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Prevention of mother-to-child transmission (PMTCT) guidelines recommend that all HIV-infected pregnant women receive antiretroviral therapy (Option B) and HIV-infected infants should initiate therapy with a protease inhibitor-based regimen; however, implementation of these guidelines has lagged in many resource-limited settings. Tanzania only recently implemented these guidelines with little country-specific data to inform whether HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was present among infected infants under the Option A guidelines. This study aimed to identify primary resistance mutations in HIV-infected infants and to identify risk of nevirapine (NVP) resistance based on maternal and infant NVP exposure. Infant dried blood spots (DBSs) were sent to the zonal reference laboratory at Kilimanjaro Christian Medical Centre Clinical Laboratory and underwent DNA polymerase chain reaction testing for HIV as standard of care. Using the clinical laboratory registry, HIV-positive DBS cards, stored at ambient temperature, were identified and sent for further viral load testing, nucleotide sequencing, and analysis. Clinical information was obtained from the PMTCT clinical sites and the National PMTCT registry for information regarding maternal and infant demographics and PMTCT treatment regimen. Results demonstrated that infants exposed to NVP were more likely to have high level resistance mutations (HLRMs) to NVP than those infants not exposed to NVP (p = .002). The most common HLRMs to NVP were K103 N, Y181C, and Y188 L. HIV subtype A was most common, followed by subtype C. Approximately one-third of HIV-infected infants had documented referral to HIV care. This study demonstrated the ongoing need to scale up and strengthen points along the PMTCT continuum and supported the recommendation for all HIV-infected infants to initiate a lopinavir/ritonavir-based antiretroviral therapy regimen.

Background: In a randomized trial comparing nevirapine (NVP)-based versus lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) in HIV-infected children [primary endpoint discontinuation of study treatment for any reason or virologic failure by week 24] aged 2 months to 3 years, we assessed whether clinical, virologic, immunologic and safety outcomes varied by prior single-dose NVP exposure (PrNVP) for prevention of mother-to-child HIV transmission and other covariates., Methods: Efficacy was assessed by time to ART discontinuation or virologic failure, virologic failure/death and death; safety by time to ART discontinuation because of a protocol-defined toxicity and first ≥ grade 3 adverse event; immunology and growth by changes in CD4%, weight/height World Health Organization z-scores from entry to week 48. Cox proportional hazards and linear regression models were used to test whether treatment differences depended on PrNVP exposure and other covariates., Results: Over a median follow up of 48 (PrNVP) and 72 (no PrNVP) weeks, there was no evidence of differential treatment effects by PrNVP exposure or any other covariates. LPV/r-based ART was superior to NVP-based ART for efficacy and safety outcomes; however, those on NVP had larger improvements in CD4%, weight and height z-scores. Lower pretreatment CD4% and higher HIV-1 RNA levels were associated with reduced efficacy, lower pretreatment CD4% with shorter time to ART discontinuation because of a protocol-defined toxicity, and no PrNVP with shorter time to first grade ≥ 3 adverse event., Conclusions: Differences between LPV/r and NVP ART in efficacy, safety, immunologic and growth outcomes did not depend on PrNVP exposure, prior breast-feeding, sex, HIV-1 subtype, age, pretreatment CD4%, HIV-1 RNA or World Health Organization disease stage. This finding should be considered when selecting an ART regimen for young children.

Background: Mother to child transmission (MTCT) of HIV-1 remains an important problem in sub-Saharan Africa where most new pediatric HIV-1 infections occur. Early infant diagnosis of HIV-1 using dried blood spot (DBS) PCR among exposed infants provides an opportunity to assess current MTCT rates., Methods: We conducted a retrospective data analysis on mother-infant pairs from all PMTCT programs in three regions of northern Tanzania to determine MTCT rates from 2008-2010. Records of 3,016 mother-infant pairs were assessed to determine early transmission among HIV-exposed infants in the first 75 days of life., Results: Of 2,266 evaluable infants in our cohort, 143 had a positive DBS PCR result at ≤ 75 days of life, for an overall transmission rate of 6.3%. Transmission decreased substantially over the period of study as more effective regimens became available. Transmission rates were tightly correlated to maternal regimen: 14.9% (9.5, 20.3) of infants became infected when women received no therapy; 8.8% (6.9, 10.7) and 3.6% (2.4, 4.8) became infected when women received single-dose nevirapine (sdNVP) or combination prophylaxis, respectively; the lowest MTCT rates occurred when women were on HAART, with 2.1% transmission (0.3, 3.9). Treatment regimens changed dramatically over the study period, with an increase in combination prophylaxis and a decrease in the use of sdNVP. Uptake of DBS PCR more than tripled over the period of study for the three regions surveyed., Conclusions: Our study demonstrates significant reductions in MTCT of HIV-1 in three regions of Tanzania coincident with increased use of more effective PMTCT interventions. The changes we demonstrate for the period of 2008-2010 occurred prior to major changes in WHO PMTCT guidelines.

