Pharmacokinetics of mefloquine and its effect on sulfamethoxazole and trimethoprim steady-state blood levels in intermittent preventive treatment (IPTp) of pregnant HIV-infected women in Kenya..

Abstract Background Intermittent preventive treatment in pregnancy with sulfadoxine/pyrimethamine is contra-indicated in HIV-positive pregnant women receiving sulfamethoxazole/trimethoprim prophylaxis. Since mefloquine is being considered as a replacement for sulfadoxine/pyrimethamine in this vulnerable population, an investigation on the pharmacokinetic interactions of mefloquine, sulfamethoxazole and trimethoprim in pregnant, HIV-infected women was performed. Methods A double-blinded, placebo-controlled study was conducted with 124 HIV-infected, pregnant women on a standard regimen of sulfamethoxazole/trimethoprim prophylaxis. Seventy-two subjects received three doses of mefloquine (15 mg/kg) at monthly intervals. Dried blood spots were collected from both placebo and mefloquine arms four to 672 h post-administration and on day 7 following a second monthly dose of mefloquine. A novel high-performance liquid chromatographic method was developed to simultaneously measure mefloquine, sulfamethoxazole and trimethoprim from each blood spot. Non-compartmental methods using a naïve-pooled data approach were used to determine mefloquine pharmacokinetic parameters. Results Sulfamethoxazole/trimethoprim prophylaxis did not noticeably influence mefloquine pharmacokinetics relative to reported values. The mefloquine half-life, observed clearance (CL/f), and area-under-the-curve (AUC0→∞) were 12.0 days, 0.035 l/h/kg and 431 µg-h/ml, respectively. Although trimethoprim steady-state levels were not significantly different between arms, sulfamethoxazole levels showed a significant 53 % decrease after mefloquine administration relative to the placebo group and returning to pre-dose levels at 28 days. Conclusions Although a transient decrease in sulfamethoxazole levels was observed, there was no change in hospital admissions due to secondary bacterial infections, implying that mefloquine may have provided antimicrobial protection

An Analysis of Pregnancy-Related Mortality in the KEMRI/CDC Health and Demographic Surveillance System in Western Kenya

Background Pregnancy-related (PR) deaths are often a result of direct obstetric complications occurring at childbirth. Methods and Findings To estimate the burden of and characterize risk factors for PR mortality, we evaluated deaths that occurred between 2003 and 2008 among women of childbearing age (15 to 49 years) using Health and Demographic Surveillance System data in rural western Kenya. WHO ICD definition of PR mortality was used: “the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the cause of death”. In addition, symptoms and events at the time of death were examined using the WHO verbal autopsy methodology. Deaths were categorized as either (i) directly PR: main cause of death was ascribed as obstetric, or (ii) indirectly PR: main cause of death was non-obstetric. Of 3,223 deaths in women 15 to 49 years, 249 (7.7%) were PR. One-third (34%) of these were due to direct obstetric causes, predominantly postpartum hemorrhage, abortion complications and puerperal sepsis. Two-thirds were indirect; three-quarters were attributable to human immunodeficiency virus (HIV/AIDS), malaria and tuberculosis. Significantly more women who died in lower socio-economic groups sought care from traditional birth attendants (p = 0.034), while less impoverished women were more likely to seek hospital care (p = 0.001). The PR mortality ratio over the six years was 740 (95% CI 651–838) per 100,000 live births, with no evidence of reduction over time (χ2 linear trend = 1.07; p = 0.3). Conclusions These data supplement current scanty information on the relationship between infectious diseases and poor maternal outcomes in Africa. They indicate low uptake of maternal health interventions in women dying during pregnancy and postpartum, suggesting improved access to and increased uptake of skilled obstetric care, as well as preventive measures against HIV/AIDS, malaria and tuberculosis among all women of childbearing age may help to reduce pregnancy-related mortality

Successful clinical outcomes following decentralization of tertiary paediatric HIV care to a community-based paediatric antiretroviral treatment network, Chiangrai, Thailand, 2002 to 2008

