Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-24 (of 24 Records) |
Query Trace: Kumwenda J[original query] |
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Isoniazid-associated pellagra during mass scale-up of tuberculosis preventive therapy: a case-control study
Nabity SA , Mponda K , Gutreuter S , Surie D , Zimba SB , Chisuwo L , Moffitt A , Williams AM , Sharma AJ , Marshall RE , Chiwaula MJ , da Silva R , Kumwenda T , Chilikutali L , Mwamale S , Nagoli E , Mwenyeheri G , Ngongonda D , Kaunda E , Mtoto F , Mhango V , Mbewe K , Melgar M , Odo M , Jahn A , Buono N , Maida A , Girma B , Kalua T , Nyirenda R , Sunguti J , Woelk G , Gunde LJ , Mekonnen TF , Maphosa T , Kim EJ , Auld AF , Muula AS , Oeltmann JE . Lancet Glob Health 2022 10 (5) e705-e714 BACKGROUND: Pellagra is caused by niacin (vitamin B3) deficiency and patients with pellagra present with a characteristic rash. Isoniazid disrupts intracellular niacin synthesis and might induce niacin deficiency. In 2017, Malawi scaled up continuous isoniazid preventive treatment (IPT) for tuberculosis prevention among people living with HIV. In addition, an under-diversified diet based on subsistence maize, as is commonly the case in Malawi, is a risk factor for pellagra. We aimed to investigate whether large-scale isoniazid exposure in Malawi contributed to the cumulative risk for pellagra in a nutritionally vulnerable population. METHODS: We did a matched case-control study to evaluate the association between daily, continuous isoniazid exposure and pellagra. We matched sequentially enrolled patients with pellagra each with four control participants by sex and age from referral dermatology centres in three IPT scale-up districts in Malawi (Lilongwe, Blantyre, and Zomba) to evaluate isoniazid as a risk for pellagra using multivariable conditional logistic regression. We established a community clinic referral system surrounding the dermatology clinic in each district to enhance case-finding and included all patients with pellagra, regardless of referral status. The primary outcome was dermatologist-diagnosed pellagra. We calculated the interval between isoniazid initiation and rash onset and assessed 30-day clinical outcomes after multi-B vitamin treatment containing 300 mg nicotinamide daily. FINDINGS: Between Feb 5 and Aug 9, 2019, we enrolled 197 patients with pellagra and 781 matched controls. Isoniazid exposure was associated with an increased risk of pellagra (adjusted odds ratio 42·6 [95% CI 13·3-136·6]). Significant covariates included HIV infection, referral status, food insecurity, underweight, excess alcohol consumption, and, among women, lactation. The median time from isoniazid initiation to rash onset was shorter during the season of food scarcity (5 months [IQR 3-7]) compared with the harvest season (9 months [8-11]; hazard ratio 7·2 [95% CI 3·2-16·2], log-rank p<0·0001). Those with isoniazid-associated pellagra who discontinued isoniazid and adhered to multi-B vitamin treatment showed 30-day clinical improvement. INTERPRETATION: Continuous IPT scale-up and the annual period of food scarcity both increased the risk of pellagra in Malawi. Use of shorter rifamycin-based regimens for tuberculosis prevention and food fortification in populations with undernutrition might reduce this risk. Niacin-containing multi-B vitamin co-administration with isoniazid as pellagra prevention is worth exploring further. FUNDING: This study was supported by the President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention under project 7173. |
Brief report: No differences between lopinavir/ritonavir and nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy on clearance of plasmodium falciparum subclinical parasitemia in adults living with HIV starting treatment (A5297)
Shaffer D , Kumwenda J , Chen H , Akelo V , Angira F , Kosgei J , Tonui R , Ssali F , McKhann A , Hogg E , Stewart VA , Murphy SC , Coombs R , Schooley R . J Acquir Immune Defic Syndr 2022 89 (2) 178-182 BACKGROUND: HIV protease inhibitors anti-Plasmodium falciparum activity in adults remains uncertain. METHODS: Adults with HIV CD4+ counts >200 cells/mm3 starting antiretroviral therapy (ART) with P. falciparum subclinical parasitemia (Pf SCP) were randomized 1:1 to (step 1) protease inhibitor lopinavir/ritonavir (LPV/r)-based (arm A) or nonnucleoside reverse transcriptase inhibitor (nNRTI)-based ART (arm B) for 15 days. In step 2, participants received nNRTI-based ART and trimethoprim/sulfamethoxazole prophylaxis for 15 days. P. falciparum SCP clearance was measured by polymerase chain reaction. The Fisher exact test [95% exact confidence interval (CI)] was used to compare proportions of P. falciparum SCP clearance (<10 parasites/L on 3 occasions within 24 hours) between LPV/r and nNRTI arms at day 15. The Kaplan-Meier method and log-rank test were used to compare time-to-clearance. RESULTS: Fifty-two adults from Kenya, Malawi, and Uganda with a median age = 31 (Q1, Q3: 24-39) years, 33% women, with baseline median CD4+ counts of 324 (259-404) cells/mm3, median HIV-1 RNA viremia of 5.18 log10 copies/mL (4.60-5.71), and median estimated P. falciparum density of 454 parasites/L (83-2219) enrolled in the study. Forty-nine (94%) participants completed the study. At day 15, there was no statistically significant difference in the proportions of P. falciparum SCP clearance between the LPV/r (23.1% clearance; 6 of the 26) and nNRTI (26.9% clearance; 7 of the 26) arms [between-arm difference 3.9% (95% CI, -21.1% to 28.4%; P = 1.00)]. No significant difference in time-to-clearance was observed between the arms (P = 0.80). CONCLUSIONS: In a small randomized study of adults starting ART with P. falciparum SCP, no statistically significant differences were seen between LPV/r- and nNRTI-based ART in P. falciparum SCP clearance after 15 days of treatment. |
Evaluation of phylogenetic methods for inferring the direction of HIV transmission: HPTN 052.