Objectives: To estimate the prevalence of nasopharyngeal bacterial colonisation (NPBC) patterns in young Tanzanian HIV-exposed infants and to analyse the influence of maternal NPBC and of the infant's HIV status on the NPBC pattern., Methods: Longitudinal cohort study of neonates born to HIV-infected mothers visiting Kilimanjaro Christian Medical Centre, Tanzania, between 2005 and 2009. Demographic and clinical data and nasopharyngeal bacterial cultures were obtained at the age of 6 weeks, 3 and 6 months, and at one time point, a paired mother-infant nasopharyngeal swab was taken., Results: Four hundred and twenty-two swabs were taken from 338 eligible infants. At 6 weeks of age, colonisation rates were 66% for Staphylococcus aureus, 56% for Streptococcus pneumoniae, 50% for Moraxella catarrhalis and 14% for Haemophilus influenzae. Colonisation with S. aureus diminished over time and was more common in HIV-infected infants. S. pneumoniae and H. influenzae colonisation rose over time and was more prevalent in HIV-uninfected children. Co-colonisation of S. pneumoniae with H. influenzae or M. catarrhalis was mostly noticed in HIV-infected infants. S. pneumoniae and M.catarrhalis colonisation of the mother was a risk factor for colonisation in HIV-uninfected infants, while maternal S. aureus colonisation was a risk factor for colonisation in HIV-infected infants. Among the 104 S. pneumoniae isolates, 19F was most prevalent, and 57 (55%) displayed capsular serotypes represented in the 13-valent pneumococcal conjugate vaccine., Conclusions: NPBC was common in Tanzanian HIV-exposed infants. The significant prevalence of pneumococcal vaccine serotypes colonising this paediatric population justifies the use of the 13-valent pneumococcal vaccine to reduce the burden of pneumococcal invasive disease., (© 2013 Blackwell Publishing Ltd.)

Background: Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established., Methods: In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24., Results: A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06)., Conclusions: Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

Background: Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown., Methods: We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board., Results: A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events., Conclusions: Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.).

Background: Many HIV care and treatment programs in resource-limited settings rely on clinical and immunologic monitoring of antiretroviral therapy (ART), but accuracy of this strategy to detect virologic failure (VF) among children has not been evaluated., Methods: A cross-sectional sample of HIV-infected children aged 1-16 years on ART >or=6 months receiving care at a Tanzanian referral center underwent clinical staging, CD4 lymphocyte measurement, plasma HIV-1 RNA level, and complete blood count. Associations with VF (HIV-1 RNA >or=400 copies/mL) were determined utilizing bivariable and multivariate analyses; accuracy of current clinical and immunologic guidelines in identifying children with VF was assessed., Findings: Of 206 children (median age 8.7 years, ART duration 2.4 years), 65 (31.6%) demonstrated VF at enrollment. Clinical and immunological criteria identified 2 (3.5%) of 57 children with VF on first-line therapy, exhibiting 3.5% sensitivity and 100% specificity. VF was associated with younger age, receipt of nevirapine vs. efavirenz-based regimen, CD4% < 25%, and physician documentation of maladherence (P < 0.05 on bivariable analysis); the latter 2 factors remained significant on multivariate logistic regression., Interpretation: This study demonstrates poor performance of clinical and immunologic criteria in identifying children with virologic failure. Affordable techniques for measuring HIV-1 RNA level applicable in resource-limited settings are urgently needed.

