UNC Project

Lilongwe, Malawi

UNC Project

Lilongwe, Malawi
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PubMed | University of Witwatersrand, Kenya Medical Research Institute, Stanford University, Frontier Science and 18 more.
Type: Journal Article | Journal: Lancet (London, England) | Year: 2016

Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per L. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 25 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080.Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per L (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 35-78) for empirical group and for isoniazid preventive therapy (95% CI 34-78); absolute risk difference of -006% (95% CI -305 to 294). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.

Jamieson D.J.,Centers for Disease Control and Prevention | Chasela C.S.,UNC Project | Hudgens M.G.,University of North Carolina at Chapel Hill | King C.C.,Centers for Disease Control and Prevention | And 19 more authors.
The Lancet | Year: 2012

Background: In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks. Methods: The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per μL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00164736. Findings: 676 mother-infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternalanti-retroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5-9) than in the maternalanti- retroviral (4%, 3-6; p=0·0273) or the infant-nevirapine (4%, 2-5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29-48 weeks than during the intervention phase (1·1 [95% CI 1·0-1·2] vs 0·7 [0·7-0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group). Interpretation: In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity.

Rutstein S.E.,University of North Carolina at Chapel Hill | Kamwendo D.,UNC Project | Lugali L.,Johns Hopkins University | Thengolose I.,UNC Project | And 9 more authors.
Journal of Clinical Virology | Year: 2014

Background: Viral suppression is a key indicator of antiretroviral therapy (ART) response among HIV-infected patients. Dried blood spots (DBS) are an appealing alternative to conventional plasma-based virologic testing, improving access to monitoring in resource-limited settings. However, validity of DBS obtained from fingerstick in field settings remains unknown. Objectives: Investigate feasibility and accuracy of DBS vs plasma collected by healthcare workers in real-world settings of remote hospitals in Malawi. Compare venous DBS to fingerstick DBS for identifying treatment failure. Study design: We recruited patients from ART clinics at two district hospitals in Malawi, collecting plasma, venous DBS (vDBS), and fingerstick DBS (fsDBS) cards for the first 149 patients, and vDBS and fsDBS only for the subsequent 398 patients. Specimens were tested using Abbott RealTime HIV-1 Assay (lower detection limit 40 copies/ml (plasma) and 550 copies/ml (DBS)). Results: 21/149 (14.1%) had detectable viremia (>1.6 log copies/ml), 13 of which were detectable for plasma, vDBS, and fsDBS. Linear regression demonstrated high correlation for plasma vs. DBS (vDBS: β=1.19, R2=0.93 (p<0.0001); fsDBS β=1.20, R2=0.90 (p<0.0001)) and vDBS vs. fsDBS (β=0.88, R2=0.73, (p<0.0001)). Mean difference between plasma and vDBS was 1.1 log copies/ml [SD: 0.27] and plasma and fsDBS 1.1 log copies/ml [SD: 0.31]. At 5000 copies/ml, sensitivity was 100%, and specificity was 98.6% and 97.8% for vDBS and fsDBS, respectively, compared to plasma. Conclusions: DBS from venipuncture and fingerstick perform well at the failure threshold of 5000 copies/ml. Fingerstick specimen source may improve access to virologic treatment monitoring in resource-limited settings given task-shifting in high-volume, low-resource facilities. © 2014 Elsevier B.V.

Gao F.,Duke University | Bonsignori M.,Duke University | Liao H.-X.,Duke University | Kumar A.,Duke University | And 24 more authors.
Cell | Year: 2014

Development of strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs) by vaccines is a priority. Determining the steps of bnAb induction in HIV-1-infected individuals who make bnAbs is a key strategy for immunogen design. Here, we study the B cell response in a bnAb-producing individual and report cooperation between two B cell lineages to drive bnAb development. We isolated a virus-neutralizing antibody lineage that targeted an envelope region (loop D) and selected virus escape mutants that resulted in both enhanced bnAb lineage envelope binding and escape mutant neutralization - traits associated with increased B cell antigen drive. Thus, in this individual, two B cell lineages cooperated to induce the development of bnAbs. Design of vaccine immunogens that simultaneously drive both helper and broadly neutralizing B cell lineages may be important for vaccine-induced recapitulation of events that transpire during the maturation of neutralizing antibodies in HIV-1-infected individuals. © 2014 Elsevier Inc.