Zhang Y , Wymant C , Laeyendecker O , Grabowski MK , Hall M , Hudelson S , Piwowar-Manning E , McCauley M , Gamble T , Hosseinipour MC , Kumarasamy N , Hakim JG , Kumwenda J , Mills LA , Santos BR , Grinsztejn B , Pilotto JH , Chariyalertsak S , Makhema J , Chen YQ , Cohen MS , Fraser C , Eshleman SH . Clin Infect Dis 2021 72 (1) 30-37 BACKGROUND: Phylogenetic analysis can be used to assess human immunodeficiency virus (HIV) transmission in populations. We inferred the direction of HIV transmission using whole-genome HIV sequences from couples with known linked infection and known transmission direction. METHODS: Complete next-generation sequencing (NGS) data were obtained for 105 unique index-partner sample pairs from 32 couples enrolled in the HIV Prevention Trials Network (HPTN) 052 study (up to 2 samples/person). Index samples were obtained up to 5.5 years before partner infection; partner samples were obtained near the time of seroconversion. The bioinformatics method, phyloscanner, was used to infer transmission direction. Analyses were performed using samples from individual sample pairs, samples from all couples (1 sample/person; group analysis), and all available samples (multisample group analysis). Analysis was also performed using NGS data from defined regions of the HIV genome (gag, pol, env). RESULTS: Using whole-genome NGS data, transmission direction was inferred correctly (index to partner) for 98 of 105 (93.3%) of the individual sample pairs, 99 of 105 (94.3%) sample pairs using group analysis, and 31 of the 32 couples (96.9%) using multisample group analysis. There were no cases where the incorrect transmission direction (partner to index) was inferred. The accuracy of the method was higher with greater time between index and partner sample collection. Pol region sequences performed better than env or gag sequences for inferring transmission direction. CONCLUSIONS: We demonstrate the potential of a phylogenetic method to infer the direction of HIV transmission between 2 individuals using whole-genome and pol NGS data. |
The effect of TB treatment on health-related quality of life for people with advanced HIV
Opollo V , Sun X , Lando R , Miyahara S , Torres TS , Hosseinipour MC , Bisson GP , Kumwenda J , Gupta A , Nyirenda M , Katende K , Suryavanshi N , Beulah F , Shah NS . Int J Tuberc Lung Dis 2020 24 (9) 910-915 BACKGROUND: Study A5274 was an open-label trial of people with HIV (PLHIV) with CD4 cell count <50 cells/µL who were randomized to empirical TB treatment vs. isoniazid preventive therapy (IPT) in addition to antiretroviral therapy (ART). We evaluated health-related quality of life (HRQoL) by study arm, changes over time, and association with sociodemographic and clinical factors.METHODS: Participants aged >13 years were enrolled from outpatient clinics in 10 countries. HRQoL was assessed at Weeks 0, 8, 24 and 96 with questions about daily activity, hospital or emergency room visits, and general health status. We used logistic regression to examine HRQoL by arm and association with sociodemographic and clinical factors.RESULTS: Among 850 participants (424 empiric arm, 426 IPT arm), HRQoL improved over time with no difference between arms. At baseline and Week 24, participants with WHO Stage 3 or 4 events, or those who had Grade 3 or 4 signs/symptoms, were significantly more likely to report poor HRQoL using the composite of four HRQoL measures.CONCLUSION: HRQoL improved substantially in both arms during the study period. These findings show that ART, TB screening, and IPT can not only reduce mortality, but also improve HRQoL in PLHIV with advanced disease. |
Phylogenetic methods inconsistently predict direction of HIV transmission among heterosexual pairs in the HPTN052 cohort.
