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ABSTRACT: Over the past 10 years substantial progress has been made in the implementation of prevention of mother-to child transmission of HIV (PMTCT) interventions in Sub-Saharan Africa (SSA). In spite of this, new pediatric infections remain unacceptably high, contributing the majority (>90%) of the estimated 390,000 infections globally in 2010; and yet prolonged breastfeeding remains the norm and crucial to overall infant survival. However, there is reason for optimism given the 2010 World Health Organization PMTCT recommendations: to start HIV infected pregnant women with CD4 cell counts less than 350 cells/mm3 on lifelong antiretroviral therapy (ART); and for mothers not eligible for ART to provide efficacious maternal and/or infant PMTCT antiretroviral (ARV) regimens to be taken during pregnancy, labor/delivery and through breastfeeding. Current attention is on whether to extend maternal ARVs for life once triple ARV PMTCT regimens are started. To dramatically reduce new pediatric infections, individual countries need to politically commit to rapid scale-up of a multi-pronged PMTCT effort: including primary prevention to reduce HIV incidence among women of reproductive age; increased access to family planning services; HIV screening of all pregnant and breastfeeding women followed by ART or ARVs for PMTCT; and comprehensive care for HIV affected families. Efforts to achieve population-level success in SSA need to critically address operational issues and challenges to implementation (health system) and utilization (social, economic and cultural barriers), at the country, health centre and client level that have led to the relatively slow progress in the scale-up of PMTCT strategies.
Current HIV research 02/2013; · 1.98 Impact Factor
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Peter K Mudiope,
Soyeon Kim,
Deo Wabwire,
Louis Nyende,
Danstan Bagenda,
Mike Mubiru,
Robinah Mulira,
Sawsan Elbireer,
Zikulah Namukwaya, Mary Glenn Fowler,
Philippa Musoke
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ABSTRACT: OBJECTIVES: To determine and compare the clinical and immunologic outcomes for HIV-infected women initiated on antiretroviral therapy (ART), with and without previous exposure to single-dose nevirapine in the MTCT-Plus programme - Kampala, Uganda, from 2003 to 2011. METHODS: Retrospective comparison of prospectively collected programmatic data of clinical and immunologic treatment outcomes among HIV-infected Ugandan women, with and without prior exposure to sdNVP, who received NNRTI-based ART for a median follow-up of 6 years. RESULTS: Of the 408 women in the programme, 289 (70.8%) were started on ART, of whom 205 (70.9%) had prior exposure to sdNVP. Clinical, immunologic and combined (clinical and or immunologic) treatment failure occurred in 29 (10.0%), 132 (45.7%) and 142 (49.1%) women, respectively. There was no significant difference in the distribution of time to immunologic failure for women by exposure to sdNVP (log-rank P = 0.98). In Cox proportional hazard modelling, exposure to sdNVP was not associated with immunologic failure [adjusted hazard ratio (HR) = 0.89, 95% confidence interval (CI): 0.61-1.30]. CD4 count >100 cells/mm(3) at initiation was associated with reduced incidence of immunologic failure in adjusted analyses (HR = 0.32, 95% CI: 0.22-0.48). CONCLUSIONS: HIV-infected Ugandan women initiated on an NVP-based ART regimen had similar immunologic treatment outcomes irrespective of previous NVP exposure. CD4 cell count prior to initiating HAART was a key prognostic factor for successful long-term immunologic treatment outcomes. In poor settings, regular follow-up of patients on HAART with adequate counselling to promote adherence and safe disclosure may promote low clinical failure rates.
Tropical Medicine & International Health 01/2013; · 2.80 Impact Factor
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Maria M James,
Oliver Laeyendecker,
Jin Sun,
Donald R Hoover,
Caroline E Mullis,
Matthew M Cousins,
Thomas Coates,
Richard D Moore,
Gabor D Kelen, Mary Glenn Fowler,
Johnstone J Kumwenda,
Lynne M Mofenson,
Newton I Kumwenda,
Taha E Taha,
Susan H Eshleman
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ABSTRACT: The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women.