Ahmed S.,Baylor College of Medicine | Kim M.H.,Baylor College of Medicine | Dave A.C.,Baylor College of Medicine | Sabelli R.,Baylor College of Medicine | And 9 more authors.
Journal of the International AIDS Society | Year: 2015

Background: Early identification and entry into care is critical to reducing morbidity and mortality in children with HIV. The objective of this report is to describe the impact of the Tingathe programme, which utilizes community health workers (CHWs) to improve identification and enrolment into care of HIV-exposed and infected infants and children. Methods: Three programme phases are described. During the first phase, Mentorship Only (MO) (March 2007-February 2008) on-site clinical mentorship on paediatric HIV care was provided. In the second phase, Tingathe-Basic (March 2008-February 2009), CHWs provided HIV testing and counselling to improve case finding of HIV-exposed and infected children. In the final phase, Tingathe-PMTCT (prevention of mother-to-child transmission) (March 2009-February 2011), CHWs were also assigned to HIV-positive pregnant women to improve mother-infant retention in care. We reviewed routinely collected programme data from HIV testing registers, patient mastercards and clinic attendance registers from March 2005 to March 2011. Results: During MO, 42 children (38 HIV-infected and 4 HIV-exposed) were active in care. During Tingathe-Basic, 238 HIV-infected children (HIC) were newly enrolled, a six-fold increase in rate of enrolment from 3.2 to 19.8 per month. The number of HIV-exposed infants (HEI) increased from 4 to 118. During Tingathe-PMTCT, 526 HIC were newly enrolled over 24 months, at a rate of 21.9 patients per month. There was also a seven-fold increase in the average number of exposed infants enrolled per month (9.5-70 patients per month), resulting in 1667 enrolled with a younger median age at enrolment (5.2 vs. 2.5 months; p <0.001). During the Tingathe-Basic and Tingathe-PMTCT periods, CHWs conducted 44, 388 rapid HIV tests, 7658 (17.3%) in children aged 18 months to 15 years; 351 (4.6%) tested HIV-positive. Over this time, 1781 HEI were enrolled, with 102 (5.7%) found HIV-infected by positive PCR. Additional HIC entered care through various mechanisms (including positive linkage by CHWs and transfer-ins) such that by February 2011, a total of 866 HIC were receiving care, a 23-fold increase from 2008. Conclusions: A multipronged approach utilizing CHWs to conduct HIV testing, link HIC into care and provide support to PMTCT mothers can dramatically improve the identification and enrolment into care of HIV-exposed and infected children. Copyright: - 2015 Ahmed S et al.

Kim M.H.,Baylor College of Medicine | Ahmed S.,Baylor College of Medicine | Buck W.C.,Baylor College of Medicine | Preidis G.A.,Baylor College of Medicine | And 10 more authors.
Journal of the International AIDS Society | Year: 2012

Introduction: Loss to follow-up is a major challenge in the prevention of mother to child transmission of HIV (PMTCT) programme in Malawi with reported loss to follow-up of greater than 70%. Tingathe-PMTCT is a pilot intervention that utilizes dedicated community health workers (CHWs) to create a complete continuum of care within the PMTCT cascade, improving service utilization and retention of mothers and infants.We describe the impact of the intervention on longitudinal care starting with diagnosis of the mother at antenatal care (ANC) through final diagnosis of the infant. Methods: PMTCT service utilization, programme retention and outcomes were evaluated for pregnant women living with HIV and their exposed infants enrolled in the Tingathe-PMTCT programme between March 2009 and March 2011. Multivariate logistic regression was done to evaluate maternal factors associated with failure to complete the cascade. Results: Over 24 months, 1688 pregnant women living with HIV were enrolled. Median maternal age was 27 years (IQR, 23.8 to 30.8); 333 (19.7%) were already on ART. Among the remaining women, 1328/1355 (98%) received a CD4 test, with 1243/1328 (93.6%) receiving results. Of the 499 eligible for ART, 363 (72.8%) were successfully initiated. Prior to, delivery there were 93 (5.7%) maternal/foetal deaths, 137 (8.1%) women transferred/moved, 51 (3.0%) were lost and 58 (3.4%) refused ongoing PMTCT services. Of the 1318 live births to date, 1264 (95.9%) of the mothers and 1285 (97.5%) of the infants received ARV prophylaxis; 1064 (80.7%) infants were tested for HIV by PCR and started on cotrimoxazole. Median age at PCR was 1.7 months (IQR, 1.5 to 2.5). Overall transmission at first PCR was 43/1047 (4.1%). Of the 43 infants with positive PCR results, 36 (83.7%) were enrolled in ART clinic and 33 (76.7%) were initiated on ART. Conclusions: Case management and support by dedicated CHWs can create a continuum of longitudinal care in the PMTCT cascade and result in improved outcomes. Copyright: © 2012 Kim MH et al; licensee International AIDS Society.

