TB Modeling and Translational Epi Group

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- May 2019 -

Reply to Chen, Song, and Liu. (2019). Hong H., Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 70, 547-548

The economic case for typhoid conjugate vaccines in countries with medium and high incidence of infection. (2019). Jo Y., Dowdy DW, The Lancet. Infectious diseases, 19, 675-676

Assessment of lung function in successfully treated tuberculosis reveals high burden of ventilatory defects and COPD. (2019). Gupte AN., Paradkar M., Selvaraju S., Thiruvengadam K., Shivakumar SVBY., Sekar K., Marinaik S., Momin A., Gaikwad A., Natrajan P., Prithivi M., Shivaramakrishnan G., Pradhan N., Kohli R., Raskar S., Jain D., Velu R., Karthavarayan B., Lokhande R., Suryavanshi N., Gupte N., Murali L., Salvi S., Checkley W., Golub J., Bollinger R., Mave V., Padmapriyadarasini C., Gupta A, PloS one, 14, e0217289

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BACKGROUND: Burden, phenotype and risk-factors of lung function defects in successfully treated tuberculosis cases are unclear. METHODS: We performed spirometry with bronchodilators in new drug-sensitive adult (≥18 years) pulmonary tuberculosis cases during the 12 months following successful treatment in India. Airflow obstruction was defined as pre-bronchodilator FEV1/FVC<5th percentile of Global Lung Initiative mixed-ethnicity reference (lower limit of normal [LLN]). Chronic obstructive pulmonary disease (COPD) was defined as post-bronchodilator FEV1/FVC

Point of care Xpert MTB/RIF versus smear microscopy for tuberculosis diagnosis in southern African primary care clinics: a multicentre economic evaluation. (2019). Pooran A., Theron G., Zijenah L., Chanda D., Clowes P., Mwenge L., Mutenherwa F., Lecesse P., Metcalfe J., Sohn H., Hoelscher M., Pym A., Peter J., Dowdy D., Dheda K, The Lancet. Global health, 7, e798-e807

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BACKGROUND: Rapid on-site diagnosis facilitates tuberculosis control. Performing Xpert MTB/RIF (Xpert) at point of care is feasible, even when performed by minimally trained health-care workers, and when compared with point-of-care smear microscopy, reduces time to diagnosis and pretreatment loss to follow-up. However, whether Xpert is cost-effective at point of care remains unclear. METHODS: We empirically collected cost (US$, 2014) and clinical outcome data from participants presenting to primary health-care facilities in four African countries (South Africa, Zambia, Zimbabwe, and Tanzania) during the TB-NEAT trial. Costs were determined using an bottom-up ingredients approach. Effectiveness measures from the trial included number of cases diagnosed, initiated on treatment, and completing treatment. The primary outcome was the incremental cost-effectiveness of point-of-care Xpert relative to smear microscopy. The study was performed from the perspective of the health-care provider. FINDINGS: Using data from 1502 patients, we calculated that the mean Xpert unit cost was lower when performed at a centralised laboratory (Lab Xpert) rather than at point of care ($23·00 [95% CI 22·12-23·88] vs $28·03 [26·19-29·87]). Per 1000 patients screened, and relative to smear microscopy, point-of-care Xpert cost an additional $35 529 (27 054-40 025) and was associated with an additional 24·3 treatment initiations ([-20·0 to 68·5]; $1464 per treatment), 63·4 same-day treatment initiations ([27·3-99·4]; $511 per same-day treatment), and 29·4 treatment completions ([-6·9 to 65·6]; $1211 per completion). Xpert costs were most sensitive to test volume, whereas incremental outcomes were most sensitive to the number of patients initiating and completing treatment. The probability of point-of-care Xpert being cost-effective was 90% at a willingness to pay of $3820 per treatment completion. INTERPRETATION: In southern Africa, although point-of-care Xpert unit cost is higher than Lab Xpert, it is likely to offer good value for money relative to smear microscopy. With the current availability of point-of-care nucleic acid amplification platforms (eg, Xpert Edge), these data inform much needed investment and resource allocation strategies in tuberculosis endemic settings. FUNDING: European Union European and Developing Countries Clinical Trials Partnership.