Rose R , Hall M , Redd AD , Lamers S , Barbier AE , Porcella SF , Hudelson SE , Piwowar-Manning E , McCauley M , Gamble T , Wilson EA , Kumwenda J , Hosseinipour MC , Hakim JG , Kumarasamy N , Chariyalertsak S , Pilotto JH , Grinsztejn B , Mills LA , Makhema J , Santos BR , Chen YQ , Quinn TC , Fraser C , Cohen MS , Eshleman SH , Laeyendecker O . J Infect Dis 2018 220 (9) 1406-1413 Background: We evaluated use of phylogenetic methods to predict the direction of HIV transmission. Methods: For 33 index-partner pairs with genetically-linked infection, samples were collected from partners and indexes close to time of partners' seroconversion (SC); 31 indexes also had an earlier sample. Phylogenies were inferred using env next-generation sequences (one tree per pair/subtype). Direction of transmission (DoT) predicted from each tree was classified as correct or incorrect based on which sequences (index or partner) were closest to the root. DoT was also assessed using maximum-parsimony to infer ancestral node states for 100 bootstrap trees. Results: DoT was predicted correctly for both single pair and subtype-specific trees in 22 pairs (67%) using SC samples and 23 pairs (74%) using early index samples. DoT was predicted incorrectly for four pairs (15%) using SC or early index samples. In the bootstrap analysis, DoT was predicted correctly for 18 pairs (55%) using SC samples and 24 pairs (73%) using early index samples. DoT was predicted incorrectly for seven pairs (21%) using SC samples and four pairs (13%) using early index samples. Conclusions: Phylogenetic methods based solely on tree topology of HIV env sequences, particularly without consideration of phylogenetic uncertainty, may be insufficient for determining DoT. |
Complexities and dilemmas in community consultation on the design of a research project logo in Malawi
Nyirenda D , Gooding K , Lora W , Kumwenda M , McMorrow M , Everett D , Desmond N . PLoS One 2018 13 (10) e0205737 BACKGROUND: Community engagement on research design is widely highlighted as an important approach for ethical research. This article reports the experience of consulting with communities on the logo used for an influenza study in Malawi. The logo was designed for use on badges worn by study researchers, participant information sheets and other project documents, and could affect perceptions of the study and consequent engagement in the research. METHODS: Four focus group discussions were conducted with populations targeted by the influenza study: pregnant women, people with HIV, mothers and community members. The focus groups incorporated a participatory matrix exercise focusing on key themes emerging from the discussions such as: attractiveness, comprehension, acceptability and suggestions for improvement. Findings from the focus groups were analyzed according to these key themes. RESULTS: The consultation highlighted important benefits of discussion with communities on research design, including providing new perspectives and helping to avoid harm. For example, people living with HIV felt that one of the possible logos could increase stigma within communities. The experience also indicated potential challenges of consultation. In particular, there were contrasting perspectives among the groups, such that the consultation did not provide a clear answer about which logo should be selected. CONCLUSIONS: Our experience adds to current evidence on community engagement by reporting on an area where there is less discussion of community consultation for design of a study logo. The consultation exercise reaffirmed the value of community engagement, but also the difficulty of relying on a brief consultation for decision-making in research design. Further ethical guidance is required on how to negotiate contradictory views during consultations. |
HIV drug resistance in adults receiving early versus delayed antiretroviral therapy: HPTN 052
Palumbo PJ , Fogel JM , Hudelson SE , Wilson EA , Hart S , Hovind L , Piwowar-Manning E , Wallis C , Papathanasopoulos MA , Morgado MG , Saravanan S , Tripathy S , Eron JJ , Gallant JE , Mph , McCauley M , Gamble T , Hosseinipour MC , Kumarasamy N , Hakim JG , Pilotto JH , Kumwenda J , Akelo V , Godbole SV , Santos BR , Grinsztejn B , Panchia R , Chariyalertsak S , Makhema J , Badal-Faesen S , Chen YQ , Cohen MS , Eshleman SH . J Acquir Immune Defic Syndr 2017 77 (5) 484-491 INTRODUCTION: We evaluated HIV drug resistance in adults who received early versus delayed antiretroviral therapy (ART) in a multi-national trial (HPTN 052, enrollment 2005-2010). In HPTN 052, 1,763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm3 (early ART arm) or <250 cells/mm3 (delayed ART arm). In May 2011, interim study results showed benefit of early ART, and all participants were offered ART regardless of CD4 cell count; the study ended in 2015. METHODS: Virologic failure was defined as two consecutive viral loads >1,000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pre-treatment (baseline) and failure samples from participants with virologic failure. RESULTS: HIV genotyping results were obtained for 211/249 participants (128 early ART arm; 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared to delayed ART arm, p=0.06; compared to delayed ART arm with ART initiation before May 2011, p=0.032). In multivariate analysis, higher baseline viral load (p=0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared to other regimens, p=0.024) were independently associated with higher risk of new resistance at failure. CONCLUSIONS: In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load. |
Emergence of double- and triple-gene reassortant G1P[8] rotaviruses possessing a DS-1-like backbone post rotavirus vaccine introduction in Malawi.