Samples collected at enrollment (N = 2,561) and 12-24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67).
In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non-recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non-recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection.
Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection.
PLoS ONE 01/2013; 8(2):e57350. · 4.09 Impact Factor
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Kenneth Kintu,
Philip Andrew,
Philippa Musoke,
Paul Richardson,
Brenda Asiimwe-Kateera,
Teopista Nakyanzi,
Lei Wang, Mary Glenn Fowler,
Lynda Emel,
San-San Ou,
Lynn Baglyos,
Sanjay Gurunathan,
Sheryl Zwerski,
J Brooks Jackson,
Laura Guay
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ABSTRACT: BACKGROUND:: The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) for prevention mother-to-child transmission of HIV would significantly advance the goal of eliminating HIV infection in children. Safety and feasibility results from Phase I, randomized, double blind, placebo-controlled trial of ALVAC-HIV vCP1521 in infants born to HIV-1-infected women in Uganda are reported. METHODS:: HIV exposed infants were enrolled at birth and randomized (4:1) to receive vaccine or saline placebo intramuscular injections at birth, 4, 8 and 12 weeks of age. Vaccine reactogenicity was assessed at vaccination, and days 1 and 2 post-vaccination. Infants were followed until 24 months of age. HIV infection status was determined by HIV DNA PCR. FINDINGS:: From October 2006 to May 2007, 60 infants (48 vaccine, 12 placebo) were enrolled with 98% retention at 24 months. One infant was withdrawn, but there were no missed visits or vaccinations among the 59 infants retained. Immune responses elicited by Diptheria, Polio, Hepatitis B and Heamophilus influenzae type B and measles vaccination were similar in the two arms. The vaccine was well tolerated with no severe or life-threatening reactogenicity events. Adverse events were equally distributed across both study arms. Four infants were diagnosed as HIV infected [3 at birth (2 vaccine, 1 placebo) and one in vaccine arm at 2 weeks of age]. INTERPRETATION:: The ALVAC-HIV vCP1521 vaccination was feasible and safe in infants born to HIV-infected women in Uganda. The conduct of high quality infant HIV vaccine trials is achievable in Africa.
JAIDS Journal of Acquired Immune Deficiency Syndromes 12/2012; · 4.43 Impact Factor
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Jessica M Fogel,
Taha E Taha,
Jin Sun,
Donald R Hoover,
Teresa L Parsons,
Johnstone J Kumwenda,
Lynne M Mofenson, Mary Glenn Fowler,
Craig W Hendrix,
Newton I Kumwenda,
Susan H Eshleman,
Mark Mirochnick
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ABSTRACT: First-line antiretroviral treatment regimens in resource-limited settings used in breastfeeding mothers often include stavudine (d4T). Limited data describing d4T concentrations in breast milk are available. We analyzed d4T concentrations in 52 mother-infant pairs using ultra-performance liquid chromatography-tandem mass spectrometry (lower limit of quantification: 5 ng/mL in plasma, 20 ng/mL in breast milk). Median (interquartile range) d4T concentrations were 86 (36-191) ng/mL in maternal plasma, 151 (48-259) ng/mL in whole milk, 190 (58-296) ng/mL in skim milk, and <5 (<5 to <5) ng/mL in infant plasma. Although d4T is concentrated in breast milk relative to maternal plasma, the infant d4T dose received from breast milk is very small and not clinically significant.
JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2012; 60(5):462-5. · 4.43 Impact Factor
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ABSTRACT: To determine kinetics after single-dose nevirapine and the impact on HIV RNA [viral load (VL)] in maternal plasma and breast milk (BM).
Cohort of 120 HIV-1-infected pregnant Ugandan women received perinatal single-dose nevirapine alone and followed up with their infants through 24 weeks postdelivery. We assessed the relationship of nevirapine concentration (tandem mass spectroscopy) and HIV-1 VL (Roche AMPLICOR HIV-1 Kit, version 1.5) in maternal plasma and BM over time.
