Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis.

Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

Reducing HIV-associated post-hospital mortality through home-based care in South Africa: a randomized controlled trial.

BACKGROUND: Twenty-three percent of people with HIV (PWH) die within 6-months of hospital discharge. We tested the hypothesis whether a series of structured home visits could reduce mortality. METHODS: We designed a disease neutral home visit package with up to 6 home visits starting 1-week post-hospitalization and every 2 weeks thereafter. The home visit team used a structured assessment algorithm to evaluate and triage social and medical needs of the participant and provide nutritional support. We compared all-cause mortality 6-months following discharge for the intervention compared to usual care in a pilot randomized trial conducted in South Africa. To inform potential scale-up we also included and separately analyzed a group of people without HIV (PWOH). RESULTS: We enrolled 125 people with HIV and randomized them 1:1 to the home visit intervention or usual care. Fourteen were late exclusions because of death prior to discharge or delayed discharge leaving 111 for analysis. The median age was 39 years, 31% were men; and 70% had advanced HIV disease. At six months among PWH 4 (7.3%) in the home visit arm and 10 (17.9%) in the usual care arm (p = 0.09) had died. Among the 70 PWOH enrolled overall 6-month mortality was 10.1%. Of those in the home visit arm, 91% received at least one home visit. CONCLUSIONS: We demonstrated feasibility of delivering post-hospital home visits and demonstrated preliminary efficacy among PWH with a substantial, but not statistically significant, effect size (59% reduction in mortality). COVID-19 related challenges resulted in under-enrollment.

Undiagnosed Pulmonary Tuberculosis (TB) and Coronavirus Disease 2019 (COVID-19) in Adults Dying at Home in a High-TB-Burden Setting, Before and During Pandemic COVID-19: An Autopsy Study.

BACKGROUND: Missing or undiagnosed patients with tuberculosis (TB) or coronavirus disease 2019 (COVID-19) are of concern. Identifying both infections in patients with no diagnosis prior to death contributes to understanding the burden of disease. To confirm reports of global reduction in TB incidence, a 2012 autopsy study of adults dying at home of natural causes in a high-TB-burden setting was repeated, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assessments after the first COVID-19 surge in South Africa. METHODS: Adult decedents who died at home with insufficient information to determine cause of death, no recent hospitalization, and no current antemortem TB or COVID-19 diagnosis were identified between March 2019 and October 2020 with a 4-month halt during lockdown. A standardized verbal autopsy followed by minimally invasive needle autopsy (MIA) was performed. Biopsies were taken for histopathology from liver, bilateral brain and lung; bronchoalveolar lavage fluid was collected for Xpert (MTB/RIF) and mycobacterial culture, and blood for human immunodeficiency virus (HIV) polymerase chain reaction (PCR) testing. After the start of the COVID-19 pandemic, a nasopharyngeal swab and lung tissue were subjected to SARS-CoV-2 PCR testing. RESULTS: Sixty-six MIAs were completed in 25 men and 41 women (median age, 60 years); 68.2% had antemortem respiratory symptoms and 30.3% were people with HIV. Overall, TB was diagnosed in 11 of 66 (16.7%) decedents, and 14 of 41 (34.1%) in the COVID-19 pandemic were SARS-CoV-2 positive. CONCLUSIONS: Undiagnosed TB in adults dying at home has decreased but remains unacceptably high. Forty percent of decedents had undiagnosed COVID-19, suggesting that estimates of excess deaths may underestimate the impact of SARS-CoV-2 on mortality.

The burden of RSV-associated illness in children aged < 5 years, South Africa, 2011 to 2016.