Jere KC , Chaguza C , Bar-Zeev N , Lowe J , Peno C , Kumwenda B , Nakagomi O , Tate JE , Parashar UD , Heyderman RS , French N , Cunliffe NA , Miren IG . J Virol 2017 92 (3) To combat the high burden of rotavirus gastroenteritis, multiple African countries have introduced rotavirus vaccines into their childhood immunisation programmes. Malawi incorporated a G1P[8] rotavirus vaccine (Rotarix) into its immunisation schedule in 2012. Utilising a surveillance platform of hospitalised rotavirus gastroenteritis cases, we examined the phylodynamics of G1P[8] rotavirus strains that circulated in Malawi before (1998 - 2012) and after (2013 - 2014) vaccine introduction. Analysis of whole genomes obtained through next generation sequencing revealed that all randomly-selected pre-vaccine G1P[8] strains sequenced (n=32) possessed a Wa-like genetic constellation, whereas post-vaccine G1P[8] strains (n=18) had a DS-1-like constellation. Phylodynamic analyses indicated that post-vaccine G1P[8] strains emerged through reassortment events between human Wa- and DS-1-like rotaviruses that circulated in Malawi from the 1990's, hence classified as atypical DS-1-like reassortants. The time to the most recent common ancestor for G1P[8] strains was from 1981-1994; their evolutionary rates ranged from 9.7 x 10-4-4.1 x 10-3 nucleotide/substitutions/site/year. Three distinct G1P[8] lineages chronologically replaced each other between 1998 and 2014. Genetic drift was the likely driver for lineage turnover in 2005, whereas replacement in 2013 was due to reassortment. Amino acid substitution within the outer glycoprotein VP7 of G1P[8] strains had no impact on the structural conformation of the antigenic regions, suggesting that it is unlikely that they would affect recognition by vaccine-induced neutralizing antibodies. While the emergence of DS-1-like G1P[8] rotavirus reassortants in Malawi was therefore likely due to natural genotype variation, vaccine effectiveness against such strains needs careful evaluation.ImportanceThe error-prone RNA-dependent RNA polymerase and the segmented RNA genome predispose rotaviruses to genetic mutation and genome reassortment, respectively. These evolutionary mechanisms generate novel strains and have the potential to lead to the emergence of vaccine-escape mutants. While multiple African countries have introduced rotavirus vaccine, there are few data describing the evolution of rotaviruses that circulated before and after vaccine introduction. We report the emergence of atypical DS-1-like G1P[8] strains during the post-vaccine era in Malawi. Three distinct G1P[8] lineages circulated chronologically from 1998-2014; mutation and reassortment drove lineage turnover in 2005 and 2013, respectively. Amino acid substitutions within the outer capsid VP7 glycoprotein did not affect the structural conformation of mapped antigenic sites, suggesting limited effect in recognition of G1 specific vaccine-derived antibodies. The genes that constitute the remaining genetic backbone may play important roles in immune evasion, and vaccine effectiveness against such atypical strains needs careful evaluation. |
The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1.
Cornick JE , Tastan Bishop O , Yalcin F , Kiran AM , Kumwenda B , Chaguza C , Govindpershad S , Ousmane S , Senghore M , du Plessis M , Pluschke G , Ebruke C , McGee L , Sigauque B , Collard JM , Bentley SD , Kadioglu A , Antonio M , von Gottberg A , French N , Klugman KP , Heyderman RS , Alderson M , Everett DB . Vaccine 2017 35 (6) 972-980 Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (<2%). The vast majority of the observed variation was predicted to have no impact on the efficaciousness of a protein vaccine incorporating a single variant of SP0148, SP1912 and/or SP2108 from S. pneumoniae TIGR4. Our findings emphasise the importance of taking geographic differences into account when designing global vaccine interventions and support the continued development of SP0148, SP1912 and SP2108 as protein vaccine candidates against this important pneumococcal serotype. |
Antiretroviral Therapy for the Prevention of HIV-1 Transmission.