What will it take to eliminate drug-resistant tuberculosis? (2019). Kendall EA., Sahu S., Pai M., Fox GJ., Varaine F., Cox H., Cegielski JP., Mabote L., Vassall A., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 535-546

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Drug-resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but this situation is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new DR-TB as an essential first step. The DR-TB epidemic that is ongoing should also be directly addressed. First-line drug resistance must be rapidly detected using universal molecular testing for resistance to at least rifampin and, preferably, other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly effective, broadly indicated regimens, paired with point-of-care drug susceptibility testing, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination; however, achieving this goal will require substantial global investment plus political and societal commitment at national and local levels.

Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes. (2019). Ramachandran G., Chandrasekaran P., Gaikwad S., Agibothu Kupparam HK., Thiruvengadam K., Gupte N., Paradkar M., Dhanasekaran K., Sivaramakrishnan GN., Kagal A., Thomas B., Pradhan N., Kadam D., Hanna LE., Balasubramanian U., Kulkarni V., Murali L., Golub J., Gupte A., Shivakumar SVBY., Swaminathan S., Dooley KE., Gupta A., Mave V, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 70, 1463-1470

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BACKGROUND: The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood. METHODS: We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models. RESULTS: Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]). CONCLUSIONS: Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.

Diabetes mellitus and tuberculosis in Korean adults: impact on tuberculosis incidence, recurrence and mortality. (2019). Golub JE., Mok Y., Hong S., Jung KJ., Jee SH., Samet JM, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 507-513

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SETTING The prevalence of diabetes mellitus (DM) worldwide is increasing markedly, and many countries with rising rates also have a high incidence rate of tuberculosis (TB). OBJECTIVE To investigate the relationships of fasting serum glucose (FSG) and DM with TB incidence, recurrence and mortality risk in a prospective cohort study in South Korea. DESIGN Our study comprised 1 267 564 Koreans who received health insurance from the National Health Insurance System, had an initial medical evaluation between 1997 and 2000 and were prospectively followed biennially. RESULTS Participants with DM had a higher risk for incident TB (hazard ratio [HR] 1.81, 95%CI 1.71-1.91 in males, HR 1.33; 95%CI 1.20-1.47 in females) than those without DM. There was a strong positive trend for TB risk with rising FSG among males. The risk for recurrent TB among those with previous TB was significantly higher in males (HR 1.58, 95%CI 1.43-1.75) and in females with DM (HR 1.38, 95%CI 1.08-1.76). The increased risk of death from TB during follow-up was also significant in men (HR 1.91, 95%CI 1.87-1.95) and in women (HR 1.71, 95%CI 1.65-1.77). CONCLUSIONS A diagnosis of DM is a risk factor for TB, TB recurrence and death from TB. Screening for TB should be considered among people living with DM in Korea, particularly those with severe DM. .

Respiratory health status is associated with treatment outcomes in pulmonary tuberculosis. (2019). Gupte AN., Selvaraju S., Paradkar M., Danasekaran K., Shivakumar SVBY., Thiruvengadam K., Dolla C., Shivaramakrishnan G., Pradhan N., Kohli R., John S., Raskar S., Jain D., Momin A., Subramanian B., Gaikwad A., Lokhande R., Suryavanshi N., Gupte N., Salvi S., Murali L., Checkley W., Golub JE., Bollinger R., Chandrasekaran P., Mave V., Gupta A, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 450-457

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BACKGROUND The association between respiratory impairment and tuberculosis (TB) treatment outcomes is not clear. METHODS We prospectively evaluated respiratory health status, measured using the Saint George's Respiratory Questionnaire (SGRQ), in a cohort of new adult pulmonary TB cases during and up to 18 months following treatment in India. Associations between total SGRQ scores and poor treatment outcomes of failure, recurrence and all-cause death were measured using multivariable Poisson regression. RESULTS We enrolled 455 participants contributing 619 person-years at risk; 39 failed treatment, 23 had recurrence and 16 died. The median age was 38 years (interquartile range 26-49); 147 (32%) ever smoked. SGRQ scores at treatment initiation were predictive of death during treatment (14% higher risk per 4-point increase in baseline SGRQ scores, 95%CI 2-28, P = 0.01). Improvement in SGRQ scores during treatment was associated with a lower risk of failure (1% lower risk for every per cent improvement during treatment, 95%CI 1-2, P = 0.05). Clinically relevant worsening in SGRQ scores following successful treatment was associated with a higher risk of recurrence (15% higher risk per 4-point increase scores, 95%CI 4-27, P = 0.004). CONCLUSION Impaired respiratory health status was associated with poor TB treatment outcomes. The SGRQ may be used to monitor treatment response and predict the risk of death in pulmonary TB. .

