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Newton Kumwenda

Publications and source records attributed to Newton Kumwenda.

At least 19 recordsLinked to original sources
PubMed2006

Quantitative analysis of HIV-1 variants with the K103N resistance mutation after single-dose nevirapine in women with HIV-1 subtypes A, C, and D.

INTRODUCTION: We used a sensitive point mutation assay, LigAmp, to detect and quantify K103N-containing variants in African women who received single-dose nevirapine (NVP) to prevent mother-to-child HIV-1 transmission. METHODS: Plasma for testing was collected 6 to 8 weeks postpartum from 301 women (144 subtype A, 63 subtype C, and 94 subtype D). RESULTS: The portion of women with 0.5% or more K103N-containing variants was lowest for subtype A (60/144, 41.7%) and highest for subtype C (44/63, 69.8%; P < 0.0001). K103N was rarely detected in pre-NVP samples. In a multivariate model, K103N detection was associated with HIV-1 subtype (C > A), after adjusting for log10 delivery viral load, the number of days between NVP dosing and sample collection, age, and parity. Among women with K103N detected: (1) the median %K103N was lower for subtype A (2.2%) than C (11.7%, P = 0.0001) or D (5.5%, P = 0.04), and (2) in a multivariate linear model, higher log10 (%K103N) was associated with HIV subtype (C > A, P = 0.0001; D > A, P = 0.01; and C vs D, no difference), but not other factors. CONCLUSIONS: After administration of single-dose NVP, K103N was detected more frequently and at higher levels in women with subtypes C and D than A. Further studies are needed to evaluate the clinical significance of NVP-resistant variants in this setting.

Amino Acid Substitution↗
PubMed2006

Association between the replication capacity and mother-to-child transmission of HIV-1, in antiretroviral drug-naive Malawian women.

Replication capacity and transmission of human immunodeficiency virus (HIV)-1 in antiretroviral drug-naive Malawian women who had subtype C infection were investigated. Infant children of these women received either 1 dose of nevirapine or 1 dose of nevirapine plus 1 week of daily doses of zidovudine. PhenoSense HIV was used to determine replication capacity in 49 women whose infants were infected with HIV-1 and in 47 women whose infants were uninfected by 6-8 weeks of age. Mean replication capacity was higher in transmitters than in nontransmitters (P=.01). In a multivariate model, higher replication capacity was associated with transmission (odds ratio, 1.45 for each 10% increase in replication capacity [95% confidence interval, 1.11-1.90]; P = .0063), after adjustment for maternal HIV-1 load and other factors.

Adult↗
PubMed2006

Higher in utero and perinatal HIV infection risk in girls than boys.

OBJECTIVE: This study analyzed mother-to-child HIV transmission rates by sex and exposure time for babies born to HIV-infected, untreated African women. METHODS: Data were analyzed from 2 independent studies done in Malawi during the 1990s. Infections were established by polymerase chain reaction on blood samples. Odds ratios (ORs) for transmission were examined by period at risk: in utero (infected in umbilical cord blood), perinatal (infected in 1st postnatal blood > or =4 weeks), and postnatal (later postnatal infection). RESULTS: Among 1394 singleton births, girls were more likely to become infected than boys. For in utero transmission, the OR was 1.4 (95% CI: 0.9 to 2.2). For transmission during early life (umbilical cord blood not available) the OR was 2.7 (95% CI: 1.5 to 4.9). However, transmission risks in the perinatal and postnatal infection periods did not differ in boys and girls. Among 303 tested twin-birth pairs, girls were at higher risk than boys for in utero (OR: 2.6; 95% CI: 1.2 to 5.8) and perinatal (OR: 1.9; 95% CI: 1.0 to 3.7) infection. Recognized mother-to-child transmission risk factors did not explain the higher risk of infection in girls. CONCLUSIONS: Girls were at higher risk of early (in utero and perinatal) HIV infection than boys. It is proposed that minor histocompatibility reactions between maternal lymphocytes and infant Y chromosome-derived antigens reduce the risk of HIV transmission in boys.

Disease Susceptibility↗
PubMed2006

HIV incidence among women of reproductive age in Malawi and Zimbabwe.