Cohen MS , Chen YQ , McCauley M , Gamble T , Hosseinipour MC , Kumarasamy N , Hakim JG , Kumwenda J , Grinsztejn B , Pilotto JH , Godbole SV , Chariyalertsak S , Santos BR , Mayer KH , Hoffman IF , Eshleman SH , Piwowar-Manning E , Cottle L , Zhang XC , Makhema J , Mills LA , Panchia R , Faesen S , Eron J , Gallant J , Havlir D , Swindells S , Elharrar V , Burns D , Taha TE , Nielsen-Saines K , Celentano DD , Essex M , Hudelson SE , Redd AD , Fleming TR . N Engl J Med 2016 375 (9) 830-9 Background An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. Methods We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis. Results Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant. Conclusions The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581). |
Maternal highly active antiretroviral therapy and child HIV-free survival in Malawi, 2004-2009
Schwartz SR , Kumwenda N , Kumwenda J , Chen S , Mofenson LM , Taylor AW , Fowler MG , Taha TE . Matern Child Health J 2015 20 (3) 542-9 OBJECTIVES: Highly active antiretroviral therapy (HAART) provision to eligible HIV-infected pregnant and post-partum women is critical for optimizing maternal health. We assessed the impact of maternal HAART on HIV-free survival of breastfed infants in Malawi. METHODS: The post-exposure prophylaxis of infants-Malawi trial (2004-2009) enrolled mothers/infants during labor or immediately post-partum to evaluate 14-week extended infant antiretroviral prophylaxis for preventing HIV transmission through breastfeeding. Mothers meeting national HAART guidelines were referred for therapy. Child HIV-free survival-survival without HIV infection-was compared by maternal HAART status. RESULTS: Overall, 3022 mother-infant pairs contributed 4214 infant/person-years (PY) at-risk for HIV infection or death, with 532 events (incidence 12.6/100 PY, 95 % confidence interval [CI] 11.6-13.7). During follow-up, 349 mothers were HAART initiated; 581 remained HAART naive with CD4 cell counts <250 cells/mm3, and 2092 were never HAART-eligible. By 3 months, 11 % of infants with HAART naive mothers (CD4 < 250) were infected with HIV or died versus 7 % of infants of HAART-initiated mothers and 4 % of infants of HAART-ineligible mothers. Maternal HAART was associated with a 46 % reduction in infant HIV infection or death as compared to infants with HAART naive mothers (CD4 < 250) (adjusted hazards ratio 0.54, 95 % CI 0.36-0.81). Among HIV-exposed, uninfected infants, breastfeeding, but not HAART, was significantly associated with decreased child mortality. CONCLUSIONS: HIV infection and mortality are high during the first 3 months post-partum in infants of mothers with advanced HIV, and rapid maternal HAART initiation can significantly improve HIV-related infant outcomes. CLINICAL TRIALS REGISTRATION: This study is registered at http://clinicaltrials.gov/ under trial number NCT00115648. |
Association of HIV-1 envelope-specific breast milk IgA responses with reduced risk of postnatal mother-to-child transmission of HIV-1
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 , Permar SR . J Virol 2015 89 (19) 9952-61 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 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 virus in breast milk. Remarkably, the transmission rate is low, suggesting that immune factors in 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 magnitude of the breast milk IgA and secretory IgA response against HIV-1 envelope proteins was 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 development of strategies to enhance milk envelope-specific IgA responses to reduce mother-to-child HIV transmission and promote an HIV-free generation. |
Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial
Grinsztejn B , Hosseinipour MC , Ribaudo HJ , Swindells S , Eron J , Chen YQ , Wang L , Ou SS , Anderson M , McCauley M , Gamble T , Kumarasamy N , Hakim JG , Kumwenda J , Pilotto JH , Godbole SV , Chariyalertsak S , de Melo MG , Mayer KH , Eshleman SH , Piwowar-Manning E , Makhema J , Mills LA , Panchia R , Sanne I , Gallant J , Hoffman I , Taha TE , Nielsen-Saines K , Celentano D , Essex M , Havlir D , Cohen MS . Lancet Infect Dis 2014 14 (4) 281-90 BACKGROUND: Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. METHODS: The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. FINDINGS: 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per muL in patients assigned to the early treatment group and 428 (357-522) cells per muL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per muL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0.73, 95% CI 0.52-1.03; p=0.074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0.64, 0.43-0.96; p=0.031), tuberculosis developed in 17 versus 34 patients, respectively (0.49, 0.28-0.89, p=0.018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24.9 per 100 person-years, 95% CI 22.5-27.5) versus 585 in the delayed treatment group (29.2 per 100 person-years, 26.5-32.1; p=0.025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. INTERPRETATION: Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. FUNDING: US National Institute of Allergy and Infectious Diseases. |
Undisclosed antiretroviral drug use in a multinational clinical trial (HIV Prevention Trials Network 052)