BACKGROUND: Vaccines and monoclonal antibodies to protect the very young infant against the respiratory syncytial virus (RSV)-associated illness are effective for limited time periods. We aimed to estimate age-specific burden to guide implementation strategies and cost-effectiveness analyses. METHODS: We combined case-based surveillance and ecological data to generate a national estimate of the burden of RSV-associated acute respiratory illness (ARI) and severe acute respiratory illness (SARI) in South African children aged < 5 years (2011-2016), including adjustment for attributable fraction. We estimated the RSV burden by month of life in the < 1-year age group, by 3-month intervals until 2 years, and then 12 monthly intervals to < 5 years for medically and non-medically attended illness. RESULTS: We estimated a mean annual total (medically and non-medically attended) of 264,112 (95% confidence interval (CI) 134,357-437,187) cases of RSV-associated ARI and 96,220 (95% CI 66,470-132,844) cases of RSV-associated SARI (4.7% and 1.7% of the population aged < 5 years, respectively). RSV-associated ARI incidence was highest in 2-month-old infants (18,361/100,000 population, 95% CI 9336-28,466). The highest incidence of RSV-associated SARI was in the < 1-month age group 14,674/100,000 (95% CI 11,175-19,645). RSV-associated deaths were highest in the first and second month of life (110.8 (95% CI 74.8-144.5) and 111.3 (86.0-135.8), respectively). CONCLUSIONS: Due to the high burden of RSV-associated illness, specifically SARI cases in young infants, maternal vaccination and monoclonal antibody products delivered at birth could prevent significant RSV-associated disease burden.

The economic burden of RSV-associated illness in children aged < 5 years, South Africa 2011-2016.

BACKGROUND: Data on the economic burden of RSV-associated illness will inform decisions on the programmatic implementation of maternal vaccines and monoclonal antibodies. We estimated the cost of RSV-associated illness in fine age bands to allow more accurate cost-effectiveness models to account for a limited duration of protection conferred by short- or long-acting interventions. METHODS: We conducted a costing study at sentinel sites across South Africa to estimate out-of-pocket and indirect costs for RSV-associated mild and severe illness. We collected facility-specific costs for staffing, equipment, services, diagnostic tests, and treatment. Using case-based data we calculated a patient day equivalent (PDE) for RSV-associated hospitalizations or clinic visits; the PDE was multiplied by the number of days of care to provide a case cost to the healthcare system. We estimated the costs in 3-month age intervals in children aged < 1 year and as a single group for children aged 1-4 years. We then applied our data to a modified version of the World Health Organization tool for estimating the mean annual national cost burden, including medically and non-medically attended RSV-associated illness. RESULTS: The estimated mean annual cost of RSV-associated illness in children aged < 5 years was US dollars ($)137,204,393, of which 76% ($111,742,713) were healthcare system incurred, 6% ($8,881,612) were out-of-pocket expenses and 13% ($28,225,.801) were indirect costs. Thirty-three percent ($45,652,677/$137,204,393) of the total cost in children aged < 5 years was in the < 3-month age group, of which 52% ($71,654,002/$137,204,393) were healthcare system incurred. The costs of non-medically attended cases increased with age from $3,307,218 in the < 3-month age group to $8,603,377 in the 9-11-month age group. CONCLUSIONS: Among children < 5 years of age with RSV in South Africa, the highest cost burden was in the youngest infants; therefore, interventions against RSV targeting this age group are important to reduce the health and cost burden of RSV-associated illness.

Remote Ischaemic Conditioning in STEMI Patients in Sub-Saharan AFRICA: Rationale and Study Design for the RIC-AFRICA Trial.

PURPOSE: Despite evidence of myocardial infarct size reduction in animal studies, remote ischaemic conditioning (RIC) failed to improve clinical outcomes in the large CONDI-2/ERIC-PPCI trial. Potential reasons include that the predominantly low-risk study participants all received timely optimal reperfusion therapy by primary percutaneous coronary intervention (PPCI). Whether RIC can improve clinical outcomes in higher-risk STEMI patients in environments with poor access to early reperfusion or PPCI will be investigated in the RIC-AFRICA trial. METHODS: The RIC-AFRICA study is a sub-Saharan African multi-centre, randomized, double-blind, sham-controlled clinical trial designed to test the impact of RIC on the composite endpoint of 30-day mortality and heart failure in 1200 adult STEMI patients without access to PPCI. Randomized participants will be stratified by whether or not they receive thrombolytic therapy within 12 h or arrive outside the thrombolytic window (12-24 h). Participants will receive either RIC (four 5-min cycles of inflation [20 mmHg above systolic blood pressure] and deflation of an automated blood pressure cuff placed on the upper arm) or sham control (similar protocol but with low-pressure inflation of 20 mmHg and deflation) within 1 h of thrombolysis and applied daily for the next 2 days. STEMI patients arriving greater than 24 h after chest pain but within 72 h will be recruited to participate in a concurrently running independent observational arm. CONCLUSION: The RIC-AFRICA trial will determine whether RIC can reduce rates of death and heart failure in higher-risk sub-optimally reperfused STEMI patients, thereby providing a low-cost, non-invasive therapy for improving health outcomes.