At week 1 postpartum, NVP (≥10 ng/mL) was detected in all 53 plasma and 47 of 51 (92.2%) BM samples with median (interquartile ranges) of, respectively, 171 (78-214) ng/mL and 112 (64-158) ng/mL, P = 0.075, which decreased subsequently with traces persisting through week 4 in plasma. Plasma and BM VL dropped by week 1 and were highly correlated at delivery (R = 0.71, P < 0.001) and week 1 (R = 0.69, P < 0.001) but not thereafter. At week 1, VL correlated inversely with NVP concentration in plasma (R = 0.39, P = 0.004) and BM (R = 0.48, P = 0.013). There was a VL rebound in both compartments, which peaked at week 4 to levels greater than those at week 1 [significantly in plasma (P < 0.001) but not in BM] and remained stable thereafter. Median VL was consistently greater (11- to 50-fold) in plasma than BM at all time points (all P < 0.001).
After single-dose nevirapine, NVP concentration was comparably high through week 1, accompanied by suppression of plasma and BM VL. A longer "tail" (>1 week) of potent postnatal antiretroviral drugs is warranted to minimize the observed VL rebound and potential for NVP resistance as a result of persistent NVP traces.
JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2012; 60(5):483-8. · 4.43 Impact Factor
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Advances in experimental medicine and biology 01/2012; 743:3-25. · 1.09 Impact Factor
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Newton I Kumwenda,
Tiwonge Khonje,
Linda Mipando,
Kondwani Nkanaunena,
Pauline Katundu,
Irene Lubega,
Ali Elbireer,
Steve Bolton,
Danstan Bagenda,
Michael Mubiru, Mary Glenn Fowler,
Taha E Taha
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ABSTRACT: Data on paediatric reference laboratory values are limited for sub-Saharan Africa.
To describe the distribution of haematological and chemical pathology values among healthy infants from Malawi and Uganda.
A cross-sectional study was conducted among healthy infants, 0-6 months old, born to HIV-uninfected mothers recruited from two settings in Blantyre, Malawi and Kampala, Uganda. Chemical pathology and haematology parameters were determined using standard methods on blood samples. Descriptive analyses by age-group were performed based on 2004 Division of AIDS Toxicity Table age categories. Mean values and interquartile ranges were compared by site and age-group.
A total of 541 infants were included altogether, 294 from Malawi and 247 from Uganda. Overall, the mean laboratory values were comparable between the two sites. Mean alkaline phosphatase levels were lower among infants aged ≤21 days while aspartate aminotransferase, creatinine, total bilirubin and gamma-glutamyl transferase were higher in those aged 0-7 days than in older infants. Mean haematocrit, haemoglobin and neutrophil counts were higher in the younger age-groups (<35 days) and overall were lower than US norms. Red and white blood cell counts tended to decrease after birth but increased after ∼2 months of age. Mean basophil counts were higher in Malawi than in Uganda in infants aged 0-1 and 2-7 days; mean counts for eosinophils (for age groups 8-21 or older) and platelets (for all age groups) were higher in Ugandan than in Malawian infants. Absolute lymphocyte counts increased with infant age.
The chemical pathology and haematological values in healthy infants born to HIV-uninfected mothers were comparable in Malawi and Uganda and can serve as useful reference values in these settings.
Paediatrics and international child health. 01/2012; 32(4):213-27.
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Hoosen M Coovadia,
Elizabeth R Brown, Mary Glenn Fowler,
Tsungai Chipato,
Dhayendre Moodley,
Karim Manji,
Philippa Musoke,
Lynda Stranix-Chibanda,
Vani Chetty,
Wafaie Fawzi, [......],
Laura Guay,
Anthony Mwatha,
Diana J Lynn,
Susan H Eshleman,
Paul Richardson,
Kathleen George,
Philip Andrew,
Lynne M Mofenson,
Sheryl Zwerski,
Yvonne Maldonado
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ABSTRACT: Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1 via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months.
In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primary efficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412.
Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1·1% (95% CI 0·3-1·8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2·4% (1·3-3·6) of controls (difference 1·3%, 95% CI 0-2·6), equating to a 54% reduction in transmission (p=0·049). However, mortality (1·2% for nevirapine vs 1·1% for placebo; p=0·81) and combined HIV infection and mortality rates (2·3%vs 3·2%; p=0·27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups.
Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age.
US National Institutes of Health.
The Lancet 12/2011; 379(9812):221-8. · 38.28 Impact Factor
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ABSTRACT: Nevirapine and cotrimoxazole are associated with hematologic toxicities and skin-rash. Safety of their concurrent use for prophylaxis over extended periods among HIV-exposed uninfected infants has not been previously assessed.
Secondary data analysis of the 'HIV Prevention Trials Network-046 protocol' (version 2.0), a phase-III, randomized, placebo-controlled trial that assessed efficacy and safety of nevirapine prophylaxis against breast milk transmission of HIV-1.
Trial infants received 6-month study nevirapine/placebo, and standard-of-care peripartum single-dose nevirapine+/- zidovudine 'tail', and cotrimoxazole prophylaxis from 6 weeks through breastfeeding cessation. Adverse events were monitored using United States Division of AIDS Toxicity Tables (2004). Risk of neutropenia, anemia and skin-rash in the cotrimoxazole + nevirapine and the cotrimoxazole + placebo groups were compared using negative-binomial regression.
Incidence of neutropenia and/or anemia, and skin-rash was highest during the first 6 weeks of life and declined, thereafter, regardless of study group. Time to first adverse event after 6 weeks was similar in cotrimoxazole + nevirapine and cotrimoxazole + placebo groups: hazard ratio (95% confidence interval) was 1.26 (0.96-1.66) for neutropenia and/or anemia (all grades), 1.27 (0.80-2.03) for neutropenia and/or anemia (grade ≥3) and 1.16 (0.46-2.90) for skin-rash (grade ≥2). There were no statistically significant differences in immediate (6 weeks-6 months) and long-term (6-12 months) adverse event risk among infants on cotrimoxazole + nevirapine versus cotrimoxazole + placebo.
Extended nevirapine and cotrimoxazole prophylaxis through 6 months of age among HIV-exposed uninfected infants did not appear to increase the immediate or long-term risk of neutropenia, anemia or skin-rash. Concurrent use beyond 6 months, however, needs to be evaluated.
AIDS (London, England) 11/2011; 26(3):325-33. · 4.91 Impact Factor
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Philip J Peters,
Nicholas Polle,
Clement Zeh,
Rose Masaba,
Craig B Borkowf,
Boaz Oyaro,
Paul Omolo,
Paul Ogindo,
Richard Ndivo,
Frank Angira,
Richard Lando, Mary Glenn Fowler,
Paul J Weidle,
Timothy K Thomas
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ABSTRACT: Background: Few studies have evaluated the risk of nevirapine (NVP)-associated hepatotoxicity among HIV-infected pregnant women with a CD4 count ≥250 cells/mm(3).
We enrolled HIV-infected pregnant Kenyan women who initiated triple antiretroviral therapy (ART) at 34 weeks gestation. We compared the rates of severe hepatotoxicity (grades 3-4 hepatotoxicity) and rash-associated hepatotoxicity (rash with ≥grade 2 hepatotoxicity) with NVP and nelfinavir (NFV), respectively.
We initiated triple ART in 522 pregnant women; severe hepatotoxicity and rash-associated hepatotoxicity occurred in 14 (3%) and 9 (2%) women, respectively. Women who initiated NVP had higher rates of severe hepatotoxicity (5% vs 1%; P = .03) and rash-associated hepatotoxicity (4% vs 0%; P = .003) when compared with NFV. Among women who initiated NVP (n = 254), a baseline CD4 count ≥250 cells/mm(3) was not associated with severe hepatotoxicity (5% vs 3%; P = .52) or rash-associated hepatotoxicity (4% vs 3%; P = .69).
Nevirapine use but not CD4 count ≥250 cells/mm(3) was associated with hepatotoxicity.
Journal of the International Association of Physicians in AIDS Care (JIAPAC) 10/2011; 11(2):142-9.