Fogel JM , Wang L , Parsons TL , Ou SS , Piwowar-Manning E , Chen Y , Mudhune VO , Hosseinipour MC , Kumwenda J , Hakim JG , Chariyalertsak S , Panchia R , Sanne I , Kumarasamy N , Grinsztejn B , Makhema J , Pilotto J , Santos BR , Mayer KH , McCauley M , Gamble T , Bumpus NN , Hendrix CW , Cohen MS , Eshleman SH . J Infect Dis 2013 208 (10) 1624-8 The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings. |
Role of intestinal mucosal integrity in HIV transmission to infants through breastfeeding: the BAN Study
Kourtis AP , Ibegbu CC , Wiener J , King CC , Tegha G , Kamwendo D , Kumwenda J , Pal KS , Flax V , Ellington S , Kacheche Z , Kayira D , Chasela C , van der Horst C , Jamieson DJ . J Infect Dis 2013 208 (4) 653-61 BACKGROUND: Increased intestinal permeability may be one of the mechanisms of transmission of HIV to the infant through breastfeeding. It correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS). METHODS: We evaluated levels of plasma LPS (Limulus Amoebocyte Lysate assay), and immune activation markers in serial specimens of HIV-exposed uninfected and HIV-infected infants from the Breastfeeding, Antiretrovirals and Nutrition (BAN) Study. RESULTS: Plasma LPS levels increased after infants in BAN weaned from the breast at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (p=0.004). Infants with HIV infection had higher LPS levels compared with uninfected infants (p= 0.004). Pre-infection plasma LPS levels were a significant predictor of infant HIV infection through breastfeeding (HR=1.60 for every unit increase in plasma LPS, p=0.01) and for lower infant length-for-age (p=0.02). CONCLUSIONS: These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to the infant through breastfeeding. 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 breastfeeding transmission of HIV. |
Pooled individual data analysis of 5 randomized trials of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission
Hudgens MG , Taha TE , Omer SB , Jamieson DJ , Lee H , Mofenson LM , Chasela C , Kourtis AP , Kumwenda N , Ruff A , Bedri A , Jackson JB , Musoke P , Bollinger RC , Gupte N , Thigpen MC , Taylor A , van der Horst C . Clin Infect Dis 2013 56 (1) 131-9 BACKGROUND: In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission. METODS: Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks. RESULTS: The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%-7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%-5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%-6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%-3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P < .001). Cox regression models with nevirapine as a time-varying covariate, stratified by trial site and adjusted for maternal CD4 cell count and infant birth weight, indicated that nevirapine reduces the rate of HIV-1 infection by 71% (95% CI, 58%-80%; P < .001) and reduces the rate of HIV infection or death by 58% (95% CI, 45%-69%; P < .001). CONCLUSIONS: Extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection. Longer duration of prophylaxis results in a greater reduction in the risk of infection. |
Prevention of HIV-1 infection with early antiretroviral therapy
Cohen MS , Chen YQ , McCauley M , Gamble T , Hosseinipour MC , Kumarasamy N , Hakim JG , Kumwenda J , Grinsztejn B , Pilotto JH , Godbole SV , Mehendale S , Chariyalertsak S , Santos BR , Mayer KH , Hoffman IF , Eshleman SH , Piwowar-Manning E , Wang L , Makhema J , Mills LA , de Bruyn G , Sanne I , Eron J , Gallant J , Havlir D , Swindells S , Ribaudo H , Elharrar V , Burns D , Taha TE , Nielsen-Saines K , Celentano D , Essex M , Fleming TR . N Engl J Med 2011 365 (6) 493-505 BACKGROUND: Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. METHODS: In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. RESULTS: As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). CONCLUSIONS: The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.). |
Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial
Taha TE , Li Q , Hoover DR , Mipando L , Nkanaunena K , Thigpen MC , Taylor A , Kumwenda J , Fowler MG , Mofenson LM , Kumwenda NI . J Acquir Immune Defic Syndr 2011 57 (4) (4) 319-325 BACKGROUND: This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. 2011 by Lippincott Williams & Wilkins. |
Association of recent HIV infection and in utero HIV-1 transmission: findings from the PEPI-Malawi trial
Taha TE , James MM , Hoover DR , Sun J , Laeyendecker O , Mullis CE , Kumwenda JJ , Lingappa JR , Auvert B , Morrison CS , Mofensen LM , Taylor A , Fowler MG , Kumenda NI , Eshleman SH . AIDS 2011 25 (11) 1357-64 INTRODUCTION: We previously developed a multi-assay 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. METHODS: Plasma samples were collected at delivery from 2,561 HIV-infected women in the PEPI-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). RESULTS: 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 to 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% CI: 1.30-4.78, P = 0.006), log10 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). CONCLUSIONS: 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. |
Initiation of antiretroviral treatment in women after delivery can induce multiclass drug resistance in breastfeeding HIV-infected infants.