An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter, Randomized Controlled Clinical Trial (the NExT Study).

Rationale: Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides). Methods: Participants were randomly assigned (1:1 ratio) to a ∼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa. Measurements and Main Results: In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10 of 44]; risk ratio, 2.2 [1.2-4.1]; P = 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7% [17 of 49]; P = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% [31 of 55] vs. 32.1% [17 of 56]; P = 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18 of 55]; P = 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 [1.4-4.9]; P = 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms; P = 0.01). Conclusions: Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).

Epidemiology of Pertussis in Individuals of All Ages Hospitalized With Respiratory Illness in South Africa, January 2013-December 2018.

BACKGROUND: Policy recommendations on pertussis vaccination need to be guided by data, which are limited from low- and middle-income countries. We aimed to describe the epidemiology of pertussis in South Africa, a country with high human immunodeficiency virus (HIV) prevalence and routine pertussis vaccination for 6 decades including the acellular vaccine since 2009. METHODS: Hospitalized patients of all ages were enrolled at 5 sentinel sites as part of a pneumonia surveillance program from January 2013 through December 2018. Nasopharyngeal specimens and induced sputum were tested by polymerase chain reaction (PCR) for Bordetella pertussis. In addition, demographic and clinical information were collected. Incidence rates were calculated for 2013-2016, and multivariable logistic regression performed to identify factors associated with pertussis. RESULTS: Over the 6-year period 19 429 individuals were enrolled, of which 239 (1.2%) tested positive for B. pertussis. Detection rate was highest in infants aged <6 months (2.8%, 155/5524). Mean annual incidence was 17 cases per 100 000 population, with the highest incidence in children <1 year of age (228 per 100 000). Age-adjusted incidence was 65.9 per 100 000 in HIV-infected individuals compared to 8.5 per 100 000 in HIV-uninfected individuals (risk ratio 30.4, 95% confidence interval: 23.0-40.2). Ten individuals (4.2%) with pertussis died; of which 7 were infants aged <6 months and 3 were immunocompromised adults. CONCLUSIONS: Pertussis continues to be a significant cause of illness and hospitalization in South Africa, despite routine vaccination. The highest burden of disease and death occurred in infants; however, HIV-infected adults were also identified as an important group at risk of B. pertussis infection.

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing.

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.

Decline of influenza and respiratory syncytial virus detection in facility-based surveillance during the COVID-19 pandemic, South Africa, January to October 2020.

BackgroundIn South Africa, COVID-19 control measures to prevent SARS-CoV-2 spread were initiated on 16 March 2020. Such measures may also impact the spread of other pathogens, including influenza virus and respiratory syncytial virus (RSV) with implications for future annual epidemics and expectations for the subsequent northern hemisphere winter.MethodsWe assessed the detection of influenza and RSV through facility-based syndromic surveillance of adults and children with mild or severe respiratory illness in South Africa from January to October 2020, and compared this with surveillance data from 2013 to 2019.ResultsFacility-based surveillance revealed a decline in influenza virus detection during the regular season compared with previous years. This was observed throughout the implementation of COVID-19 control measures. RSV detection decreased soon after the most stringent COVID-19 control measures commenced; however, an increase in RSV detection was observed after the typical season, following the re-opening of schools and the easing of measures.ConclusionCOVID-19 non-pharmaceutical interventions led to reduced circulation of influenza and RSV in South Africa. This has limited the country's ability to provide influenza virus strains for the selection of the annual influenza vaccine. Delayed increases in RSV case numbers may reflect the easing of COVID-19 control measures. An increase in influenza virus detection was not observed, suggesting that the measures may have impacted the two pathogens differently. The impact that lowered and/or delayed influenza and RSV circulation in 2020 will have on the intensity and severity of subsequent annual epidemics is unknown and warrants close monitoring.

Post-trial perceptions of a symptom-based TB screening intervention in South Africa: implementation insights and future directions for TB preventive healthcare services.

