specificity, Viremia blood, Viremia virology, Dried Blood Spot Testing methods, HIV Infections blood, HIV Infections diagnosis, Viral Load methods
- Abstract
Background: Viral suppression is a key indicator of antiretroviral therapy (ART) response among HIV-infected patients. Dried blood spots (DBS) are an appealing alternative to conventional plasma-based virologic testing, improving access to monitoring in resource-limited settings. However, validity of DBS obtained from fingerstick in field settings remains unknown., Objectives: Investigate feasibility and accuracy of DBS vs plasma collected by healthcare workers in real-world settings of remote hospitals in Malawi. Compare venous DBS to fingerstick DBS for identifying treatment failure., Study Design: We recruited patients from ART clinics at two district hospitals in Malawi, collecting plasma, venous DBS (vDBS), and fingerstick DBS (fsDBS) cards for the first 149 patients, and vDBS and fsDBS only for the subsequent 398 patients. Specimens were tested using Abbott RealTime HIV-1 Assay (lower detection limit 40 copies/ml (plasma) and 550 copies/ml (DBS))., Results: 21/149 (14.1%) had detectable viremia (>1.6 log copies/ml), 13 of which were detectable for plasma, vDBS, and fsDBS. Linear regression demonstrated high correlation for plasma vs. DBS (vDBS: β=1.19, R(2)=0.93 (p<0.0001); fsDBS β=1.20, R(2)=0.90 (p<0.0001)) and vDBS vs. fsDBS (β=0.88, R(2)=0.73, (p<0.0001)). Mean difference between plasma and vDBS was 1.1 log copies/ml [SD: 0.27] and plasma and fsDBS 1.1 log copies/ml [SD: 0.31]. At 5000 copies/ml, sensitivity was 100%, and specificity was 98.6% and 97.8% for vDBS and fsDBS, respectively, compared to plasma., Conclusions: DBS from venipuncture and fingerstick perform well at the failure threshold of 5000 copies/ml. Fingerstick specimen source may improve access to virologic treatment monitoring in resource-limited settings given task-shifting in high-volume, low-resource facilities., (Copyright © 2014 Elsevier B.V. All rights reserved.)
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- 2014
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26. Plasma and breast-milk selenium in HIV-infected Malawian mothers are positively associated with infant selenium status but are not associated with maternal supplementation: results of the Breastfeeding, Antiretrovirals, and Nutrition study.
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Flax VL, Bentley ME, Combs GF Jr, Chasela CS, Kayira D, Tegha G, Kamwendo D, Daza EJ, Fokar A, Kourtis AP, Jamieson DJ, van der Horst CM, and Adair LS
- Subjects
- Adult, Child Development, Female, HIV Infections blood, HIV Infections drug therapy, Humans, Infant, Lactation blood, Malawi, Nutritional Status, Selenium blood, Selenium deficiency, Selenium therapeutic use, Sodium Selenite administration & dosage, Young Adult, Anti-Retroviral Agents therapeutic use, Dietary Supplements, HIV Infections metabolism, Lactation metabolism, Maternal Nutritional Physiological Phenomena, Milk, Human chemistry, Selenium metabolism
- Abstract
Background: Selenium is found in soils and is essential for human antioxidant defense and immune function. In Malawi, low soil selenium and dietary intakes coupled with low plasma selenium concentrations in HIV infection could have negative consequences for the health of HIV-infected mothers and their exclusively breastfed infants., Objective: We tested the effects of lipid-based nutrient supplements (LNS) that contained 1.3 times the Recommended Dietary Allowance of sodium selenite and antiretroviral drugs (ARV) on maternal plasma and breast-milk selenium concentrations., Design: HIV-infected Malawian mothers in the Breastfeeding, Antiretrovirals, and Nutrition study were randomly assigned at delivery to receive: LNS, ARV, LNS and ARV, or a control. In a subsample of 526 mothers and their uninfected infants, we measured plasma and breast-milk selenium concentrations at 2 or 6 (depending on the availability of infant samples) and 24 wk postpartum., Results: Overall, mean (± SD) maternal (range: 81.2 ± 20.4 to 86.2 ± 19.9 μg/L) and infant (55.6 ± 16.3 to 61.0 ± 15.4 μg/L) plasma selenium concentrations increased, whereas breast-milk selenium concentrations declined (14.3 ± 11.5 to 9.8 ± 7.3 μg/L) from 2 or 6 to 24 wk postpartum (all P < 0.001). Compared with the highest baseline selenium tertile, low and middle tertiles were positively associated with a change in maternal plasma or breast-milk selenium from 2 or 6 to 24 wk postpartum (both P < 0.001). With the use of linear regression, we showed that LNS that contained selenium and ARV were not associated with changes in maternal plasma and breast-milk selenium, but maternal selenium concentrations were positively associated with infant plasma selenium at 2 or 6 and 24 wk postpartum (P < 0.001) regardless of the study arm., Conclusions: Selenite supplementation of HIV-infected Malawian women was not associated with a change in their plasma or breast-milk selenium concentrations. Future research should examine effects of more readily incorporated forms of selenium (ie, selenomethionine) in HIV-infected breastfeeding women.