Fogel J , Li Q , Taha TE , Hoover DR , Kumwenda NI , Mofenson LM , Kumwenda JJ , Fowler MG , Thigpen MC , Eshleman SH . Clin Infect Dis 2011 52 (8) 1069-76 BACKGROUND: 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/microliter 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. |
Analysis of nevirapine resistance in HIV-infected infants who received extended nevirapine or nevirapine/zidovudine prophylaxis
Fogel J , Hoover DR , Sun J , Mofenson LM , Fowler MG , Taylor AW , Kumwenda N , Taha TE , Eshleman SH . AIDS 2011 25 (7) 911-917 BACKGROUND: In the Post Exposure Prophylaxis of Infants (PEPI)-Malawi trial, infants received up to 14 weeks of extended nevirapine (NVP) or extended NVP with zidovudine (NVP + ZDV) to prevent postnatal HIV transmission. We examined emergence and persistence of NVP resistance in HIV-infected infants who received these regimens prior to HIV diagnosis. METHODS: Infant plasma samples collected at 14 weeks of age were tested using the ViroSeq HIV Genotyping System and a sensitive point mutation assay, LigAmp (for K103N and Y181C). Samples collected at 6 and 12 months of age were analyzed using LigAmp. RESULTS: At 14 weeks of age, NVP resistance was detected in samples from 82 (75.9%) of 108 HIV-infected infants. Although the frequency of NVP resistance detected by ViroSeq was lower in the extended NVP + ZDV arm than in the extended NVP arm, the difference was not statistically significant (38/55 = 69.1% vs. 44/53 = 83.0%, P = 0.12). Similar results were obtained using LigAmp. Using LigAmp, the proportion of infants who still had detectable NVP resistance at 6 and 12 months was similar among infants in the two study arms (at 6 months: 17/20 = 85.0% for extended NVP vs. 21/26 = 80.8% for extended NVP + ZDV, P = 1.00; at 12 months: 9/16 = 56.3% for extended NVP vs.10/13 = 76.9% for extended NVP + ZDV, P = 0.43). CONCLUSION: Infants exposed to extended NVP or extended NVP + ZDV had high rates of NVP resistance at 14 weeks of age, and resistant variants frequently persisted for 6-12 months. Frequency and persistence of NVP resistance did not differ significantly among infants who received extended NVP only vs. extended NVP + ZDV prophylaxis. |
Addition of extended zidovudine to extended nevirapine prophylaxis reduces nevirapine resistance in infants who were HIV-infected in utero
Lidstrom J , Li Q , Hoover DR , Kafulafula G , Mofenson LM , Fowler MG , Thigpen MC , Kumwenda N , Taha TE , Eshleman SH . AIDS 2009 24 (3) 381-6 BACKGROUND: In the Post-Exposure Prophylaxis of Infants (PEPI)-Malawi trial, most women received single-dose nevirapine (NVP) at delivery, and infants in the extended study arms received single-dose NVP along with 1 week of daily zidovudine (ZDV), followed by either extended daily NVP or extended daily NVP and ZDV up to 14 weeks of age. Although extended NVP prophylaxis reduces the risk of postnatal HIV transmission, it may increase the risk of NVP resistance among infants who are HIV-infected despite prophylaxis. METHODS: We analyzed 88 infants in the PEPI-Malawi trial who were HIV-infected in utero and who received prophylaxis for a median of 6 weeks prior to HIV diagnosis. HIV genotyping was performed using the ViroSeq HIV Genotyping System. RESULTS: At 14 weeks of age, the proportion of infants with NVP resistance was lower in the extended NVP and ZDV arm than in the extended NVP arm (28/45, 62.2% vs. 37/43, 86.0%; P = 0.015). None of the infants had ZDV resistance. Addition of extended ZDV to extended NVP was associated with reduced risk of NVP resistance at 14 weeks if prophylaxis was stopped by 6 weeks (54.5 vs. 85.7%, P = 0.007) but not if prophylaxis was continued beyond 6 weeks (83.3 vs. 87.5%, P = 1.00). CONCLUSION: Addition of extended ZDV to extended NVP prophylaxis significantly reduced the risk of NVP resistance at 14 weeks in infants who were HIV-infected in utero, provided that HIV infection was diagnosed and the prophylaxis was stopped by 6 weeks of age. |
