Enhanced Adherence Support Research Articles

Possible depression in new tuberculosis patients in the Free State province, South Africa.

Despite compelling evidence of comorbidity between tuberculosis (TB) and depression, little is known about the prevalence and determinants of depression among TB patients in the Free State province in South Africa. This study assessed the prevalence and factors associated with possible depression among new drug susceptible TB patients attending primary health care facilities. The study followed a cross-sectional design. Trained fieldworkers conducted face-to-face interviews with conveniently selected patients. Depression was assessed using the Patient Health Questionnaire-9. Data were subjected to descriptive and binomial logistic regression analyses. Out of 208 patients, 46.2% screened positive for possible depression - 22.6%, 18.8%, and 4.8% presenting with mild, moderate, and severe symptoms, respectively. Possible depression odds were three times higher among females than males (adjusted odds ratio [AOR]: 3.0; 95% confidence interval [CI]: 1.25-7.32) and 2.7 times higher among extrapulmonary TB (EPTB) than pulmonary TB patients (95% CI: 1.03-7.21). Longer TB treatment duration was protective (AOR: 0.8; 95% CI: 0.70-0.95) against depression. Among human immunodeficiency virus-positive patients, those on antiretroviral therapy (ART) had 2.5 times higher odds of depression (95% CI: 1.13-5.46) than those who were not. The results highlight a significant burden of possible depression among new TB patients, particularly among females, EPTB patients, and ART recipients. Longer TB treatment duration may offer some protection against depression symptoms, suggesting a need for enhanced adherence support. The results suggest that strengthening TB and mental health service integration is critical to improving treatment outcomes, overall well-being of TB patients, and the performance of the Free State TB programme.

Antiretroviral Therapy Adherence During and Postbreastfeeding Cessation Measured by Tenofovir Levels in Hair.

Background:We examined change in antiretroviral treatment (ART) adherence after breastfeeding (BF) cessation using hair tenofovir (TFV) concentrations as an objective metric of medication consumption.Methods:A subset of postpartum women in Zimbabwe randomized in IMPAACT PROMISE to take ART while BF and post-BF cessation had hair TFV measured longitudinally. Using linear mixed-effect models, we estimated differences in hair TFV levels after BF cessation, accounting for trends in levels over time regardless of BF status and change in slope after breastfeeding cessation. We also estimated the relative risk of viremia (>50 copies/mL) per doubling of hair TFV concentration.Results:Among 55 women (median age 26, interquartile range 24–29 years), hair TFV levels (n = 305) were available for a median of 9 visits per woman between 3 and 29 months postpartum. Hair TFV levels ranged from undetected to 0.25 ng/mg (median 0.04 ng/mg). Controlling for trends since delivery [decline of 2.2% per month, 95% confidence interval (CI): −5.3 to 1.0], TFV levels averaged 24.4% higher (95% CI: −5.1 to 63.1) post-BF cessation than during BF, with no change in slope (0.0% per month, 95% CI: −3.8 to 3.9). Postpartum, 42% of women were ever viremic. Higher TFV levels were strongly protective; relative risk of viremia per doubling of TFV was 0.52 (95% CI: 0.43 to 0.63; P < 0.0001).Conclusions:Leveraging an objective metric of ART use, we observed modestly declining adherence across the postpartum period, but no additional decline associated with breastfeeding cessation. High viremia frequency and varying postpartum TFV levels observed highlight the importance of enhanced adherence support with viral load monitoring among postpartum women.

Accuracy of measures for antiretroviral adherence in people living with HIV.

BackgroundGood patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource‐limited settings.ObjectivesTo determine the accuracy of simple measures of ART adherence (including patient self‐report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non‐suppressed viral load in people living with HIV and receiving ART treatment.Search methodsThe Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African‐Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases.Selection criteriaWe included studies of all designs that evaluated a simple measure of adherence (index test) such as self‐report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity.Data collection and analysisWe screened studies, extracted data, and assessed risk of bias using QUADAS‐2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta‐analysis or comparison of adherence measures. We explored heterogeneity using pre‐defined subgroup analysis.Main resultsWe included 51 studies involving children and adults with HIV, mostly living in low‐ and middle‐income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self‐report.‐ Self‐report questionnaires (25 studies, 9211 participants; very low‐certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%.‐ Self‐report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low‐certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%.‐ Tablet counts (12 studies, 3466 participants; very low‐certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%.‐ Electronic monitoring devices (3 studies, 186 participants; very low‐certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%.‐ Pharmacy records or secondary databases (6 studies, 2254 participants; very low‐certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%.‐ Composite measures (9 studies, 1513 participants; very low‐certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%.Across all included studies, the ability of adherence measures to detect viral non‐suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision.The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results.Authors' conclusionsWe encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non‐suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions.