OBJECTIVE: The objective of this study was to determine the incidence of HIV-1. GOAL: The goal of this study was to inform HIV prevention and vaccine trials by conducting a multisite study in Malawi and Zimbabwe. STUDY DESIGN: Women of reproductive age were enrolled in a prospective study. They received 5 intensive HIV counseling and condom promotion sessions over 2 months. Subsequently, HIV-negative women completed quarterly follow-up visits. HIV incidence rates and predictors of HIV acquisition were assessed. RESULTS: A total of 2016 HIV-negative women were enrolled in the condom promotion and counseling phase of the study. Of these, 1679 were tested for HIV during follow up and 113 women seroconverted, resulting in an overall HIV incidence rate of 4.7 per 100 women-years (95% confidence interval = 3.8-5.6). Incidence rates were similar across sites. The major predictors of HIV acquisition were young age, presence of sexually transmitted infections, being unmarried, and higher educational level. CONCLUSION: The incidence of HIV continues to be high among women in both Malawi and Zimbabwe despite counseling and condom promotion.

Adult↗
PubMed2006

Sensitivity of the ViroSeq HIV-1 genotyping system for detection of the K103N resistance mutation in HIV-1 subtypes A, C, and D.

The US Food and Drug Administration-cleared ViroSeq HIV-1 Genotyping System (ViroSeq) and other population sequencing-based human immunodeficiency virus type 1 (HIV-1) genotyping methods detect antiretroviral drug resistance mutations present in the major viral population of a test sample. These assays also detect some mutations in viral variants that are present as mixtures. We compared detection of the K103N nevirapine resistance mutation using ViroSeq and a sensitive, quantitative point mutation assay, LigAmp. The LigAmp assay measured the percentage of K103N-containing variants in the viral population (percentage of K103N). We analyzed 305 samples with HIV-1 subtypes A, C, and D collected from African women after nevirapine administration. ViroSeq detected K103N in 100% of samples with >20% K103N, 77.8% of samples with 10 to 20% K103N, 71.4% of samples with 5 to 10% K103N, and 16.9% of samples with 1 to 5% K103N. The sensitivity of ViroSeq for detection of K103N was similar for subtypes A, C, and D. These data indicate that the ViroSeq system reliably detects the K103N mutation at levels above 20% and frequently detects the mutation at lower levels. Further studies are needed to compare the sensitivity of different assays for detection of HIV-1 drug resistance mutations and to determine the clinical relevance of HIV-1 minority variants.

Anti-HIV Agents↗
PubMed2005

Resistance after single-dose nevirapine prophylaxis emerges in a high proportion of Malawian newborns.

The administration of single-dose nevirapine to women in labor and their infants can prevent HIV-1 mother-to-child transmission. We examined nevirapine resistance in infants who were HIV-1 infected despite single-dose nevirapine prophylaxis, including 18 Ugandan infants (HIVNET 012 trial, nine subtype A and nine subtype D) and 23 Malawian infants (NVAZ trial, all subtype C). Nevirapine resistance was more frequent in infants with subtype C than with subtypes A and D (87 versus 50%, P = 0.016).

Anti-HIV Agents↗
PubMed2005

Safety, acceptability, and potential efficacy of a topical penile microbicide wipe.

Innovative, low-cost, and acceptable measures are needed to reduce sexually transmitted infections (STIs) including HIV. Use of a topical microbicide wipe for penile cleaning before and after sex might be effective in preventing STIs. However, evaluation of this simple method has not been done. Two studies were conducted in Malawi to determine the safety, acceptability, and potential efficacy of a benzalkonium chloride topical penile microbicide wipe. The first study was a phase 1 dose-escalating clinical trial among low-risk circumcised or uncircumcised HIV-negative men. The second study was a pilot before-after efficacy study among uncircumcised HIV-negative or -positive men. In the first study 24 circumcised and 27 uncircumcised men were enrolled. During the entire study period, 18 adverse events (AEs) were reported, and 3 AEs were confirmed by physical examination. Acceptability concerns did not increase with dose escalation, and adherence to use of the wipe ranged from 89%-95%. In the second study, 27 men were enrolled. Gram stain and culture tests showed significant reductions in frequency of several organisms after use of the wipe, including STI-associated bacteria. This penile wipe is safe, acceptable, and can decrease the frequency of penile colonization with microorganisms. The clinical relevance remains to be determined in larger clinical trials.

Adolescent↗
PubMed2005

Nevirapine (NVP) resistance in women with HIV-1 subtype C, compared with subtypes A and D, after the administration of single-dose NVP.