Contact tracing versus facility-based screening for active TB case finding in rural South Africa: A pragmatic cluster-randomized trial (Kharitode TB). (2019). Hanrahan CF., Nonyane BAS., Mmolawa L., West NS., Siwelana T., Lebina L., Martinson N., Dowdy DW, PLoS medicine, 16, e1002796

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BACKGROUND: There is a dearth of comparative effectiveness research examining the implementation of different strategies for active tuberculosis (TB) case finding, particularly in rural settings, which represent 60% of the population of sub-Saharan Africa. METHODS AND FINDINGS: We conducted a pragmatic, cluster-randomized comparative effectiveness trial of two TB case finding strategies (facility-based screening and contact tracing) in 56 public primary care clinics in two largely rural districts of Limpopo Province, South Africa. In the facility-based screening arm, sputum Xpert MTB/RIF was performed on all patients presenting (for any reason) with TB symptoms to 28 study clinics, and no contact tracing was performed. In the contact-tracing arm, contacts of patients with active TB were identified (via household tracing in 14 clinics and using small monetary incentives in the other 14 clinics), screened for TB symptoms, and offered Xpert MTB/RIF testing. The primary outcome was the number of newly identified patients with TB started on treatment. The analysis used multivariable Poisson regression adjusted for historical clinic-level TB case volumes and district. The trial was registered with ClinicalTrials.gov (NCT02808507). From July 18, 2017, to January 17, 2019, a total of 3,755 individuals started TB treatment across 56 study clinics in the 18-month period. Clinic characteristics and clinic-level averages of patient characteristics were similar across the two arms: 40/56 (71%) clinics were in a rural location, 2,136/3,655 (58%) patients were male, and 2,243 (61%) were HIV positive. The treatment initiation ratio comparing the yield of TB patients started on treatment in the facility-based arm compared to that from the contact-tracing arm was 1.04 (95% confidence interval [CI] 0.83-1.30, p = 0. 73). In the contact-tracing arm, 1,677 contacts of 788 new TB index patients were screened, yielding 12 new patients with TB. Prespecified subgroup analyses resulted in similar results, with estimated treatment initiation ratios of 0.96 (95% CI 0.64-1.27; p = 0.78) and 1.23 (95% CI 0.87-1.59; p = 0.29) among historically smaller and historically larger clinics, respectively. This ratio was 1.02 (95% CI 0.66-1.37; p = 0.93) and 1.08 (95% CI 0.74-1.42; p = 0.68) in the Vhembe and Waterberg districts, respectively. The estimated treatment initiation ratio was unchanged in sensitivity analyses excluding 24 records whose TB registration numbers could not be verified (1.03, 95% CI 0.82-1.29; p = 0.78) and excluding transfers-in (1.02, 95% CI 0.80-1.29; p = 0.71). Study limitations include the possibility of imbalance on cluster size owing to changes in catchment population over time and the inability to distinguish the independent effects of the two contact investigation strategies. CONCLUSIONS: Contact tracing based on symptom screening and Xpert MTB/RIF testing did not increase the rate of treatment initiation for TB relative to the less resource-intensive approach of facility-based screening in this rural sub-Saharan setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02808507.