The role of health facility and individual level characteristics on medication adherence among PLHIV on second-line antiretroviral therapy in Northeast Ethiopia: use of multi-level model

BackgroundMedication adherence plays a pivotal role in achieving the desired treatment outcomes. The proportion of HIV patients on second-line antiretroviral therapy is becoming a growing public health concern. However, to date, little attention has been given to second-line antiretroviral medication adherence. Moreover, the association between health facility characteristics and medication adherence has yet not been tested. Thus, this research was conducted to determine the magnitude of medication adherence and examine the role of facility-level determinants among HIV patients on second-line ART.MethodsA cross-sectional study was conducted on 714 HIV patients on second-line therapy who were selected via systematic random sampling in twenty public health facilities. Medication adherence was measured using the six-item Simplified Medication Adherence Questionnaire (SMAQ) tool. Data were collected in a personal interview as well as document reviews. A multi-level binary logistic regression was used to uncover individual and facility-level determinants. The effect size was presented using an adjusted odds ratio (AOR), and statistical significance was declared at a P value less than 0.05.ResultsThe magnitude of optimal medication adherence among HIV patients on second-line antiretroviral therapy was 69.5% (65.9–72.7%). Medication adherence was positively associated with the use of adherence reminder methods [AOR = 3.37, (95% CI 2.03–5.62)], having social support [AOR = 1.11, (95% CI 1.02–1.23)], and not having clinical depression [AOR = 3.19, (95% CI 1.93–5.27). The number of adherence counselors [AOR = 1.20, (95% CI 1.04–1.40)], teamwork for enhanced adherence support [AOR = 1.82, (95% CI 1.01–3.42)], and caseloads at ART clinics were all significantly correlated with ARV medication adherence at the facility level.ConclusionsA large proportion of HIV patients on second-line antiretroviral therapy had adherence problems. Both facility-level and individual-level were linked with patient medication adherence. Thus, based on the identified factors, individual and system-level interventions should be targeted.

Factors Associated with Viral Suppression Among Adolescents on Antiretroviral Therapy in Homa Bay County, Kenya: A Retrospective Cross-Sectional Study.

BackgroundDespite the success in initiating adolescents living with HIV on antiretroviral therapy (ART), questions remain about factors affecting viral suppression. In Kenya, only 63% of adolescents (aged 10–19 years) on ART had achieved viral suppression in 2016. We investigated factors associated with viral suppression among adolescents initiated on ART before November 30, 2017 in Homa Bay County, Kenya.MethodsA retrospective cross-sectional analysis of 908 adolescents registered on ART for at least 6 months and with at least one documented viral load in the last 12 months, in six health facilities in Homa Bay County was conducted. Data were extracted from the electronic medical records and exported into an excel spreadsheet. Bivariate and multivariate logistic regression analyses were conducted to identify factors associated with viral suppression and adjust for confounding, using Stata 12.0.ResultsOut of all participants, 80% (726) had achieved viral suppression (<1,000 copies of viral RNA/mL of blood at latest viral load count). After adjusting for other covariates, adolescents with good adherence to ART (AOR=2.3, 95% CI=1.38–3.84) and a most recent CD4 count of above 500 cells/mm3 (AOR=1.87, 95% CI=1.13–3.08), were more likely to be virally suppressed. Adolescents on second line ART treatment (AOR=0.45, 95% CI=0.28–0.73) and having inadequate adherence to ART (AOR=0.26, 95% CI=0.11–63) were less likely to be virally suppressed.ConclusionViral suppression for adolescents on ART in this study is significantly higher than the national prevalence in 2016 (80% vs 63%), but it is still below the WHO target of 90%. Enhanced adherence support for adolescents on ART should be implemented to improve long-term adherence. Specific interventions are needed to “rescue” adolescents on second-line ART regimens who may have a history of poor adherence.

Establishing targets for advanced HIV disease: A call to action.

