key: cord-0850183-f89m0420
authors: Fekadu, Ginenus; Jiang, Xinchan; Yao, Jiaqi; You, Joyce H.S.
title: Cost-effectiveness of video-observed therapy for ambulatory management of active tuberculosis during COVID-19 pandemic in a high-income country
date: 2021-10-22
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.10.029
sha: 19a57f9c8c2522615c604695f8bbcb0ff2dac1c3
doc_id: 850183
cord_uid: f89m0420

Objective The coronavirus-2019 (COVID-19) pandemic caused suspension of directly observed therapy (DOT) for active tuberculosis (TB). We aimed to estimate the outcomes of pandemic-related DOT suspension and cost-effectiveness of VOT during the pandemic. Methods A decision-analytic model was constructed to project outcomes of adult patients with active TB from the perspective of US healthcare provider. Two model-based analyses were conducted: (1) before (with DOT) and during (with self-administered therapy (SAT)) the pandemic; (2) VOT versus SAT during the pandemic. Primary outcome measures were direct medical costs and disability-adjusted life years (DALYs). Results In base-case analysis, the care during pandemic (with SAT) increased both cost (by USD285) and DALYs (by 0.2155) per patient. VOT reduced DALY (by 0.4870) and saved cost (by USD1,797). In probabilistic sensitivity analysis, the care during pandemic (with SAT) increased DALYs in 100% of 10,000 simulations and increased cost in 55.52% of the time. The care with VOT reduced DALYs and cost in 99.7% and 68.79% of the time, respectively. The probability of VOT to be cost-effective was 99.4% at the willingness-to-pay threshold of 50,000 USD/DALY. Conclusion DOT suspension during pandemic worsened treatment outcomes. VOT was cost-effective for active TB care in outpatient setting.

There were approximately10 million cases of tuberculosis (TB) worldwide in 2019, and 2.9% were in the Americas (World Health Organization, 2020) . The data and statistics of the Centers for Diseases Control and Prevention indicated that there were 8,916 reported TB cases in 2019 (2.7 per 100,000 persons) (Centres for Disease Control and Prevention, 2020).

Despite the low incidence of TB in the US, the cost of TB management is still substantial.

The estimated direct medical cost per case in the US, a high-income country, was USD19,000 in 2018 (Marks et al., 2014; Aslam et al., 2018) .

Inadequate level of patient adherence with TB treatment is a well-documented risk of treatment failure and drug resistance (Weis et al., 1994) . A systematic review and metaanalysis on association of adherence interventions and TB treatment outcomes found that applying directly observed therapy (DOT) was significantly associated with improved treatment outcomes (Alipanah et al., 2018) .

The global outbreak of the coronavirus disease 2019 pandemic has drawn the resources away from the usual programmatic TB services . Patient-staff interaction of usual TB management was re-engineered, and DOT was suspended to comply with social-distancing (Burzynski et al., 2020) . In 2017, the World Health Organization endorsed that video-observed therapy (VOT) can be a suitable alternative to DOT for monitoring treatment and has published guidance on its implementation (World Health Organization, 2017) . Clinical findings have showed that VOT was preferred by most patients with high adherence in developed countries (Story et al., 2019; Garfein et al., 2018) . Since the outbreak of COVID-19 pandemic, some healthcare systems had swiftly implemented telehealth (delivery of healthcare services at a distance using digital technology) services to reduce the non-urgent clinic visits Burzynski et al., 2020; Visca et al., 2020) . This study aimed to estimate the impact of pandemic-related DOT suspension on TB treatment outcomes and evaluate the cost-effectiveness of applying VOT for patients with active TB in the ambulatory care setting of a high-income country during the pandemic.

A decision-analytic model was constructed to evaluate the clinical and economic outcomes of a hypothetical cohort of adult patients with active drug-susceptible TB managed at the ambulatory setting. A two-part model-based analysis was performed to simulate the health outcomes of TB management, including direct medical costs and disability-adjusted life year (DALY), over a one-year timeframe.

In part-1 (outcome) analysis, the TB treatment outcomes in the scenarios of before and during the pandemic were examined. In both scenarios, TB patients were treated with the recommended 6-month drug regimen for drug-susceptible TB: 2-month intensive phase (7 days/week) of isoniazid, rifampicin, pyrazinamide and ethambutol; and 4-month continuation phase (7 days/week) with isoniazid and rifampicin (Nahid et al., 2016) . Usual in-person clinic visits were also provided to TB patients in both scenarios (Burzynski et al., 2020) . In the scenario prior to the pandemic, DOT had been one of the standard activities for TB case management. The case management applied DOT 5 days per week for weekdays at a healthcare facility and self-administered therapy (SAT) for the weekend doses (loaded in a pillbox) (Nahid et al., 2016) . In the scenario with the pandemic (DOT suspended), SAT was applied for the TB case management. The TB patients, received DOT or SAT, might experience treatment success (cured or treatment completed). Those who did not achieve treatment success might belong to one of the following outcomes: Treatment failure (not cured or treatment incomplete), death and lost to follow up (if treatment failure or death was not documented) (World Health Organization, 2013) (Figure 1 ).