- April 2019 -

Differentiated Care Preferences of Stable Patients on Antiretroviral Therapy in Zambia: A Discrete Choice Experiment. (2019). Eshun-Wilson I., Mukumbwa-Mwenechanya M., Kim HY., Zannolini A., Mwamba CP., Dowdy D., Kalunkumya E., Lumpa M., Beres LK., Roy M., Sharma A., Topp SM., Glidden DV., Padian N., Ehrenkranz P., Sikazwe I., Holmes CB., Bolton-Moore C., Geng EH, Journal of acquired immune deficiency syndromes (1999), 81, 540-546

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BACKGROUND: Although differentiated service delivery (DSD) models for stable patients on antiretroviral therapy (ART) offer a range of health systems innovations, their comparative desirability to patients remains unknown. We conducted a discrete choice experiment to quantify service attributes most desired by patients to inform model prioritization. METHODS: Between July and December 2016, a sample of HIV-positive adults on ART at 12 clinics in Zambia were asked to choose between 2 hypothetical facilities that differed across 6 DSD attributes. We used mixed logit models to explore preferences, heterogeneity, and trade-offs. RESULTS: Of 486 respondents, 59% were female and 85% resided in urban locations. Patients strongly preferred infrequent clinic visits [3- vs. 1-month visits: β (ie, relative utility) = 2.84; P < 0.001]. Milder preferences were observed for waiting time for ART pick-up (1 vs. 6 hours.; β = -0.67; P < 0.001) or provider (1 vs. 3 hours.; β = -0.41; P = 0.002); "buddy" ART collection (β = 0.84; P < 0.001); and ART pick-up location (clinic vs. community: β = 0.35; P = 0.028). Urban patients demonstrated a preference for collecting ART at a clinic (β = 1.32, P < 0.001), and although most rural patients preferred community ART pick-up (β = -0.74, P = 0.049), 40% of rural patients still preferred facility ART collection. CONCLUSIONS: Stable patients on ART primarily want to attend clinic infrequently, supporting a focus in Zambia on optimizing multimonth prescribing over other DSD features-particularly in urban areas. Substantial preference heterogeneity highlights the need for DSD models to be flexible, and accommodate both setting features and patient choice in their design.

Operational characteristics of antiretroviral therapy clinics in Zambia: a time and motion analysis. (2019). Tampi RP., Tembo T., Mukumba-Mwenechanya M., Sharma A., Dowdy DW., Holmes CB., Bolton-Moore C., Sikazwe I., Tucker A., Sohn H, BMC health services research, 19, 244

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BACKGROUND: The mass scale-up of antiretroviral therapy (ART) in Zambia has taken place in the context of limited infrastructure and human resources resulting in many operational side-effects. In this study, we aimed to empirically measure current workload of ART clinic staff and patient wait times and service utilization. METHODS: We conducted time and motion (TAM) studies from both the healthcare worker (HCW) and patient perspectives at 10 ART clinics throughout Zambia. Trained personnel recorded times for consecutive discrete activities based on direct observation of clinical and non-clinical activities performed by counselors, clinical officers, nurses, and pharmacy technicians. For patient TAM, we recruited consenting patients and recorded times of arrival and departure and major ART services utilized. Data from 10 clinics were pooled to evaluate median time per patient spent for each activity and patient duration of stay in the clinic. RESULTS: The percentage of observed clinical time for direct patient interaction (median time per patient encounter) was 43.1% for ART counselors (4 min, interquartile range [IQR] 2-7), 46.1% for nurses (3 min, IQR 2-4), 57.2% for pharmacy technicians (2 min, IQR 1-2), and 78.5% for clinical officers (3 min, IQR 2-5). Patient workloads for HCWs were heaviest between 8 AM and 12 PM with few clinical activities observed after 2 PM. The length of patient visits was inversely associated with arrival time - patients arriving prior to 8 AM spent 61% longer at the clinic than those arriving after 8 AM (277 vs. 171 min). Overall, patients spent 219 min on average for non-clinical visits, and 244 min for clinical visits, but this difference was not significant in rural clinics. In comparison, total time patients spent directly with clinic staff were 9 and 12 min on average for non-clinical and clinical visits. CONCLUSION: Current Zambian ART clinic operations include substantial inefficiencies for both patients and HCWs, with workloads heavily concentrated in the first few hours of clinic opening, limiting HCW and patient interaction time. Use of a differentiated care model may help to redistribute workloads during operational hours and prevent backlogs of patients waiting for hours before clinic opening, which may substantially improve ART delivery in the Zambian context.