The World Health Organization (WHO) has published a guideline for the management of individuals with advanced HIV disease (AHD) to reduce HIV-related deaths. The guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (TB), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. Currently no clear targets exist for these key interventions. Emerging programmatic data from Uganda, Tanzania and Nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or TB testing, highlighting the remaining challenges to the effective implementation of WHO-recommended AHD packages of care in real-world resource-limited settings. The absence of mortality indicators for the leading causes of HIV-related deaths, because of the lack of mechanisms to ascertain cause of death, has had a negative impact on establishing interventions to reduce mortality. We suggest that setting 95-95-95 targets for CD4 testing, cryptococcal antigen and TB testing, and treatment that are aligned to the WHO AHD package of care would be a step in the right direction to achieving the greater goal of the WHO End TB strategy and the proposed new strategy to end cryptococcal meningitis deaths. However, these targets will only be achieved if there is healthcare worker training, expanded access to bedside point-of-care diagnostics for hospitalised patients and those in outpatient care who meet the criteria for AHD, and health systems strengthening to minimise delays in initiating the WHO-recommended therapies for TB and cryptococcal disease.

PrEP uptake, persistence, adherence, and effect of retrospective drug level feedback on PrEP adherence among young women in southern Africa: Results from HPTN 082, a randomized controlled trial.

BackgroundPre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study.Methods and findingsHIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV–negative women ages 16–25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted.ConclusionsIn this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population.Trial registrationClinicalTrials.gov NCT02732730.

Factors Associated With Peripartum Virologic Suppression in Eastern Cape Province, South Africa: A Retrospective Cross-Sectional Analysis.

BackgroundThis study describes the characteristics of pregnant women on antiretroviral therapy (ART) and the rate of peripartum virologic suppression in a large prevention of mother-to-child transmission cohort who delivered in some selected maternity centers in Eastern Cape Province, South Africa. In addition, the study examines the factors associated with virologic suppression in the cohort.MethodsThis multicenter, retrospective cross-sectional analysis included medical data of 1709 women with human immunodeficiency virus between September 2015 and May 2016 in Eastern Cape Province. The main outcome measure was the rate of peripartum virologic suppression, defined as viral load (VL) <1000 copies/mL and undetectable viremia (VL <20 copies/mL). Correlates of peripartum virologic suppression and undetectable viremia were examined by fitting logistic regression model analysis.ResultsOf 1463 women with available VL results, the overall rate of peripartum suppression was 82%, and undetectable viremia was 56.9%. Being aged 24 years or younger (adjusted odds ratio [AOR], 0.68 [95% confidence interval {CI}, .48–.94]), smoking during pregnancy (AOR, 0.50 [95% CI, .28–.90]), and starting ART in the first trimester were associated with lower odds of viral suppression (<1000 copies/mL). Women who had never defaulted ART had an increased odds of having an undetectable VL (AOR, 3.09 [95% CI, 2.12–4.49]) and virologic suppression (AOR, 3.88 [95% CI, 2.62–5.74]) compared to those who defaulted.ConclusionsMore than half of the women achieved undetectable VL, and 4 in 5 women achieved viral suppression at delivery in the region. Early antenatal booking, combined with enhanced adherence support for pregnant women on ART, would be crucial toward achieving the goal of elimination of mother-to-child transmission in the region.

Brief Report: Discrepancies Between Self-Reported Adherence and a Biomarker of Adherence in Real-World Settings.

Pre-exposure prophylaxis (PrEP) is only effective in preventing new HIV infections when taken consistently. In clinical practice, asking a patient about their adherence (self-report) is the predominant method of assessing adherence to PrEP. Although inexpensive and noninvasive, self-report is subject to social desirability and recall biases. Several clinical trials demonstrate a discrepancy between self-reported adherence and biomarker-based recent adherence. Less is known about the accuracy of self-report in real-world clinical settings. This brief report addresses this knowledge gap and describes the concordance between self-reported adherence and biomarker-based adherence in real-world clinical settings. A liquid chromatography-mass spectrometry urine test for tenofovir was developed and used clinically to detect recent nonadherence (no dose in at least 48 hours) for each individual. Two clinics' standard operating procedures recommend utilization of the urine-based adherence test for patients who self-report that they are not struggling with adherence. Those who self-report struggling with adherence receive enhanced adherence support without the need for additional testing. The number of results indicating recent nonadherence from these 2 clinics were analyzed to assess the concordance between self-reported adherence and biomarker-based adherence. Across 2 clinics, 3987 tests were conducted from patients self-reporting as "adherent," and 564 [14.1%; 95% confidence interval (CI): 13.1% to 15.2%] demonstrated recent nonadherence with the liquid chromatography-mass spectrometry test. At clinic #1 in Florida, 3200 tests were conducted, and 465 (14.5%; 95% CI: 13.3% to 15.8%) demonstrated recent nonadherence. At clinic #2 in Texas, 787 tests were conducted, and 99 (12.6%; 95% CI: 10.4% to 14.9%) demonstrated recent nonadherence. Utilization of biomarker-based adherence monitoring at these 2 clinics resulted in 564 additional patients receiving enhanced adherence support who otherwise would not have been identified as nonadherent to their prescribed PrEP regimen. These findings suggest that objective adherence monitoring can be used clinically to enable providers to identify nonadherent patients and allocate support services accordingly.

