Combination Therapy With Tenofovir and Peginterferon May Not Be Translated Into Current Clinical Practice.

1 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Dear Editor: We read with great interest the paper by Marcellin et al published in Gastroenterology. The authors demonstrated that combination therapy with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (Peg-IFN) for 48 weeks could result in higher rate of hepatitis B surface antigen (HBsAg) loss than either monotherapy in the multicenter international trial. However, the key question is whether the new strategy is good enough to be translated into current clinical practice. In this trial, the TDF þ Peg-IFN combination group indeed had higher rate of HBsAg loss than Peg-IFN monotherapy group (Kaplan-Meier estimate, 9.1% vs 2.8%; P 1⁄4 .003). However, this improvement was mainly observed in genotype A patients (2.7% [5/185] in Peg-IFN monotherapy group vs 8.6% [16/186] in the combination group); a previous study had demonstrated that genotype A was associated with better response to Peg-IFN treatment than other genotypes. Meanwhile, for the subgroups of genotype B and C, which are the most prevalent genotypes in Asia Pacific area (also the highly endemic area), the potential benefit of TDF þ Peg-IFN on HBsAg loss, is limited. At week 72, the TDF þ Peg-IFN group only had 1 or 2 additional patients with HBsAg loss than PegIFN monotherapy among genotype B and C patients. Therefore, considering the cost of combination therapy in HBV endemic areas, the strategy may not be a suitable strategy for the majority of chronic hepatitis B patients worldwide. The proportion of patients with HBsAg loss at week 72 was estimated by Kaplan-Meier method in the trial. If we calculate the HBsAg loss rate by simply using the division method (missing 1⁄4 failure), the average rate of HBsAg loss among hepatitis B e antigen (HBeAg)-negative patients treated with Peg-IFN based therapy (ie, TDF þ Peg-IFN group and Peg-IFN group) was 4.5% (7/157), which was actually similar to that reported in Peg-IFN phase III registration trial (3.4% [12/356]). Moreover, it is interesting that the rate of HBeAg seroconversion is significantly higher in TDF þ Peg-IFN group than that in Peg-IFN monotherapy group (23.1% vs 12.3%) at week 48, but the rates between the 2 groups were comparable at week 72, indicating that the combination therapy might “speed up” but not improve HBeAg seroconversion. Similarly, it is also possible that the combination therapy just speed up HBsAg clearance in the short term. Long-term follow-up studies in HBeAg-positive and -negative patients treated with Peg-IFN for 3 years showed that 11% and 8.7% could