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- 2014
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27. Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post-partum: results of the BAN Study.
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Corbett AH, Kayira D, White NR, Davis NL, Kourtis AP, Chasela C, Martinson F, Phiri G, Musisi B, Kamwendo D, Hudgens MG, Hosseinipour MC, Nelson JA, Ellington SR, Jamieson DJ, van der Horst C, and Kashuba A
- Subjects
- Adult, Anti-HIV Agents administration & dosage, CD4 Lymphocyte Count, Drug Monitoring, Female, HIV Infections diagnosis, Humans, Infant, Male, Milk, Human, Time Factors, Viral Load, Young Adult, Anti-HIV Agents pharmacokinetics, Breast Feeding, HIV Infections drug therapy, HIV Infections virology, Mothers
- Abstract
Background: An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral and Nutrition (BAN) Study was performed to describe drug exposure and antiviral response., Methods: Women using Combivir(®) (zidovudine [ZDV] + lamivudine [3TC]) +Aluvia(®) (lopinavir/ritonavir [LPV/RTV]) were enrolled. Breast milk (BM), mother plasma (MP) and infant plasma (IP) samples were obtained over 6 h after observed dosing at 6, 12 or 24 weeks post-partum for drug concentrations and HIV RNA., Results: A total of 30 mother/infant pairs (10 each at 6, 12 and 24 weeks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, respectively, whereas LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24 weeks. The majority (98.3%) of BM concentrations were >HIV(wt) IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA., Conclusions: ZDV and 3TC concentrated in BM whereas LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low antiretroviral concentrations in IP suggest prevention of transmission while breastfeeding may be due to antiretroviral effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.
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- 2014
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28. Role of intestinal mucosal integrity in HIV transmission to infants through breast-feeding: the BAN study.
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Kourtis AP, Ibegbu CC, Wiener J, King CC, Tegha G, Kamwendo D, Kumwenda J, Kaur SP, Flax V, Ellington S, Kacheche Z, Kayira D, Chasela C, van der Horst C, and Jamieson DJ
- Subjects
- Bacterial Translocation, Female, Humans, Infant, Infant, Newborn, Limulus Test, Lipopolysaccharides blood, Male, Pregnancy, Breast Feeding, HIV Infections transmission, Infectious Disease Transmission, Vertical, Intestinal Mucosa immunology, Intestinal Mucosa physiology
- Abstract
Background: Increased intestinal permeability may be one of the mechanisms of transmission of human immunodeficiency virus (HIV) to infants through breast-feeding. Intestinal permeability correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS)., Methods: We evaluated levels of plasma LPS (by the Limulus amebocyte lysate assay) and immune activation markers in serial specimens from infants exposed to but uninfected with HIV and infants infected with HIV from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study., Results: Plasma LPS levels increased after infants in the BAN study were weaned from the breast, at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (P = .004). Infants with HIV infection had higher LPS levels, compared with uninfected infants (P = .004). Higher preinfection plasma LPS levels were a significant predictor of infant HIV infection through breast-feeding (hazard ratio = 1.60 for every unit increase in plasma LPS level; P = .01) and of lower infant length-for-age z scores (P = .02)., Conclusions: These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to infants through breast-feeding. Weaning from breast milk and use of antibiotic prophylaxis was associated with increased levels of microbial translocation, which could facilitate HIV entry through the intestine. Complementary approaches to enhance intestinal mucosal integrity in the infant may further reduce breast-feeding transmission of HIV.