Prevalence and Predictors of Virological Failure Among Adults Living with HIV in South Wollo Zone, Northeast Ethiopia: A Retrospective Cohort Study.

BackgroundHighly active antiretroviral therapy has dramatically altered progression of HIV infection and significantly improved patients’ quality of life. However, drug resistance with consequent treatment failure raises the need for much more expensive and toxic second-line regimens. Thus, this study aimed at investigating the predictors of virologic failure among adults in Northeast Ethiopia.MethodsA retrospective cohort study was carried out among adults who started first-line antiretroviral treatment from September 2005 to January 2018. Data were collected from patients’ medical records, entered and validated using EpiData version 3.1 and then exported to SPSS version 20 for analysis. Binary logistic regression was carried out; odds ratio with 95% CI was used to identify covariates associated with virologic failure. Statistical significance was considered at p-value <0.05.ResultsA total of 384 patients with mean age of 35.73±9.44 years were consecutively enrolled; of which, 213 (55.5%) were females, 255 (66.4%) had WHO clinical stage III/IV, and 130 (33.9%) had baseline CD4 count <100 cells/mm3. Mean baseline CD4 count was 179 cells/mm3 (range: 2–853 cells), and 158 (41.1%) participants were on AZT/3TC/NVP. Virological failure was diagnosed among 61 (15.9%) patients. The mean time to virologic failure after initiation of ART was 63.80 months (range: 17–150 months). After adjusting for other confounders, risk of experiencing virologic failure was significantly associated with being divorced (AOR 3.40, 95% CI 1.20–9.59), being naïve to ART (AOR 2.55, 95% CI 1.23–5.28), low (<100) baseline CD4 count (AOR 2.39, 95% CI 1.03–5.54) and nonadherence (AOR 6.73, 95% CI 3.29–13.76).ConclusionIn this study, the prevalence of antiretroviral treatment failure was 15.9%. Being divorced, being naïve to antiretroviral therapy, low (<100 cells/mm3) baseline CD4 count and nonadherence were found to be significant predictors of virologic failure. ART programs should focus on early HIV diagnosis and ART initiation as well as enhanced adherence support.

Adherence to HIV post-exposure prophylaxis for children/adolescents who have been sexually assaulted: A systematic review of barriers, enablers, and interventions

Post-exposure prophylaxis (PEP) is a key intervention for preventing HIV acquisition, including following sexual assault. However, uptake and completion rates for HIV PEP are lowest following sexual assault, with only 40% reporting completing the 28-day course. We undertook a systematic review to assess barriers and enablers to adherence to PEP in children and adolescents following sexual assault and identify potential interventions.Five databases and one conference abstract library were searched using adapted search strategies to identify quantitative and qualitative studies reporting patient-reported barriers and enablers to PEP and randomized trials assessing interventions to improve PEP adherence and completion rates. All searches were conducted up to October 2016; the search was updated in PubMed up to 31 July 2018.14 studies reported barriers and enablers to PEP adherence. The most commonly cited patient/caregiver reported barriers to PEP adherence/completion included side effects, forgetting, stigma/blame, being busy, poor knowledge, and mental health problems. The most commonly reported factors associated with PEP adherence/completion (reported across 7 studies) included health provider encouragement to take PEP (type of encouragement not described), perpetrator known to be HIV-positive, monetary support for transport, the victim of assault attending counseling, being reminded by family/peers to take PEP, and “one-stop” services offering both HIV testing and PEP at initial consultation. Three randomized trials provided limited evidence supporting the potential benefit of enhanced adherence support for HIV PEP; however, data for children were lacking.Despite low completion rates, there is limited research into causes of and interventions to improve adherence to PEP following sexual assault, and no direct evidence for children.

Treatment adherence and support for people who inject drugs taking direct-acting antiviral therapy for hepatitis C infection.