Frequency of gastroenteritis and gastroenteritis-associated mortality with early weaning in HIV-1-uninfected children born to HIV-infected women in Malawi
Kafulafula G , Hoover DR , Taha TE , Thigpen M , Li Q , Fowler MG , Kumwenda NI , Nkanaunena K , Mipando L , Mofenson LM . J Acquir Immune Defic Syndr 2009 53 (1) 6-13 BACKGROUND: We assessed gastroenteritis (GE) burden in 2 randomized trials conducted in Malawi to reduce postnatal HIV transmission before and after World Health Organization recommendations regarding exclusive breastfeeding for HIV-exposed infants were adopted. The 2 trials were the nevirapine/AZT (NVAZ, 2000-2003 with prolonged breastfeeding) and the Postexposure Prophylaxis to the Infant (PEPI, 2004-2007 with breastfeeding cessation by 6 months). METHODS: From NVAZ and PEPI trials data, GE frequency through age 12 months among HIV-negative exposed infants was evaluated. Overall and GE-related cumulative mortality rates were estimated using Kaplan-Meier curves. RESULTS: The frequency of at least one GE-related hospitalization was greater in PEPI vs. NVAZ after age 6 months (respectively, 2.9% vs. 0.1%, at 7-9 months and 1.6% vs. 0.2% at 10-12 months, P < 0.001). Cumulative GE-related mortality was significantly higher in PEPI than in NVAZ after age 6 months; at ages 9 and 12 months GE-related mortality was 19 and 24 per 1000 infants in PEPI vs. 7 and 12 per 1000 infants in NVAZ (P = 0.0002). CONCLUSIONS: Early weaning was associated with increased risk of severe GE and GE-related mortality among HIV-exposed infants. Strategies are urgently needed which allow longer breastfeeding while reducing the risk of HIV breast milk transmission in resource-limited settings. |
Postnatal HIV-1 transmission after cessation of infant extended antiretroviral prophylaxis and effect of maternal highly active antiretroviral therapy
Taha TE , Kumwenda J , Cole SR , Hoover DR , Kafulafula G , Fowler MG , Thigpen MC , Li Q , Kumwenda NI , Mofenson L . J Infect Dis 2009 200 (10) 1490-7 BACKGROUND: The association between postnatal human immunodeficiency virus type 1 (HIV-1) transmission and maternal highly active antiretroviral therapy (HAART) after infant extended antiretroviral prophylaxis was assessed. METHODS: A follow-up study was conducted for the Post-Exposure Prophylaxis of Infants trial in Blantyre, Malawi (PEPI-Malawi). In PEPI-Malawi, breast-feeding infants of HIV-infected women were randomized at birth to receive a either control regimen (single-dose nevirapine plus 1 week of zidovudine); the control regimen plus nevirapine to age 14 weeks; or the control regimen plus nevirapine and zidovudine to age 14 weeks. Infant HIV infection, maternal CD4 cell count, and HAART use were determined. Maternal HAART use was categorized as HAART eligible but untreated (CD4 cell count of <250 cells/muL, no HAART received), HAART eligible and treated (CD4 cell count of <250 cells/muL, HAART received), and HAART ineligible (CD4 cell count of 250 cells/muL). The incidence of HIV infection and the association between postnatal HIV transmission and maternal HAART were calculated among infants who were HIV negative at 14 weeks. RESULTS: Of 2318 infants, 130 (5.6%) acquired HIV infection, and 310 mothers (13.4%) received HAART. The rates of HIV transmission (in cases per 100 person-years) were as follows: for the HAART-eligible/untreated category, 10.56 (95% confidence interval [CI], 7.91-13.82); for the HAART-eligible/treated category, 1.79 (95% CI, 0.58-4.18); and for the HAART-ineligible category, 3.66 (95% CI, 2.86-4.61). The HIV transmission rate ratio for the HAART-eligible/treated category versus the HAART-eligible/untreated category, adjusted for infant prophylaxis, was 0.18 (95% CI, 0.07-0.44). CONCLUSIONS: Postnatal HIV transmission continues after cessation of infant prophylaxis. HAART-eligible women should start treatment early for their own health and to reduce postnatal HIV transmission to their infants. |
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