Cost-effectiveness analysis of different rescue therapies in patients with lamivudine-resistant chronic hepatitis B in China

A Markov model consisting of 8 mutually exclusive health states was developed to track the potential lifetime courses of CHB. These states characterize the different health conditions associated with CHB, as shown schematically in Figure 1. A hypothetical cohort of 45-year-old patients with genotypic or clinical LAM-resistant CHB entered the model in the initial state, i.e., “lamivudine-resistant CHB.” Patients could move among eight health states after one year, as indicated by arrows in the Figure 1. According to the treatment response for each rescue therapy, defined as HBV DNA<300-400 copies/ml by quantitative PCR, a patient could transition from the initial state to either “virological response” or “multi-resistant CHB.” Patients with a “virological response” could also develop virological breakthrough due to new antiviral resistance and transition to the multi-resistant CHB health state. One important issue in the course of CHB is the progression from CHB to cirrhosis and hepatocellular carcinoma. The risk of disease progression is independently associated with the serum HBV DNA level [25]. Patients in any of the three states (“virological response,” “lamivudine-resistant CHB” and “multi-resistant CHB”) could develop compensated cirrhosis and hepatocellular carcinoma. However, patients in the virological response state would have a lower risk of disease progression than patients in the other two groups. Patients who develop compensated cirrhosis would be at risk for decompensated cirrhosis and hepatocellular carcinoma. Liver transplantation would be considered for patients in the decompensated cirrhosis and hepatocellular carcinoma states. The annual mortality of the progressed disease was also accounted for in the model for estimation of the health outcomes. The current analysis did not account for the natural mortality for other causes. We extrapolated the lifetime outcomes until all are dead or at the expected life-year (74 year of age in China) [26].

The annual rates of progression were primarily derived from the literature, as shown in Table 1. The REVEAL-HBV study previously indicated that serum HBV DNA levels are an independent marker for predicting the progression of CHB (cirrhosis and HCC). Therefore, we assume that the progression depends on the serum HBV DNA level, regardless of nucleoside resistance. Patients with undetectable HBV DNA would be at the lowest risk for developing compensated cirrhosis and HCC. The proportions likely to receive liver transplantation for decompensated cirrhosis and HCC were derived from our previously reported article [5].

Efficacy and resistance data (Table 2) for ADV monotherapy, combination therapy, ETV monotherapy and TDF monotherapy were estimated from clinical trials. A long-term clinical trial reported the four-year virological response and resistance of ADV monotherapy for HBeAg(+) and HBeAg(−) patients with lamivudine resistance [9]. Cumulative virological responses at four years were about 41.2% and 51.0% for the HBeAg(+) and HBeAg(−) cohorts, and the cumulative resistance rates were 51.6% and 42.4%, respectively. Data for combination therapy in patients with lamivudine-resistant HBeAg(+) CHB and data on resistance were derived from a clinical trial that included 132 lamivudine-resistant CHB patients; the cumulative virological response at two years was 68.0% [29]. For the HBeAg(−) cohort, the cumulative virological response at three years was 97.0% [30]. The cumulative resistance rate at four years was 8%; we assumed that there was no difference in resistance for the two cohorts. For ETV and TDF monotherapy, it was also assumed that the response and resistance rates for both cohorts was similar due to the absence of clinical data. The response rate for ETV in lamivudine-refractory CHB was estimated from a 96-week study [20]. The ETV resistance rate (21% at first year and 39.5% at second year) for patients with lamivudine resistance was estimated to be as high as 36.4%, based on a four-year assessment [23]. Because few studies have reported the efficacy of TDF for lamivudine-resistant CHB, we used data on TDF as a rescue therapy for patients following the failure of both lamivudine and adefovir. The cumulative virological responses at one and two years was 45.8% and 64.4, respectively [22]. The response to TDF was independent of mutations conferring ADV resistance. Due to no evidence of response and resistance data beyond the timeframe of clinical trial, we assume that no health benefit will be obtained from continuing the initial recue therapies beyond the clinical observation time, and patients who did not achieve a virological response would be considered resistant to the initial recue therapies and enter into the multi-resistant CHB state. We also assume that the resistances beyond the observation period were similar to those in the last year of the observation period. In our current analysis, we assumed the resistance rate was identical with relapsed rate.

Direct health resource consumption was estimated from the perspective of Chinese health care, including the cost of medications, examinations, physician visits and laboratory tests (Table 3). Indirect costs such as lost productivity were not included. The annual costs of the four rescue therapies were calculated from the price of the antiviral drugs obtained from the Shanghai Municipal Bureau of Pricing. Several generic varieties of ADV are available on the current Chinese market. Because the median price of the generics was lower than Hepsera (the brand name for ADV from GlaxoSmithKline), we input the price of the generics into the model in the base-case analysis. At present, TDF is still awaiting approval from the Chinese State Food and Drug Administration, and no accurate price estimate is available. We assumed that the cost of TDF (300 mg dosage) would be similar to that of ETV ($6 per 500 mg dosage) in China because, as first-line antiviral options for naïve CHB, the costs of the two agents have been similar in other contexts [31, 32]. Cost-related data for health states were obtained from previous studies [5, 33]. All costs were converted to U.S. dollars (US $1 = CNY 6.5).

Health state utility values were derived from a recently published study using the standard gamble utility elicitation technique (Table 3) [34]. The utilities for lamivudine-resistant and multi-resistant CHB were assumed to be equal to those for naïve CHB.

The annual discount rate for costs and utilities was assigned as 3% in the current analysis [5].

