A randomised trial of "Fresh Start" text messaging to improve return to care in people living with HIV who missed appointments in South Africa.

OBJECTIVE: Treatment interruptions are a barrier to successful antiretroviral therapy (ART). "Fresh start messages", which leverage significant days on the calendar (e.g., new year, public holiday) in order to prompt action, have the potential to encourage people living with HIV to return to care. We evaluated a "fresh start" intervention (text messages) to increase return to care in PLHIV who had missed their last appointment. DESIGN: A three arm 1:1:1 individual randomised controlled trial. METHODS: We randomized adults in Capricorn District who had missed ART appointments by more than 28 days to: a) no text message; b) unframed messages (fresh start not mentioned); or c) framed messages (fresh start mentioned). Randomisation was stratified by treatment interruption duration and across two holidays (Youth Day, Mandela Day). The primary outcome was an ART-related clinic visit at ≤45 days of the first message. RESULTS: 9143 participants were randomised. For Youth Day, 1474 and 1468 were sent unframed and framed messages respectively, with 13.4% sent these messages having an ART visit vs 11.9% not sent a message (aOR 1.2; 95% CI:1.0-1.4, p-value = 0.075). For Mandela Day, 1336 and 1334 were sent unframed and framed messages respectively, with 6.7% sent these messages having an ART-related clinic visit vs 5.4% not sent a message (aOR 1.2; 95% CI: 1.0-1.6; p-value = 0.100). CONCLUSIONS: Low-cost text messages sent around a "fresh start" date may increase the likelihood that patients who miss appointments return to care. This study suggests the potential of text messaging for motivating return to care.

A Single Question on Maternal HIV Status Can Improve Identification of Children Living With HIV in South Africa.

INTRODUCTION: Screening tools to improve identification of children living with HIV (CLHIV) have been validated and used in various settings. The aim of our study was to optimize a screening tool for Primary Healthcare Clinics (PHCs) in South Africa (SA). METHODS: A cross-sectional study was conducted at PHCs in Johannesburg and Mopani Districts, between June 2021 and June 2022. Children 5-14 years of age with HIV negative or unknown status accompanied by their mothers, or appropriate caregivers, were enrolled. Demographic data, responses to the screening tool questions, and HIV test results were captured. Logistic regression modeling was used to optimize an existing 10-item screening tool, and sensitivity, specificity, and number needed to test (NNT) used to choose the final tool. RESULTS: We enrolled 14,147 children in the study, with 62 children testing HIV positive (HIV positivity of 0.4%). The 10-item tool with a single positive response had a sensitivity of 91.9% and specificity of 43.3%. An optimal combination of 5-items with two positive responses had the lowest NNT of 72, 82.3% sensitivity and 74.2% specificity. Maternal HIV status alone, HIV positive or unknown, had a 95.2% sensitivity, 65.0% specificity and NNT of 84. The 1-item tool only would have missed 5% of CLHIV (N = 3) compared with the 5-item tool that missed 18% (n = 11). CONCLUSIONS: A 1-item screening tool asking about maternal HIV status can improve efficiency of testing of children in primary healthcare facilities in SA and improve identification of CLHIV who are not on treatment.

Exploring barriers to switching "on time" to second-line antiretroviral therapy among nurses in primary health care facilities, Ekurhuleni Health District, South Africa.