BACKGROUND: Tuberculosis is a top-10 cause of under-5 mortality, despite policies promoting tuberculosis preventive therapy (TPT). We previously conducted a cluster randomized trial to evaluate the effectiveness of symptom-based versus tuberculin skin-based screening on child TPT uptake. Symptom-based screening did not improve TPT uptake and nearly two-thirds of child contacts were not identified or not linked to care. Here we qualitatively explored healthcare provider perceptions of factors that impacted TPT uptake among child contacts. METHODS: Sixteen in-depth interviews were conducted with key informants including healthcare providers and administrators who participated in the trial in Matlosana, South Africa. The participants' experience with symptom-based screening, study implementation strategies, and ongoing challenges with child contact identification and linkage to care were explored. Interviews were systematically coded and thematic content analysis was conducted. RESULTS: Participants' had mixed opinions about symptom-based screening and high acceptability of the study implementation strategies. A key barrier to optimizing child contact screening and evaluation was the supervision and training of community health workers. CONCLUSIONS: Symptom screening is a simple and effective strategy to evaluate child contacts, but additional pediatric training is needed to provide comfort with decision making. New clinic-based child contact files were highly valued by providers who continued to use them after trial completion. Future interventions to improve child contact management will need to address how to best utilize community health workers in identifying and linking child contacts to care. TRIAL REGISTRATION: The results presented here were from research related to NCT03074799 , retrospectively registered on 9 March 2017.

Improving Tuberculosis Preventive Therapy Uptake: A Cluster-randomized Trial of Symptom-based Versus Tuberculin Skin Test-based Screening of Household Tuberculosis Contacts Less Than 5 Years of Age.

BACKGROUND: Tuberculosis preventive therapy (TPT) is highly effective at preventing tuberculosis disease in household child contacts (<5 years), but is poorly implemented worldwide. In 2006, the World Health Organization recommended symptom-based screening as a replacement for tuberculin skin testing (TST) to simplify contact evaluation and improve implementation. We aimed to determine the effectiveness of this recommendation. METHODS: We conducted a pragmatic, cluster-randomized trial to determine whether contact evaluation using symptom screening improved the proportion of identified child contacts who initiated TPT, compared to TST-based screening, in Matlosana, South Africa. We randomized 16 clinics to either symptom-based or TST-based contact evaluations. Outcome data were abstracted from customized child contact management files. RESULTS: Contact tracing identified 550 and 467 child contacts in the symptom and TST arms, respectively (0.39 vs 0.32 per case, respectively; P = .27). There was no significant difference by arm in the adjusted proportion of identified child contacts who were screened (52% in symptom arm vs 60% in TST arm; P = .39). The adjusted proportion of identified child contacts who initiated TPT or tuberculosis treatment was 51.5% in the symptom clinics and 57.1% in the TST clinics (difference -5.6%, 95% confidence interval -23.7 to 12.6; P = .52). Based on the district's historic average of 0.7 child contacts per index case, 14% and 15% of child contacts completed 6 months of TPT in the symptom and TST arms, respectively (P = .89). CONCLUSIONS: Symptom-based screening did not improve the proportion of identified child contacts evaluated or initiated on TPT, compared to TST-based screening. Further research is needed to identify bottlenecks and evaluate interventions to ensure all child contacts receive TPT. CLINICAL TRIALS REGISTRATION: NCT03074799.

Secure Delivery of HIV-Related and Tuberculosis Laboratory Results to Patient Cell Phones: A Pilot Comparative Study.

South Africa processes 5.1 million HIV CD4, viral load (VL), and tuberculosis (TB) tests annually. This pilot non-randomized trial in South Africa explored an intervention ("MatlaMobile") to deliver laboratory results via mobile phone. Adults completing CD4, VL, and/or TB laboratory tests were enrolled-either receiving results by returning to clinic (control, n = 174) or mobile phone (intervention, n = 226). Study staff instructed control participants to return within 6 days (standard-of-care). MatlaMobile instructed intervention participants with clinically actionable results requiring intervention or treatment change (i.e., < 200 CD4 cells per milliliter, ≥ 400 viral copies per milliliter, or TB positive) to return immediately. A greater proportion of intervention participants than controls saw their results within 7 days of enrollment (73% vs. 8.6%, p < 0.001). Among participants instructed to return, more intervention participants (20%, n = 14/70) returned than controls (8.6%, n = 15/174, p = 0.02). MatlaMobile demonstrated that patients can quickly receive and respond appropriately to digital delivery of health information.

