Factors Associated With Viral Suppression and Drug Resistance in Children and Adolescents Living With HIV in Care and Treatment Programs in Southern Tanzania.

BACKGROUND: Achieving viral suppression (VS) for persons living with HIV is key to reaching epidemic control. We assessed the prevalence of VS and the frequency of HIV drug resistance mutations (HIVDRM) among children and adolescents living with HIV (CALHIV) in the Southern Highland zone of Tanzania. METHODS: From 2019 to 2021, we enrolled CALHIV aged 1-19 years on ART for >6 months in a cross-sectional study. Participants had viral load (VL) testing; those with VL ≥ 1000 copies/mL underwent HIVDRM testing. VS (<1000 copies/mL) prevalence estimates were calculated and robust Poisson regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for associations with potential predictors of VS. RESULTS: Of 707 participants, 595 had VS (PR: 0.84, 95% CI: 0.81-0.87). Use of an integrase strand transfer inhibitor-containing regimen (aPR 1.15, 95% CI: 0.99-1.34), age 5-9 years (aPR 1.16, 95% CI: 1.07-1.26), and seeking care at a referral center (aPR 1.12, 95% CI: 1.04-1.21) were associated with VS. Factors inversely associated with VS included having one (aPR 0.82, 95% CI: 0.72-0.92) or two or more (aPR 0.79, 95% CI: 0.66-0.94) referrals for adherence counselling, and self-reporting missing one to two (aPR 0.88, 95% CI: 0.78-0.99) or three or more (aPR 0.77, 95% CI: 0.63-0.92) doses of ART in the past month. Of 74 participants with PRRT and INT sequencing done, 60 (81.1%) had HIVDRMs at the following frequencies: 71.6%, 67.6%, 1.4%, and 4.1% for major NNRTI, NRTI, PI, and INSTI respectively. CONCLUSIONS: Higher rates of VS were observed in this cohort, and HIVDRMs were common in those without VS. This evidence supports ART optimization using dolutegravir-based regimens. However, better strategies to improve adherence are needed.

Early warning indicators of HIV drug resistance in the southern highlands region of Tanzania: Lessons from a cross-sectional surveillance study.

The World Health Organization early warning indicators (EWIs) permit surveillance of factors associated with the emergence of HIV drug resistance (HIVDR). We examined cross- and within-region performance on HIVDR EWIs for selected HIV care and treatment clinics (CTCs) in five regions of southern Tanzania. We retrospectively abstracted EWI data from 50 CTCs for the January to December 2013 period. EWIs included the following: on time ART pick-up, retention on ART, ARV stockouts, and pharmacy prescribing and dispensing practices. Data for pediatric and adult people living with HIV were abstracted from source files, and frequencies and proportions were calculated for each EWI overall, as well as stratified by region, facility, and age group. Across and within all regions, on average, on-time pick-up of pills (63.0%), retention on ART (76.0%), and pharmacy stockouts (69.0%) were consistently poor for the pediatric population. Similarly, on-time pill pick up (66.0%), retention on ART (72.0%) and pharmacy stockouts (53.0%) for adults were also poor. By contrast, performance on pharmacy prescribing and dispensing practices were as desired for both pediatric and adult populations with few facility-level exceptions. In this study, regions and facilities in the southern highlands of Tanzania reported widespread presence of HIVDR risk factors, including sub-optimal timeliness of pill pickup, retention on ART, and drug stockouts. There is an urgent need to implement the WHO EWIs monitoring to minimize the emergence of preventable HIV drug resistance and to maintain the effectiveness of first and second-line ART regimens. This is particularly critical in the context of new ART drug roll-out such as dolutegravir during the COVID-19 pandemic when resultant HIV service disruptions require careful monitoring, and for virologic suppression as countries move closer to epidemic control.

Prevalence and Correlates of Viral Load Suppression and Human Immunodeficiency Virus (HIV) Drug Resistance Among Children and Adolescents in South Rift Valley and Kisumu, Kenya.