Aminoglycoside-induced Hearing Loss Among Patients Being Treated for Drug-resistant Tuberculosis in South Africa: A Prediction Model. (2019). Hong H., Dowdy DW., Dooley KE., Francis HW., Budhathoki C., Han HR., Farley JE, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 70, 917-924

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BACKGROUND: Individuals treated for drug-resistant tuberculosis (DR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss, yet there is no practical method to identify those at higher risk. We sought to develop a clinical prediction model of AG-induced hearing loss among patients initiating DR-TB treatment in South Africa. METHODS: Using nested, prospective data from a cohort of 379 South African adults being treated for confirmed DR-TB with AG-based regimens we developed the prediction model using multiple logistic regression. Predictors were collected from clinical, audiological, and laboratory evaluations conducted at the initiation of DR-TB treatment. The outcome of AG-induced hearing loss was identified from audiometric and clinical evaluation by a worsened hearing threshold compared with baseline during the 6-month intensive phase. RESULTS: Sixty-three percent of participants (n = 238) developed any level of hearing loss. The model predicting hearing loss at frequencies from 250 to 8000 Hz included weekly AG dose, human immunodeficiency virus status with CD4 count, age, serum albumin, body mass index, and pre-existing hearing loss. This model demonstrated reasonable discrimination (area under the receiver operating characteristic curve [AUC] = 0.71) and calibration (χ2[8] = 6.10, P = .636). Using a cutoff of 80% predicted probability of hearing loss, the positive predictive value of this model was 83% and negative predictive value was 40%. Model discrimination was similar for ultrahigh-frequency hearing loss (frequencies >9000 Hz; AUC = 0.81) but weaker for clinically determined hearing loss (AUC = 0.60). CONCLUSIONS: This model may identify patients with DR-TB who are at highest risk of developing AG-induced ototoxicity and may help prioritize patients for AG-sparing regimens in clinical settings where access is limited.

- March 2019 -

From Epidemiologic Knowledge to Improved Health: A Vision for Translational Epidemiology. (2019). Windle M., Lee HD., Cherng ST., Lesko CR., Hanrahan C., Jackson JW., McAdams-DeMarco M., Ehrhardt S., Baral SD., D'Souza G., Dowdy DW, American journal of epidemiology, 188, 2049-2060

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Epidemiology should aim to improve population health; however, no consensus exists regarding the activities and skills that should be prioritized to achieve this goal. We performed a scoping review of articles addressing the translation of epidemiologic knowledge into improved population health outcomes. We identified 5 themes in the translational epidemiology literature: foundations of epidemiologic thinking, evidence-based public health or medicine, epidemiologic education, implementation science, and community-engaged research (including literature on community-based participatory research). We then identified 5 priority areas for advancing translational epidemiology: 1) scientific engagement with public health; 2) public health communication; 3) epidemiologic education; 4) epidemiology and implementation; and 5) community involvement. Using these priority areas as a starting point, we developed a conceptual framework of translational epidemiology that emphasizes interconnectedness and feedback among epidemiology, foundational science, and public health stakeholders. We also identified 2-5 representative principles in each priority area that could serve as the basis for advancing a vision of translational epidemiology. We believe an emphasis on translational epidemiology can help the broader field to increase the efficiency of translating epidemiologic knowledge into improved health outcomes and to achieve its goal of improving population health.

Gonorrhoea and chlamydia diagnosis as an entry point for HIV pre-exposure prophylaxis: a modelling study. (2019). Kasaie P., Schumacher CM., Jennings JM., Berry SA., Tuddenham SA., Shah MS., Rosenberg ES., Hoover KW., Gift TL., Chesson H., German D., Dowdy DW, BMJ open, 9, e023453

