Pharmacokinetic study of praziquantel enantiomers and its main metabolite R-trans-4-OH-PZQ in plasma, blood and dried blood spots in Opisthorchis viverrini-infected patients

Praziquantel (PZQ) is the treatment of choice for infections with the liver fluke Opisthorchis viverrini, a major health problem in Southeast Asia. However, pharmacokinetic (PK) studies investigating the disposition of PZQ enantiomers (R- and S-PZQ) and its main metabolite, R-trans-4-OH-PZQ, in diseased patients are lacking. The implementation of a dried blood spot (DBS) sampling technique would ease the performance of PK studies in remote areas without clinical facilities. The aim of the present study is to provide data on the disposition of PZQ enantiomers and R-trans-4-OH-PZQ in opisthorchiasis patients and to validate the use of DBS compared to plasma and blood sampling.; PZQ was administered to nine O. viverrini-infected patients at 3 oral doses of 25 mg/kg in 4 h intervals. Plasma, blood and DBS were simultaneously collected at selected time points from 0 to 24 h post-treatment. PK parameters were determined using non-compartmental analysis. Drug concentrations and areas under the curve (AUC0-24h) measured in the 3 matrices were compared using Bland-Altman analysis. We observed plasma AUC0-24hs of 1.1, 9.0 and 188.7 μg/ml*h and half-lives of 1.1, 3.3 and 6.4 h for R-PZQ, S-PZQ and R-trans-4-OH, respectively. Maximal plasma concentrations (Cmax) of 0.2, 0.9 and 13.9 μg/ml for R-PZQ, S-PQZ and R-trans-4-OH peaked at 7 h for PZQ enantiomers and at 8.7 h for the metabolite. Individual drug concentration measurements and patient AUC0-24hs displayed ratios of blood or DBS versus plasma between 79-94% for R- and S-PZQ, and between 108-122% for R-trans-4-OH.; Pharmacodynamic (PD) in vitro studies on PZQ enantiomers and R-trans-4-OH-PZQ are necessary to be able to correlate PK parameters with efficacy. DBS appears to be a valid alternative to conventional venous sampling for PK studies in PZQ-treated patients

The HIV Care Cascade from HIV diagnosis to viral suppression in sub-Saharan Africa: a systematic review and meta-regression analysis protocol.

BACKGROUND: In 2014, UNAIDS announced the 90-90-90 treatment targets to curb the HIV epidemic by 2020: 90% of people living with HIV know their HIV status, 90% of people who know their HIV status access treatment and 90% of people on treatment have suppressed viral loads. Monitoring and evaluation are needed to track linkage and retention throughout the continuum of care. We propose a systematic review and meta-regression to identify the different methodological approaches used to define the steps in the HIV care cascade in sub-Saharan Africa (SSA), where most people with HIV live, and to assess the proportion of participants retained at each step. METHODS: We will include cohort and cross-sectional studies published between 2004 and 2016 that report on the HIV care cascade among adults in SSA. The PubMed, Embase and CINAHL databases will be searched. Two reviewers will independently screen titles and abstracts, assess the full texts for eligibility and extract data. Disagreements will be resolved by consensus or consultation with a third reviewer. We will assess the number and proportion of individuals retained in the HIV care cascade from HIV diagnosis to linkage to care, engagement in pre-ART care, initiation of ART, retention on ART, and viral suppression. The data will be analysed using random effects meta-regression analysis. Publication bias will be assessed by funnel plots. DISCUSSION: This review will contribute to a better understanding of the HIV care cascade in SSA. It will help programs identify gaps and approaches to improve care and treatment for people living with HIV and reduce HIV transmission. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055863

Data for Thinking Healthy Programme Pakistan trial (THPP-Pakistan)

An anonymised dataset of 570 women (one row per woman) who gave informed consent to participate in a cluster randomised, parallel, superiority, controlled trial in Rawalpindi, Pakistan in 2014-2017. The intervention was an adapted version of the Thinking Healthy Programme, delivered by peers; the control was enhanced usual care. Further details are available in the published protocol and paper. The dataset contains records of variables on stratified randomisation and clusters, socio-demographic information, depression and related outcomes, and therapy adherence. Visits occurred at baseline, and 3 and 6 months post-natal

Data for Thinking Healthy Programme India trial (THPP-India)

An anonymised dataset of 280 women (one row per woman) who gave informed consent to participate in an individually-randomised, parallel, superiority, controlled trial in Goa, India in 2014-2016. The intervention was an adapted version of the Thinking Healthy Programme, delivered by peers; the control was enhanced usual care. Further details are available in the published protocol and paper. The dataset contains records of variables on stratified randomisation, socio-demographic information, depression and related outcomes, and therapy adherence. Visits occurred at baseline, and 3 and 6 months post-natal

The HIV care cascade in sub-Saharan Africa: systematic review of published criteria and definitions.