BACKGROUND: Children and adolescents living with HIV (CALHIV) face unique challenges, including poorer treatment outcomes, risk for drug-resistance mutations (HIVDRMs), and limited drug formulations. We estimated viral suppression (VS) prevalence and evaluated predictors of VS and HIVDRMs in Kenya. METHODS: From 2018-2020, CALHIV 1-19 years on antiretroviral therapy (ART) >6 months were enrolled in this cross-sectional study. Participants underwent viral load (VL) testing; those with VL ≥1000 copies/mL had HIVDRM testing. Sociodemographic questionnaires and medical record abstraction were completed. VS prevalence (VL <1000 copies/mL) was estimated; robust Poisson regression models were used to estimate prevalence ratios (PRs) and 95% CIs for associations between potential predictors of VS. RESULTS: Nine hundred and sixty-nine participants were enrolled. VS prevalence was .80 (95% CI: .78-.83). Being on ART >24 months (adjusted PR [aPR]: 1.22; 95% CI: 1.06-1.41), an integrase strand transfer inhibitor-containing regimen (1.13; 1.02-1.26), and attending a level 3 health facility (1.23; 1.11-1.36) were associated with VS. Missing ≥3 doses of ART in the past month (aPR: .73; 95% CI: .58-.92), having a viremic mother with HIV (.72; .53-.98), and having 3-7 (.90; .83-.97), 8-13 (.89; .82-.97), or ≥14 (.84; .77-.92) compared with <2 adherence counseling referrals were inversely associated with VS. A high proportion (n = 119, 81.5%) of unsuppressed participants had evidence of any major HIVDRM. CONCLUSIONS: HIV treatment programs should target interventions for pediatric patients at risk for treatment failure-namely, those with a caregiver with failed VS and those struggling with adherence.

Pretreatment and Acquired Antiretroviral Drug Resistance Among Persons Living With HIV in Four African Countries.

BACKGROUND: Emerging HIV drug resistance (HIVDR) could jeopardize the success of standardized HIV management protocols in resource-limited settings. We characterized HIVDR among antiretroviral therapy (ART)-naive and experienced participants in the African Cohort Study (AFRICOS). METHODS: From January 2013 to April 2019, adults with HIV-1 RNA >1000 copies/mL underwent ART history review and HIVDR testing upon enrollment at 12 clinics in Uganda, Kenya, Tanzania, and Nigeria. We calculated resistance scores for specific drugs and tallied major mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) using Stanford HIVDB 8.8 and SmartGene IDNS software. For ART-naive participants, World Health Organization surveillance drug resistance mutations (SDRMs) were noted. RESULTS: HIVDR testing was performed on 972 participants with median age 35.7 (interquartile range [IQR] 29.7-42.7) years and median CD4 295 (IQR 148-478) cells/mm3. Among 801 ART-naive participants, the prevalence of SDRMs was 11.0%, NNRTI mutations 8.2%, NRTI mutations 4.7%, and PI mutations 0.4%. Among 171 viremic ART-experienced participants, NNRTI mutation prevalence was 83.6%, NRTI 67.8%, and PI 1.8%. There were 90 ART-experienced participants with resistance to both efavirenz and lamivudine, 33 (36.7%) of whom were still prescribed these drugs. There were 10 with resistance to both tenofovir and lamivudine, 8 (80.0%) of whom were prescribed these drugs. CONCLUSIONS: Participants on failing ART regimens had a high burden of HIVDR that potentially limited the efficacy of standardized first- and second-line regimens. Management strategies that emphasize adherence counseling while delaying ART switch may promote drug resistance and should be reconsidered.

Decreasing time to antiretroviral therapy initiation after HIV diagnosis in a clinic-based observational cohort study in four African countries.

INTRODUCTION: World Health Organization (WHO) guidelines have shifted over time to recommend earlier initiation of antiretroviral therapy (ART) and now encourage ART initiation on the day of HIV diagnosis, if possible. However, barriers to ART access may delay initiation in resource-limited settings. We characterized temporal trends and other factors influencing the interval between HIV diagnosis and ART initiation among participants enrolled in a clinic-based cohort across four African countries. METHODS: The African Cohort Study enrols adults engaged in care at 12 sites in Uganda, Kenya, Tanzania and Nigeria. Participants provide a medical history, complete a physical examination and undergo laboratory assessments every six months. Participants with recorded dates of HIV diagnosis were categorized by WHO guideline era (<2006, 2006 to 2009, 2010 to 2012, 2013 to 2015, ≥2016) at the time of diagnosis. Cox proportional hazard modelling was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for time to ART initiation. RESULTS AND DISCUSSION: From January 2013 to September 2019, a total of 2888 adults living with HIV enrolled with known diagnosis dates. Median time to ART initiation decreased from 22.0 months (interquartile range (IQR) 4.0 to 77.3) among participants diagnosed prior to 2006 to 0.5 months (IQR 0.2 to 1.8) among those diagnosed in 2016 and later. Comparing those same periods, CD4 nadir increased from a median of 166 cells/mm3 (IQR: 81 to 286) to 298 cells/mm3 (IQR: 151 to 501). In the final adjusted model, participants diagnosed in each subsequent WHO guideline era had increased rates of ART initiation compared to those diagnosed before 2006. CD4 nadir ≥500 cells/mm3 was independently associated with a lower rate of ART initiation as compared to CD4 nadir <200 cells/mm3 (HR: 0.32; 95% CI: 0.28 to 0.37). Age >50 years at diagnosis was independently associated with shorter time to ART initiation as compared to 18 to 29 years (HR: 1.38; 95% CI: 1.19 to 1.61). CONCLUSIONS: Consistent with changing guidelines, the interval between diagnosis and ART initiation has decreased over time. Still, many adults living with HIV initiated treatment with low CD4, highlighting the need to diagnose HIV earlier while improving access to immediate ART after diagnosis.