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OBJECTIVES: Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) increase the risk of HIV transmission among men who have sex with men (MSM). Diagnosis of NG/CT may provide an efficient entry point for prevention of HIV through the delivery of pre-exposure prophylaxis (PrEP); however, the additional population-level impact of targeting PrEP to MSM diagnosed with NG/CT is unknown. DESIGN: An agent-based simulation model of NG/CT and HIV cocirculation among MSM calibrated against census data, disease surveillance reports and the US National HIV Behavioral Surveillance study. SETTING: Baltimore City, Maryland, USA. INTERVENTIONS: PrEP implementation was modelled under three alternative scenarios: (1) PrEP delivery at NG/CT diagnosis (targeted delivery), (2) PrEP evaluation at NG/CT screening/testing and (3) PrEP evaluation in the general community (untargeted). MAIN OUTCOME: The projected incidence of HIV after 20 years of PrEP delivery under two alternatives: when equal numbers of MSM are (1) screened for PrEP or (2) receive PrEP in each year. RESULTS: Assuming 60% uptake and 60% adherence, targeting PrEP to MSM diagnosed with NG/CT could reduce HIV incidence among MSM in Baltimore City by 12.4% (95% uncertainty range (UR) 10.3% to 14.4%) in 20 years, relative to no PrEP. Expanding the coverage of NG/CT screening (such that individuals experience a 50% annual probability of NG/CT screening and evaluation for PrEP on NG/CT diagnosis) can further increase the impact of targeted PrEP to generate a 22.0% (95% UR 20.1% to 23.9%) reduction in HIV incidence within 20 years. When compared with alternative implementation scenarios, PrEP evaluation at NG/CT diagnosis increased impact of PrEP on HIV incidence by 1.5(95% UR 1.1 to 1.9) times relative to a scenario in which PrEP evaluation happened at the time of NG/CT screening/testing and by 1.6 (95% UR 1.2 to 2.2) times relative to evaluating random MSM from the community. CONCLUSIONS: Targeting MSM infected with NG/CT increases the efficiency and effectiveness of PrEP delivery. If high levels of sexually transmitted infection screening can be achieved at the community level, NG/CT diagnosis may be a highly effective entry point for PrEP initialisation.

Screening for tuberculosis: time to move beyond symptoms. (2019). Yoon C., Dowdy DW., Esmail H., MacPherson P., Schumacher SG, The Lancet. Respiratory medicine, 7, 202-204

- January 2019 -

Xpert at 8 years: where are we now, and what should we do next? (2019). Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 23, 3-4

Siyaphambili protocol: An evaluation of randomized, nurse-led adaptive HIV treatment interventions for cisgender female sex workers living with HIV in Durban, South Africa. (2019). Comins CA., Schwartz SR., Phetlhu DR., Guddera V., Young K., Farley JE., West N., Parmley L., Geng E., Beyrer C., Dowdy D., Mishra S., Hausler H., Baral S, Research in nursing & health, 42, 107-118

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In South Africa, 60% of female sex workers are estimated to be living with human immunodeficiency virus (HIV). Many of these women face structural and individual-level barriers to initiating, accessing, and adhering to antiretroviral therapy (ART). While data are limited, it is estimated that less than 40% of sex workers living with HIV achieve viral suppression, leading to suboptimal clinical outcomes and sustained risks of onward sexual and vertical HIV transmission. Siyaphambili, a NINR/NIH-funded study, focuses on studying optimal implementation strategies for meeting HIV treatment needs among cisgender female sex workers living with HIV who are not virally suppressed. Here, we present the study protocol of this sequential multiple assignment randomized trial. In total, 800 viremic female sex workers will be enrolled into an 18-month adaptive implementation study to 1) compare the effectiveness and durability of a nurse-led decentralized ART treatment program versus an individualized case management approach, in isolation or in combination to achieve viral suppression and 2) estimate incremental cost-effectiveness of interventions and combinations of interventions. The primary outcome is a combined intention-to-treat outcome of retention in ART care and viral suppression at 18 months with secondary implementation outcomes. Siyaphambili aims to inform the implementation of and scale-up of HIV treatment services for female sex workers by determining the minimal package of services needed to achieve viral suppression and by characterizing individuals in need of more intensive HIV treatment approaches.