OBJECTIVE: In the Human Immunodeficiency Virus (HIV) Network for Prevention Trials (HIVNET) 012 trial in Uganda, 6-8 weeks after single-dose nevirapine (SD-NVP), NVP resistance mutations were detected at a higher rate in women with HIV-1 subtype D than in women with subtype A. Here, we evaluate the rate of NVP resistance mutations in women with subtype C. METHODS: NVP resistance mutations were detected using the ViroSeq HIV-1 Genotyping System. RESULTS: The portion of women with any NVP resistance mutation was higher in those with subtype C (45/65 [69.2%] in the NVP and zidovudine trial, Malawi) than in those in the HIVNET 012 trial with either subtype A (28/144 [19.4%]; P<.0001) or subtype D (35/97 [36.1%]; P<.0001). In a multivariate model, subtype (C vs. A: odds ratio [OR], 8.73 [95% confidence interval {CI}, 4.29-17.76]; C vs. D: OR, 3.38 [95% CI, 1.65-6.93]) and viral load at delivery (OR, 2.35 [95% CI, 1.62-3.40]) independently predicted NVP resistance mutations, but maternal age, parity, and time between SD-NVP and the 6-8-week visit did not. CONCLUSIONS: The rate of NVP resistance mutations after SD-NVP was significantly higher in women with HIV-1 subtype C than in women with subtype A or D. Studies are needed to assess the clinical significance of this finding.

Adult↗
PubMed2005

Viral dynamics and CD4+ T cell counts in subtype C human immunodeficiency virus type 1-infected individuals from southern Africa.

Defining viral dynamics in natural infection is prognostic of disease progression and could prove to be important for vaccine trial design as viremia may be a likely secondary end point in phase III HIV efficacy trials. There are limited data available on the early course of plasma viral load in subtype C HIV-1 infection in Africa. Plasma viral load and CD4+ T cell counts were monitored in 51 recently infected subjects for 9 months. Individuals were recruited from four southern African countries: Zambia, Malawi, Zimbabwe, and South Africa and the median estimated time from seroconversion was 8.9 months (interquartile range, 5.7-14 months). All were infected with subtype C HIV-1 and median viral loads, measured using branched DNA, ranged from 3.82-4.02 log10 RNA copies/ml from 2-24 months after seroconversion. Viral loads significantly correlated with CD4+ cell counts (r=-0.5, p<0.0001; range, 376-364 cells/mm3) and mathematical modeling defined a median set point of 4.08 log10 (12 143 RNA copies/ml), which was attained approximately 17 months after seroconversion. Comparative measurements using three different viral load platforms (bDNA, Amplicor, and NucliSens) confirmed that viremia in subtype C HIV-1-infected individuals within the first 2 years of infection did not significantly differ from that found in early subtype B infection. In conclusion, the course of plasma viremia, as described in this study, will allow a useful baseline comparator for understanding disease progression in an African setting and may be useful in the design of HIV-1 vaccine trials in southern Africa.

Africa, Southern↗
PubMed2005

Breast milk retinol concentrations are not associated with systemic inflammation among breast-feeding women in Malawi.

The acute phase response and inflammation are associated with lower plasma retinol concentrations, but their effect on breast milk retinol concentrations is unclear. We measured plasma retinol concentrations, acute phase proteins, and breast milk retinol concentrations in 237 breast-feeding women at 2 wk postpartum in Blantyre, Malawi; 16.5% of the women had plasma retinol < 0.70 micromol/L and 14.8% had breast milk retinol < 1.05 micromol/L. Among women with and without inflammation [alpha(1)-acid glycoprotein (AGP) > 1 g/L and/or C-reactive protein (CRP) > 5 mg/L], geometric mean (95% CI) plasma retinol was 0.89 (0.84, 0.94) and 1.05 (1.01, 1.17) mumol/L, respectively (P < 0.0001). Among women with and without inflammation, geometric mean (95% CI) breast milk retinol was 2.12 (1.89, 2.36) and 2.05 (1.75, 2.39) micromol/L, respectively (P = 0.74). In multiple linear regression models adjusting for age, parity, education, BMI, and days postpartum, plasma retinol concentrations were associated with plasma AGP and CRP concentrations (P < 0.0001 and P = 0.01, respectively), whereas breast milk retinol concentrations were unaffected by plasma AGP and CRP concentrations (P = 0.22 and P = 0.86, respectively). These findings suggest that breast milk retinol concentrations are not affected by systemic inflammation.