The Fraction of Rhinovirus Detections Attributable to Mild and Severe Respiratory Illness in a Setting of High Human Immunodeficiency Virus Prevalence, South Africa, 2013-2015.

BACKGROUND: The association of rhinovirus (RV) detection to illness is poorly understood. METHODS: We enrolled case patients hospitalized with severe respiratory illness (SRI) at 2 hospitals and outpatients with influenza-like illness (ILI) and asymptomatic individuals (controls) from 2 affiliated clinics during 2013-2015. We compared the RV prevalence among ILI and SRI cases to those of controls stratified by human immunodeficiency virus (HIV) serostatus using penalized logistic regression. The attributable fraction (AF) was calculated. RESULTS: During 2013-2015, RV was detected in 17.4% (368/2120), 26.8% (979/3654), and 23.0% (1003/4360) of controls, ILI cases, and SRI cases, respectively. The RV AF (95% confidence interval) was statistically significant among children aged <5 years (ILI: 44.6% [30.7%-55.7%] and SRI: 50.3% [38.6%-59.9%]; P < .001) and individuals aged ≥5 years (ILI: 62.9% [54.4%-69.8%] and SRI: 51.3% [38.7%-61.3%]; P < .001) as well as among HIV-infected (ILI: 59.9% [45.8%-70.3%] and SRI: 39.8% [22.3%-53.3%]; P < .001) and HIV-uninfected (ILI: 53.6% [44.7%-61.1%] and SRI: 55.3% [45.6%-63.2%]; P < .001) individuals. CONCLUSIONS: Although RV detection was common among controls, it was also associated with a substantial proportion of clinical illness across age groups, irrespective of HIV status.

Quantifying How Different Clinical Presentations, Levels of Severity, and Healthcare Attendance Shape the Burden of Influenza-associated Illness: A Modeling Study From South Africa.

BACKGROUND: Burden estimates of medically and nonmedically attended influenza-associated illness across syndromes and levels of severity are lacking. METHODS: We estimated the national burden of medically and nonmedically attended influenza-associated illness among individuals with different clinical presentations (all-respiratory, all-circulatory, and nonrespiratory/noncirculatory) and levels of severity (mild, fatal, and severe, nonfatal) using a combination of case-based (from laboratory-confirmed influenza surveillance) and ecological studies, as well as data from healthcare utilization surveys in South Africa during 2013-2015. In addition, we compared estimates of medically attended influenza-associated respiratory illness, obtained from case-based and ecological studies. Rates were reported per 100 000 individuals in the population. RESULTS: The estimated mean annual number of influenza-associated illness episodes was 10 737 847 (19.8% of 54 096 705 inhabitants). Of these episodes, 10 598 138 (98.7%) were mild, 128 173 (1.2%) were severe, nonfatal, and 11 536 (0.1%) were fatal. There were 2 718 140 (25.6%) mild, 56 226 (43.9%) severe, nonfatal, and 4945 (42.8%) medically attended should be after fatal episodes. Influenza-associated respiratory illness accounted for 99.2% (10 576 146) of any mild, 65.5% (83 941) of any severe, nonfatal, and 33.7% (3893) of any fatal illnesses. Ecological and case-based estimates of medically attended, influenza-associated, respiratory mild (rates: ecological, 1778.8, vs case-based, 1703.3; difference, 4.4%), severe, nonfatal (rates: ecological, 88.6, vs case-based, 75.3; difference, 15.0%), and fatal (rates: ecological, 3.8, vs case-based, 3.5; difference, 8.4%) illnesses were similar. CONCLUSIONS: There was a substantial burden of influenza-associated symptomatic illness, including severe, nonfatal and fatal illnesses, and a large proportion was nonmedically attended. Estimates, including only influenza-associated respiratory illness, substantially underestimated influenza-associated, severe, nonfatal and fatal illnesses. Ecological and case-based estimates were found to be similar for the compared categories.

Intensified household contact tracing, prevention and treatment support versus enhanced standard of care for contacts of tuberculosis cases in South Africa: study protocol for a household cluster-randomised trial.