In part-2 (cost-effectiveness) analysis, the cost and DALYs of applying VOT versus SAT for TB case management during the pandemic was examined. In both VOT and SAT arms, patients were treated with the 6-month drug regimen (as described above) and followed up in usual clinic visits. In the VOT group, patients communicated daily with a healthcare provider using a video-conferencing platform (Holzman et al., 2018; Browne et al., 2019) . The healthcare provider observed the administration of medication by patients via videoconferencing. Patients in both VOT and SAT groups might experience treatment success, treatment failure, lost to follow up or death.

All model inputs are shown in to 2021, using keywords such as -tuberculosis‖, -self-administered therapy‖, -directly observed therapy‖, -video-observed therapy‖, -telehealth‖, -telemedicine‖, -tuberculosis treatment outcomes‖. The inclusion criteria of published articles were (1) reports written in English, (2) patients aged 18 years or older with active TB, (3) adherence intervention (SAT, DOT or VOT) was applied, and (4) treatment outcomes were reported. A study was included if data relevant to the model inputs were available. Preferred study types were meta-analysis and randomized controlled trial. If multiple sources were found for a model input, the weighted average was used as the base-case value, and the high and low values formed the range for sensitivity analysis.

A meta-analysis (n=129 clinical trials) evaluated the association between treatment adherence interventions and TB outcomes (Alipanah et al., 2018) . The weighted average event rates associated with the SAT arm were first pooled from studies included in the metaanalysis, and were adopted as the event rates of the SAT group in the present model. The risk ratios of event in the patients who used DOT (versus SAT) and VOT (versus DOT) were estimated from the pooled event rates in studies with the DOT and VOT groups (Alipanah et al., 2018) .

The proportions of patients who achieved ≥80% compliance of DOT and VOT were adopted from the findings of a multicenter, randomized, controlled trial of VOT versus DOT in active TB patients (n=226) (Story et al., 2019) . The TB-related hospitalization rate was retrieved from the findings of a 10-year disease burden study of patients with active TB (n=1,957) in an US health system (Wada et al., 2020) .

The expected DALY was estimated using the patient time spent in a health state and the corresponding utility reduction of the health state (when compared with the age-specific health utility). The base-case value of age (52 years) of TB patients was retrieved from the disease burden study of TB in the US (Wada et al., 2020) , and the age-specific health utilities derived from the US national health measures and surveys were adopted (Gold et al., 1998) .

The utilities of TB-related health states (treatment success, treatment failure and lost to follow-up) were estimated from the findings of health-related quality of life studies in TB patients (Kittikraisak et al., 2012; Guo et al., 2008) and adopted from the utility input of model-based health economic analysis on treatment of active TB (Wirth et al., 2017) . The DALYs resulted from TB-related mortality was approximated by the age-specific remaining life expectancy (from US life tables (Arias et al., 2020) ) and age-specific health utilities. The mortality-related DALY was discounted to year 2021 by an annual rate of 3%.

The cost analysis was performed from the perspective of US healthcare provider. Cost items included direct medical costs of DOT, VOT, drug treatment, outpatient clinic visit, and TB-related hospitalization. The costs per session of DOT and VOT were adopted from the findings of a cost-minimization analysis of various types of observed therapy for TB management in the US (Lam et al., 2019) . The cost per case of TB outpatient clinic care was retrieved from the results of a direct cost analysis of TB in the US (Oh et al., 2015) . The drug treatment cost was estimated using the drug cost listed in online pharmacy (Drugs.com, 2021) . The inpatient cost was retrieved from diagnosis-related groups data reported by the Centers for Medicare and Medicaid Services (Centers for Medicare and Medicaid Services, 2016). The length of hospital stay for active TB in the US was reported to be 9.5 days in the TB disease burden study in the US (Wada et al., 2020) . All costs were adjusted to year 2021.

All analyses were performed using TreeAge Pro 2021 (TreeAge Software Inc Expected direct medical cost and DALYs were calculated for the part-1 (outcome) analysis and part-2 (cost-effectiveness) analysis. In the part-2 (cost-effectiveness) analysis, a strategy was dominated when it gained higher DALYs at higher cost than another option, and the dominated option was eliminated from further cost-effectiveness analysis. If a strategy resulted in lower DALYs at higher cost than another alternative, incremental cost per DALY averted (ICER) of the more effective strategy was calculated: ICER=∆Cost/∆DALYs A willingness-to-pay (WPT) threshold of 50,000 USD/DALY was adopted in the present cost-effectiveness analysis. A strategy was preferred if it (1) resulted in lower DALYs at lower cost, or (2) resulted in lower DALYs at an increased cost and the ICER was less than the WTP threshold.