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Carolyne Onyango-Makumbi,
Saad B Omer,
Michael Mubiru,
Lawrence H Moulton,
Clemensia Nakabiito,
Philippa Musoke,
Francis Mmiro,
Sheryl Zwerski,
Hans Wigzell,
Lars Falksveden,
Britta Wahren,
Gretchen Antelman, Mary Glenn Fowler,
Laura Guay,
J Brooks Jackson
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ABSTRACT: This phase III, randomized, clinical trial compared single-dose nevirapine (sdNVP) plus HIV hyperimmune globulin (HIVIGLOB) with sdNVP alone for preventing maternal-to-child transmission of HIV. Primary objectives were to determine rates of HIV infection among infants and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants.
Mother-infant pairs were randomized to receive 200 mg of nevirapine to women in labor and 2 mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240-mL dose of HIVIGLOB given to women at 36- to 38-week gestation and a single intravenous 24-mL dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6, and 12 months of age.
Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm vs. the sdNVP arm [18.7% vs. 15.0%; risk ratio = 1.240 (95% confidence interval: 0.833 to 1.846); P = 0.290]. Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively, for mothers (18.9% vs. 19.3%; P = 0.91) and infants (62.6% vs. 59.5%; P = 0.51) was not significantly different.
Giving mother-infant pairs an infusion of peripartum HIV hyperimmune globulin in addition to sdNVP for preventing maternal-to-child transmission was as safe as sdNVP alone but was no more effective than sdNVP alone in preventing HIV transmission.
JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2011; 58(4):399-407. · 4.43 Impact Factor
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The Journal of Infectious Diseases 08/2011; 204(4):493-4. · 6.41 Impact Factor
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ABSTRACT: We assessed morbidity rates during short intervals that accompanied weaning and cumulative mortality among HIV-exposed, uninfected infants enrolled in the postexposure prophylaxis of infants in Malawi (PEPI-Malawi) trial.
Women were counseled to stop breastfeeding (BF) by 6 months in the PEPI-Malawi trial. HIV-uninfected infants were included in this analysis starting at age 6 months. Breastfeeding and morbidity (illness and/or hospital admission and malnutrition [weight-for-age Z-score, ≤2]) were assessed during age intervals of 6-9, 9-12, and 12-15 months. BF was defined as any BF at the start and end of the interval and no breastfeeding (NBF) was defined as NBF at any time during the interval. The association of NBF with morbidity at each mutually exclusive interval was assessed using Poisson regression models controlling for other factors. Cumulative mortality among infants aged 6-15 months with BF and NBF was assessed using an extended Kaplan-Meier method.
At age 6 months, 1761 HIV-uninfected infants were included in the study. The adjusted rate ratios for illnesses and/or hospital admission for NBF, compared with BF, was 1.7 (P < .0001) at 6-9 months, 1.66 (P = .0001) at 9-12 months, and 1.75 (P = .0008) at 12-15 months. The rates of morbidity were consistently higher among NBF infants during each age interval, compared with BF infants. The 15 months cumulative mortality among BF and NBF children was 3.5% and 6.4% (P = .03), respectively.
Cessation of BF is associated with acute morbidity events and cumulative mortality. Prolonged BF should be encouraged, in addition to close monitoring of infant health and provision of support services.
Clinical Infectious Diseases 08/2011; 53(4):388-95. · 9.15 Impact Factor
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Taha E Taha,
Maria M James,
Donald R Hoover,
Jin Sun,
Oliver Laeyendecker,
Caroline E Mullis,
Johnstone J Kumwenda,
Jairam R Lingappa,
Bertran Auvert,
Charles S Morrison,
Lynne M Mofensen,
Allan Taylor, Mary G Fowler,
Newton I Kumenda,
Susan H Eshleman
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ABSTRACT: We previously developed a multiassay algorithm (MAA) to identify recent HIV infection that includes the BED-capture enzyme immunoassay, an avidity assay based on the Genetic Systems HIV-1/HIV-2 + O enzyme immunoassay, CD4 cell count, and HIV viral load. We used this MAA to evaluate the association between recent maternal HIV infection and in-utero transmission of HIV.