Rutstein S.E.,University of North Carolina at Chapel Hill | Brown L.B.,University of North Carolina at Chapel Hill | Biddle A.K.,University of North Carolina at Chapel Hill | Wheeler S.B.,University of North Carolina at Chapel Hill | And 7 more authors.
Health Policy and Planning | Year: 2014

Provider-initiated partner notification for HIV effectively identifies new cases of HIV in sub-Saharan Africa, but is not widely implemented. Our objective was to determine whether provider-based HIV partner notification strategies are cost-effective for preventing HIV transmission compared with passive referral. We conducted a cost-effectiveness analysis using a decision-analytic model from the health system perspective during a 1-year period. Costs and outcomes of all strategies were estimated with a decision-tree model. The study setting was an urban sexually transmitted infection clinic in Lilongwe, Malawi, using a hypothetical cohort of 5000 sex partners of 3500 HIV-positive index cases. We evaluated three partner notification strategies: provider notification (provider attempts to notify indexes' locatable partners), contract notification (index given 1 week to notify partners then provider attempts notification) and passive referral (index is encouraged to notify partners, standard of care). Our main outcomes included cost (US dollars) per transmission averted, cost per new case identified and cost per partner tested. Based on estimated transmissions in a 5000-person cohort, provider and contract notification averted 27.9 and 27.5 new infections, respectively, compared with passive referral. The incremental cost-effectiveness ratio (ICER) was $3560 per HIV transmission averted for contract notification compared with passive referral. Provider notification was more expensive and slightly more effective than contract notification, yielding an ICER of $51 421 per transmission averted. ICERs were sensitive to the proportion of partners not contacted, but likely HIV positive and the probability of transmission if not on antiretroviral therapy. The costs per new case identified were $36 (provider), $18 (contract) and $8 (passive). The costs per partner tested were $19 (provider), $9 (contract) and $4 (passive). We conclude that, in this population, provider-based notification strategies are potentially cost-effective for identifying new cases of HIV. These strategies offer a simple, effective and easily implementable opportunity to control HIV transmission. © 2013 The Author .

McCollum E.D.,UNC Project | Johnson D.C.,UNC Project | Chasela C.S.,UNC Project | Siwande L.D.,Baylor College of Medicine | And 5 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2012

Objective: Although the Malawian government recommends HIV-exposed infants receive early infant diagnosis (EID) of HIV at "under-five" pediatric clinics (U5Cs), most never enroll. Therefore, we evaluated the integration of EID testing into an immunization clinic (IC) compared with the current standard of EID testing at an U5C. Design: Prospective observational study. Methods: Using routine provider-initiated HIV testing and counseling (PITC) registers, we prospectively studied 1757 children offered PITC at a government IC and U5C. Infants tested by HIV DNA polymerase chain reaction (PCR) were followed until PCR result disclosure or defaulting. Results: We sampled 877 and 880 consecutive PITC recipients at U5C and IC, respectively. Overall, a 7-fold greater proportion received PITC at IC (84.2% vs. 11.4%, P < 0.001). PITC recipients at IC were more than 14 months younger (2.6 vs. 17.0, P < 0.001), with greater proportions HIV exposed (17.6% vs. 5.3%, P < 0.001) and PCR eligible (7.9% vs. 3.5%, P < 0.001). A higher percentage of IC infants accepted PCR testing (100.0% vs. 90.3%, P = 0.03). Additionally, IC PCR recipients were 2.5 months younger (3.1 vs. 5.6, P < 0.001) with 4 times less testing PCR positive (7.1% vs. 32.1%, P < 0.001). Importantly, a more than 3-fold greater proportion of HIV-exposed infants at IC returned for their PCR result and enrolled into care (78.6% vs. 25.0%, P < 0.001). Conclusions: Compared with an U5C, integrating EID testing into an IC is more acceptable, more feasible, enrolls more infants into EID at younger ages, and would likely strengthen Malawi's EID services if expanded. © 2012 by Lippincott Williams & Wilkins.

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