The high prevalence and morbidity of CHB pose heavy social and financial burdens for China. Because of limited health resources, most naïve CHB patients can afford only LAM as their first-line antiviral therapy; ETV and TDF are too expensive. Consequently, about 70% of patients will develop LAM resistance after 5 years. Selection of a cost-effective rescue therapy is an important issue not only for patients but also for physicians and decision-makers. The current economic analysis supplies health and economic information on the four main rescue therapies for LAM-resistant CHB patients.
The current analysis suggests that the initiation of rescue therapies for LAM-resistant CHB with combination therapy is likely to be more cost-effective than ADV, ETV or TDF monotherapy. But for patients HBeAg positive (Figure
5) the probabilistic sensitivity analysis comparing combination therapy with TDF shows that the probability to be costeffective is 11,2% for combination therapy compared to TDF under the $11,034 threshold . ADV monotherapy was the least expensive of the four rescue therapies, but its long-term health outcomes were poorest. Although ADV monotherapy was dominant, with the lowest ICER in HBeAg-negative patients, we believe that combination therapy is the optimal option. Results from PSA show it to be under the ICER threshold of $11,034; it would be more cost-effective compared to ADV monotherapy for about 96.1% of patients. In contrast, TDF monotherapy offered the greatest health outcomes for HBeAg-positive patients but was more resource-intensive than combination therapy (Table
4). In the HBeAg-positive CHB cohort, TDF monotherapy resulted in greater health benefits but was more expensive than combination therapy. Consequently, TDF monotherapy might be preferred in contexts with a high ICER or WTP threshold (such as $38,376 per QALY). However, among HBeAg-negative patients, TDF monotherapy did not show extended dominance; rather, it may contribute to a lower rate of virological response than combination therapy. Because few studies on TDF as a rescue therapy for HBeAg-negative CHB exist, the current estimation of the virological response rate was derived from a study in which only 33% of the patients had HBeAg-negative CHB. We suggest that TDF monotherapy could offer greater health benefits because the virological response was greater in the HBeAg-negative CHB cohort than in the HBeAg-positive CHB cohort
. These findings are generally consistent with the recommendations for managing LAM-resistant CHB, which involve the addition of ADV to LAM or TDF monotherapy
Constrained economic conditions result in different treatment options. Each province and city in China has its own health care system, which determines medical coverage based on local economic conditions
[42, 43]. Our analysis shows how health decision-makers could select affordable, cost-effective therapies. For example, using 3× per capita GDP of Shanghai city as the WTP threshold
, TDF monotherapy might be recommended for LAM-resistant HBeAg-positive CHB because this therapy achieves the greatest probability of cost-effectiveness in comparison with no treatment and other rescue therapies. However, from the perspective of the rest of China, when the threshold decreases to $11,034, combination therapy might be most affordable and cost-effective.
Our analysis includes two other important findings. First, based on recommendations by professional society guidelines and expert opinion, surveillance for resistance by monitoring of HBV DNA levels should be performed for all patients receiving nucleoside analogs. Our scenario analysis showed that an earlier age of rescue therapy initiation is related to a lower ICER for all four therapies. Second, our previous studies have shown that the utilities for CHB and virological response health states have substantial impact on the results of the model
. The current analysis finds a similar phenomenon. To the best of our knowledge, the prejudice and bias confronted by a person with CHB in China lead to worse sociocultural conditions than are faced by patients in western societies. CHB patients in China may be discriminated against in employment, marriage and education, as reflected in the lower utility values
. It would be reasonable to expect that improvement of the quality of life for patients with CHB would increase the QALYs.
The analysis presented here has several limitations that deserve consideration. First, most of the data for the virological response and resistance were not estimated from large-scale clinical trials. At present, ETV and TDF are widely used for naïve CHB patients; in the future it will be even more difficult to obtain large-scale data on the management of LAM-resistant CHB. Second, no clinical trial reporting virological response and resistance data lasted longer than five years. We used assumed data to calculate the lifetime outcomes. If long-term data become available, the accuracy of the results could be improved. Third, because no head-to-head trial has directly compared the efficacy of the four rescue therapies, our estimates were derived from various studies with varying design, patient cohort, follow-up, and quality. However, we examined the potential uncertainty of the variables with a sensitivity analysis. The final result was robust. Fourth, we did not evaluate potential treatment after a patient developed multiple resistance. In a constrained economic situation, such as China, many patients cannot afford expensive rescue therapies and would cease antiviral therapy after developing multiple resistance. Fifth, the current analysis did not include interferon-based strategies for dealing with LAM resistance. Some studies have suggested that a significant proportion of patients with LAM resistance who switched to pegIFNa-2a from LAM had a similar response to pegIFNa-2a as treatment-naïve patients
. Sixth, the utility scores for patients with LAM-resistant and multi-resistant CHB were assumed to be equal to those for naïve CHB. However, these scores might be worse in practice. One-way sensitivity analysis found that lower utilities of LAM-resistant and multi-resistant CHB would yield more health benefit. Finally, cumulative virological response and HBV resistance probabilities of ETV and TDF were assumed to be similar for both cohorts. If new data is available, an update analysis is necessary. However, the clinical data call for further study and a wider assessment. Nonetheless, because the current analysis reflects the current clinical practice for dealing with LAM-resistant CHB, we believe that the results will be helpful for patients, physicians and decision-makers.