Plasma samples were collected at delivery from 2561 HIV-infected women in the postexposure prophylaxis of infants-Malawi trial. The MAA described above was used to identify women with recent HIV infection. Logistic regression models assessed association between recent HIV infection and in-utero HIV transmission (defined as a positive infant HIV DNA test at birth).
Seventy-three women were identified as recently infected using the MAA. Those women were younger and had lower parity than women who were identified as not recently infected using the MAA (P < 0.0001 for age and parity). The frequency of in-utero HIV transmission was 17.8% among women identified as recently infected, compared with 6.7% among women identified as not recently infected (13/73 vs. 166/2488, P = 0.001). In a multivariate model, three factors were independently associated with in-utero HIV transmission: recent infection [adjusted odds ratio (AOR): 2.49, 95% confidence interval (CI): 1.30-4.78, P = 0.006], log(10) HIV viral load at delivery (AOR: 2.01, 95% CI: 1.60-2.51, P < 0.0001), and younger age (per 10 year increase, AOR: 0.66, 95% CI: 0.43-0.93, P = 0.02).
Results obtained using a MAA suggest that recent maternal HIV acquisition is strongly associated with in-utero HIV transmission, independent of HIV viral load at delivery.
AIDS (London, England) 05/2011; 25(11):1357-64. · 4.91 Impact Factor
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ABSTRACT: The World Health Organization currently recommends initiation of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)-infected lactating women with CD4+ cell counts <350 cells/μL or stage 3 or 4 disease. We analyzed antiretroviral drug resistance in HIV-infected infants in the Post Exposure Prophylaxis of Infants trial whose mothers initiated HAART postpartum (with a regimen of nevirapine [NVP], stavudine, and lamivudine). Infants in the trial received single-dose NVP and a week of zidovudine (ZDV) at birth; some infants also received extended daily NVP prophylaxis, with or without extended ZDV prophylaxis.
We analyzed drug resistance in plasma samples collected from all HIV-infected infants whose mothers started HAART in the first postpartum year. Resistance testing was performed using the first plasma sample collected within 6 months after maternal HAART initiation. Categorical variables were compared by exact or trend tests; continuous variables were compared using rank-sum tests.
Multiclass resistance (MCR) was detected in HIV from 11 (29.7%) of 37 infants. Infants were more likely to develop MCR infection if their mothers initiated HAART earlier in the postpartum period (by 14 weeks vs after 14 weeks and up to 6 months vs after 6 months, P = .0009), or if the mother was exclusively breastfeeding at the time of HAART initiation (exclusive breastfeeding vs mixed feeding vs no breastfeeding, P = .003).
Postpartum maternal HAART initiation was associated with acquisition of MCR in HIV-infected breastfeeding infants. The risk was higher among infants whose mothers initiated HAART closer to the time of delivery or were still exclusively breastfeeding when they first reported HAART use.
Clinical Infectious Diseases 04/2011; 52(8):1069-76. · 9.15 Impact Factor
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Timothy K Thomas,
Rose Masaba,
Craig B Borkowf,
Richard Ndivo,
Clement Zeh,
Ambrose Misore,
Juliana Otieno,
Denise Jamieson,
Michael C Thigpen,
Marc Bulterys,
Laurence Slutsker,
Kevin M De Cock,
Pauli N Amornkul,
Alan E Greenberg, Mary Glenn Fowler
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ABSTRACT: Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention.
HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34-36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load. Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm(3) were 8.4% (95% confidence interval [CI] 5.8%-12.0%) and 4.1% (1.8%-8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%-7.8%) and 8.7% (6.1%-12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%-19.4%).
This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.
PLoS Medicine 03/2011; 8(3):e1001015. · 16.27 Impact Factor
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Clement Zeh,
Paul J Weidle,
Lillian Nafisa,
Humphrey M Lwamba,
Jully Okonji,
Emily Anyango,
Philip Bondo,
Rose Masaba, Mary Glenn Fowler,
John N Nkengasong,
Michael C Thigpen,
Timothy Thomas
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ABSTRACT: Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants.