BACKGROUND: Household contact tracing of index TB cases has been advocated as a key part of TB control for many years, but has not been widely implemented in many low-resource setting because of the current dearth of high quality evidence for effectiveness. Innovative strategies for earlier, more effective treatment are particularly important in contexts with hyper-endemic levels of HIV, where levels of TB infection remain extremely high. METHODS: We present the design of a household cluster-randomised controlled trial of interventions aimed at improving TB-free survival and reducing childhood prevalence of Mycobacterium tuberculosis infection among household contacts of index TB cases diagnosed in two provinces of South Africa. Households of index TB cases will be randomly allocated in a 1:1 ratio to receive either an intensified home screening and linkage for TB and HIV intervention, or enhanced standard of care. The primary outcome will compare between groups the TB-free survival of household contacts over 15 months. All participants, or their next-of-kin, will provide written informed consent to participate. DISCUSSION: Evidence from randomised trials is required to identify cost-effective approaches to TB case-finding that can be applied at scale in sub-Saharan Africa. TRIAL REGISTRATION: ISRCTN16006202 (01/02/2017: retrospectively registered) and NHREC4399 (11/04/2016: prospectively registered). Protocol version: 4.0 (date: 18th January 2018).

Challenges and clinical relevance of molecular detection of Bordetella pertussis in South Africa.

BACKGROUND: We assessed the utility of a multi-target, real-time PCR assay for Bordetella pertussis detection and diagnosis in patients with severe respiratory illness (SRI), influenza-like illness (ILI), and asymptomatic controls. METHODS: Real-time PCR detection of IS481, pIS1001, hIS1001 and ptxS1 was performed on nasopharyngeal specimens (SRI, ILI and controls) and induced sputum (SRI) collected from June 2012 to May 2016 through respiratory illness surveillance. Using PCR cycle threshold (Ct) value cut-offs, IS481 positive cases were classified as confirmed (Ct < 35) or possible (Ct 35-39) pertussis disease. RESULTS: Among 12,922 samples, 146 (1.1%) were IS481 positive of which 62% (90/146) were classified as confirmed. The attributable fraction (AF) was 92.2% (95% CI, 65.6 to 98.2%) and 90.5% (95% CI, 57.5 to 97.9%) amongst SRI and ILI PCR-confirmed pertussis cases, respectively. Amongst possible pertussis cases, AF was 36.9% (95% CI, - 142.3 to 83.6%) and 67.5% (95% CI, - 30.6 to 91.9%) in the SRI and ILI groups, respectively. CONCLUSION: All IS481 positive specimens could be considered as B. pertussis infection, and potentially pertussis disease with supportive clinical information.

Prevalence and Correlates of Snuff Use, and its Association With Tuberculosis, Among Women Living With HIV in South Africa.

INTRODUCTION: A higher proportion of people living with HIV (PLWH) smoke compared to the general population, but little information exists about the prevalence and correlates of smokeless tobacco use among PLWH. In South Africa, dry powdered tobacco is inhaled nasally as snuff. METHODS: A cross-sectional survey among PLWH attending three HIV clinics was conducted. Snuff use was assessed via self-report and urine cotinine. RESULTS: Given the low (3%) prevalence of snuff use among men, analysis was restricted to n = 606 nonsmoking women living with HIV. Half (n = 298, 49%) were snuff users, the majority of whom (n = 244, 84%) had a positive urine cotinine test. In adjusted analysis, snuff use was negatively associated with higher education (relative risk [RR] 0.55; 95% confidence interval [CI]: 0.39, 0.77) and mobile phone ownership (RR 0.83; 95% CI: 0.71, 0.98), and positively associated with ever having tuberculosis (TB) (RR 1.22; 95% CI: 1.03, 1.45). In adjusted analysis, with current TB as the outcome, snuff use was marginally statistically significantly associated with a twofold increase in odds of a current TB diagnosis (odds ratio [OR] 1.99; 95% CI: 0.98, 4.15). DISCUSSION: A high proportion of nonsmoking South African women living with HIV use snuff, which was a risk factor for TB. Additional research is needed to understand the relationship between snuff, TB, and other potential health risks. IMPLICATIONS: PLWH have a higher prevalence of smoking than their seronegative peers, but there is a paucity of research on smokeless tobacco use in this population, especially in low-resource settings. TB is the leading cause of death among PLWH, and with improvements to HIV treatment and care, PLWH are at greater risk of tobacco-related diseases. We report an extremely high prevalence of snuff use among women living with HIV in South Africa. Further, in this population snuff use is positively associated with ever having a TB diagnosis, as well as currently having TB.