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- 2013
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29. Diversity of T cell epitopes in Plasmodium falciparum circumsporozoite protein likely due to protein-protein interactions.
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Aragam NR, Thayer KM, Nge N, Hoffman I, Martinson F, Kamwendo D, Lin FC, Sutherland C, Bailey JA, and Juliano JJ
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- Amino Acid Sequence, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology, Models, Molecular, Molecular Sequence Data, Mutagenesis, Phylogeny, Protein Binding, Protein Conformation, Protozoan Proteins genetics, Protozoan Proteins immunology, Epitopes, T-Lymphocyte chemistry, Epitopes, T-Lymphocyte metabolism, Plasmodium falciparum immunology, Protozoan Proteins chemistry, Protozoan Proteins metabolism
- Abstract
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.
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- 2013
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30. Use of massively parallel pyrosequencing to evaluate the diversity of and selection on Plasmodium falciparum csp T-cell epitopes in Lilongwe, Malawi.
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Bailey JA, Mvalo T, Aragam N, Weiser M, Congdon S, Kamwendo D, Martinson F, Hoffman I, Meshnick SR, and Juliano JJ
- Subjects
- Adult, Child, Preschool, DNA, Protozoan chemistry, DNA, Protozoan genetics, Epitopes, T-Lymphocyte genetics, Female, Haplotypes, High-Throughput Nucleotide Sequencing, Humans, Infant, Malawi, Male, Middle Aged, Molecular Sequence Data, Plasmodium falciparum genetics, Plasmodium falciparum isolation & purification, Protozoan Proteins genetics, Epitopes, T-Lymphocyte immunology, Genetic Variation, Malaria, Falciparum immunology, Malaria, Falciparum parasitology, Plasmodium falciparum immunology, Protozoan Proteins immunology
- Abstract
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.
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- 2012
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31. Prevalence of HIV drug resistance before and 1 year after treatment initiation in 4 sites in the Malawi antiretroviral treatment program.
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Wadonda-Kabondo N, Bennett D, van Oosterhout JJ, Moyo K, Hosseinipour M, Devos J, Zhou Z, Aberle-Grasse J, Warne TR, Mtika C, Chilima B, Banda R, Pasulani O, Porter C, Phiri S, Jahn A, Kamwendo D, Jordan MR, Kabuluzi S, Chimbwandira F, Kagoli M, Matatiyo B, Demby A, and Yang C
- Subjects
- Adolescent, Adult, Anti-Retroviral Agents pharmacology, Drug Resistance, Viral, Female, HIV drug effects, HIV genetics, HIV Infections virology, Humans, Malawi epidemiology, Male, Medication Adherence, National Health Programs, Prevalence, Prospective Studies, Treatment Outcome, Anti-Retroviral Agents therapeutic use, HIV Infections drug therapy, HIV Infections epidemiology
- Abstract
Since 2004, the Malawi antiretroviral treatment (ART) program has provided a public health-focused system based on World Health Organization clinical staging, standardized first-line ART regimens, limited laboratory monitoring, and no patient-level monitoring of human immunodeficiency virus drug resistance (HIVDR). The Malawi Ministry of Health conducts periodic evaluations of HIVDR development in prospective cohorts at sentinel clinics. We evaluated viral load suppression, HIVDR, and factors associated with HIVDR in 4 ART sites at 12-15 months after ART initiation. More than 70% of patients initiating ART had viral suppression at 12 months. HIVDR prevalence (6.1%) after 12 months of ART was low and largely associated with baseline HIVDR. Better follow-up, removal of barriers to on-time drug pickups, and adherence education for patients 16-24 years of age may further prevent HIVDR.
