FeedbackRecommendation 8.1 HCV and MDR/RR-TB treatment
Remarks
- This recommendation applies to people with confirmed MDR/RR-TB and HCV.
- Treatment initiation should take into account potential DDI and other comorbidities.
Rationale
The rationale for this recommendation is based on the expert evidence and considerations detailed in the next subsections.
Globally, an estimated 400 000 people (95% UI: 360 000–440 000) developed MDR/RR-TB in 2023. There have been steady improvements in the treatment success rate for people diagnosed with MDR/RR-TB, but the rate remains alarmingly low. Globally in 2021, the treatment success rate was 68%, up from 60% in 2019 and 50% in 2012. MDR/RR-TB treatment poses many challenges, which are further exacerbated for those with pre-existing liver disease due to the potential hepatotoxicity of some anti-TB medicines, which may increase the risk of drug-induced liver injury (5).
There is a substantial overlap in the epidemiology of chronic hepatitis C and TB owing to common risk factors (e.g. injection drug use, homelessness or incarceration). Chronic viral hepatitis C or B may negatively impact TB treatment by increasing the risk of hepatotoxicity related to TB drugs, and thus affecting drug choices; in turn, this may reduce the rate of TB treatment success. The global HCV antibody seroprevalence in TB patients has been estimated to be 10.4%, surpassing the general population’s average of 1.4%. Moreover, studies among TB patients who inject illicit drugs show an HCV prevalence of 92.5% (95% CI: 80.8–99.0) (139).
Curative short-course (12–24 weeks) oral direct-acting antivirals (DAAs) have transformed the landscape of HCV treatment, with high rates of cure – more than 90% of patients attain a sustained virologic response (SVR), indicating virus clearance – alongside an excellent safety profile and high tolerability. Known DDIs with rifamycins preclude co-administration of DAAs in the context of drugsusceptible TB (few or no interactions are anticipated to occur with drugs for MDR/RR-TB treatment) (140). However, relatively little is known about how to manage chronic HCV infection among MDR-TB patients, and national policies and practices vary, highlighting the need for global guidance. There is limited clinical research evidence on the safety and efficacy of TB treatment in patients with signs of liver toxicity; most pivotal trials exclude participants with liver enzymes more than three times the upper limit of normal values. Despite the limited direct evidence, concomitant therapy for HCV and MDR/RR-TB seems feasible and potentially beneficial for patients with co-infection. To address this need, WHO commissioned a systematic review of the literature on the co-administration of treatment for DR-TB and hepatitis C. The results of this systematic review highlighted that published evidence on this subject is minimal (141).
Expert evidence has been defined as the observations or experience obtained from a person who is knowledgeable about or skilful in a particular area (142). This approach can be considered under certain circumstances if there is little or no published direct evidence. To address this knowledge gap, “expert evidence” can be considered in the same way as case reports or case series are used within the GRADE framework, as if systematic and transparent methods are used for its collection, and the description of the evidence minimizes interpretation of the extent to which it supports a conclusion.
Despite the lack of general data and potential DDI, concomitant treatment for HCV and MDR/RR-TB seems feasible, halting the viral replication. This reasoning suggests that the overall benefits will probably outweigh the potential harms.
Summary of evidence
This section provides the PICO questions, data and studies considered to answer the questions; the methods used for analysis and data synthesis; a summary of evidence on desirable and undesirable effects and certainty of evidence; and a summary of other evidence considered during the recommendation’s development.
PICO question
The recommendation in this section results from assessments of the PICO question listed below.
PICO question (DR-TB, 2022): Should HCV treatment be co-administered with MDR-TB treatment in patients co-infected by MDR/RR-TB and HCV?
Data and studies considered
In 2022, a systematic review identified a total of 106 studies reporting on the prevalence of HCV among TB patients. The review reported that the global pooled prevalence of HCVAb positivity across studies was 10.4% (95% CI: 8.5–12.5). Pooled prevalence of HCVAb positivity by WHO region was highest in the European Region at 17.5% (95% CI: 12.2–23.5), followed by South-East Asia at 7.9% (95% CI: 3.5–13.9), the Americas at 7.5% (95% CI: 5.2–10.1), the Western Pacific at 6.2% (95% CI: 3.6–9.5), the Eastern Mediterranean at 5.7% (95% CI: 3.1–8.9) and Africa at 3.5% (95% CI: 0–16.1) (142, 143).
