Worldwide about 400 million human beings are infected by HBV causing severe liver complications, as well as decompensated cirrhosis and HCC . The global population of about 45% live in areas that have high incidence of chronic HBV infections in which chronic carriers of about 75% live in the Western Pacific and Asia. Around 15-40% of HBV infection progress to liver cirrhosis, fibrosis and HCC, and 0.5-1.2 million HBV patients pass the infection per year. Because of the high HBV-related mortality and morbidity, the Hepatitis B worldwide disease burden is significant . The exact incidence of HBV is yet obscure in Pakistan however at least 10 million peoples are probably supposed to be infected with chronic Hepatitis B (CHB) infection .
In this study we have investigated the efficacy of entecavir (ETV) monotherapy and entecavir plus Tenofovir Disoproxil Fumarate (TDF) combination therapy in HBV infected patients in the war affected tribal belt of Pakistan. The therapeutic outcomes of these antivirals were also correlated with various factors such as age group, gender, and various demographic regions of tribal belt following six and twelve month’s treatment. Overall, the response rate was a little higher for the 12 months with 27% and 36% of patients showed sustained virologic response (SVR) respectively for 6 and 12 months of antiviral treatment. Previously, it has been observed that ETV does not affect significantly the HBV viral load after three months treatment, however, it inhibits HBV completely in 54% of patients following six months’ therapy . Another study reports SVR in 43% of patients following six months treatment . When various factors such as gender, age and geographic regions were assessed for their influence upon the SVR of antivirals following six and twelve month treatment, it was observed that males are relatively more responsive towards twelve month antiviral therapy but showed significantly low level of response as compared to the female at end of six month treatment. Duration of treatment had no effect on the SVR among the female. Male relatively proved less responsive towards both ETV monotherapy and combination therapy of ETV and TDF for six month duration, however, comparable rate of response was observed among the both gender for the twelve month treatment of ETV alone or ETV plus TDF. Earlier studies have also highlighted the effect of gender on disease progression and treatment response among the different genders of HBV patients. One study reported that HBV infection progresses relatively more rapid in men than women and the women show better response towards the HBV therapy because it might be the intervening of sexual hormone with the viral replication and estrogen mediated boosting of immune responses towards HBV . The gender based differential response might be explained by the mechanism of adherence and non-adherence of drug. The ETV and TDF might require more time to adhere in the male than female and because of this female exhibit more response towards the therapy for six months whereas a relatively improved response will be observed in male than female following twelve-month treatment .
Similarly, ETV monotherapy had comparable efficacy both for the 6 and 12 month treatment but improved significantly at the end of 12 months for the combination therapy of ETV plus TDF. Previous reports demonstrate contradictory findings about the therapeutic outcomes of monotherapy and combination therapy in association with different duration of antiviral therapy. Comparable potency of ETV monotherapy and ETV plus TDF combination therapy has also been observed earlier . Besides similar potency of monotherapy and combination, similar therapeutic outcomes were also observed in the same report following six and twelve-month therapy (Anna et al., 2012). Furthermore, a much higher potency has also been reported for the combination therapy of ETV and TDF with SVR achieved in 97% and 83% of HBV respectively following six and twelve-month therapy .
Correlation of age factor and antiviral efficacy was also explored in HBV patients. Patients below 40 years did not show any significant difference in SVR both for the six and twelve month antiviral therapy, however, the rate of SVR has improved significantly in patient who were above 40 years after twelve months treatment as compared to six month therapy. Furthermore, antiviral therapy of ETV plus TDF for twelve month proved relatively more effective in patient of younger and older age. Previously patients above 40 years have shown higher response towards combination therapy of ETV and ADV/LAM than monotherapy of ETV or ADV . However, the response of LAM and ETV was much higher in patients of young age. Immunity is the main reason for the good response among the patients of young age towards the antivirals  because HBV clearance has been observed in about 90% of infected adults which is a strong evidence for the role of immunity in young people .
In the current study response rate of the HBV patients was also assessed among the various tribal regions and it was found that patients from Khyber and Waziristan agencies show relatively good response towards the antiviral therapy following six-month treatment. Monotherapy and combination therapy has differential findings at the end of six month among the patients of various tribal regions. Monotherapy is comparatively more effective among the patients of Bajour and Kurrum regions whereas patients from rest of the regions show improvement in SVR following six months treatment. Following twelve month treatment duration the combination therapy proved very effective among the patients of different regions except Malakand. Earlier studies also show geographic effect on therapeutic outcomes of antiviral against the HBV the infection that might be because of different HBV genotypes circulating in different demographic regions. Differential response of ETV/LAM and ETV plus TDF was observed in HBV patients from Turkey (41.2%), Denmark (9.7%), Austria (28.3%), and Italy 20.8% following 12-months therapy . The genotype specific response of HBV towards nucleoside analogue and interferons has also been studied in different geographic areas of Japan and it was found that genotypes C and D was relatively low responsive than genotype A and B .