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- 2012
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32. Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance.
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Makoka MH, Miller WC, Hoffman IF, Cholera R, Gilligan PH, Kamwendo D, Malunga G, Joaki G, Martinson F, and Hosseinipour MC
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- Adolescent, Adult, Aged, Aged, 80 and over, Bacteria isolation & purification, Child, Child, Preschool, Cross-Sectional Studies, Female, Humans, Infant, Infant, Newborn, Malawi epidemiology, Male, Microbial Sensitivity Tests, Middle Aged, Young Adult, Anti-Bacterial Agents pharmacology, Bacteria classification, Bacteria drug effects, Bacterial Infections epidemiology, Drug Resistance, Bacterial
- Abstract
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.
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- 2012
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33. Validation of rapid HIV antibody tests in 5 African countries.
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Piwowar-Manning EM, Tustin NB, Sikateyo P, Kamwendo D, Chipungu C, Maharaj R, Mushanyu J, Richardson BA, Hillier S, and Brooks Jackson J
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- Africa, Humans, Sensitivity and Specificity, HIV Antibodies blood, HIV Infections diagnosis, Reagent Kits, Diagnostic
- Abstract
The sensitivity and specificity of 3 rapid HIV antibody tests were assessed at 5 clinical trial sites in Africa and 1 site in the United States using a minimum of 100 HIV antibody positive samples and 100 HIV antibody negative samples at each site. The overall sensitivity and specificity for the OraSure OraQuick, Abbott Determine, and Trinity Unigold tests were 99.3%, 99.8%, and 98.5%, respectively, and 99.3%, 99.4%, and 99.5%, respectively. There were no instances at any site in which false-negative or false-positive results were obtained for the same sample on more than 1 rapid test kit. The results of this study provide assurance that for these diverse sites in Africa, the accuracy of these kits is quite good. Given the excellent accuracy, relatively fast turnaround time, and minimal infrastructure required, these rapid tests for HIV antibody provide a very attractive and accurate testing format.
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- 2010
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34. Neisseria gonorrhoeae antimicrobial susceptibility in Lilongwe, Malawi, 2007.
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Brown LB, Krysiak R, Kamanga G, Mapanje C, Kanyamula H, Banda B, Mhango C, Hoffman M, Kamwendo D, Hobbs M, Hosseinipour MC, Martinson F, Cohen MS, and Hoffman IF
- Subjects
- Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Doxycycline pharmacology, Doxycycline therapeutic use, Gentamicins therapeutic use, Gonorrhea diagnosis, Gonorrhea drug therapy, Gonorrhea microbiology, Humans, Malawi, Male, Microbial Sensitivity Tests methods, Neisseria gonorrhoeae drug effects, Neisseria gonorrhoeae isolation & purification, Syndrome, Urethritis drug therapy, Urethritis microbiology, Gentamicins pharmacology
- Abstract
Background: Malawi adopted syndromic management of sexually transmitted infections in 1993. Based on clinical efficacy and cost, gentamicin 240 mg intramuscularly, and doxycycline 100 mg twice daily x 7 days was selected as the first line regimen to treat urethritis. We sought to establish current laboratory-based Neisseria gonorrhoeae antibiotic susceptibility patterns for Malawi and describe the pattern of susceptibility since syndromic management began., Methods: Between May 15 and August 10, 2007, 126 men with urethritis attending the STD clinic at Kamuzu Central Hospital in Lilongwe had history, genital exam, and urethral swabs taken. All were treated with gentamicin and doxycycline in accordance with Malawi guidelines. Gonorrhea was diagnosed by Gram stain and culture. Antimicrobial susceptibility patterns in gonococcal isolates were determined by disk diffusion and E-test minimum inhibitory concentration (MIC) determination and agar dilution MIC determination., Results: One hundred six isolates were cultured, and MICs were determined for 100. High levels of resistance to tetracycline and penicillin were observed, but isolates were uniformly susceptible to both gentamicin and ciprofloxacin. Susceptibility patterns identified by the agar dilution MIC and E-test MIC agreed., Conclusions: The most recent study continues the trend of high susceptibility of gonococcal isolates to gentamicin in Malawi after 14 years of use and suggests agar dilution MICs may be substituted with the simpler E-test methods in future susceptibility testing. However because of the lack of susceptibility criteria for aminoglycosides for N. gonorrhoeae and the difficulty obtaining clinical/in vitro correlates in this setting, caution should be exercised in using these data for modifying treatment regimens.