As a follow-up to this review, an online survey was designed to gather expert evidence on treatment strategies for patients co-infected with HCV and MDR/RR-TB.
The above-mentioned PICO question was originally put forward, and a systematic review was conducted to gather relevant data from published research studies. This systematic review identified only one small study fulfilling the eligibility criteria. Two additional small studies described concomitant treatment and suggested that co-administration of treatment may be well tolerated and associated with SVR for HCV infection. None of the studies compared the outcomes of patients receiving co-administered treatment with those of patients receiving MDR/RR-TB treatment alone. Given the current state of evidence, no conclusion could be drawn with regards to co-administration of MDR/ RR-TB and HCV treatment and MDR/RR-TB outcomes based on available research studies.
Collection of expert evidence was identified as a solution for addressing a guideline question where published research evidence is lacking for completion of a GRADE EtD framework. It follows previously developed concepts and established steps used with GDGs (142, 143). After identifying an external group of experts to survey for the collection of data about co-administration of treatment for patients with MDR-TB and HCV co-infection, WHO contacted its regional offices to identify experts with relevant experience in this area. In addition to providing patient outcome data to inform the PICO question, experts were asked for input on other criteria for decision-making including costs, feasibility, and acceptability of co-administration of MDR-TB and HCV treatments. The expert evidence was collected using an online survey, and a quality check of data submitted was completed (e.g. checking that the sum of health outcomes added up correctly across patients), with contact and email follow-up of individual respondents if any clarifications were required.
Methods used for analysis and data synthesis
Data collected from respondents who treated at least one patient with MDR/RR-TB and HCV treatment co-administration (i.e. the intervention arm) and at least one patient with MDR/RR-TB treatment with delay of HCV treatment (i.e. the comparator arm) were included in a comparative analysis. The analysis calculated the risk ratio (RR) to assess treatment effects for the outcomes of interest (i.e. TB treatment success, TB treatment failure, death, LTFU, AEs, hepatic AEs and HCV treatment success).
Forest plots were constructed to calculate pooled effect estimates, with 95% CIs, using randomeffects meta-analysis. RRs were pooled using the Mantel-Haenszel method, which is robust in the case of sparse data (144). The estimate of heterogeneity was calculated using the restricted maximumlikelihood method (145) and the standard error of the pooled effect estimate was derived from the Hartung-Knapp-Sidik-Jonkman method (146). Extensive simulations have shown that these methods are less biased than the alternatives, and more robust to changes in the heterogeneity variance estimate (147). In instances of zero events in one arm, an adaptive continuity correction inversely proportional to the relative group size was applied, improving upon a constant correction. The method considers sparse data and imbalanced groups (148). Between-study heterogeneity was assessed using Cochran’s Q test (149), with a 0.10 significance threshold and the I-squared metric (150) (>50% indicating significant heterogeneity). For descriptive analysis, the pooled proportions of the seven outcomes of interest were calculated in the groups of patients receiving MDR-TB and HCV treatment co-administration and, separately, in the groups receiving MDR-TB treatment with delay of HCV treatment. The single-arm proportions were pooled by fitting binomial generalized linear mixed models with a logit link. Although the analysis of comparative data was used for decision-making, the pooled proportions (which included additional data, albeit from a mix of comparative and noncomparative cohorts) were also considered, to support the GDG’s discussions (e.g. when considering the direction of effects).
Summary of evidence on desirable and undesirable effects and certainty of evidence
Sixteen respondents (expert clinicians) from nine countries provided patient outcome data in the expert evidence survey, with outcomes reported for a total of 135 patients who received co-administration of treatment for MDR-TB and HCV, and 439 patients who received treatment for MDR-TB only, with delay of HCV treatment. Among these responses, eight respondents contributed data from both cohorts (i.e. intervention and comparator) for the comparative analysis, and the other eight contributed data only for the intervention or comparator cohorts for the descriptive analysis. The overall certainty of the evidence was very low, with the calculated estimates of effects based on outcome data from recall or records obtained from the expert evidence survey; hence, there was a very serious risk of bias due to potential confounding, selection bias, and recall (i.e. outcome assessment) bias, as well as imprecision in the effect estimates for most outcomes.