In the one-way sensitivity analysis, each model input was varied over the range of sensitivity analysis (specified in Table 1 ) to examine the most influential parameters on the base-case results. The probabilistic sensitivity analysis was performed using Monte Carlo simulation to examine the impact of uncertainty in all variables simultaneously. The direct cost and DALYs were recalculated 10,000 times by randomly drawing each of the model input from the parameter-specific distribution ( Table 1 ). The probability of each alternative to be accepted as the preferred option was determined over a wide range of WTP from 0-100,000 USD/DALY by the acceptability curves.

Compared with the outcomes of DOT (before the pandemic), suspension of DOT (care with SAT) during the pandemic increased both the cost by USD285 and DALYs by 0.2155 per patient ( Table 2) .

One-way deterministic sensitivity analyses were conducted for all model inputs. The basecase DALYs were robust to the variation of all model inputs, and the base-case cost was sensitive to the risk ratio of treatment success with DOT versus SAT. The TB outpatient care during the pandemic (with SAT) would become less costly than the care with DOT (before pandemic) if the risk ratio of treatment success with DOT versus SAT was <1.10 (base-case value: 1.14) (Figure 2) .

The change in direct medical cost and DALYs by TB outpatient care with SAT during pandemic (versus care before pandemic with DOT) in the 10,000 Monte-Carlo simulations were shown in a scatterplot (Figure 3) . The TB care during pandemic (with SAT) increased both the DALYs by 0.1954 0. (95% CI 0.1941 0. -0.1966 p<0.01) , and cost by USD277 (95% CI USD245-310; p<0.01). Compared with the TB care before pandemic (with DOT), the care during pandemic (with SAT) resulted in higher DALYs in 100% of simulations and increased cost in 55.52% of the time.

The base-case expected cost and DALYs of each strategy during the pandemic are shown in Table 2 . The TB care with VOT reduced DALYs (by 0.4870) and saved cost by USD1,797 (ICER= -3,690 USD/DALY), and the VOT was therefore the preferred costeffective option.

The base-case results were robust to the variation of all model inputs in the one-way sensitivity analysis, and no threshold value was identified. Six influential parameters (changed the ICER value by more than 15% from the base-case ICER) were shown in the tornado diagram (Figure 4) , and the risk ratio of treatment success with VOT versus DOT was the most influential parameter on the base-case ICER. The one-way analysis was further performed on the direct medical cost and DALYs separately. The TB care with VOT remained to avert DALYs when compared to the care with SAT throughout the variation of all model inputs. The cost of TB care with VOT became higher than that of the care with SAT when the risk ratio of treatment success with VOT (versus DOT) was <0.89 (base-case value: 1.0).

Probabilistic sensitivity analysis was performed by recalculating the cost and DALYs 10,000 times with Monte Carlo simulation. The incremental cost against DALY averted by the TB care with VOT versus SAT were shown in a scatterplot (Figure 5) . Compared to the TB care with SAT, the care with VOT reduced DALYs by 0.4299 (95%CI 0.4358-0.4440; p<0.01) with a cost-saving of USD1,871 (95%CI USD1,797-1,944; p<0.01). The care with VOT reduced DALYs and cost in 99.7% and 68.79% of the time, respectively. It averted DALYs at higher cost in 30.91% of the time (30.61% and 0.3% were below and above the WTP threshold, correspondingly).

The probabilities of each strategy to be accepted as cost-effective during the pandemic were presented in the acceptability curves over a range of WTP (0-100,000 USD/DALY).

The VOT was accepted to be cost-effective in 99.4% of the time at the WTP threshold of 50,000 USD/DALY (Figure 6 ).

This is the first outcome analysis to estimate the impact of COVID-19 pandemic on TB treatment outcomes in the ambulatory care setting when DOT was suspended and evaluate the cost-effectiveness of switching to VOT for active TB management during the pandemic in the US. Compared to the standard care (with DOT) before COVID-19, care with SAT during the pandemic increased the cost of TB management (by USD285 per patient) and resulted in higher DALYs (by 0.2155 per patient) in a one-year period. At the beginning of the pandemic in the US, routine in-person services for TB management were restricted to implement social distancing. Volume of in-person clinic visits were largely reduced and DOT was suspended (Burzynski et al., 2020) . The findings of one-way sensitivity analysis showed that the increased DALYs associated with pandemic-related DOT suspension was robust to variation of all model inputs. The direct medical cost during the pandemic (DOT suspended) was sensitive to the variation of risk ratio of treatment success with DOT versus SAT.