A community-based public health facility in Sydney, Australia, the Kirketon Road Centre (KRC), provides health care to people who inject drugs (PWID), homeless and other marginalized people. Since March 2016, KRC has provided treatment for chronic hepatitis C virus (HCV) with direct-acting antivirals (DAAs). We aimed to evaluate treatment adherence amongst clients taking DAAs in a highly marginalized population. All clients who commenced DAA therapy prior to March 2018 at KRC were included in this observational cohort with a subset of clients attending daily or weekly for enhanced adherence support and dosing. Demographic, behavioural, clinical measures and medication dosing were recorded, and adherence was calculated as the proportion of doses taken during the expected treatment duration. Factors associated with adherence were examined using logistic regression. A total of 242 individuals commenced DAA therapy, of whom 79 (32%) received enhanced adherence support. Enhanced support was associated with homelessness, daily injecting, Aboriginality, mental health co-morbidity and poly-drug use (all P<.001). Overall adherence was 86%, and 92% of patients missed one or more doses (median 10, IQR 4-24). At least 90% adherence during planned duration was seen in 38%, but increased to 66% by continuing therapy beyond planned duration. Intention-to-treat SVR12 was 68% and 66% in the enhanced adherence support sub-population, with 29% lost to follow-up by SVR12 testing. There were only 2 (0.8%) documented virological failures. Per-protocol SVR12 was 99% and 96% in the enhanced adherence support sub-population. In conclusion, adherence support may benefit those with multiple markers of marginalization. Extension of therapy beyond planned duration is a pragmatic strategy to enhance completion. Strategies to improve follow-up, particularly post-treatment are required.

Simplifying switch to second-line antiretroviral therapy in sub Saharan Africa: predicted effect of using a single viral load to define efavirenz-based first-line failure.

Background:Many individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality.Methods:To assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART.Findings:The use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14–20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6–30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8–49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67–3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually.Interpretation:As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.

Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial

Antiretroviral therapy (ART) non-adherence causes HIV treatment failure. Past behaviour might predict future behaviour; failing second-line ART could indicate ongoing risk for subsequent non-adherence. We aimed to find out whether a two-way mobile phone-based communication intervention would increase HIV treatment success by improving medication adherence. We did a multinational, randomised controlled trial of patients at 17 sites in nine lower-income and middle-income countries in Africa, Asia, and the Americas. Patients aged 18 years and older, with HIV infection, and on second-line protease-inhibitor-based antiretroviral regimens, were randomly assigned (1:1) to either two-way mobile phone intervention plus standard of care (MPI + SOC) adherence support or standard-of-care alone (SOC). Our study was nested within a strategy study of ART after second-line ART failure (the main study, A5288). The main study had four cohorts, which were assigned regimens according to ART history and real-time genotype. Randomisation was stratified by the main study cohort with dynamic institutional balancing. Only the clinical management committee was masked, not the participants or site personnel. Text messages were sent over 48 weeks starting once a day and tapering down to once per week; participants were to respond once to each message if taking ART without issues. Repeated non-response to three messages over a 2-week period for the first 8 weeks, and then two messages over a 2-week period for the remainder of the study, triggered problem-solving counselling by staff. For this study, the primary endpoint was plasma HIV-1 RNA 200 copies per mL or less at 48 weeks and the secondary endpoint was virological failure (two consecutive HIV-1 RNA ≥1000 copies per mL) at 24 or more weeks. Prespecified intention-to- treat analyses were adjusted for cohort. Follow-up continued until the last participant had reached 48 weeks, with a median follow-up time of 72 weeks. The trial is registered with ClinicalTrials.gov, number . Enrolment began on Feb 22, 2013, and ended on Dec 21, 2015, with the last participant completing follow-up on Feb 13, 2017. Of 545 participants in the main study, 521 (96%) were enrolled and randomly assigned to MPI + SOC (n=257) or SOC alone (n=264). 52% of patients were men and the median HIV-1 RNA 4-4 log10 copies per mL (IQR 3.5 to 5-2). At week 48, HIV-1 RNA 200 copies per mL or less was reached in 169 (66%) of 257 patients in the MPI + SOC group and 164 (62%) of 264 patients in the SOC group (estimated difference 3-6% [95% CI -4-6% to 11-9%]; p=0-39). The adjusted odds ratio comparing MPI + SOC and SOC was 1-23 (0-82 to 1-84; p=0-32). Virological failure occurred in 66 (26%) patients in the MPI + SOC group and 89 (34%) patients in the SOC group during the median 72 weeks follow-up (adjusted p=0-027). Observed difference in virological failure favoured MPI + SOC in all cohorts. 23 (4%) participants died, 11 (4%) in the MPI + SOC group and 12 (5%) in the SOC group (p=0-89), with none of the deaths ascribed to ART, the MPI, or study procedures. Two-way MPI did not significantly improve week 48 suppression, but it did modestly affect virological failure. People failing second-line ART might not achieve benefits from phone-based triggers or enhanced adherence support (or both). More effective strategies are needed.