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- 2010
- Full Text
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35. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi.
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Nussbaum JC, Jackson A, Namarika D, Phulusa J, Kenala J, Kanyemba C, Jarvis JN, Jaffar S, Hosseinipour MC, Kamwendo D, van der Horst CM, and Harrison TS
- Subjects
- AIDS-Related Opportunistic Infections microbiology, AIDS-Related Opportunistic Infections mortality, Administration, Oral, Adult, Aged, Antifungal Agents administration & dosage, Antifungal Agents adverse effects, Cerebrospinal Fluid microbiology, Cryptococcus isolation & purification, Drug Therapy, Combination, Female, Fluconazole administration & dosage, Fluconazole adverse effects, Flucytosine administration & dosage, Flucytosine adverse effects, HIV Infections complications, Humans, Malawi, Male, Meningitis, Cryptococcal microbiology, Meningitis, Cryptococcal mortality, Middle Aged, Treatment Outcome, Young Adult, AIDS-Related Opportunistic Infections drug therapy, Antifungal Agents therapeutic use, Fluconazole therapeutic use, Flucytosine therapeutic use, Meningitis, Cryptococcal drug therapy
- Abstract
Background: Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole., Methods: From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality., Results: Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4(+) cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity +/- standard deviation -0.28 +/- 0.17 log colony-forming units [CFU]/mL per day vs -0.11 +/- 0.09 log CFU/mL per day; P < .001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events., Conclusions: The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351.
- Published
- 2010
- Full Text
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36. The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy.
- Author
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Hosseinipour MC, van Oosterhout JJ, Weigel R, Phiri S, Kamwendo D, Parkin N, Fiscus SA, Nelson JA, Eron JJ, and Kumwenda J
- Subjects
- Adult, CD4 Lymphocyte Count, Drug Resistance, Viral drug effects, Female, Genotype, HIV Infections genetics, HIV-1 drug effects, Humans, Malawi, Male, Middle Aged, Phenotype, Public Health, RNA, Viral genetics, Treatment Failure, Anti-HIV Agents therapeutic use, Drug Resistance, Viral genetics, HIV Infections drug therapy, HIV-1 genetics, Reverse Transcriptase Inhibitors therapeutic use
- Abstract
Background: Over 150,000 Malawians have started antiretroviral therapy (ART), in which first-line therapy is stavudine/lamivudine/nevirapine. We evaluated drug resistance patterns among patients failing first-line ART on the basis of clinical or immunological criteria in Lilongwe and Blantyre, Malawi., Methods: Patients meeting the definition of ART failure (new or progressive stage 4 condition, CD4 cell count decline more than 30%, CD4 cell count less than that before treatment) from January 2006 to July 2007 were evaluated. Among those with HIV RNA of more than 1000 copies/ml, genotyping was performed. For complex genotype patterns, phenotyping was performed., Results: Ninety-six confirmed ART failure patients were identified. Median (interquartile range) CD4 cell count, log10 HIV-1 RNA, and duration on ART were 68 cells/microl (23-174), 4.72 copies/ml (4.26-5.16), and 36.5 months (26.6-49.8), respectively. Ninety-three percent of samples had nonnucleoside reverse transcriptase inhibitor mutations, and 81% had the M184V mutation. The most frequent pattern included M184V and nonnucleoside reverse transcriptase inhibitor mutations along with at least one thymidine analog mutation (56%). Twenty-three percent of patients acquired the K70E or K65R mutations associated with tenofovir resistance; 17% of the patients had pan-nucleoside resistance that corresponded to K65R or K70E and additional resistance mutations, most commonly the 151 complex. Emergence of the K65R and K70E mutations was associated with CD4 cell count of less than 100 cells/microl (odds ratio 6.1) and inversely with the use of zidovudine (odds ratio 0.18). Phenotypic susceptibility data indicated that the nucleoside reverse transcriptase inhibitor backbone with the highest activity for subsequent therapy was zidovudine/lamivudine/tenofovir, followed by lamivudine/tenofovir, and then abacavir/didanosine., Conclusion: When clinical and CD4 cell count criteria are used to monitor first-line ART failure, extensive nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance emerges, with most patients having resistance profiles that markedly compromise the activity of second-line ART.