INTRODUCTION The HIV care cascade examines the attrition of people living with HIV from diagnosis to the use of antiretroviral therapy (ART) and suppression of viral replication. We reviewed the literature from sub-Saharan Africa to assess the definitions used for the different steps in the HIV care cascade. METHODS We searched PubMed, Embase and CINAHL for articles published from January 2004 to December 2020. Longitudinal and cross-sectional studies were included if they reported on at least one step of the UNAIDS 90-90-90 cascade or two steps of an extended 7-step cascade. A step was clearly defined if authors reported definitions for numerator and denominator, including the description of the eligible population and methods of assessment or measurement. The review protocol has been published and registered in Prospero. RESULTS AND DISCUSSION Overall, 3364 articles were screened, and 82 studies from 19 countries met the inclusion criteria. Most studies were from Southern (38 studies, 34 from South Africa) and East Africa (29 studies). Fifty-eight studies (71.6%) were longitudinal, with a median follow-up of three years. The medium number of steps covered out of 7 steps was 3 (interquartile range [IQR] 2 to 4); the median year of publication was 2015 (IQR 2013 to 2019). The number of different definitions for the numerators ranged from four definitions (for step "People living with HIV") to 21 (step "Viral suppression"). For the denominators, it ranged from three definitions ("Diagnosed and aware of HIV status") to 14 ("Viral suppression"). Only 12 studies assessed all three of the 90-90-90 steps. Most studies used longitudinal data, but denominator-denominator or denominator-numerator linkages over several steps were rare. Also, cascade data are lacking for many countries. Our review covers the academic literature but did not consider other data, such as government reports on the HIV care cascade. Also, it did not examine disengagement and reengagement in care. CONCLUSIONS The proportions of patients retained at each step of the HIV care cascade cannot be compared between studies, countries and time periods, nor meta-analysed, due to the many different definitions used for numerators and denominators. There is a need for standardization of methods and definitions

Preparedness of Tanzanian Health Facilities for Outpatient\ud Primary care of Hypertension and Diabetes: A Cross-sectional\ud Survey

\ud Historically, health facilities in sub-Saharan Africa have mainly managed acute, infectious diseases. Few data exist for the preparedness of African health facilities to handle the growing epidemic of chronic, non-communicable diseases (NCDs). We assessed the burden of NCDs in health facilities in northwestern Tanzania and investigated the strengths of the health system and areas for improvement with regard to primary care management of selected NCDs. Between November, 2012, and May, 2013, we undertook a cross-sectional survey of a representative sample of 24 public and not-for-profit health facilities in urban and rural Tanzania (four hospitals, eight health centres, and 12 dispensaries). We did structured interviews of facility managers, inspected resources, and administered self-completed questionnaires to 335 health-care workers. We focused on hypertension, diabetes, and HIV (for comparison). Our key study outcomes related to service provision, availability of guidelines and supplies, management and training systems, and preparedness of human resources. Of adult outpatient visits to hospitals, 58% were for chronic diseases compared with 20% at health centres, and 13% at dispensaries. In many facilities, guidelines, diagnostic equipment, and first-line drug therapy for the primary care of NCDs were inadequate, and management, training, and reporting systems were weak. Services for HIV accounted for most chronic disease visits and seemed stronger than did services for NCDs. Ten (42%) facilities had guidelines for HIV whereas three (13%) facilities did for NCDs. 261 (78%) health workers showed fair knowledge of HIV, whereas 198 (59%) did for hypertension and 187 (56%) did for diabetes. Generally, health systems were weaker in lower-level facilities. Front-line health-care workers (such as non-medical-doctor clinicians and nurses) did not have knowledge and experience of NCDs. For example, only 74 (49%) of 150 nurses had at least fair knowledge of diabetes care compared with 85 (57%) of 150 for hyptertension and 119 (79%) of 150 for HIV, and only 31 (21%) of 150 had seen more than five patients with diabetes in the past 3 months compared with 50 (33%) of 150 for hypertension and 111 (74%) of 150 for HIV. Most outpatient services for NCDs in Tanzania are provided at hospitals, despite present policies stating that health centres and dispensaries should provide such services. We identified crucial weaknesses (and strengths) in health systems that should be considered to improve primary care for NCDs in Africa and identified ways that HIV programmes could serve as a model and structural platform for these improvements.\u

Transitioning to Dolutegravir in a Programmatic Setting: Virological Outcomes and Associated Factors Among Treatment-Naive Patients With HIV-1 in the Kilombero and Ulanga Antiretroviral Cohort in Rural Tanzania.

