Virtual Touch Quantification to diagnose and monitor liver fibrosis in chronic hepatitis B and C

The company submitted a de novo cost analysis evaluating VTq plus liver biopsy (where needed) compared with transient elastography plus liver biopsy (where needed) and against liver biopsy alone. Costs were modelled from an NHS and personal social services perspective using 2013 prices. The population included in the model was patients with chronic hepatitis B or C needing assessment of liver fibrosis. The model structure was a decision tree based on a cohort of 1,000 patients referred by GPs and stratified according to the presence or absence of fibrosis, then sequentially across 3 groups according to stage of fibrosis determined by METAVIR score (F2, F3/F4, or F4). The External Assessment Centre confirmed that the model was internally valid.

The company used the estimated prevalence of fibrosis to stratify the cohort into the 3 stages, and applied the sensitivity and specificity of each diagnostic strategy (VTq plus liver biopsy, transient elastography plus liver biopsy and liver biopsy alone) for each stage, creating estimated numbers of true or false negatives or positives. The External Assessment Centre generally agreed with this approach.

The model was based mainly on fibrosis assessment and did not include any treatment or monitoring costs for patients in the F2 group and the F3/F4 group. For F4 fibrosis (cirrhosis), patients in the true‑positive group had antiviral therapy and those in the false‑negative group had liver biopsy. According to the diagram of the company's model in its submission, false positives had antiviral therapy and true negatives had a biopsy. The External Assessment Centre questioned the rationale for this approach and whether this assumption was actually included in the model calculations.

The company did not state the time horizon for the model, but the External Assessment Centre considered that the outcomes were likely to be realised using a 1‑year horizon, based on the duration of antiviral therapy.

The company's estimates of fibrosis prevalence at each stage were based mainly on clinical expert advice and on 1 study in patients with cirrhosis, because exact figures were difficult to determine. The External Assessment Centre sought additional clinical expert advice to validate these assumptions but the experts consulted were not able to provide any figures.

The diagnostic accuracy figures for VTq and transient elastography were taken from the available literature and liver biopsy was assumed to have 100% sensitivity and specificity. The External Assessment Centre agreed with the approach taken for liver biopsy and transient elastography (figures taken from a meta‑analysis), but considered that the figures used for VTq were not sufficiently robust. The External Assessment Centre addressed this issue in its own meta‑analysis of the clinical evidence.

The company included direct costs for VTq, transient elastography and liver biopsy, calculating the costs of VTq and transient elastography using a bottom‑up approach which included capital, infrastructure, maintenance, staffing, training and consumable costs. The cost for transient elastography was calculated based on a nurse carrying out the test with a throughput of 2,500 patients per year over the device lifespan (7 years), giving a per‑patient cost of £25.33. This was compared with a report published by the Centre for Evidence‑based Purchasing (Stamuli et al. 2009), which gave a per‑patient cost of £18.68 (corrected for inflation by the company to £22.91). The cost for VTq was based on the purchase of the software and a Siemens Acuson S2000 machine, and use by a radiographer. It was assumed that VTq assessments would take up 10% of the ultrasound machine use and so this proportion of the annual capital, staffing and consumables costs was used in the estimation. The cost was calculated based on a throughput of 500 patients per year over the device lifespan (5 years), giving a per‑patient cost of £15.02. The cost for liver biopsy was estimated from the 2013–14 payment by results tariff to be £615, based on a mix of procedures.

The External Assessment Centre agreed with the estimates for these costs but considered that they could be further explored in sensitivity analyses. The capital costs for VTq and transient elastography were not estimated using the annuity method, and the company did not describe the exact mix of procedures used to calculate the biopsy cost. The cost of antiviral therapy was estimated to be £10,000 per patient in the executable model; the External Assessment Centre was unsure about the rationale behind this figure.

The company carried out deterministic 1‑way and multi‑way sensitivity analyses varying the prevalence of liver disease, prevalence for different liver fibrosis stages, the diagnostic accuracy of VTq, technology and treatment costs and whether or not liver biopsy was done. The External Assessment Centre generally agreed with the company's approach but commented that the company did not explain the rationale for the variations in prevalence which it used.

The results of the company's base case indicated that VTq could result in a cost saving of £10.31 per patient when compared with transient elastography and £599.08 per patient when compared with liver biopsy.

Findings from the company's sensitivity analysis showed that if each patient had a biopsy, increasing the overall prevalence of liver fibrosis from 10% to 30% lowered the cost saving per patient from £527 to £447 (assuming the best‑case diagnostic accuracy of VTq) and from £496 to £419 (assuming the worst‑case diagnostic accuracy of VTq). If only 20% of patients had a biopsy, the cost savings for VTq were reduced, and at high fibrosis prevalence levels or lower diagnostic accuracy it became cost‑incurring. The cost of antiviral therapy was also varied from the base case assumption of £10,000 to £6,500. Over this range, assuming that 20% of patients had a biopsy, the cost savings for VTq varied from around £60 to £8.

The External Assessment Centre considered that the model addressed the decision problem in the scope, but that its structure did not accurately reflect current clinical pathways for people with liver fibrosis. It also did not include all the relevant costs and outcomes for diagnosing and treating the condition. No monitoring or treatment costs were included for patients in the F2 or F3/F4 fibrosis groups. The External Assessment Centre considered that this was erroneous, because people with less severe fibrosis may benefit from treatment.