Objectives: We evaluated changes in characteristics of clients presenting for voluntary counseling and testing (VCT) before and during care and treatment center (CTC) scale-up activities in Moshi, Tanzania, between November 2003 and December 2007., Methods: Consecutive clients were surveyed after pretest counseling, and rapid HIV antibody testing was performed. Trend tests were used to assess changes in seroprevalence and client characteristics over time. Multivariable logistic regression models were used to estimate the contribution of changes in sociodemographic and behavioral risk characteristics, and symptoms, to changes in seroprevalence before and during CTC scale-up., Results: Data from 4391 first-time VCT clients were analyzed. HIV seroprevalence decreased from 26.2% to 18.9% after the availability of free antiretroviral therapy and expansion of CTCs beyond regional and referral hospitals. Seroprevalence decreased by 27 % for females (P = 0.0002) and 34% for males (P = 0.0125). Declines in seropositivity coincided with decreases in symptoms among males and females (P < 0.0001) and a more favorable distribution of sociodemographic risks among females (P = 0.002). No changes in behavioral risk characteristics were observed., Conclusions: Concurrent with the scale-up of CTCs, HIV seroprevalence and rates of symptoms declined sharply at an established freestanding VCT site in Moshi, Tanzania. If more HIV-infected persons access VCT at sites where antiretrovirals are offered, freestanding VCT sites may become a less cost-effective means for HIV case finding.

Objective: To assess technical and operational performance of a dried blood spot (DBS)-based HIV-1 RNA service for remote healthcare facilities in a low-income country., Design: A method comparison and operational evaluation of DBS RNA against conventional tests for early infant diagnosis of HIV and HIV RNA quantitation under field conditions in Tanzania., Methods: DBSs were prepared and plasma was frozen at -80 degrees C. DBSs were mailed and plasma couriered to a central laboratory for testing using the Abbott m2000 system. Infant diagnosis DBSs were also tested for HIV-1 DNA by ROCHE COBAS AmpliPrep/COBAS TaqMan System. Results of DBS RNA were compared with conventional tests; program performance was described., Results: Among 176 infant diagnosis participants, using a threshold of at least 1000 copies/ml, sensitivity and specificity of DBS versus plasma RNA were 1.00 and 0.99, and of DBS RNA versus DBS DNA were 0.97 and 1.00. Among 137 viral load monitoring participants, when plasma and DBS RNA were compared, r value was 0.9709; r value was 0.9675 for at least 5000 copies/ml but was 0.7301 for less than 5000 copies/ml. The highest plasma RNA value at which DBS RNA was not detected was 2084 copies/ml. Median (range) turnaround time from sample collection to result receipt at sites was 23 (4-69) days. The Tanzania mail service successfully transmitted all DBS and results between sites and the central laboratory., Conclusion: Under program conditions in Tanzania, DBS provided HIV-1 RNA results comparable to conventional methods to remote healthcare facilities. DBS RNA testing is an alternative to liquid plasma for HIV-1 RNA services in remote areas.

Background: The World Health Organization (WHO) has recommended the use of clinical staging alone and with total lymphocyte count to identify HIV infected children in need of antiretroviral therapy (ART) in resource-limited settings, when CD4 cell count is not available., Methods: We prospectively enrolled children obtaining care for HIV infection at the Kilimanjaro Christian Medical Centre Pediatric Infectious Diseases Clinic in Moshi, Tanzania between March 2004 and May 2006 for this cohort study., Results: One hundred ninety two (89.7%) of 214 children met WHO ART initiation criteria based on clinical staging or CD4 cell count. Several low-cost measures identified individuals who met WHO ART initiation criteria to the following degree: WHO stages 3 or 4 had 87.5% (95% CI, 82.8-92.1) sensitivity and, by definition, 100% (CI, 100-100) specificity; WHO recommended advance disease TLC cutoffs: sensitivity = 23.9% (95% CI, 17.3-30.5) specificity = 78.2% (95% CI, 67.3-89.1). Low TLC was a common finding, (50 of 214; 23%); however, it did not improve the sensitivity or specificity of clinical staging in identifying the severely immunosuppressed stage 2 children. Growth failure or use of total lymphocyte counts in isolation were not reliable indicators of severe immunosuppression or need to initiate ART., Conclusion: The use of total lymphocyte count does not improve the ability to identify children in need of ART compared with clinical staging alone. Low absolute lymphocyte count did not correlate with severe immunosuppression based on CD4 cell count in this cohort.