BACKGROUND Virological outcome data after programmatic transition from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based to dolutegravir (DTG)-based antiretroviral therapy (ART) regimens in sub-Saharan Africa (SSA) outside of clinical trials are scarce. We compared viral suppression and associated factors in treatment-naïve people living with HIV (PLHIV) starting DTG- based versus NNRTI-based ART. METHODS We compared virological suppression at 12 months, after treatment initiation in the two cohorts of participants aged ≥15 years, initiating DTG- and NNRTI-based ART. Drug resistance was assessed among participants with viremia ≥50 copies/mL on DTG. RESULTS Viral suppression was achieved for 165/195 (85%) and 154/211 (73%) participants in the DTG- and NNRTI- cohorts, respectively (P = 0.003). DTG-based ART was associated with >2 times the odds of viral suppression versus NNRTI-based ART (adjusted odds ratio, 2.10 [95% confidence interval {CI}, 1.12-3.94]; adjusted risk ratio, 1.11 [95% CI, 1.00-1.24]). HIV-1 genotypic resistance testing (GRT) before ART initiation was done in 14 of 30 viremic participants on DTG, among whom nucleoside reverse transcriptase inhibitor (NRTI), NNRTI, and protease inhibitors resistance was detected in 0 (0%), 2 (14%) and 1 (7%), respectively. No resistance was found in the 2 of 30 participants with available GRT at the time of viremia ≥50 copies/mL. CONCLUSIONS Virological suppression at 1 year was higher in participants initiating DTG- versus NNRTI-based ART. In those with viremia ≥50 copies/mL on DTG-based ART, there was no pretreatment or acquired resistance to the DTG co-administered NRTIs, although the number of samples tested was small

Switch to second-line versus continued first-line antiretroviral therapy for patients with low-level HIV-1 viremia: an open-label randomized controlled trial in Lesotho

Current World Health Organization (WHO) antiretroviral therapy (ART) guidelines define virologic failure as two consecutive viral load (VL) measurements ≥1,000 copies/mL, triggering empiric switch to next-line ART. This trial assessed if patients with sustained low-level HIV-1 viremia on first-line ART benefit from a switch to second-line treatment.; This multicenter, parallel-group, open-label, superiority, randomized controlled trial enrolled patients on first-line ART containing non-nucleoside reverse transcriptase inhibitors (NNRTI) with two consecutive VLs ≥100 copies/mL, with the second VL between 100-999 copies/mL, from eight clinics in Lesotho. Consenting participants were randomly assigned (1:1), stratified by facility, demographic group, and baseline VL, to either switch to second-line ART (switch group) or continued first-line ART (control group; WHO guidelines). The primary endpoint was viral suppression (<50 copies/mL) at 36 weeks. Analyses were by intention to treat, using logistic regression models, adjusted for demographic group and baseline VL. Between August 1, 2017, and August 7, 2019, 137 individuals were screened, of whom 80 were eligible and randomly assigned to switch (n = 40) or control group (n = 40). The majority of participants were female (54 [68%]) with a median age of 42 y (interquartile range [IQR] 35-51), taking tenofovir disoproxil fumarate/lamivudine/efavirenz (49 [61%]) and on ART for a median of 5.9 y (IQR 3.3-8.6). At 36 weeks, 22/40 (55%) participants in the switch versus 10/40 (25%) in the control group achieved viral suppression (adjusted difference 29%, 95% CI 8%-50%, p = 0.009). The switch group had significantly higher probability of viral suppression across different VL thresholds (<20, <100, <200, <400, and <600 copies/mL) but not for <1,000 copies/mL. Thirty-four (85%) participants in switch group and 21 (53%) in control group experienced at least one adverse event (AE) (p = 0.002). No hospitalization or death or other serious adverse events were observed. Study limitations include a follow-up period too short to observe differences in clinical outcomes, missing values in CD4 cell counts due to national stockout of reagents during the study, and limited generalizability of findings to other than NNRTI-based first-line ART regimens.; In this study, switching to second-line ART among patients with sustained low-level HIV-1 viremia resulted in a higher proportion of participants with viral suppression. These results endorse lowering the threshold for virologic failure in future WHO guidelines.; The trial is registered at ClinicalTrials.gov, NCT03088241