The External Assessment Centre also questioned the assumption that patients falsely classified as negative for fibrosis would not incur any treatment costs and would re‑enter the model as new patients. It considered that this was a misleading approach, because misdiagnosis may incur additional costs (from further diagnostic tests, inpatient or emergency episodes and treatment). The External Assessment Centre considered that a mortality arm would have been appropriate to account for the small increased risk associated with liver biopsy, but acknowledged that this was likely to have been incorporated in the chosen tariff cost. The External Assessment Centre also noted that the company had used a cohort approach rather than a per‑patient approach as specified in NICE's methodology.

The External Assessment Centre revised some parameters and re‑ran the company's model to address these issues. The revised model included true positives, false positives, true negatives and false negatives at each of the F≥2, F≥3 and F4 stages. Revised prevalence and diagnostic accuracy parameters for the model were taken mainly from the External Assessment Centre's meta‑analysis and applied at each sequential stage for VTq, transient elastography and liver biopsy. Liver biopsy was treated as the reference standard with 100% sensitivity and specificity.

Key assumptions made by the External Assessment Centre in its revisions to the company's model were as follows:

• Patients categorised as false negative for fibrosis would return and be re‑diagnosed as true positive within 1 year.

• Prevalence rates for stages of fibrosis were different for VTq and transient elastography based on the External Assessment Centre's meta‑analysis. The combined hepatitis B and C prevalence rates for VTq were used for transient elastography and liver biopsy in the model to ensure compatibility.

• Combined hepatitis B and C prevalence and diagnostic accuracy figures for F3 fibrosis were not available from the meta‑analysis. The External Assessment Centre therefore used figures for hepatitis C across the model for this stage.

• Treatment delay resulting from misdiagnosis was unlikely to have a clinical effect and so long‑term modelling of disease progression was not needed. According to published clinical evidence and expert advice gathered by the External Assessment Centre, progression in both hepatitis B and C is relatively slow.

• Patients diagnosed as being at stage F2 had fibrosis and those at stage F≤1 did not.

• Most misclassified (false positive) patients for VTq and transient elastography would be diagnosed as having F2 fibrosis. A proportion of those with F2 fibrosis would be misclassified as having F3 or F4 fibrosis. These proportions were chosen arbitrarily and subjected to sensitivity analyses.

• Patients diagnosed with F3 or F4 fibrosis would have antiviral therapy.

• A mortality risk of 0.003 would apply to liver biopsy, based on available literature.

The unit costs for VTq and transient elastography were estimated using an annuity method and discounted at 3%, to give per‑test figures of £15.24 for VTq and £25.90 for transient elastography. The cost for liver biopsy was estimated from tariff costs to be £622. The costs for antiviral therapy were based on duration of treatment, which was estimated to be 12 weeks for patients with F3 fibrosis and 24 weeks for patients with F4 fibrosis, based on NICE technology appraisal guidance on peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. Costs for a compatible Siemens ultrasound machine were modelled in 2 scenarios: 1 including purchase costs and 1 assuming that a machine was already available.

Findings from the base case (incorporating the External Assessment Centre's revised parameters) showed that in a scenario where a compatible Siemens ultrasound machine would be purchased along with the VTq software, using VTq would generate cost savings of £53 per patient compared with transient elastography and £434 compared with liver biopsy. If a compatible ultrasound machine was already available, the cost savings for VTq increased slightly to £57 compared with transient elastography and £438 compared with liver biopsy.

The External Assessment Centre carried out deterministic sensitivity analyses varying prevalence rates, sensitivity and specificity for VTq and transient elastography, distribution of false positives between stages F2 and F3, unit costs of VTq and transient elastography, usage levels of transient elastography and antiviral therapy costs. Findings from the sensitivity analyses showed that VTq remained cost‑saving across all scenarios. The key drivers affecting the cost savings per patient were prevalence of liver fibrosis, the distribution of false positives to other fibrosis stages, the specificity of VTq and transient elastography for stages F2 and F3, unit costs of VTq and transient elastography and antiviral treatment costs.

The External Assessment Centre acknowledged some limitations in its revised parameters. The lack of clear data on prevalence and diagnostic accuracy at each stage of fibrosis meant that figures were extrapolated for the stages in a sequential model, rather than each stage being presented separately. Figures for hepatitis C at stage F3 fibrosis were applied to the whole population because combined data were not available. Several assumptions were made to calculate technology and comparator costs, but the External Assessment Centre varied these parameters in sensitivity analyses to address uncertainty.

The Committee recognised the limitations in the cost modelling presented by the company and in the adjustments made by the External Assessment Centre, but considered these revisions sufficiently robust to be plausible. The Committee considered that the External Assessment Centre's sensitivity analyses addressed the uncertainties in the evidence base and it concluded that cost savings for VTq compared with transient elastography and liver biopsy were likely to be realised in practice.

The Committee was satisfied that the cost modelling indicated that use of the VTq software would generate cost savings regardless of whether a compatible Siemens ultrasound machine was purchased.

The Committee noted that the cost modelling included the assumption that the Siemens ultrasound machine would be used for VTq measurements for only 10% of the time and for other scanning procedures for the rest of the time: it was advised by experts that this was reasonable. The External Assessment Centre stated that the findings from the model were robust even when the proportionate use of the machine for VTq (and so VTq's test costs) was raised in sensitivity analyses.

The External Assessment Centre also stated that the findings remained robust if treatment costs (for antiviral therapy) were not included in the model.

For the guidance review, the External Assessment Centre noted that the differences between the updated pooled estimates for the sensitivity and specificity of VTq for hepatitis C compared with the pooled estimates used in the original model (see tables 3 and 4) are minor, as seen in table 7. [2020]