BACKGROUND: Ensuring that all HIV-infected people receive antiretroviral therapy (ART) and achieve viral suppression are key South African strategies to end the AIDS epidemic in the country. National HIV treatment guidelines recommend an immediate switch to second-line ART following virological failure with first-line ART. Nurses based in district health facilities are at the forefront of implementing this recommendation. While there are often delays in switching and in some instances no switch, the reasons for and barriers to delayed switching are not well understood at the primary care level. AIM: To explore the views of frontline nursing staff about factors contributing to delayed switching of patients who have failed first-line ART regimen in Ekurhuleni district, South Africa. METHODS: A qualitative study was conducted among 21 purposively sampled nurses who provide HIV treatment and care to patients in 12 primary health care (PHC) facilities in Ekurhuleni Health District, Gauteng Province, South Africa. Individual in-depth interviews explored nurses' experiences regarding their recognition of virological failure and understanding of "on time" switching to second-line ART. Interviews probed the circumstances contributing to delays in switching. After digital audio recording and transcription, manual inductive thematic analysis was used to analyse the data. FINDINGS: Multiple barriers were identified: 1) Healthcare provider factors included a lack of knowledge and confidence coupled with demotivation in the workplace; 2) Patient issues similarly comprised a lack of knowledge as well as resistance to being switched to another drug regimen and loss to follow up; 3) Systems factors were poor facility leadership, shortages of medication, staffing constraints, and the inability to trace laboratory results, especially for migrant patients. CONCLUSION: Reasons for delayed switching of patients to second-line ART are multifactorial and require integrated interventions at health provider, patient and health system levels.

Tobacco use among a population of women attending cervical cancer screening programs in primary health care clinics in South Africa: a cross-sectional study.

Introduction: we determined the prevalence, patterns and factors associated with tobacco use among women presenting for cervical cancer screening in primary health care clinics in Gauteng province, South Africa. Methods: this study utilized data from an ongoing cross-sectional study commenced in September 2018, in which 749 participants had responded to an interviewer-administered semi-structured questionnaire on socio-demographics, HIV status, tobacco use, family planning methods, sexual and cervical cancer screening behaviours. Data were entered into the web-based research electronic data capture (REDCap). We performed descriptive data analysis and included multivariate logistic regression. We considered a p-value < 0.05 statistically significant. Results: participants´ median age was 38 years (interquartile range: 31-38) with 43.9% (328) reporting being HIV-positive. The prevalence of ever and current tobacco use were 24.3% (182/749) and 17.1% (128/749) respectively. In multivariable logistic regression, participants who self-identified as racial ethnicity other than Black African and those who were HIV positive and not on antiretroviral treatment, had increased odds of reporting current tobacco use ((adjusted odds ratio (AOR)= 5.6, 95% CI: 3.2-9.8) and (AOR= 8.2, 95% CI: 2.0-34.1) respectively). Conclusion: current tobacco use is common among women attending cervical cancer screening programs in primary health care clinics in Gauteng Province. Furthermore, study findings suggest the need to integrate tobacco cessation treatments into women´s health and HIV treatment programs.

Adult medical emergency unit presentations due to adverse drug reactions in a setting of high HIV prevalence.

INTRODUCTION: South Africa has the world's largest antiretroviral treatment programme, which may contribute to the adverse drug reaction (ADR) burden. We aimed to determine the proportion of adult non-trauma emergency unit (EU) presentations attributable to ADRs and to characterise ADR-related EU presentations, stratified according to HIV status, to determine the contribution of drugs used in management of HIV and its complications to ADR-related EU presentations, and identify factors associated with ADR-related EU presentation. METHODS: We conducted a retrospective folder review on a random 1.7% sample of presentations over a 12-month period in 2014/2015 to the EUs of two hospitals in Cape Town, South Africa. We identified potential ADRs with the help of a trigger tool. A multidisciplinary panel assessed potential ADRs for causality, severity, and preventability. RESULTS: We included 1010 EU presentations and assessed 80/1010 (7.9%) as ADR-related, including 20/239 (8.4%) presentations among HIV-positive attendees. Among HIV-positive EU attendees with ADRs 17/20 (85%) were admitted, versus 22/60 (37%) of HIV-negative/unknown EU attendees. Only 5/21 (24%) ADRs in HIV-positive EU attendees were preventable, versus 24/63 (38%) in HIV-negative/unknown EU attendees. On multivariate analysis, only increasing drug count was associated with ADR-related EU presentation (adjusted odds ratio 1.10 per additional drug, 95% confidence interval 1.03 to 1.18), adjusted for age, sex, HIV status, comorbidity, and hospital. CONCLUSIONS: ADRs caused a significant proportion of EU presentations, similar to findings from other resource-limited settings. The spectrum of ADR manifestations in our EUs reflects South Africa's colliding epidemics of infectious and non-communicable diseases. ADRs among HIV-positive EU attendees were more severe and less likely to be preventable.