- Published
- 2009
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37. Evaluating nurses' implementation of an infant-feeding counseling protocol for HIV-infected mothers: The Ban Study in Lilongwe, Malawi.
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Ferguson YO, Eng E, Bentley M, Sandelowski M, Steckler A, Randall-David E, Piwoz EG, Zulu C, Chasela C, Soko A, Tembo M, Martinson F, Tohill BC, Ahmed Y, Kazembe P, Jamieson DJ, van der Horst C, Adair L, Ahmed Y, Ait-Khaled M, Albrecht S, Bangdiwala S, Bayer R, Bentley M, Bramson B, Bobrow E, Boyle N, Butera S, Chasela C, Chavula C, Chimerang'ambe J, Chigwenembe M, Chikasema M, Chikhungu N, Chilongozi D, Chiudzu G, Chome L, Cole A, Corbett A, Corneli A, Duerr A, Eliya H, Ellington S, Eron J, Farr S, Ferguson YO, Fiscus S, Galvin S, Guay L, Heilig C, Hoffman I, Hooten E, Hosseinipour M, Hudgens M, Hurst S, Hyde L, Jamieson D, Joaki G, Jones D, Kacheche Z, Kamanga E, Kamanga G, Kampani C, Kamthunzi P, Kamwendo D, Kanyama C, Kashuba A, Kathyola D, Kayira D, Kazembe P, Knight R, Kourtis A, Krysiak R, Kumwenda J, Loeliger E, Luhanga M, Madhlopa V, Majawa M, Maida A, Marcus C, Martinson F, Thoofer N, Matika C, Mayers D, Mayuni I, McDonough M, Meme J, Merry C, Mita K, Mkomawanthu C, Mndala G, Mndala I, Moses A, Msika A, Msungama W, Mtimuni B, Muita J, Mumba N, Musis B, Mwansambo C, Mwapasa G, Nkhoma J, Pendame R, Piwoz E, Raines B, Ramdas Z, Rublein J, Ryan M, Sanne I, Sellers C, Shugars D, Sichali D, Snowden W, Soko A, Spensley A, Steens JM, Tegha G, Tembo M, Thomas R, Tien HC, Tohill B, van der Horst C, Waalberg E, Wiener J, Wilfert C, Wiyo P, Zgambo O, and Zimba C
- Subjects
- Adult, Female, HIV Infections transmission, Humans, Infant, Infant, Newborn, Malawi, Weaning, Breast Feeding, HIV Infections prevention & control, Infectious Disease Transmission, Vertical prevention & control, Nurse-Patient Relations, Patient Education as Topic methods
- Abstract
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.
- Published
- 2009
- Full Text
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38. CCR5 haplotypes and mother-to-child HIV transmission in Malawi.