A tool for estimating antiretroviral medication coverage for HIV-infected women during pregnancy (PMTCT-ACT).

BACKGROUND: In the typical prevention of mother to child transmission (PMTCT) of HIV cascade of care discussion or analysis, the period of analysis begins at the first visit for antenatal care (ANC) for that pregnancy. This starting point is problematic for two reasons: (1) a large number of HIV-infected women are already on life-long antiretroviral therapy (ART) when presenting for ANC; and (2) women present to ANC at different gestational ages. The PMTCT ART Coverage Tool (PMTCT-ACT), which estimates the proportion of days covered (PDC) with ART, was developed to address each of these problems. METHODS: PDC is a preferred method to measure adherence to chronic medications, such as ART. For evaluating the PMTCT cascade of care, as indicated by PDC with ART over various time periods, a "starting point" based on a specific day before delivery must be defined that applies to all women (treatment experienced or naïve at the first ANC visit at any gestational age). Using the example of 168 days prior to delivery (24 weeks), PMTCT-ACT measures PDC with ART during that period. PMTCT-ACT is provided as a STATA do-file. Using an example dataset for two women (ID1 is treatment experienced; ID2 is treatment naïve), the details of each major portion of the tool (Parts 1-5) are presented. PMTCT-ACT along with the intermediate datasets created during the analysis are provided as supplemental files. CONCLUSIONS: Evaluating the PMTCT cascade of care requires a standard definition of the follow-up period during pregnancy that applies to all HIV-infected pregnant women and a standard measure of adherence. PMTCT-ACT is a new tool that fits this purpose. PMTCT-ACT can also be easily adjusted to evaluate other ante- and post-natal periods (e.g., final 4 weeks, final 8 weeks, complete pregnancy period, initial 24 weeks postpartum, time periods consistent with infant HIV testing guidelines).

Association of the US President's Emergency Plan for AIDS Relief's Funding With Prevention of Mother-to-Child Transmission of HIV in Kenya.

Importance: From 2004 to 2014, the US President's Emergency Plan for AIDS Relief (PEPFAR) invested more than $248 000 000 in the prevention of mother-to-child transmission (PMTCT) of HIV in Kenya. Concurrently, child mortality in Kenya decreased by half. Objective: To identify the extent to which the decrease in child mortality in Kenya is associated with PEPFAR funding for PMTCT of HIV. Design, Setting, and Participants: This population-based survey study conducted in Kenya estimated the association between annual per capita PEPFAR funding for PMTCT (annual PCF) and cumulative per capita PEPFAR funding for PMTCT (cumulative PCF), extracted using 2004-2014 country operational reports as well as individual-level health outcomes, extracted from the 2003, 2008-2009, and 2014 Kenya Demographic and Health Surveys and the 2007 and 2012 Kenya AIDS Indicator Surveys. The study included children of female respondents to the 2003, 2008-2009, and 2014 Kenya Demographic and Health Surveys who were born 1 to 60 months (for neonatal mortality) or 12 to 60 months (for infant mortality) before the survey, as well as female respondents who had recently given birth and reported on HIV testing during antenatal care (ANC) during the 2007-2014 surveys. Results were adjusted for year, province, and survey respondent characteristics. Statistical analysis was performed from July 8, 2016, to December 10, 2018. Main Outcomes and Measures: Neonatal mortality was defined as death within the first month of life and infant mortality was defined as death within the first year of life. HIV testing during ANC was defined as receiving counseling on PMTCT, undergoing an HIV test, and receiving test results during ANC. Results: The analysis included 33 181 neonates (16 870 boys), 26 876 infants (13 679 boys), and 20 775 mothers (mean [SD] age, 28.0 [6.7] years). PEPFAR funding was not associated with neonatal mortality. A $0.33 increase in annual PCF, corresponding to the difference between the 75th and 25th (interquartile range) percentiles of funding, was significantly associated with a 16% (95% CI, 4%-27%) reduction in infant mortality after a 1-year lag. A 14% to 16% reduction persisted after 2- and 3-year lags, and comparable reductions were observed for unlagged and 1-year lagged cumulative PCF. An increase of 1 interquartile range in cumulative PCF was associated with a 7% (95% CI, 3%-11%) increase in HIV testing during ANC, which intensified with subsequent lags. Between 2004 and 2014, sustained funding levels of $0.33 annual PCF could have averted 118 039 to 273 924 infant deaths. Conclusions and Relevance: Evidence from publicly available data suggests that PEPFAR's PMTCT funding was associated with a reduction in infant mortality and an increase in HIV testing during ANC in Kenya. The full outcome of funding may not be realized until several years after allocation.