Adult↗
PubMed2005

Affordable, abbreviated roche monitor assay for quantification of human immunodeficiency virus type 1 RNA in plasma.

The cost for the Roche Monitor assay kit can be reduced 50% by using only the 1:1, 1:25, and 1:625 human immunodeficiency virus (HIV) and the 1:1 quantitation standard dilutions. This abbreviated test applied to 1,774 mostly African samples had results nearly identical to those obtained following the package insert instructions. To make this approach feasible, Roche would have to provide additional lysis buffer and master mix.

Female↗
PubMed2005

Status of carotenoids, vitamin A, and vitamin E in the mother-infant dyad and anthropometric status of infants in Malawi.

This prospective study was carried out during February 2000-April 2003 to characterize the relationship between the status of carotenoids, vitamin E, and retinol and anthropometric status in apparently healthy infants and their mothers in Blantyre, Malawi. Anthropometric status of infants and concentrations of carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene), retinol, and alpha-tocopherol in plasma were measured in 173 infants at 12 months of age, and concentrations of carotenoids, retinol, and a-tocopherol in plasma were measured in their mothers two weeks postpartum. In multivariate analyses, concentrations of retinol, total carotenoids, non-provitamin A carotenoids, and alpha-tocopherol in infants were associated with under-weight (p = 0.05). Concentrations of a-tocopherol were associated with wasting (p = 0.04). Concentrations in mothers and infants were all correlated (correlation coefficients from 0.230 to 0.502, p < 0.003). The findings suggest that poor status of carotenoids, retinol, and alpha-tocopherol in infants is associated with their poor anthropometric status, and status of carotenoids, retinol, and alpha-tocopherol in mothers and infants has a low-to-moderate association in the mother-infant dyad.

Adult↗
PubMed2004

Novel and promiscuous CTL epitopes in conserved regions of Gag targeted by individuals with early subtype C HIV type 1 infection from southern Africa.

Characterization of optimal CTL epitopes in Gag can provide crucial information for evaluation of candidate vaccines in populations at the epicenter of the HIV-1 epidemic. We screened 38 individuals with recent subtype C HIV-1 infection using overlapping consensus C Gag peptides and hypothesized that unique HLA-restricting alleles in the southern African population would determine novel epitope identity. Seventy-four percent of individuals recognized at least one Gag peptide pool. Ten epitopic regions were identified across p17, p24, and p2p7p1p6, and greater than two-thirds of targeted regions were directed at: TGTEELRSLYNTVATLY (p17, 35%); GPKEPFRDYVDRFFKTLRAEQATQDV (p24, 19%); and RGGKLDKWEKIRLRPGGKKHYMLKHL (p17, 15%). After alignment of these epitopic regions with consensus M and a consensus subtype C sequence from the cohort, it was evident that the regions targeted were highly conserved. Fine epitope mapping revealed that five of nine identified optimal Gag epitopes were novel: HLVWASREL, LVWASRELERF, LYNTVATLY, PFRDYVDRFF, and TLRAEQATQD, and were restricted by unique HLA-Cw*08, HLA-A*30/B*57, HLA-A*29/B*44, and HLA-Cw*03 alleles, respectively. Notably, three of the mapped epitopes were restricted by more than one HLA allele. Although these epitopes were novel and restricted by unique HLA, they overlapped or were embedded within previously described CTL epitopes from subtype B HIV-1 infection. These data emphasize the promiscuous nature of epitope binding and support our hypothesis that HLA diversity between populations can shape fine epitope identity, but may not represent a constraint for universal recognition of Gag in highly conserved domains.

Africa, Southern↗
PubMed2004

Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins by CD8+ T cells: correlation with viral load.