Introduction: Most paediatric antiretroviral treatments (ARTs) in Thailand are limited to tertiary care hospitals. To decentralize paediatric HIV treatment and care, Chiangrai Prachanukroh Hospital (CRH) strengthened a provincial paediatric HIV care network by training community hospital (CH) care teams to receive referrals of children for community follow-up. In this study, we assessed factors associated with death and clinical outcomes of HIV-infected children who received care at CRH and CHs after implementation of a community-based paediatric HIV care network. Methods: Clinical records were abstracted for all children who initiated ART at CRH. Paired Wilcoxon signed rank tests were used to assess CD4% and virological change among all children. Cox proportional hazard models were used to assess factors associated with death. Treatment outcomes (CD4%, viral load (VL) and weight-for-age Z-score (WAZ)) were compared between CRH and CH children who met the criteria for analysis. Results: Between February 2002 and April 2008, 423 HIV-infected children initiated ART and 410 included in the cohort analysis. Median follow-up for the cohort was 28 months (interquartile range (IQR)=12 to 42); 169 (41%) children were referred for follow-up at CH. As of 31 March 2008, 42 (10%) children had died. Baseline WAZ (<−2 (p=0.001)) and baseline CD4% (<5% (p=0.015)) were independently associated with death. At 48 months, 86% of ART-naïve children in follow-up had VL<400 copies/ml. For sub-group analysis, 133 children at CRH and 154 at CHs were included for comparison. Median baseline WAZ was lower in CH children than in CRH children (p=0.001); in both groups, WAZ, CD4% and VL improved after ART with no difference in rate of WAZ and CD4% gain (p=0.421 and 0.207, respectively). Conclusions: Children at CHs had more severe immunological suppression and low WAZ at baseline. Community- and tertiary care-based paediatric ART follow-ups result in equally beneficial outcomes with the strengthening of a provincial referral network between tertiary and community care. Nutrition interventions may benefit children in community-based HIV treatment and care

Associations of Sociodemographic and Clinical Factors with Late Presentation for Early Infant HIV Diagnosis (EID) Services in Kenya

Background: Understanding the missed opportunities in early infant HIV testing within the PMTCT program is essential to address any gaps. The study set out to describe the clinical and sociodemographic characteristics of the infants presenting late for early infant diagnosis in Kenya. Methods: We abstracted routinely collected clinical and sociodemographic characteristics, in a cross-sectional study, on all HIV-infected infants with a positive polymerase chain reaction (PCR) test from 1,346 President’s Emergency Plan for AIDS Relief (PEPFAR) supported health facilities for the period October 2016 to September 2018. We used multivariate logistic regression to examine the association of sociodemographic and clinical characteristics with late (>2 months after birth) presentation for infant HIV testing. Results: Of the 4,011 HIV-infected infants identified, the median infant age at HIV diagnosis was 3 months [interquartile range (IQR), 1-16 months], and two-thirds [2,669 (66.5%)] presented late for infant HIV testing. Factors that were associated with late presentation for infant testing were: maternal ANC non-attendance, adjusted odds ratio (aOR) 1.41 (95% confidence interval (CI) 1.18 -1.69); new maternal HIV diagnosis, aOR 1.45, (95%CI 1.24 -1.7); and lack of maternal antiretroviral therapy(ART), aOR 1.94, (95% CI 1.64 - 2.30). There was a high likelihood of identifying HIV-infected infants among infants who presented for medical services in the outpatient setting (aOR 18.9; 95% CI 10.2 - 34.9) and inpatient setting (aOR 12.2; 95% CI 6.23-23.9) compared to the infants who presented late in maternity. Conclusion and Global Health Implications: Gaps in early infant HIV testing suggest the need to increase maternal pre-pregnancy HIV diagnosis, timely antenatal care, early infant diagnosis services, early identification of mothers who seroconvert during pregnancy or breastfeeding and improved HIV screening in outpatient and inpatient settings. Early referral from the community and access to health facilities should be strengthened by the implementation of national PMTCT guidelines.publishedVersio

Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-infected women receiving cotrimoxazole prophylaxis: a multicenter randomized placebo-controlled trial.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs). METHODS AND FINDINGS: A total of 1,071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27-0.82]; p=0.008), placental malaria (RR, 0.52 [95% CI 0.29-0.90]; p=0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37-0.95]; p=0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p=0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14-3.33]; p=0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis. CONCLUSIONS: An effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440 Please see later in the article for the Editors' Summary

Economic evaluation of an alternative drug to sulfadoxine-pyrimethamine as intermittent preventive treatment of malaria in pregnancy.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended in HIV-negative women to avert malaria, while this relies on cotrimoxazole prophylaxis (CTXp) in HIV-positive women. Alternative antimalarials are required in areas where parasite resistance to antifolate drugs is high. The cost-effectiveness of IPTp with alternative drugs is needed to inform policy. METHODS: The cost-effectiveness of 2-dose IPTp-mefloquine (MQ) was compared with IPTp-SP in HIV-negative women (Benin, Gabon, Mozambique and Tanzania). In HIV-positive women the cost-effectiveness of 3-dose IPTp-MQ added to CTXp was compared with CTXp alone (Kenya, Mozambique and Tanzania). The outcomes used were maternal clinical malaria, anaemia at delivery and non-obstetric hospital admissions. The poor tolerability to MQ was included as the value of women's loss of working days. Incremental cost-effectiveness ratios (ICERs) were calculated and threshold analysis undertaken. RESULTS: For HIV-negative women, the ICER for IPTp-MQ versus IPTp-SP was 136.30 US$(2012 US$) (95%CI 131.41; 141.18) per disability-adjusted life-year (DALY) averted, or 237.78 US$(95$ (95%CI 4.22; 9.70). In HIV-negative women, moderate shifts of variables such as malaria incidence, drug cost, and IPTp efficacy increased the ICERs above the cost-effectiveness threshold. In HIV-positive women the intervention remained cost-effective for a substantial (up to 21 times) increase in cost per tablet. CONCLUSIONS: Addition of IPTp with an effective antimalarial to CTXp was very cost-effective in HIV-positive women. IPTp with an efficacious antimalarial was more cost-effective than IPTp-SP in HIV-negative women. However, the poor tolerability of MQ does not favour its use as IPTp. Regardless of HIV status, prevention of malaria in pregnancy with a highly efficacious, well tolerated antimalarial would be cost-effective despite its high price. TRIALS REGISTRATION: ClinicalTrials.gov NCT 00811421; Pan African Trials Registry PACTR2010020001429343 and PACTR2010020001813440

Rates and Predictors of Non-Adherence to Antiretroviral Therapy among HIV-Positive Individuals in Kenya: Results from the Second Kenya AIDS Indicator Survey, 2012.

Understanding the levels and associated factors of non-adherence to antiretroviral therapy (ART) is crucial in designing interventions to improve adherence and health outcomes of ART. We assessed non-adherence to ART among HIV-infected persons reporting ART use in a nationally representative survey in Kenya.The Kenya AIDS Indicator Survey 2012 was a population-based, household survey of persons aged 18 months-64 years conducted in 2012-2013. Self-reported information was collected on demographics, sexual behaviour, HIV status, and ART use. Blood was collected for HIV testing, and if HIV infected, CD4 and viral load testing. HIV-positive specimens were tested for the presence of antiretroviral (ARV) drugs using a qualitative ARV assay using liquid chromatography-tandem mass spectrometry. HIV-positive persons who reported receiving ART but did not have the ARV biomarker present were defined as being non-adherent to their ARV medication. We restricted our analysis to HIV-infected persons aged 15-64 years who reported receiving ART and had laboratory-confirmed results from ARV testing. Multivariate logistic regression was used to identify variables associated with non-adherence.A total of 648 (5.6%; CI 4.9-6.3) tested HIV-positive of whom 559 (86.3%) had sufficient volume of blood to be tested for ARV drugs. Of those, 271 (47.7%; CI 41.8-53.6) self-reported HIV-positive status during the interview and 186 (69.1%; CI 62.2-76.0) of those reported taking ART. The ARV biomarker was absent in 18 of 186 individuals (9.4%; CI 4.9-13.8) who thus were defined as being non-adherent to ART. Non-adherence was associated with being aged 15-29 years (AOR 8.39; CI 2.26-31.22, p = 0.002) compared to aged 30-64 years, rural residence (AOR 5.87; CI 1.39-25.61, p = 0.016) compared with urban residence and taking recreational drugs in the past 30 days (AOR 5.89; CI 1.30-26.70, p = 0.022).Overall, less than 10% of Kenyans aged 15-64 years on ART were not adhering to their HIV medication, highlighting the success of the Kenyan national ART program. Our findings, however, point to the need for targeted interventions particularly for young persons, those in rural areas to improve adherence outcomes, as well as delivery of treatment programs that include psychosocial support as a preventative measure to minimize substance abuse and the risk of treatment failure

