With the intent of aiding policy decision makers on which CHB drugs should be included in the NLED, our study was the first to compare the cost-utility of each drug therapy according to the THASL clinical practice guidelines with palliative care in patients with HBeAg-positive CHB based on a societal perspective. Even though the ICER results indicated that these three alternatives were dominant due to higher effectiveness and lower costs when compared with palliative care, it is evidenced that both tenofovir monotherapy and generic lamivudine with the addition of tenofovir when drug resistance occurred were more superior than generic lamivudine with tenofovir added based on the roadmap guideline when taking the uncertainty of all parameters in the model into account. The results have shown that the total cost of generic lamivudine with tenofovir added based on the roadmap guideline was higher compared with generic lamivudine plus tenofovir when drug resistance, whereas total LYs and QALYs obtained from both interventions were not different. As a result, when compared with providing generic lamivudine plus tenofovir added based on the road map guideline providing generic lamivudine plus tenofovir when drug resistance could save healthcare costs of approximately 70,000 THB (USD 2,333) per patient due to the cost avoidance of serious complications in the future. Thus, when considering the provision of CHB treatment to HBeAg-positive CHB patients above 30 years of age (i.e., 40-70 years), providing generic lamivudine plus tenofovir when drug resistance occurred and tenofovir monotherapy were dominant and cost-saving interventions compared with palliative care.
Furthermore, generic lamivudine, which has already been included in the NLED, should be considered as the first-line drug for the treatment of HBeAg-positive CHB patients above 30 years of age (i.e., 40-70 years) who require the treatment. In contrast to the findings of other previously published studies, entecavir [8–17], adefovir [6, 7], telbivudine , and pegylated interferon [21, 23, 24] were more cost-effective compared with lamivudine. This could be explained by the fact that our study considered drug resistance due to lamivudine to imitate the real current clinical practice. Moreover, generic lamivudine, which is very inexpensive in Thailand, was also included as one of the interventions.
Although lamivudine can cause HBV DNA suppression in most HBeAg-positive CHB patients, it is also associated with a high rate of drug resistance . Our study indicated that tenofovir, which was a cost-saving option, should be used as either the first- or second-line drug for the management of drug resistance due to nucleoside analog such as lamivudine. Similarly, the study of Buti et al. revealed that tenofovir was associated with lower costs and higher efficacy than entecavir, telbivudine, and adefovir . At the time of the study, no other CHB treatments with low rates of drug resistance (e.g., tenofovir) had been included in the NLED yet, even though tenofovir demonstrated high antiviral efficacy and low drug resistance for patients with CHB [3, 4]. Therefore, we submitted the cost-effectiveness information of CHB treatments along with policy recommendations to the Subcommittees for Development of NLED in May 2012 that tenofovir should be included in the NLED . After the meeting, it was announced that tenofovir would be included in the NLED only for CHB patients with drug resistance due to nucleoside analog such as lamivudine under the condition that tenofovir should be used as an alternative and not as the first-line therapy.
However, based on the expert’s opinion, if both lamivudine and tenofovir were included in the NLED, using tenofovir as the first-line drug would be the better option given that tenofovir has a very low resistance rate. It would be more convenient for clinicians to provide tenofovir as the first-line treatment in order to reduce the time and cost of drug resistance management compared with providing lamivudine as the first-line drug. Even if the patients taking tenofovir developed drug resistance, lamivudine could be added later. It should be noted though that tenofovir has also been implicated in causing renal toxicity. Tenofovir can also cause acute renal failure, Fanconi syndrome, proteinuria or tubular necrosis. These side effects are due to accumulation of the drug in proximal tubules .
Moreover, three major issues (i.e., the prices of tenofovir and lamivudine, resistance rate of tenofovir, and costs of all complications and adverse drug events) need to be addressed. First, it was noted that the price of tenofovir in this study was obtained from the current market price of tenofovir in Thailand, which is relatively inexpensive due to the discounted price (43 THB or USD 1.43) proposed by the pharmaceutical company. At present, the price of tenofovir is approximately equal to that of entecavir in many countries. If the maximum expected price of tenofovir was assumed to be equal to the price of entecavir (235 THB or USD 7.83 per tablet), the ICER value would change from a dominant value to 100,000 THB (USD 3,333) per QALY gained when compared with palliative care. Similarly, if the price of lamivudine was adjusted to the price of original lamivudine, the ICER would be adjusted to 81,000 THB (USD 2,700) per QALY gained. Therefore, when changing the prices to current market prices, tenofovir monotherapy or lamivudine would still be cost-effective in the Thai context although they would not be cost-saving interventions .
Second, according to the current studies related to drug resistance, the resistance rate of tenofovir used in this study was 0% . If the resistance rate of tenofovir was assumed to be equal to that of entecavir based on expert opinion, it would still be a cost-effective intervention in the Thai context with an ICER of 8,000 THB (USD 267) per a QALY gained compared with palliative care.
Third, the direct medical costs of complication states in this study were obtained from a published multi-center observational study of hepatitis C conducted at five major tertiary care hospitals in Thailand . The costs of all complications (i.e., compensated cirrhosis, decompensated cirrhosis, and HCC) in patients with hepatitis C might be lower than those conducted in CHB patients. Based on the sensitivity analysis results, the costs of all complications had the greatest effect on the changes in ICER values. It is suggested that providing generic lamivudine plus tenofovir when drug resistance occurred and tenofovir monotherapy would be cost-effective options since the ICER values were lower than one times the Thai GDP per capita . In addition, the costs of treatment of the adverse drug events were not considered in the study. In particularly, generic lamivudine may result in more adverse drug events or side-effects. However, it is expected that the adverse drug reactions of generic lamivudine and tenofovir may have little effect on an increase in the ICER values. Lok et al.’s study showed that lamivudine treatment had an excellent safety profile in HBeAg-positive CHB patients  and nausea was the only adverse event that occurred more frequently in CHB patients receiving tenofovir, which may cause little impact on the cost .
It is important that the limitations of this study need to be addressed. Due to the lack of transitional probabilities data for CHB patients in Thailand, some transitional probabilities were obtained from published articles in other countries [27, 28, 31–44]. However, we specifically performed a meta-analysis which could yield the most reliable evidence . Furthermore, the utility data of CHB has been gathered but not for all complication states (i.e., compensated cirrhosis, decompensated cirrhosis, and HCC) in Thai CHB patients; therefore, the utility data of CHB patients with complications were obtained from a multinational study .