Desirable effects
Co-administration of MDR-TB and HCV treatments as compared to MDR-TB treatment only with delay of HCV treatment may result in an increase in MDR-TB treatment success, but the evidence is very uncertain (RR: 1.25; 95% CI: 1.07 to 1.46; very low certainty in the evidence of effects); this corresponds to 163 more MDR-TB treatment successes per 1000 patients (95% CI: 46 more to 300 more). Use of MDR-TB and HCV treatment co-administration may also result in fewer cases of MDR-TB treatment failure, but again the evidence is very uncertain (RR: 0.30; 95% CI: 0.12 to 0.74; very low certainty in the evidence of effects); this corresponds to 27 fewer failed MDR-TB treatments per 1000 patients (95% CI: 34 fewer to 10 fewer). Co-administration of treatments may also result in fewer losses to follow-up, but the evidence is very uncertain (RR: 0.42; 95% CI: 0.24 to 0.73; very low certainty in the evidence of effects); this corresponds to 103 fewer losses to follow-up per 1000 patients (95% CI: 135 fewer to 48 fewer).
Use of MDR-TB and HCV treatment co-administration may also result in a small decrease in deaths, although the evidence is again very uncertain (RR: 0.98; 95% CI: 0.22 to 4.33; very low certainty in the evidence of effects); this corresponds to two fewer deaths per 1000 patients (95% CI: 92 fewer to 391 more). For HCV treatment success, very few events were reported based on only seven patients in one of the comparative cohorts, and no conclusions could be drawn regarding this health outcome. The GDG noted the knowledge gap about HCV treatment outcomes due to insufficient data. In nine cohorts with a total of 124 patients receiving co-administration of MDR-TB and HCV treatments, the pooled estimate for HCV treatment success was 95.1% (95% CI: 84.3% to 98.6%). With respect to additional considerations, the GDG also noted the potential benefit of additional adherence support for HCV treatment while also receiving MDR-TB treatment. The GRADE evidence profile provides a complete description of the estimates of effects, as well as the descriptive analysis of pooled proportions of events from all cohorts for each of the health outcomes.
Undesirable effects
With respect to the potential harms of co-administration of MDR-TB and HCV treatments, experts were asked to report on AEs and, as a subset of these events, hepatic AEs. Co-administration of treatments may result in a decrease in overall AEs, but the evidence is very uncertain (RR: 0.72; 95% CI: 0.49 to 1.07; very low certainty in the evidence of effects); this corresponds to 223 fewer AEs per 1000 patients (95% CI: 405 fewer to 56 more). Among these AEs there may be an increase in hepatic AEs with co-administration of MDR-TB and HCV treatments, but the evidence is very uncertain (RR: 1.19; 95% CI: 0.23 to 6.16; very low certainty in the evidence of effects); this corresponds to 59 more hepatic adverse events per 1000 patients (95% CI: 240 fewer to 1000 more).
Evidence to recommendations: considerations
The GDG judged that the balance of effects probably favours co-administration of MDR-TB and HCV treatments for MDR/RR-TB patients co-infected with HCV, despite the very low certainty in the evidence for the critical outcomes, considering risk of bias in the available expert evidence as well as imprecision in the calculated effect estimates. The GDG was of the view that there is probably no important variability or uncertainty in how MDR/RR-TB patients co-infected with HCV would value the outcomes related to MDR-TB and HCV treatments, and judged that the option of co-administration of treatments would be acceptable and feasible. The GDG also noted that the option of co-administration of treatments would have presumed cost–effectiveness when both treatments were initiated together, without delay of HCV treatment. Given these considerations, the GDG issued the conditional recommendation suggesting co-administration of both MDR-TB and HCV treatments, in preference to delaying HCV treatment until after treatment of MDR/RR-TB is completed.