Cost-effectiveness of universal isoniazid preventive therapy among HIV-infected pregnant women in South Africa. (2019). Kim HY., Hanrahan CF., Martinson N., Golub JE., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 22, 1435-1442

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OBJECTIVE: To estimate the incremental cost-effectiveness of universal vs. test-directed treatment of latent tuberculous infection (LTBI) among human immunodeficiency virus (HIV) positive pregnant women in South Africa. METHODS: We compared tuberculin skin test (TST) directed isoniazid preventive therapy (IPT) (TST placement with delivery of IPT to women with positive results) against QuantiFERON(®)-TB Gold In-Tube (QGIT) directed IPT and universal IPT using decision analysis. Costs were measured empirically in six primary care public health clinics in Matlosana, South Africa. The primary outcome was the incremental cost-effectiveness ratio, expressed in 2016 US$ per disability-adjusted life-year (DALY) averted. RESULTS: We estimated that 29.2 of every 1000 pregnant women would develop TB over the course of 1 year in the absence of IPT. TST-directed IPT reduced this number to 24.5 vs. 22.6 with QGIT-directed IPT and 21.0 with universal IPT. Universal IPT was estimated to cost $640/DALY averted (95% uncertainty range $44-$3146) relative to TST-directed IPT and was less costly and more effective (i.e., dominant) than QGIT-directed IPT. Cost-effectiveness was most sensitive to the probability of developing TB and LTBI prevalence. CONCLUSION: Providing IPT to all eligible women can be a cost-effective strategy to prevent TB among HIV-positive pregnant women in South Africa.

- December 2018 -

Spatially targeted screening to reduce tuberculosis transmission in high-incidence settings. (2018). Cudahy PGT., Andrews JR., Bilinski A., Dowdy DW., Mathema B., Menzies NA., Salomon JA., Shrestha S., Cohen T, The Lancet. Infectious diseases, 19, e89-e95

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As the leading infectious cause of death worldwide and the primary proximal cause of death in individuals living with HIV, tuberculosis remains a global concern. Existing tuberculosis control strategies that rely on passive case-finding appear insufficient to achieve targets for reductions in tuberculosis incidence and mortality. Active case-finding strategies aim to detect infectious individuals earlier in their infectious period to reduce onward transmission and improve treatment outcomes. Empirical studies of active case-finding have produced mixed results and determining how to direct active screening to those most at risk remains a topic of intense research. Our systematic review of literature evaluating the effects of geographically targeted tuberculosis screening interventions found three studies in low tuberculosis incidence settings, but none conducted in high tuberculosis incidence countries. We discuss open questions related to the use of spatially targeted approaches for active screening in countries where tuberculosis incidence is highest.

- November 2018 -

Maternal Motivation to Take Preventive Therapy in Antepartum and Postpartum Among HIV-Positive Pregnant Women in South Africa: A Choice Experiment. (2018). Kim HY., Dowdy DW., Martinson NA., Kerrigan D., Tudor C., Golub J., Bridges JFP., Hanrahan CF, AIDS and behavior, 23, 1689-1697

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HIV-positive pregnant women who are initiated on lifelong antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) have lower adherence rates after delivery. We quantified maternal motivation to take preventive therapy before and after delivery among pregnant women newly diagnosed with HIV. We enrolled pregnant women (≥ 18 years) with a recent HIV diagnosis (< 6 months) at 14 public primary health clinics in Matlosana, South Africa and followed them in the postpartum period. Participants received eight choice tasks comparing two mutually exclusive sub-sets of seven possible benefits related to preventive therapy identified through literature reviews and key informant interviews. Data was analyzed using conditional logit regression in the antepartum versus postpartum periods. Coefficients are reported with 95% confidence intervals (CI). Sixty-five women completed surveys both at enrollment and in the postpartum period. All women were already on ART, while 21 (32%) were receiving IPT at enrollment. The mean CD4 count was 436 (± 246) cells/mm(3). In the antepartum period, preventing HIV transmission to partners was the most important benefit (coefficients (ß) = 0.87, 95% CI 0.64, 1.11), followed by keeping healthy for family (ß = 0.75, 95% CI 0.52, 0.97). Such prioritization significantly decreased in the postpartum period (p < 0.001). Compared to other motivators, keeping a high CD4 count was least prioritized in the antepartum period (ß = 0.19, 95% CI - 0.04, 0.43) but was most prioritized in the postpartum period (ß = 0.39, 95% CI 0.21, 0.57). These results highlight that messages on family might be particularly salient in the antepartum period, and keeping CD4 count high in the postpartum period. Understanding maternal motivation may help to design targeted health promotion messages to HIV-positive women around the time of delivery.

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