Background: We developed a simple and inexpensive thin-layer chromatography (TLC) assay for semiquantitative detection of saliva concentrations of nevirapine in resource-limited settings. The method was validated in an African target population., Methods: Paired plasma and saliva nevirapine concentrations were assayed by high-performance liquid chromatography (HPLC); saliva concentrations of nevirapine were also assayed by TLC. The rate of false-positive results was the proportion of subtherapeutic nevirapine saliva and plasma concentrations determined by HPLC that were judged to be therapeutic in saliva specimens by TLC. The rate of false-negative results was the proportion of therapeutic nevirapine saliva and plasma concentrations determined by HPLC that were judged to be subtherapeutic in saliva specimens by TLC. The extent of agreement in TLC readings between 5 technicians and 2 batches of TLC sheets was evaluated., Results: Twenty-five (9%) of 286 African adults had a subtherapeutic plasma nevirapine concentration. The median ratio of nevirapine concentrations in saliva to those in plasma was 0.51:1. The rate of false-positive results for TLC was 0% (0 of 23 specimens) when TLC results were compared with HPLC results for saliva specimens and 8% (2 of 25 specimens) when TLC results were compared with HPLC results for plasma specimens. The rate of false-negative results for TLC was 1% (3 of 263 specimens) when TLC results were compared with HPLC results for saliva specimens and 1% (3 of 261 specimens) when TLC results were compared with HPLC results for plasma specimens. The extent of agreement of TLC results was substantial for the 5 technicians (Fleiss's kappa = 0.77) and for the 2 batches of sheets (Cohen's kappa = 0.80)., Conclusions: The TLC assay was found to be sensitive, specific, and robust in the detection of subtherapeutic nevirapine concentrations in saliva specimens obtained from African HIV-infected adults. It is an attractive alternative to HPLC for therapeutic drug monitoring of nevirapine in resource-limited settings.

Few data exist on the current capacity of Tanzanian health-care facilities to deliver antiretroviral therapy (ART). We evaluated this capacity among Northern Zone facilities in 2004 using a questionnaire that addressed human resources, clinical facilities and services, and laboratory capacity. Of 19 facilities surveyed, nine (47%) had staff trained to manage ART and three (16%) prescribed ART. Two (11%) offered CD4 counts, five (26%) offered liver function tests, 16 (84%) offered chest radiography, and 18 (95%) offered acid-fast sputum staining. Of 12 (67%) facilities offering outpatient HIV/AIDS services, 12 (100%) provided co-trimoxazole to outpatients and six (50%) provided isoniazid (INH). All 19 (100%) facilities offered rapid HIV tests and full blood pictures. Overall in 2004, facilities needed strengthening to increase staff training in ART management and to implement INH for treatment of latent tuberculosis. Laboratory facilities for ART monitoring were inadequate, and outpatient ART was limited.

Hospitalized patients with HIV infection are among the most likely to benefit from the expanding availability of anti-retroviral therapy in sub-Saharan Africa. Between 1990 and 2000, 3667 people known to be HIV-infected were admitted to Kilimanjaro Christian Medical Centre (KCMC) in Moshi, northen Tanzania. The level of inpatient mortality among these patients varied from 15%-21%, and the proportion of the HIV-infected patients admitted who were female increased significantly, from 45% at the start of the study period to 52% at the end (P <0.001). When the medical records for 1683 of the HIV-infected patients who had been admitted between 1996 and 2001 were reviewed, the most prevalent diagnoses on admission were found to be pulmonary tuberculosis (21%), malaria (14%) and gastro-enteritis/diarrhoea (12%) among the adults, and non-tubercular pulmonary infection (21%), pulmonary tuberculosis (19%) and gastro-enteritis/diarrhoea (12%) among the children. The crude odds ratios (OR) for inpatient death were greatest for adults presenting with meningitis [OR=3.7; 95% confidence interval (CI)=2.1-6.7], septicaemia (OR=2.9; CI=1.2-7.3) or renal disease (OR=2.6; CI=1.2-5.7), and mortality was higher for men than for women (OR=1.4; CI=1.1-1.8). A single-day, point-prevalence survey in September 2001, among the KCMC's inpatients, identified HIV infection in 21% of those surveyed, many (44%) of the patients found positive being previously unaware of their infection. HIV infection remains a major cause of hospitalization and mortality in Moshi. A policy of routine testing would increase the number of HIV infections detected, allowing improvements in case management and in the prevention of infection.