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Pedersen BR, Kamwendo D, Blood M, Mwapasa V, Molyneux M, North K, Rogerson SJ, Zimmerman P, and Meshnick SR
- Subjects
- Female, HIV Infections complications, Humans, Infant, Newborn, Malawi epidemiology, Phylogeny, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Pregnancy, Pregnancy Complications, Infectious, HIV Infections transmission, Haplotypes, Infectious Disease Transmission, Vertical, Receptors, CCR5 genetics
- Abstract
Background: CCR5 and CCR2 gene polymorphisms (SNPs) have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Delta32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein., Methodology/principal Findings: We investigated the association between infant CCR2/CCR5 diplotype and HIV mother to child transmission (MTCT) in Malawi. Blood samples from infants (n = 552) of HIV positive women who received nevirapine were genotyped using a post-PCR multiplex ligase detection reaction and haplotypes were identified based on 8 CCR2/CCR5 SNPs and the open reading frame 32 base pair deletion. Following verification of Hardy-Weinberg equilibrium, log linear regression was performed to examine the association between mutations and MTCT. Overall, protection against MTCT was weakly associated with two CCR5 SNPs, -2459G (Risk ratio [RR], 0.78; confidence interval [CI], 0.54-1.12), and the linked CCR5 -2135T (RR, 0.78; CI, 0.54-1.13). No child carried the CCR5 Delta32 SNP. Maternal Viral Load (MVL) was found to be an effect measure modifier. Among mothers with low MVL, statistically significant protection against MTCT was observed for -2459G (RR, 0.50; CI, 0.27-0.91), and -2135T (RR, 0.51; CI, 0.28-0.92). Statistically significant protection was not found at high MVL., Conclusions/significance: Results from this study suggest that CCR5 SNPs -2459G and -2135T associated with reduced receptor expression protect against MTCT of HIV at low MVLs, whereas high MVLs may over-ride differences in coreceptor availability.
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- 2007
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39. Resistance to antimalarials in Southeast Asia and genetic polymorphisms in pfmdr1.
- Author
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Pickard AL, Wongsrichanalai C, Purfield A, Kamwendo D, Emery K, Zalewski C, Kawamoto F, Miller RS, and Meshnick SR
- Subjects
- Animals, Asia, Southeastern epidemiology, DNA Primers, Drug Resistance, Genotype, Humans, Malaria epidemiology, Mutation genetics, Plasmodium falciparum drug effects, Plasmodium falciparum metabolism, Reverse Transcriptase Polymerase Chain Reaction, Thailand epidemiology, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Antimalarials pharmacology, Malaria parasitology, Plasmodium falciparum genetics, Polymorphism, Genetic genetics
- Abstract
Resistance to antimalarial drugs is a public health problem worldwide. Molecular markers for drug-resistant malaria, such as pfcrt and pfmdr1 polymorphisms, could serve as useful surveillance tools. To evaluate this possibility, sequence polymorphisms in pfcrt (position 76) and pfmdr1 (positions 86, 184, 1034, 1042, and 1246) and in vitro drug sensitivities were measured for 65 Plasmodium falciparum isolates from Thailand, Myanmar, Vietnam, and Bangladesh. The pfcrt Thr76 polymorphism was present in 97% of samples, consistent with observations that chloroquine resistance is well established in this region. Polymorphisms in pfmdr1 clustered into four specific patterns: the wild type (category I), a Tyr86 polymorphism only (category II), a Phe184 polymorphism only (category III), and Phe184 in combination with Cys1034 and/or Asp1042 (category IV). Isolates in categories I and III were more sensitive to chloroquine and more resistant to mefloquine, artesunate, and artemisinin than isolates in categories II and IV (P = 0.01). Mefloquine resistance was significantly more common in category I and III isolates than in category II and IV isolates, with a prevalence ratio of 14.95 (95% confidence interval, 3.88 to 57.56). These categories identified mefloquine resistance with a sensitivity and a specificity of 94 and 91%, respectively. The pfmdr1 gene copy number was measured by real-time PCR as a ratio of the amount of pfmdr1 DNA to the amount of lactate dehydrogenase (ldh) DNA. Eight samples had pfmdr1 DNA/ldh DNA ratios >/=3. The isolates in all 8 samples fell into categories I and III and were significantly more resistant to mefloquine, quinine, artemisinin, and artesunate and more sensitive to chloroquine than the isolates in the 57 samples with <3 copies of the gene (P = 0.001). Thus, measurement of pfmdr1 mutations and gene copy number may be useful for surveillance of mefloquine-resistant malaria in Southeast Asia.
- Published
- 2003
- Full Text
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