The Enhanced Mentor Mother ProgrAm (EMMA) for the prevention of mother-to-child transmission of HIV in Kenya: study protocol for a cluster randomized controlled trial.

BACKGROUND: As of September 2014, Kenya implemented the WHO recommended Option B+ guidelines in which all newly diagnosed HIV-infected pregnant women are immediately eligible for triple antiretroviral therapy (ART) for life regardless of CD4 count. In addition, Kenya previously established the Kenya Mentor Mother Program (KMMP) in 2012 to improve peer education and psychosocial support services within the national prevention of mother-to-child transmission (PMTCT) program. The primary objectives of the study described in the current protocol are: (1) to evaluate implementation of these new guidelines (Option B+ with Mentor Mothers) as part of routine service delivery; and (2) to evaluate potential benefits of a package of services within the KMMP (called EMMA) to improve PMTCT service delivery. METHODS: We will conduct a cluster randomized controlled trial in western Kenya. We will allocate 12 clinics providing PMTCT services including ART to two study arms using pair matching: the standard of care (SOC) arm, which includes the KMMP as implemented by the clinics; and the intervention arm, which is the SOC (including KMMP) with the EMMA package of services (a targeted exit interview, visit reminders, and targeted follow-up). At the intervention clinics, the EMMA package of services is implemented as part of routine service delivery. A total of 360 (180 in each arm) pregnant women will be enrolled in the study at or near their first visit for antenatal care for prospective records review through 72 weeks post-partum. The primary and secondary outcomes are uninterrupted supplies of ART medications throughout the PMTCT cascade of care as well as infants completing HIV testing on schedule. DISCUSSION: The EMMA package of services provides specific structure to the use of Mentor Mothers within PMTCT programs. This strategy was developed in collaboration with local health facility and PMTCT program staff based on their experience providing PMTCT services within the integrated ART-MCH facilities. If successful, this approach has the potential to improve dramatically PMTCT service delivery with minor additional costs beyond the basic mother-mentor program and support global goals to eliminate mother-to-child transmission. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02848235 . Registered on 19 July 2016.

Nevirapine pharmacokinetics when initiated at 200 mg or 400 mg daily in HIV-1 and tuberculosis co-infected Ugandan adults on rifampicin.

BACKGROUND: rifampicin lowers nevirapine plasma concentrations by inducing cytochrome P450. However, few data are available on this interaction during the lead-in period of nevirapine treatment. METHODS: eighteen HIV-1/tuberculosis co-infected adults receiving rifampicin daily as part of anti-tuberculosis therapy were evenly randomized to nevirapine initiation by dose escalation (NVP200) or nevirapine initiation at 200 mg twice daily (NVP400). Subjects underwent 12 h intensive pharmacokinetic sampling on Days 7, 14 and 21 of nevirapine treatment. A minimum effective concentration (MEC) of 3000 ng/mL was used to interpret nevirapine concentrations 12 h after dosing (C(12)). TRIAL REGISTRATION NUMBER: NCT00617643 (www.clinicaltrials.gov). RESULTS: day 7 geometric mean nevirapine C(12) [90% confidence interval (CI)] was 1504 (1127-2115) ng/mL and 3148 (2451-4687) ng/mL in the NVP200 and NVP400 arms, respectively (P < 0.01). Nevirapine C(12) on Days 14 and 21 was similar. On Day 21, nevirapine concentration in 64% of patients was below the MEC. On Day 7, geometric mean area under the curve (AUC(0-12)) was lower in the NVP200 arm, 25 223 (90% CI, 21 978-29 695) ng·h/mL versus 43 195 (35 607-57 035) ng·h/mL in the NVP400 arm (P  <  0.01). Similarly, on Day 14, nevirapine AUC(0-12) was lower in the NVP200 arm 23 668 (18 253-32 218) ng·h/mL versus the NVP400 arm 44 918 (36 264-62 769) ng·h/mL (P = 0.03). CONCLUSIONS: in co-treated patients, nevirapine concentrations were below the MEC during initiation with dose escalation. Nevirapine initiation at the maintenance dose of 200 mg twice daily is preferred. Sub-therapeutic nevirapine concentrations were common at Day 21 with either regimen. Evaluation of higher nevirapine maintenance doses may be considered.

Patients' needs for nursing care: beyond staffing ratios.

The current focus on staffing ratios as a means to assure appropriate care for patients ignores the very real differences among patients in their needs for nursing care. Implementing a system that identifies these needs provides a more accurate indication of staffing requirements. In addition, storing the raw data from the system at their most basic level provides opportunities for more extensive analyses and informed, data-driven decision-making related to resource allocation, performance improvement, and productivity enhancement.