Genetic and non-genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus-1-infected children in Ethiopia.

Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter- and intra-individual pharmacokinetic (PK) variability are not well-characterized in children. We investigated the effects of genetic and non-genetic factors, including demographic, treatment duration, baseline clinical, and biochemical characteristics, on the PKs of EFV through population-PK modeling. Antiretroviral therapy (ART) naïve HIV infected children, 3-16 years (n = 100), were enrolled in Ethiopia and received EFV-based combination ART. EFV concentrations after the first dose and at steady-state collected over a span of 1 year were modeled using population-based methods. A one-compartment model with first-order absorption kinetics described the observed EFV data adequately. The CYP2B6*6 and ABCB1c.4036A>G genotypes were identified as major factors influencing EFV clearance. The typical estimates of oral clearance, volume of distribution, and absorption rate constant for typical 22 kg children with CYP2B6 *1/*1 and ABCB1c.4036G/G genotypes were 4.3 L/h, 124 L, and 0.776/h, respectively. Clearance was reduced by 28% and 72% in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively. Compared to week 1, clearance was higher from weeks 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes, respectively. Simulations indicated that EFV 12-h concentrations were comparable across weight bands, but more than 80% of subjects with CYP2B6*6/*6 had EFV concentrations greater than 4 µg/mL. EFV PK variability among children is partly explained by body weight, treatment duration, CYP2B6*6, and ABCB1 rs3842 genotypes. Therefore, in addition to body weight, pediatric dosing of EFV should consider pharmacogenetic variability, duration of therapy, and individual treatment outcomes.

Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study.

(1) Background: Efavirenz plasma concentration displays wide between-patient variability partly due to pharmacogenetic variation and autoinduction. Pediatric data on efavirenz pharmacokinetics and the relevance of pharmacogenetic variation are scarce, particularly from sub-Saharan Africa, where >90% of HIV-infected children live and population genetic diversity is extensive. We prospectively investigated the short- and long-term effects of efavirenz auto-induction on plasma drug exposure and the influence of pharmacogenetics among HIV-infected Ethiopian children. (2) Method: Treatment-naïve HIV-infected children aged 3-16 years old (n = 111) were enrolled prospectively to initiate efavirenz-based combination antiretroviral therapy (cART). Plasma efavirenz concentrations were quantified at 4, 8, 12, 24, and 48 weeks of cART. Genotyping for CYP2B6, CYP3A5, UGT2B7, ABCB1, and SLCO1B1 common functional variant alleles was performed. (3) Results: The efavirenz plasma concentration reached a peak at two months, declined by the 3rd month, and stabilized thereafter, with no significant difference in geometric mean over time. On average, one-fourth of the children had plasma efavirenz concentrations ≥4 µg/mL. On multivariate analysis, CYP2B6*6 and ABCB1c.3435 C > T genotypes and low pre-treatment low-density lipoprotein (LDL) were significantly associated with higher plasma efavirenz concentration regardless of treatment duration. Duration of cART, sex, age, nutritional status, weight, and SLCO1B, CYP3A5, UGT2B7, and ABCB1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and CYP2B6*6 and ABCB1c.3435 C > T genotypes predict efavirenz plasma exposure among HIV-infected children, but treatment-duration-dependent changes in plasma efavirenz exposure due to auto-induction are not statistically significant.

Group B Streptococcus colonization rate and serotype distribution among pregnant women and their newborns at Adama Hospital Medical College, Ethiopia.

Rectovaginal area of pregnant women can be colonized transiently with group B Streptococcus (GBS) without causing disease. The bacteria can be transmitted to the newborn before and during birth and cause early-onset neonatal disease. In this study, we aimed to determine the GBS colonization rate among pregnant women before delivery and their newborns and serotypes distribution of GBS. Two hundred-eighty pregnant women along with their newborns were screened for GBS colonization from June 2014 to October 2014 at Adama Hospital Medical College. Rectovaginal swabs from pregnant women before delivery and specimen from nasal area, external ear, umbilical cord and throat of newborns were collected and cultured. The serotyping of GBS was performed by using serotype-specific antisera. To collect sociodemographic and clinical data we employed a structured questionnaire. GBS colonization among pregnant women and their newborns were 13.2% 95% CI (8.9-17.5) and 7.4% 95% CI (4.6-10.6). Out of 37 GBS strains recovered from pregnant women, the prevalent serotypes were Ia 6(16.2%), Ib 8(21.6%), II 10(27%), III 3(8.1%), and V 8(21.6%). Out of 21 GBS strains recovered from newborns, prevalent serotypes were Ia 3(14.3%), Ib 6(28.6%), II 6(28.6%), III 4(19%), and V 1(4.8%). This study indicated the existence of primary risk factors for neonatal disease in Adama area. Serotype II was the common serotype detected in this study which is followed by serotype Ib, Ia, and V. As colonizing GBS serotypes could cause invasive disease among newborns, vaccine formulation which includes serotype II, Ia, V, Ib, and III can prevent of invasive disease caused by GBS in the study area.

Prevalence and Correlates of Pre-Treatment HIV Drug Resistance among HIV-Infected Children in Ethiopia.