All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR-positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo).
Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.
PLoS Medicine 03/2011; 8(3):e1000430. · 16.27 Impact Factor
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Taha E Taha,
Qing Li,
Donald R Hoover,
Linda Mipando,
Kondwani Nkanaunena,
Michael C Thigpen,
Allan Taylor,
Johnstone Kumwenda, Mary Glenn Fowler,
Lynne M Mofenson,
Newton I Kumwenda
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ABSTRACT: This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009.
Infants of breastfeeding HIV-infected women were randomized at birth to the following: (1) single-dose nevirapine (NVP) + 1-week zidovudine (ZDV) (control); (2) control + extended daily NVP (ExtNVP) through 14 weeks; (3) control + extended daily NVP + ZDV (ExtNVP/ZDV) through 14 weeks. We estimated rates of HIV infection, death and HIV infection, or death using Kaplan-Meier analysis.
This analysis includes 3126 infants uninfected at birth as follows: 1004 control, 1071 ExtNVP, and 1051 ExtNVP/ZDV. By 9 months, HIV infection rates were 5.0% in ExtNVP, 6.0% in ExtNVP/ZDV, and 11.1% in control (P < 0.001 comparing extended regimens with control). At age 24 months, HIV infection rates had risen to ~11% in the extended arms compared with 15.6% in the controls (P < 0.05). The rates of HIV infection or death were also significantly lower in extended arms. There were no differences in severe adverse events with the exception of higher possibly related events in the ExtNVP/ZDV arm.
Daily infant antiretroviral prophylaxis reduces postnatal HIV infection by ~70% during the period of prophylaxis. But continued HIV transmission after prophylaxis stops suggests more prolonged infant prophylaxis is needed.
JAIDS Journal of Acquired Immune Deficiency Syndromes 03/2011; 57(4):319-25. · 4.43 Impact Factor
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Zikulah Namukwaya,
Peter Mudiope,
Adeodata Kekitiinwa,
Philippa Musoke,
Joyce Matovu,
Sarah Kayma,
William Salmond,
Edward Bitarakwate,
Michael Mubiru,
Albert Maganda,
Moses Galla,
Josaphat Byamugisha, Mary Glenn Fowler
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ABSTRACT: Early HIV infant diagnosis and treatment have been shown to dramatically improve survival in infants. Despite these findings, infants accessing HIV diagnosis and treatment remain low in Uganda. We describe the antiretroviral (ARV) drugs given in the Mulago Hospital prevention of mother-to-child transmission (PMTCT) program from January 2007 to May 2009 and its impact on early infant HIV infection rates.
Pregnant women identified as HIV infected in the Mulago antenatal clinics received one of the following regimens: short-course ARV prophylaxis plus single-dose nevirapine (sdNVP) in labor, highly active antiretroviral therapy (HAART), or sdNVP if they presented in labor. Infants received sdNVP and zidovudine (ZDV) for 1 week. Infants HIV diagnosis was done from 6 weeks after delivery.
62.3% of HIV-infected women received combination ARVs, including HAART. Early infection rates were highest among infants with no maternal ARV [36.4; 95% confidence interval (CI): 17.2 to 59.3] or only sdNVP (11.2; 95% CI: 8.1 to 14.8). Similar rates were observed for the group that took short-course ARVs, ZDV/sdNVP (4.6; 95% CI: 3.2 to 6.4), and ZDV/lamivudine/sdNVP (4.9; 95% CI: 3.1 to 7.2) and lowest rates for those that took HAART (1.7: 95% CI: 0.8 to 2.8). Overall infection rate was 5.0% (95% CI: 4.1 to 5.9).
Findings indicate low rates of infant infection for mothers receiving combination ARVs. These findings demonstrate that provision of combination ARV for PMTCT is feasible and effective in busy referral hospital's PMTCT programs in resource-limited settings.
JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2011; 56(1):69-75. · 4.43 Impact Factor