Factors associated with virological failure and suppression after enhanced adherence counselling, in children, adolescents and adults on antiretroviral therapy for HIV in Swaziland.

IntroductionThis study explores factors associated with virological detectability, and viral re-suppression after enhanced adherence counselling, in adults and children on antiretroviral therapy (ART) in Swaziland.MethodsThis descriptive study used laboratory data from 7/5/2012 to 30/9/2013, which were linked with the national ART database to provide information on time on ART and CD4 count; information on enhanced adherence counselling was obtained from file review in health facilities. Multivariable logistic regression was used to explore the relationship between viral load, gender, age, time on ART, CD4 count and receiving (or not receiving) enhanced adherence counselling.ResultsFrom 12,063 patients undergoing routine viral load monitoring, 1941 (16%) had detectable viral loads. Children were more likely to have detectable viral loads (AOR 2.6, 95%CI 1.5–4.5), as were adolescents (AOR 3.2, 95%CI 2.2–4.8), patients with last CD4<350 cells/µl (AOR 2.2, 95%CI 1.7–2.9) or WHO Stage 3/4 disease (AOR 1.3, 95%CI 1.1–1.6), and patients on ART for longer (AOR 1.1, 95%CI 1.1–1.2). At retesting, 450 (54% of those tested) showed viral re-suppression. Children were less likely to re-suppress (AOR 0.2, 95%CI 0.1–0.7), as were adolescents (AOR 0.3, 95%CI 0.2–0.8), those with initial viral load> 1000 copies/ml (AOR 0.3, 95%CI 0.1–0.7), and those with last CD4<350 cells/µl (AOR 0.4, 95%CI 0.2–0.7). Receiving (or not receiving) enhanced adherence counselling was not associated with likelihood of re-suppression.ConclusionsChildren, adolescents and those with advanced disease were most likely to have high viral loads and least likely to achieve viral suppression at retesting; receiving adherence counselling was not associated with higher likelihood of viral suppression. Although the level of viral resistance was not quantified, this study suggests the need for ART treatment support that addresses the adherence problems of younger people; and to define the elements of optimal enhanced adherence support for patients of all ages with detectable viral loads.

Second-line failure and first experience with third-line antiretroviral therapy in Mumbai, India

BackgroundThere are limited data on the failure of second-line antiretroviral therapy (ART) and the use of third-line ART in people living with HIV in resource-limited settings. Since 2011, the Médecins Sans Frontières (MSF) HIV/tuberculosis programme in Mumbai, India, has been providing third-line ART to patients in care.ObjectiveTo describe the experiences and programmatic challenges during management of suspected second-line ART failure and third-line ART therapy for patients living with HIV, including the use of HIV viral load (VL) testing.DesignThis was a retrospective, observational cohort study of patients with suspected second-line ART treatment failure, who were followed for at least 12 months between January 2011 and March 2014.ResultsA total of 47 patients with suspected second-line failure met the inclusion criteria during the study period. Twenty-nine of them (62%) responded to enhanced adherence support, had a subsequent undetectable VL after a median duration of 3 months and remained on second-line ART. The other 18 patients had to be initiated on a third-line ART regimen, which consisted of darunavir–ritonavir, raltegravir, and one or more appropriate nucleoside or nucleotide reverse transcriptase inhibitors, based on the results of HIV genotype testing. Of the 13 patients for whom follow-up VL results were available, 11 achieved virological suppression after a median duration of 3 months on third-line ART (interquartile range: 2.5–3.0). No serious treatment-related adverse events were recorded.ConclusionsWith intensive counselling and adherence support in those suspected of failing second-line ART, unnecessary switching to more expensive third-line ART can be averted in the majority of cases. However, there is an increasing need for access to third-line ART medications such as darunavir and raltegravir, for which national ART programmes should be prepared. The cost of such medications and inadequate access to VL monitoring and HIV genotype testing are currently major barriers to optimal management of patients failing second-line ART.

Increased Immunosuppression Level Variation Is Associated With Donor Specific Antibodies in Young Renal Transplant Recipients.