Probabilistic sensitivity analysis further supported the robustness of base-case findings that care with SAT during the pandemic increased DALYs (100% of time) at increased cost (over 55% of time).

Applying VOT during the pandemic to manage patients with active TB reduced cost (by USD1,797 per patient) and averted DALYs (by 0.4870 per patient) in a one-year time frame.

The DALY reduction was generated by improved treatment success rate associated with VOT versus SAT. The cost saved by the care with VOT (versus SAT) was primarily due to a considerable decrease in hospitalization costs resulting from the higher treatment success rate. The one-way sensitivity analysis found the cost-effectiveness of VOT to be highly robust and no influential parameter (with threshold value) was identified throughout variation of all model inputs. The results of probabilistic sensitivity analysis also supported VOT to be the cost-effective and preferred strategy over a wide range of WTP threshold in the 10,000

Monte Carlo simulations. This is the first health economic analysis to evaluate the impact of pandemic-related suspension of DOT on the outcomes of TB management, measured as direct medical cost and DALYs, in a high-income country setting. Prior health economics analyses of VOT were limited to the impact on the cost component, either comparing the costs of VOT and DOT (cost-minimization analysis) (Lam et al., 2019; Beeler et al., 2020) or focusing on the cost of VOT (cost-analysis) (Mirsaeidi et al., 2015) . The present study is a full-scale health economic analysis, comparing both the cost and effectiveness (measured as DALYs) of management of active TB with VOT versus SAT during the time of pandemic. Our model included all key treatment outcomes of active TB (treatment success, treatment failure, lost to follow up and death) for estimation of the cost and DALYs of the two strategies (VOT and SAT) applied to TB case management during the pandemic.

There were some limitations in the present study. Model-based analyses are in general subject to uncertainty of model inputs. Rigorous sensitivity analyses were therefore performed to examine the impact of model input uncertainty and assumption on the base-case results. The present study used a simplified decision model to represent treatment adherence strategies and the corresponding outcomes in patients with drug-susceptible TB. The negative impact of the patient's comorbidities on TB treatment outcomes was not incorporated in the present model. The results therefore only represented the relative difference in outcomes (as measured by cost and DALYs) associated with the treatment adherence strategies (SAT, DOT and VOT). Our search of model inputs was performed in English publications, and possibly missed the relevant data published in non-English languages. The present model time horizon was limited to a short period of time (one year) to resemble the timeframe with the most stringent social distancing restrictions for COVID-19 control in the US. The cost analysis was performed from the perspective of healthcare provider, and indirect cost (productivity loss) was not considered. The cost-saving associated with VOT during the pandemic might therefore be underestimated.

DOT has long been adopted as a key component of the standard care for active TB management in high-income countries, yet it needed to be suspended to implement social distancing during the COVID-19 pandemic. The sudden global outbreak of COVID-19

shifted the treatment strategy from DOT to VOT in some settings with adequate resources and trained staff. Our findings demonstrated that without VOT, the pandemic-related suspension of DOT resulted in higher costs and worsened treatment outcomes (as indicated by the increased DALYs). In those settings where switching to VOT was feasible, the care with VOT improved treatment outcome (as indicated by reduced DALYs) and lowered direct medical cost.

Despite the well-established effectiveness of VOT for patients with active TB, many clinical settings have adopted the practice of DOT and did not have the urgency to implement VOT prior to the pandemic. The COVID-19 pandemic has speeded up the implementation of telehealth in many medical disciplines. With the global effort to control the spread of COVID-19, the pandemic will surely end. The development and sustainability of telehealth technology such as VOT in the post-pandemic era will require both clinical evidence as well as health economics findings to support the informed decision-making process of resource allocation. Furthermore, health economic evaluation of VOT-based care is also highly warranted in high TB burden and low resource settings.

In conclusion, DOT suspension in the ambulatory care of active TB during the COVID-19 pandemic appears to worsen the treatment outcomes (with higher DALYs) and increased cost. Switching to VOT during the pandemic seems to be a cost-effective option to improve treatment outcomes of active TB by reducing both DALYs and direct medical costs from the perspective of US healthcare provider.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

None Ethical Approval: Acceptability curves of care with VOT and SAT for treatment of active TB during the pandemic to be cost-effective against willingness-to-pay. DOT, directly observed therapy; TB, tuberculosis; VOT, video observed therapy; WTP, willingness-topay

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Figure 5 Scatterplot of incremental cost against DALY averted by TB care with VOT versus SAT during the pandemic in 10,000 Monte-Carlo simulations. DALY, disability-adjusted life-year

DOT, directly observed therapy; VOT, video observed therapy

WTP, willingness-to-pay