Costs and cost–effectiveness
A cost–effectiveness analysis was not performed for this review, but the experts’ survey responses revealed varying perspectives on the cost implications of co-administering MDR-TB and HCV treatments. A notable 39% (n=7) of respondents indicated additional costs incurred, 11% (n=2) noted no cost implications and 28% (n=5) were uncertain about specific cost factors. However, the GDG considered that co-administration of MDR-TB and HCV treatments may have favourable cost– effectiveness, in particular considering that this option may result in fewer losses to follow-up. Even though MDR-TB treatment is typically free of charge to patients, whereas HCV treatment may lack coverage, the overall cost remains constant whether HCV treatment is co-administered or provided with a delay. In settings where HCV treatment is not covered by national health insurance, considering generic drugs is suggested as a way to alleviate the financial burden on patients.
Subgroup considerations
Despite acknowledging the data limitations and very low certainty of the evidence, the GDG believed that extrapolating to broader patient groups, including children, is warranted, especially regarding the potential benefits of co-administration of both treatments. However, the absence of data for specific subgroups (e.g. pregnant women, PLHIV, younger children and patients with liver cirrhosis) necessitates caution in extrapolating the findings to all patients. The GDG discussed whether the specific findings could be applied to PLHIV, with reservations stemming from the absence of specific data on subgroups such as older individuals and people with comorbidities, and other factors that could not be obtained through the expert evidence survey. The GDG underscored the lack of comprehensive data for these subgroups and emphasized the necessity of cautiously approaching such extrapolations.
Implementation considerations
The GDG noted that clinicians should initiate co-administration of MDR-TB and HCV treatments in line with knowledge and consideration about DDIs and patients’ comorbidities. The group highlighted that, when implementing the recommendation, the type of evidence and very low certainty on which the recommendation is based should be made transparent and clearly communicated to patients during the decision-making process. Finally, when considering the implementation of the recommendation, it was highlighted that the unavailability of HCV treatment should not delay MDR/RR-TB treatment.
Drug–drug interaction
Although data on DDIs between newer HCV treatments (DAAs) and MDR-TB medications are limited, current evidence suggests minimal interactions. However, caution is still advised.
Bedaquiline, a key component of most MDR-TB regimens, may increase the risk of liver toxicity, particularly when co-administered with some HCV treatments. Additionally, some MDR-TB drugs (e.g. ethionamide/prothionamide and clofazimine) might interact with specific DAAs (daclatasvir) by affecting how the body processes them, although this has not been proven (151).
Owing to these potential interactions, consulting with a specialist is essential. The specialist can assess individual patient factors and recommend the optimal treatment plan that minimizes DDIs and maximizes treatment success for both HCV and MDR-TB (140).
Patient-centred approach
Efforts are required to provide patient support to enable full adherence to treatment. Supporting patient adherence may be important to retain patients on treatment even when a regimen is relatively short. WHO recommendations on care and support and a related handbook are available through the previously published WHO consolidated guidelines on tuberculosis. Module 4: Treatment – tuberculosis care and support (152) and in the chapter 3 of this consolidated document.
Monitoring and evaluation
Patients undergoing treatment for both HCV and MDR/RR-TB require close monitoring throughout the treatment course. The GDG emphasized the importance of regular clinical assessments and laboratory testing. The specific schedule of testing will be determined by the health care provider, but may include:
HCV monitoring – this typically involves HCV RNA testing to track viral load and measure treatment response. An SVR at 12 weeks after the end of treatment indicates a cure. Other tests, including liver function, are also critical to monitor for potential liver damage and have to be observed during the course of treatment (153).
MDR-TB monitoring – the treatment response should be monitored by using monthly sputum and smear microscopy and culture (ideally at the same frequency). The schedule should be similar to that for bacteriological monitoring recommended for shorter all-oral MDR TB regimens (8).
Based on guidance in current literature and clinical experience, the panel advised the following with regard to monitoring and evaluation of the safety and effectiveness of the co-administration of HCV and MDR-TB treatment regimens:
- implementation of both regimens requires access to both treatments; however, the unavailability of HCV treatment should not delay the initiation of MDR treatment;
- programmes need to have access to reliable DST for MDR-TB medicines, bacteriological tests (sputum smear microscopy and culture), and monitoring of the virological response for HCV; and
- although the data assessed did not unearth any major signals of risk, aDSM systems must be functional to conduct rigorous active monitoring of adverse events and promptly detect, manage and report suspected or confirmed drug toxicities.