Purpose: Non-adherence (defined subjectively) is associated with donor-specific antibody (DSA) development in renal transplant recipients (RTRs). We studied the relationship of objective measures of non-adherence - standard deviation (SD) and coefficient of variation (CoV) of immunosuppressant (IS) trough levels - with DSA prevalence. Methods: Retrospective analysis of SD and CoV in the 5 most recent tacrolimus or sirolimus trough levels at the time of DSA testing in 69 non-high immunologic risk RTRs followed at our center since we initiated DSA testing in 2010. Results: DSA prevalence was 46% (n=32); 50% were noted at testing initiation. Baseline demographics were similar among DSA + and - RTRs for median age at RT (10.7 vs 11.1 years) and DSA testing (15.5 vs 19 years), male gender (84% vs 65%), underlying renal diagnosis, donor type (69% vs 76% living), pre-transplant PRA < 20% (97% vs 100%) and time post-RT to DSA testing (3.1 vs 3.6 years). DSA+ RTRs were more likely black (28% vs 8%, p=0.05), less likely to have a PRA of 0 (77% vs 100%, p<0.01) and less well HLA-matched (median 4/6 vs 3/6; p<0.01) notably at class II loci (91% with any class II mismatch vs 68%, p=0.04). At the time of DSA testing, DSA+ RTRs had lower estimated GFR (median 56.5 vs 73.5 ml/min/1.73 m2 by Schwartz formula, p=0.03) but only 9 DSA+ RTRs had allograft dysfunction as defined by an increase in serum creatinine >20%. DSA+ RTRs were more likely on sirolimus (66% vs 41%, p=0.05) or steroids (56% vs 27%, p=0.02) but had similar MMF use (69% vs 62%). DSA+ RTRs had higher variations in IS trough levels, defined as a SD >2 (53% vs 27%, p=0.05) or CoV >40% (44% vs 11%, p<0.01). Multivariate logistic regression demonstrated that CoV >40% (p=0.01), steroid use (p=0.04) and sirolimus use (p=0.06) remained significantly associated with DSA prevalence. Conclusions: In our single-center sample of young renal transplant recipients, sirolimus use, steroid use and increased variation of IS levels were associated with DSA prevalence. RTRs with DSAs may thus benefit from enhanced adherence support.

Viral Load for HIV Treatment Failure Management: A Report of Eight Drug-Resistant Tuberculosis Cases Co-Infected with HIV Requiring Second-Line Antiretroviral Treatment in Mumbai, India

Dear Sir: We read with great interest the report by Satti H, McLaughlin MM, and Seung KJ describing six HIV/drug-resistant tuberculosis (HIV/DR-TB) co-infected patients who failed first-line antiretroviral treatment (ART) in Lesotho.1 We would like to share an experience treating similar patients in Mumbai, India. Although having a lower HIV prevalence compared with many African countries, India has the third largest population living with HIV, after South Africa and Nigeria, with an estimated 2,090,000 people affected in 2011.2 Furthermore, India has the highest burden of TB in the world, representing one-fifth (21%) of the global incidence. Unfortunately, India does not have national data on DR-TB prevalence, but a survey conducted in the States of Gujarat and Maharashtra in 2007 estimated the prevalence of DR-TB to be 3% in new cases and 12–17% in retreatment cases.3 Between October 2006 and July 2013, Medecins Sans Frontieres (MSF) treated 129 DR-TB patients co-infected with HIV at a clinic in Mumbai. The patients were referred to us from government ART centers, public-private ART centers, and a network of community non-governmental organizations. All HIV patients were monitored with viral load (VL) testing at least every 6 months, as recommended by Satti. Patients identified as having virological failure received adherence counseling and subsequently had the VL test rechecked at 3–6 months. Those in whom the VL test did not re-suppress were switched to a second-line ART regimen consisting of a protease inhibitor (PI) and suitable nucleoside(tide) reverse transcriptase inhibitors (NRTIs), based on genotype HIV resistance testing when necessary. Of the 129 DR-TB patients co-infected with HIV, 8 patients required second-line ART4; the median baseline CD4 count of the 8 patients before DR-TB treatment initiation was 102.5 cells/μL. Three of the 8 patients were on first-line ART at the time of DR-TB treatment initiation and had to be switched to second-line ART during the course of DR-TB treatment (Table 1). All 3 had a VL result > 5,000 copies/mL before the switch; subsequent VL testing showed a 2-log decrease in the two patients in whom a result was available. Table 1 CD4 count, viral load, and TB treatment response of patients on second-line ART In the six patients having a CD4 count available at the end of DR-TB treatment, five had an increase compared with baseline. Five out of eight patients had successful outcomes: 3 were cured and 2 successfully completed DR-TB treatment. Two patients were unfortunately lost to follow-up, and there was one death (Case 5). In this latter case, there was extensive pulmonary involvement and additional resistance of the TB strain to fluoroquinolones. We agree with the recommendation of Satti that VL testing be performed routinely in DR-TB patients co-infected with HIV. It allows for early detection of ART adherence problems, which has been shown in other reports to prevent an unnecessary switch to a second-line regimen with enhanced adherence support.5 In those in whom the VL result cannot be re-suppressed (i.e. caused by development of HIV drug resistance), an early switch to a second-line regimen is likely to increase the chances of a more successful outcome. We would like to reinforce an additional point that was implied in their Short Report, that DR-TB and HIV management be integrated in co-infected patients. Such patients are complicated and ideally should be managed in the same health facility by the same team of health care providers. At present, HIV VL testing is reserved only for suspected cases of treatment failure attending public ART centers in Mumbai and is not used for routine monitoring. Such an approach is likely to delay early detection of ART failure and contribute to the poor outcomes being seen in DR-TB patients co-infected with HIV.6 In this and other national HIV/ART programs not yet implementing routine VL testing, we ask that this be prioritized in HIV patients being treated for DR-TB. We also hope to see stronger collaboration between all HIV/ART and DR-TB programs with a view toward eventual integration of services for these complicated patients, to allow for better management.7