Prospective assessment of loss to follow-up: incidence and associated factors in a cohort of HIV-positive adults in rural Tanzania

Lifelong antiretroviral therapy (ART) improves health outcomes for HIV-positive individuals, but is jeopardized by irregular clinic attendance and hence poor adherence. Loss to follow-up (LTFU) is typically defined retrospectively but this may lead to biased inferences. We assessed incidence of and factors associated with LTFU, prospectively and accounting for recurrent LTFU episodes, in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) of HIV-positive persons in rural Tanzania.; We included adults (≥15 years) enrolled in 2005 to 2016, regardless of ART status, with follow-up through April 2017. LTFU was defined as >60 days late for a scheduled appointment. Participants could experience multiple LTFU episodes. We performed analyses based on the first (prospective) and last (retrospective) events observed during follow-up, and accounting for recurrent LTFU episodes. Time to LTFU was estimated using cumulative incidence functions. We assessed factors associated with LTFU using cause-specific proportional hazards, marginal means/rates, and Prentice, Williams and Peterson models.; Among 8087 participants (65% female, 60% aged ≥35 years, 42% WHO stage 3/4, and 47% CD4 count <200 cells/mm; 3; ), there were 8140 LTFU episodes, after which there were 2483 (31%) returns to care. One-year LTFU probabilities were 0.41 (95% confidence interval 0.40, 0.42) and 0.21 (0.20, 0.22) considering the first and last events respectively. Factors associated with LTFU were broadly consistent across different models: being male, younger age, never married, living far from the clinic, not having an HIV-positive partner, lower BMI, advanced WHO stage, not having tuberculosis, and shorter time since ART initiation. Associations between LTFU and pregnancy, CD4 count, and enrolment year depended on the analysis approach.; LTFU episodes were common and prompt tracing efforts are urgently needed. We identified socio-demographic and clinical characteristics associated with LTFU that can be used to target tracing efforts and to help inform the design of appropriate interventions. Incidence of and risk factors for LTFU differed based on the LTFU definition applied, highlighting the importance of appropriately accounting for recurrent LTFU episodes. We recommend using a prospective definition of LTFU combined with recurrent event analyses in cohorts where repeated interruptions in care are common

SESOTHO trial ("Switch Either near Suppression Or THOusand") - switch to second-line versus WHO-guided standard of care for unsuppressed patients on first-line ART with viremia below 1000 copies/mL: protocol of a multicenter, parallel-group, open-label, randomized clinical trial in Lesotho, Southern Africa

The World Health Organization (WHO) recommends viral load (VL) measurement as the preferred monitoring strategy for HIV-infected individuals on antiretroviral therapy (ART) in resource-limited settings. The new WHO guidelines 2016 continue to define virologic failure as two consecutive VL ≥1000 copies/mL (at least 3 months apart) despite good adherence, triggering switch to second-line therapy. However, the threshold of 1000 copies/mL for defining virologic failure is based on low-quality evidence. Observational studies have shown that individuals with low-level viremia (measurable but below 1000 copies/mL) are at increased risk for accumulation of resistance mutations and subsequent virologic failure. The SESOTHO trial assesses a lower threshold for switch to second-line ART in patients with sustained unsuppressed VL.; In this multicenter, parallel-group, open-label, randomized controlled trial conducted in Lesotho, patients on first-line ART with two consecutive unsuppressed VL measurements ≥100 copies/mL, where the second VL is between 100 and 999 copies/mL, will either be switched to second-line ART immediately (intervention group) or not be switched (standard of care, according to WHO guidelines). The primary endpoint is viral resuppression (VL &lt; 50 copies/mL) 9 months after randomization. We will enrol 80 patients, giving us 90% power to detect a difference of 35% in viral resuppression between the groups (assuming two-sided 5% alpha error). For our primary analysis, we will use a modified intention-to-treat set, with those lost to care, death, or crossed over considered failure to resuppress, and using logistic regression models adjusted for the prespecified stratification variables.; The SESOTHO trial challenges the current WHO guidelines, assessing an alternative, lower VL threshold for patients with unsuppressed VL on first-line ART. This trial will provide data to inform future WHO guidelines on VL thresholds to recommend switch to second-line ART.; ClinicalTrials.gov ( NCT03088241 ), registered May 05, 2017