Emtricitabine-associated red cell aplasia.

: Emtricitabine is structurally similar to lamivudine, which has been associated with red cell aplasia. We describe four patients with severe anaemia presenting soon after starting emtricitabine-containing antiretroviral therapy. Bone marrow biopsy in three patients confirmed red cell aplasia. Anaemia resolved after emtricitabine withdrawal in three patients, one patient died, and anaemia recurred on rechallenge in one patient whose anaemia persisted on lamivudine, resolving when this was stopped, suggesting a possible cross-reaction between lamivudine and emtricitabine.

Cases of antiretroviral-associated gynaecomastia reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa.

BACKGROUND: Gynaecomastia is associated with exposure to antiretroviral therapy (ART), in particular efavirenz. There is limited data on clinical characteristics of patients with ART-associated gynaecomastia in resource-limited settings and little guidance on the optimal management of this adverse drug reaction (ADR). We describe the clinical characteristics, management and outcomes of gynaecomastia cases reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa. METHODS: We identified all gynaecomastia cases in adolescent boys and men on ART reported to the hotline between June 2013 and July 2014. We collected follow up data telephonically at monthly intervals to document clinical management and outcomes. RESULTS: We received 51 reports of gynaecomastia between June 2013 and July 2014; 11% of the 475 patient-specific ADR queries to the hotline. All patients were on efavirenz-based ART. Mean age was 34 years (standard deviation 12) and seven were adolescents. The median onset of gynaecomastia was 15 months after efavirenz initiation (interquartile range 6-42). Gynaecomastia was bilateral in 29 patients (57%) and unilateral in 16 (31%). Serum testosterone was quantified in 25 of 35 patients with follow up data, and was low in 2 (8%). Efavirenz was replaced with an alternative antiretroviral in 29/35 patients (83%) and gynaecomastia improved in 20/29 (69%). CONCLUSIONS: Gynaecomastia was a frequently reported ADR in our setting, occurring with prolonged efavirenz exposure. Testosterone was low in the minority of tested cases. Most clinicians elected to switch patients off efavirenz, and gynaecomastia improved in the majority.

Adverse Drug Reactions Causing Admission to Medical Wards: A Cross-Sectional Survey at 4 Hospitals in South Africa.

Limited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions.We prospectively followed patients admitted to 4 hospitals' medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission.There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34-65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (P ≤ 0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06-2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09-1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07-1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17-3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable.In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect South Africa's high HIV and tuberculosis burden. Identification and management of these ADRs should be considered in HIV and tuberculosis care and treatment programs and should be emphasized in health care worker training programmes.

Adverse Drug Reactions Reported to a National HIV & Tuberculosis Health Care Worker Hotline in South Africa: Description and Prospective Follow-Up of Reports.

INTRODUCTION: The National HIV & Tuberculosis Health Care Worker (HCW) Hotline provides advice on the management of suspected adverse drug reactions (ADRs). We describe suspected ADRs reported to the hotline by HCWs, concordance with advice, and patient outcomes. METHODS: We reviewed suspected ADRs in HIV-infected patients, patients taking antiretrovirals and patients taking anti-tuberculosis therapy reported from May 2013 to October 2014. We performed causality assessment using the World Health Organization Uppsala Monitoring Centre (WHO-UMC) criteria. We included suspected ADRs categorized as certain, probable or possible in further analysis. RESULTS: We received 772 ADR reports, of which 87/772 (11.3%) were classified as certain, 176/772 (22.8%) as probable, 361/772 (46.8%) as possible, and 148/772 (19.2%) as unlikely or unassessable. The most frequent ADRs were rash, drug-induced liver injury (DILI) and kidney injury, comprising 110/624 (17.6%), 87/624 (13.9%), and 77/624 (12.3%), respectively. The ADR was severe in 27.3% of rashes, 36.4% of kidney injury reports and 88.5% of DILI reports. Most frequently implicated drugs, either alone or in combination with other potentially causative drugs, were efavirenz (rashes), efavirenz and anti-tuberculosis drugs (DILI) and tenofovir (kidney injury). In 383 cases with HCW follow-up, 254 (66.3%) improved, 9 (2.3%) had complete resolution, 32 (8.4%) remained unchanged, 6 (1.6%) deteriorated, 10 (2.6%) died and 72 (18.8%) had unknown outcome. Advice provided was followed in 93.2% of these cases. Of 223 ADRs with preventability data, 40 (17.9%) were preventable. CONCLUSION: Queries about rashes, DILIs and kidney injuries were common. Detection and management of these ADRs should be included in HCW training. In cases with follow-up, concordance with advice was high, and HCWs reported improvement in the majority.