To evaluate the uncertainty of parameter values and the robustness of the model, univariate sensitivity analyses were performed for each parameter in the model over the ranges shown in Tables 1, 2, 3. Ranges were sourced from reported literatures, such as 95 CI %, or a range±20% of the base case value when reported data were not available. Two-way sensitivity analysis was used to examine the uncertainty around the assumption associated with TDF, including the price and efficacy. To estimate the simultaneous impact of parameter uncertainty on the analysis, we also performed a probabilistic sensitivity analysis (PSA), in which distributions were assigned to the input parameters of the model (triangle distributions for costs, beta distributions for probability parameters and utilities). To identify the most cost-effective therapy over the range of threshold values, cost-effectiveness acceptability curves were plotted based on the result of the PSA. We generated a cost-effectiveness acceptability curve (CEAC) to identify the strategy with the greatest probability of it being cost-effective over a range of threshold values. CEAC could demonstrate the level of uncertainty associated with an option. The cost-effectiveness acceptability frontier (CEAF) is, however, constructed from the CEAC of the optimal option(s), and therefore only depicts uncertainty through the probability of not selecting the most cost-effective option [35]. Using scenario analyses, we evaluated the impact of age at initial rescue therapy by setting the age from 30 to 60 years.

In the LAM-resistant HBeAg-positive cohort, treatment with TDF monotherapy resulted in 11.17 QALYs, and the lifetime cumulative incidence of compensated cirrhosis, decompensated cirrhosis, HCC and death was 30.7%, 11.7%, 13.1% and 25.5%, respectively. The other three competing rescue therapies yielded 9.25(ADV monotherapy), 10.58(combination therapy) and 9.43(ETV monotherapy) QALYs, respectively. In the LAM-resistant HBeAg-negative cohort, treatment with combination therapy achieved greater health benefits, which resulted in 10.48 QALYs followed by10.48 (combination therapy), 8.64 (ADV monotherapy)and8.51 (ETV monotherapy) QALYs, and a lifetime cumulative incidence of compensated cirrhosis, decompensated cirrhosis, HCC and death were 59.4%, 22.0%, 18.1% and 42.0%, respectively. The clinical and economic outcomes are presented in Table 4.

We evaluated the relative cost-effectiveness according to the QALYs and costs associated with the various therapies. The more expensive strategy was TDF in both cohorts. In the HBeAg-positive cohort, ADV and ETV monotherapy presented extended dominance and are not as effective (lower QALYs) and efficient (higher ICERs) than combination therapy. Combination therapy was also acceptable and had the lowest ICER of any of the rescue therapies. TDF monotherapy achieved extended success, with more QALYs provided than combination therapy but at a higher ICER. Among HBeAg-negative patients, TDF and ETV monotherapy were dominated; the combination therapy is more effective than ADV and presents an ICER below the threshold of China and Shanghai. The results are plotted in Figure 2.

One-way sensitivity analyses revealed that the model was sensitive to some input parameters (Figure 3). In the two cohorts, the most substantial impact factors include the utilities of the CHB and virological response health states, the probability of LAM-resistant and multi-resistant CHB progression to compensated cirrhosis, and the price of ADV per 10 mg. Other parameters, such as cost of HCC and the probability of annual resistance to combination therapy beyond the four years, are less important.

In a scenario analysis in which we evaluated the economic impact of age at the initiation of rescue therapy, the ICER of the four rescue therapies compared with no treatment increased with age (Figure 4A and B). For the HBeAg-positive cohort, the ICER of the combination therapy, which was dominant, fell below the threshold of $11,034 (3× per capita GDP of China) and $38,376 (3× per capita GDP of Shanghai), regardless of age. The TDF monotherapy was lower than the threshold of $38,376 but would be higher than $11,034 if the patient’s age was greater than 54. Among HBeAg negative, only TDF exceeds the thresholds of $11,034 but it is lower than the thresholds of $38,376.

Two-way sensitivity analysis for the variable TDF cost against efficacy is shown in Figure 4C and D. Comparing with “no treatment” for LAM-resistant HBeAg-positive (C) and HBeAg-negative (D) CHB cohort, TDF strategy must lower TDF price to $4.36 and $4.13 from an initial cost of $6.0 to yield a lower than $6531.7 and$4571 ICER (where the initial efficacy equals the base-case values), respectively. However, if the initial TDF price is $6.0, ICER of TDF strategy was always higher than $6531.7 and $4571 even when the efficacy was 1.5 times of the base-case values, respectively.

A probabilistic sensitivity analysis of 1,000 simulations revealed the probabilities of meeting the ICER thresholds of $11,034 and $38,376 per additional QALY; the results are shown in Figure 5. For the HBeAg-positive cohort, the probabilities of cost-effectiveness being achieved by combination therapy compared with no treatment, ADV monotherapy, ETV monotherapy and TDF monotherapy were 87.6%, 89.7%, 100.0% and 11.2%, respectively, under the $11,034 threshold. The probabilities of cost-effectiveness under the $38,376 threshold were 99.7%, 99.5%, 100.0% and 89.5%, respectively. Among HBeAg-negative patients, the probabilities of cost-effectiveness being achieved with combination therapy were all over 95% in comparison with all other options except TDF monotherapy, regardless of whether the ICER threshold was $11,034 or $38,376. The CEACs showed that for the HBeAg-positive cohort the combination therapy and TDF monotherapy achieved the majority of probabilities of cost-effectiveness, and for the HBeAg-negative cohort no treatment yielded the majority of probabilities of cost-effectiveness when the WTP thresholds are $11,034 and $38,376 (Figure 6).