An understanding of the relationship between the breadth and magnitude of T-cell epitope responses and viral loads is important for the design of effective vaccines. For this study, we screened a cohort of 46 subtype C human immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses against a panel of peptides corresponding to the complete subtype C genome. We used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of T-cell responses across the expressed HIV-1 genome correlate with viral control. The estimated median time from seroconversion to response for the cohort was 13 months, and the order of cumulative T-cell responses against HIV proteins was as follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most intensely targeted protein, with 97.5% of the epitopes being clustered within 119 amino acids, constituting almost one-third of the responses across the expressed genome. The second most targeted region was p24, comprising 17% of the responses. There was no correlation between viral load and the breadth of responses, but there was a weak positive correlation (r = 0.297; P = 0.034) between viral load and the total magnitude of responses, implying that the magnitude of T-cell recognition did not contribute to viral control. When hierarchical patterns of recognition were correlated with the viral load, preferential targeting of Gag was significantly (r = 0.445; P = 0.0025) associated with viral control. These data suggest that preferential targeting of Gag epitopes, rather than the breadth or magnitude of the response across the genome, may be an important marker of immune efficacy. These data have significance for the design of vaccines and for interpretation of vaccine-induced responses.

Amino Acid Sequence↗
PubMed2004

Haematological changes in African children who received short-term prophylaxis with nevirapine and zidovudine at birth.

We assessed the safety of short-term antiretroviral prophylaxis to prevent mother-to-child transmission (MTCT) of HIV by monitoring haematological changes in children up to the age of 18 months. Babies of HIV-infected women were randomised at birth to receive a single dose of nevirapine (NVP) alone or with zidovudine (ZDV) twice daily for a week. Based on the time of presentation to the labour ward, mothers of these babies might or might not have received intrapartum NVP. Complete blood counts were performed at birth and at 1.5, 3, 6, 9, 12, 15 and 18 months. Babies' HIV status was determined by HIV-1 RNA testing. A total of 1755 babies were included in the study. Age-specific mean haemoglobin levels and prevalence of anaemia (haemoglobin < 10 g/dL) were not significantly different in cases where only the babies received a single dose of NVP and cases where NVP was given to mother/infant pairs or additional ZDV to the baby. Among HIV-infected children compared with uninfected children, the age-specific frequency of anaemia was significantly greater, anaemia started earlier and recovery to normal levels was slower and prolonged. A reversible granulocytopenia was observed in all children between 1.5 and 3 months of age. HIV infection significantly increased the children's risk of death. Antiretroviral prophylaxis appeared to protect against anaemia and child death. Short regimens of antiretrovirals to prevent MTCT of HIV are not associated with long-term adverse haematological changes.

Agranulocytosis↗
PubMed2003

The risk of human immunodeficiency virus-1 infection in twin pairs born to infected mothers in Africa.

We examined birth order and delivery route as risk factors for mother-to-child transmission of human immunodeficiency virus (HIV)-1 in 315 twin pairs born in Malawi during 1994-1998. No antiretroviral drugs were administered to these subjects. Infections were detected by polymerase chain reaction and were stratified as having occurred either in utero, perinatally, or postnatally. Risk of in utero infection for 630 infants (39 infections) did not differ by birth order (first born, 6.3%; second born, 6.0%). Similarly, in 260 vaginally delivered infants evaluated for perinatal infection (45 infections), risk did not differ by birth order (first born, 15.9%; second born, 18.7%); risk of perinatal infection was significantly lower in cesarean-delivered infants (odds ratio, 0.19 [95% confidence interval, 0.02-0.78]). There was no effect on postnatal transmission rates. Thus, in contrast to the authors of earlier studies, we did not find birth order to be an important risk factor for infection in twins. These findings indicate that birth-canal exposure is not a major contributor to a newborn's risk of HIV-1 infection.

Africa↗
PubMed2002

Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi.

Vitamin A is essential for immunity and growth. A controlled clinical that involved 697 human immunodeficiency virus (HIV)-infected pregnant women was conducted to determine whether vitamin A prevents anemia, low birth weight, growth failure, HIV transmission, and mortality. Women received daily doses of iron and folate, either alone or combined with vitamin A (3 mg retinol equivalent), from 18-28 weeks' gestation until delivery. In the vitamin A and control groups, respectively, the mean (+/-SE) birth weights were 2895+/-31 g and 2805+/-32 g (P=.05), the proportions of low-birth-weight infants were 14.0% and 21.1% (P=.03), the proportions of anemic infants at 6 weeks postpartum were 23.4% and 40.6% (P<.001), and the respective cumulative proportions of infants who were HIV infected at 6 weeks and 24 months of age were 26.6% and 27.8% (P=.76) and 27.7% and 32.8% (P=.21). Receipt of vitamin A improved birth weight and neonatal growth and reduced anemia, but it did not affect perinatal HIV transmission.

Adult↗