Better adherence to pre-antiretroviral therapy guidelines after implementing an electronic medical record system in rural Kenyan HIV clinics: a multicenter pre–post study

Introduction: The monitoring of pre-antiretroviral therapy (pre-ART) is a key indicator of HIV quality of care. This study investigated the association of an electronic medical record system (EMR) with adherence to pre-ART guidelines in rural HIV clinics in Kenya. Methods: A retrospective study was carried out to assess the quality of pre-ART care using three indicators: (1) the performance of a baseline CD4 test, (2) time from enrollment in care to first CD4 test, and (3) time from baseline CD4 to second CD4 test. A comparison of these indicators was made pre and post the introduction of an EMR system in 17 rural HIV clinics. Results: A total of 18 523 patients were receiving pre-ART care, of whom 38.8% in the paper group had had at least one CD4 test compared to 53.4% in the EMR group (p < 0.001). The adjusted odds of performing a CD4 test in clinics using an EMR was 1.59 (95% confidence interval 1.49–1.69). The median time from enrolment into HIV care to first CD4 test was 1.40 months (interquartile range (IQR) 0.47–4.87) for paper vs. 0.93 months (IQR 0.43–3.37) for EMR. The median time from baseline to first CD4 follow-up was 7.5 months (IQR 5.97–10.73) for paper and 6.53 months (IQR 5.57–7.87) for EMR. Conclusion: The use of the EMR system was associated with better compliance to HIV guidelines for pre-ART care. EMRs have a potential positive impact on quality of care for HIV patients in resource-constrained settings

Maternal Tenofovir Disoproxil Fumarate Use in Pregnancy and Growth Outcomes among HIV-Exposed Uninfected Infants in Kenya

Background. Tenofovir disoproxil fumarate (TDF) is commonly used in antiretroviral treatment (ART) and preexposure prophylaxis regimens. We evaluated the relationship of prenatal TDF use and growth outcomes among Kenyan HIV-exposed uninfected (HEU) infants. Materials and Methods. We included PCR-confirmed HEU infants enrolled in a cross-sectional survey of mother-infant pairs conducted between July and December 2013 in Kenya. Maternal ART regimen during pregnancy was determined by self-report and clinic records. Six-week and 9-month z-scores for weight-for-age (WAZ), weight-for-length (WLZ), length-for-age (LAZ), and head circumference-for-age (HCAZ) were compared among HEU infants with and without TDF exposure using t-tests and multivariate linear regression models. Results. Among 277 mothers who received ART during pregnancy, 63% initiated ART before pregnancy, of which 89 (32%) used TDF. No differences in birth weight (3.0 kg versus 3.1 kg, p=0.21) or gestational age (38 weeks versus 38 weeks, p=0.16) were detected between TDF-exposed and TDF-unexposed infants. At 6 weeks, unadjusted mean WAZ was lower among TDF-exposed infants (−0.8 versus −0.4, p=0.03), with a trend towards association in adjusted analyses (p=0.06). There were no associations between prenatal TDF use and WLZ, LAZ, and HCAZ in 6-week or 9-month infant cohorts. Conclusion. Maternal TDF use did not adversely affect infant growth compared to other regimens