High rate of virological re-suppression among patients failing second-line antiretroviral therapy following enhanced adherence support: A model of care in Khayelitsha, South Africa

Objective. To describe and evaluate the outcomes of a support programme for patients with virological failure while receiving second-line antiretroviral therapy (ART) in South Africa. Method. We described a comprehensive medical and counselling patient support programme for patients receiving secondline ART and with two consecutive viral loads (VLs) >1 000 copies/ml. Patients with >3 months follow-up and at least one VL measurement after inclusion in the programme were eligible for analysis. Results. Of 69 patients enrolled in the programme, 40 had at least one follow-up VL and no known drug resistance at enrolment; 27 (68%) of these re-suppressed while remaining on second-line ART following enhanced adherence support. The majority (18/27; 67%) achieved re-suppression within the first 3 months in the programme. Five patients with diagnosed second-line drug resistance achieved viral re-suppression (<400 copies/ml) after being switched to third-line ART. Seven patients (7/40; 18%) did not achieve viral re-suppression after 9 months in the programme: 6 with known adherence problems (4 without drug resistance on genotype) and 1 with a VL <1 000 copies/ml. Overall, 3 patients (4%) died, 3 (4%) were lost to follow-up and 2 (3%) were transferred out. Conclusion. Our experience from a routine programme demonstrates that with targeted adherence support, the majority of patients who were viraemic while receiving second-line ART returned to an undetectable VL within 3 months. By increasing the time receiving second-line ART and decreasing the need for genotypes and/or third-line ART, this intervention may reduce costs.

High rate of virological re-suppression among patients failing second-line antiretroviral therapy following enhanced adherence support: A model of care in Khayelitsha, South Africa

Objective. To describe and evaluate the outcomes of a support programme for patients with virological failure while receiving second-line antiretroviral therapy (ART) in South Africa.Method. We described a comprehensive medical and counselling patient support programme for patients receiving secondline ART and with two consecutive viral loads (VLs) &gt;1 000 copies/ml. Patients with &gt;3 months follow-up and at least one VL measurement after inclusion in the programme were eligible for analysis.Results. Of 69 patients enrolled in the programme, 40 had at least one follow-up VL and no known drug resistance at enrolment; 27 (68%) of these re-suppressed while remaining on second-line ART following enhanced adherence support. The majority (18/27; 67%) achieved re-suppression within the first 3 months in the programme. Five patients with diagnosed second-line drug resistance achieved viral re-suppression (&lt;400 copies/ml) after being switched to third-line ART. Seven patients (7/40; 18%) did not achieve viral re-suppression after 9 months in the programme: 6 with known adherence problems (4 without drug resistance on genotype) and 1 with a VL &lt;1 000 copies/ml. Overall, 3 patients (4%) died, 3 (4%) were lost to follow-up and 2 (3%) were transferred out.Conclusion. Our experience from a routine programme demonstrates that with targeted adherence support, the majority of patients who were viraemic while receiving second-line ART returned to an undetectable VL within 3 months. By increasing the time receiving second-line ART and decreasing the need for genotypes and/or third-line ART, this intervention may reduce costs.