Pediatric human immunodeficiency virus (HIV) care in resource-limited settings remains a major challenge to achieving global HIV treatment and virologic suppression targets, in part because the administration of combination antiretroviral therapies (cART) is inherently complex in this population and because viral load and drug resistance genotyping are not routinely available in these settings. Children may also be at elevated risk of transmission of drug-resistant HIV as a result of suboptimal antiretroviral administration for prevention of mother-to-child transmission. We investigated the prevalence and the correlates of pretreatment HIV drug resistance (PDR) among HIV-infected, cART-naive children in Ethiopia. We observed an overall PDR rate of 14%, where all cases featured resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs): ~9% of participants harbored resistance solely to NNRTIs while ~5% harbored resistance to both NNRTIs and nucleoside reverse transcriptase inhibitors (NRTIs). No resistance to protease inhibitors was observed. No sociodemographic or clinical parameters were significantly associated with PDR, though limited statistical power is noted. The relatively high (14%) rate of NNRTI resistance in cART-naive children supports the use of non-NNRTI-based regimens in first-line pediatric treatment in Ethiopia and underscores the urgent need for access to additional antiretroviral classes in resource-limited settings.

Option B+ prevention of mother-to-child transmission of HIV/AIDS service intervention outcomes in selected health facilities, Adama town, Ethiopia.

Background: Vertical HIV transmission from mother-to-child accounts for more than 90% of pediatric HIV/AIDS infection. Virtual elimination of mother-to-child transmission (MTCT) of HIV is possible by giving comprehensive prevention of HIV/AIDS mother-to-child transmission (PMTCT) care. The objective of this study was to assess Option B+ (initiation of antiretroviral therapy for all pregnant mothers) PMTCT service intervention and outcomes in selected health facilities of Adama town, Ethiopia. Methods: A retrospective study was employed. A total of 248 medical records of mother-infant cohorts were included. Data wer collected from logbooks and/or records and individual medical records using a data abstraction tool. Results: Mean±SD age of mothers was 26.8±4.3 years. Half (50.8%) of the mothers were enrolled in PMTCT at 13-24 weeks of gestational age. The majority (79.6%) of mothers' CD4 counts were ≥351/mm3. Most of the mothers (71%) were on a tenofovir-lamivudine-evafrenz regimen. One-quarter of mothers were prescribed co-trimoxazole prophylactic therapy. Loss to follow-up from the Option B+ continuum was 10 (4.2%). Almost all (98.4%) of the infants were prescribed nevirapine prophylaxis. Nearly 90% (n=223) of the HIV-exposed infants were discharged as HIV negative. Conclusions: The Option B+ PMTCT service can minimize the chances of MTCT of HIV infection if used optimally. The magnitudes of loss to follow-up and death were lower than in comparable studies. Initiating all pregnant mothers on antiretroviral therapy irrespective of their clinical stage and CD4 count may have contributed to the optimal retention in care and near elimination of MTCT of HIV infection.

Prevalence of group B streptococcus among pregnant women and newborns at Hawassa University comprehensive specialized hospital, Hawassa, Ethiopia.

BACKGROUND: Group B streptococcus (GBS) is reported as the leading cause of neonatal sepsis and meningitis. Newborns from GBS colonized pregnant women are at high risk of infection. METHOD: A Hospital based cross-sectional study was conducted at Hawassa University Comprehensive Specialized Hospital from November 05, 2014 to March 25, 2015. A total of 280 pregnant women along with their newborns were screened for GBS using standard method recommended by Center of Disease Control and Prevention. GBS strains were serotyped by using serotype specific antisera. A structured questionnaire was used to collect sociodemographic, obstetrics and clinical data of pregnant women and newborns. Data was analyzed by using chi-square and logistic regression to determine factors associated with prevalence of GBS among pregnant women and newborns. Descriptive statistics was used to determine prevalence of GBS among pregnant women and newborns. P value less than 0.05 was considered statistically significant. RESULT: Prevalence of GBS among pregnant women, newborns and vertical transmission rate at Hawassa University Comprehensive Specialized Hospital were 44(15.7%), 26(8.9%) and 59.1% respectively. Among 26 GBS colonized newborns one developed sign and symptoms of early onset disease. Serotype distribution of GBS isolates collected from pregnant women and newborns was Ia 13(18.6%), Ib 9(12.9%), II 24(34.3%), III 8(11.4%), V 14(20%), and NT 2 (2.9%). CONCLUSION: In our study we found relatively high prevalence of GBS among pregnant women and vertical transmission rate. The most prevalent GBS serotypes identified in this study were serotype II followed by V, Ia and Ib. Therefore, appropriate prevention strategies such as intrapartum antibiotic prophylaxis and vaccine development should be considered.

HIV and cART-Associated Dyslipidemia Among HIV-Infected Children.

BACKGROUND: Persistent dyslipidemia in children is associated with risks of cardiovascular accidents and poor combination antiretroviral therapy (cART) outcome. We report on the first evaluation of prevalence and associations with dyslipidemia due to HIV and cART among HIV-infected Ethiopian children. METHODS: 105 cART naïve and 215 treatment experienced HIV-infected children were enrolled from nine HIV centers. Demographic and clinical data, lipid profile, cART type, adherence to and duration on cART were recorded. Total, low density (LDLc) and high density (HDLc) cholesterol values >200 mg/dL, >130 mg/dL, <40 mg/dL, respectively; and/or, triglyceride values >150 mg/dL defined cases of dyslipidemia. Prevalence and predictors of dyslipidemia were compared between the two groups. RESULTS: prevalence of dyslipidemia was significantly higher among cART experienced (70.2%) than treatment naïve (58.1%) children (p = 0.03). Prevalence of low HDLc (40.2% versus 23.4%, p = 0.006) and hypertriglyceridemia (47.2% versus 35.8%, p = 0.02) was higher among cART experienced than naïve children. There was no difference in total hypercholesterolemia and high LDLc levels. Nutrition state was associated with dyslipidemia among cART naïve children (p = 0.01). CONCLUSION: high prevalence of cART-associated dyslipidemia, particularly low HDLc and hypertriglyceridemia was observed among treatment experienced HIV-infected children. The findings underscore the need for regular follow up of children on cART for lipid abnormalities.