Mortality from adverse drug reactions in adult medical inpatients at four hospitals in South Africa: a cross-sectional survey.

AIMS: Fatal adverse drug reactions (ADRs) are important causes of death, but data from resource-limited settings are scarce. We determined the proportion of deaths in South African medical inpatients attributable to ADRs, and their preventability, stratified by human immunodeficiency virus (HIV) status. METHODS: We reviewed the folders of all patients who died over a 30 day period in the medical wards of four hospitals. We identified ADR-related deaths (deaths where an ADR was 'possible', 'probable' or 'certain' using WHO-UMC criteria and where the ADR contributed to death). We determined preventability according to previously published criteria. RESULTS: ADRs contributed to the death of 2.9% of medical admissions and 56 of 357 deaths (16%) were ADR-related. Tenofovir, rifampicin and co-trimoxazole were the most commonly implicated drugs. 43% of ADRs were considered preventable. The following factors were independently associated with ADR-related death: HIV-infected patients on antiretroviral therapy (adjusted odds ratio (aOR) 4.4, 95% confidence interval (CI) 1.6, 12), exposure to more than seven drugs (aOR 2.5, 95% CI 1.3, 4.8) and increasing comorbidity score (aOR 1.3, 95% CI 1.1, 1.7). CONCLUSIONS: In our setting, where HIV and tuberculosis are highly prevalent, fatal in-hospital ADRs were more common than reported in high income settings. Most deaths were attributed to drugs used in managing HIV and tuberculosis. A large proportion of the ADRs were preventable, highlighting the need to strengthen systems for health care worker training and support.

Rates of switching antiretroviral drugs in a primary care service in South Africa before and after introduction of tenofovir.

INTRODUCTION: Antiretroviral changes (single drug substitutions and regimen switches) limit treatment options and introduce challenges such as increased cost, monitoring and adherence difficulties. Patterns of drug substitutions and regimen switches from stavudine (d4T) and zidovudine (AZT) regimens have been well described but data on tenofovir (TDF) are more limited. This study describes the patterns and risk factors for drug changes of these antiretroviral drugs in adults. METHOD: This retrospective cohort study included HIV positive, antiretroviral treatment (ART) naïve adults aged ≥18 years who started ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor. Follow-up was censored at first drug change and analysis focused on NRTI changes only. RESULTS: Between September 2002 and April 2011, 5095 adults initiated ART in Gugulethu. This comprised 948 subjects on TDF, 3438 on d4T and 709 subjects on AZT. Virological suppression rates at 1 year, regimen switching due to virological failure and overall losses to the programme were similar across the three groups. TDF had the lowest incidence rate of drug substitutions (2.6 per 100 P/Ys) compared to 17.9 for d4T and 8.5 per 100 P/Ys for AZT. Adverse drug reactions (ADRs) accounted for the majority of drug substitutions of d4T. Multivariate analysis showed that increasing age, female sex and d4T exposure were associated with increased hazard of drug substitution due to ADRs. Conversely, TDF exposure was associated with a substantially lower risk of substitution (adjusted hazards ratio 0.38; 95% CI 0.20-0.72). CONCLUSION: Regimen switches and virological suppression were similar for patients exposed to TDF, d4T and AZT, suggesting all regimens were equally effective. However, TDF was better tolerated with a substantially lower rate of drug substitutions due to ADRs.