This study demonstrates that 4 weeks of TBV monotherapy prior to starting PIFN leads to a steeper decline in HCV RNA with no difference in anaemia rates. While this trend is relatively consistent over the 24-week experimental period, the difference does not reach a level of statistical significance. This observation, combined with the relatively high variance in viral load at key time points, suggests that a larger study population is required to further delineate the effects of TBV pre-dosing on phase 1 viral kinetics. Alternatively, the variance in the viral decline may be a function of both the impact of having TBV at steady state when PIFN is introduced into therapy and/or increased conversion of TBV to RBV due to longer exposure.
Studies have demonstrated that compared with patients treated with PIFN alone, patients pre-dosed with RBV display enhanced induction of the IFN-related genes (STAT1, ISGF3, IRF-7 and the interferon receptor) that are initially involved in the IFN-signalling cascade. In this manner, RBV may make hepatocytes more receptive to the action of IFN and may boost endogenous IFN production.22
Merli and colleagues evaluated the safety and efficacy of pre-dosing RBV 8 weeks prior to starting 48 weeks of combination PIFN/RBV in patients who developed recurrent HCV after liver transplantation.2011
They demonstrated that RBV priming both enhanced efficacy and improved adherence, and proposed that by administering medications in this sequential manner, patients have time to adjust to the side effects of each medication. In their study, 15% of patients necessitated RBV dose reductions compared with approximately 40% of patients (range of between 24% and 92%) when PIFN/RBV was administered concurrently in studies evaluating similar patient populations post transplant.24, 25, 26, 27, 28
Their study also demonstrated that RBV priming results in improved SVR rates compared with results of published trials performed using standard combination therapy −46% vs. 29% respectively.23, 26
While our study was discontinued prior to collection of SVR data, mean log10
reductions from baseline in HCV RNA were significantly greater in the pre-dosing vs. the standard dosing arm at Day 1 [−0.34 ± 0.46 vs. 0.09 ± 0.32 (P
≤ 0.003)]. Merli et al
. also found that the extent of HCV RNA reduction pre-treatment was found to be a predictor of on-treatment response, a result consistent with the findings from our study.
Tox and colleagues pre-treated twenty patients with chronic HCV and normal ALT with 4 weeks of RBV followed by combination therapy of RBV and low-dose PIFN (50 mcg SQ q weekly) for 44 weeks, and found similar SVR rates when compared with historical controls treated with simultaneously initiated RBV and full dose PIFN.29
Larger clinical trials need to be conducted to confirm these intriguing results, especially in poorly IFN-tolerate populations.
Administered as monotherapy, RBV can normalise ALT levels,30, 31, 32, 33
improve liver histology,30, 34
and temporarily decrease HCVRNA levels by approximately 1.0 log10
RBV may act as a lethal mutagen increasing the incidence of viral mutations thus limiting HCV replication via derror catastrophe.36
While RBVs mutagenic potential on HCV remains debated,37
RBV monotherapy has been associated with an increase in the mutation rate in the NS5A and NS5B regions of HCV which correlated with SVR rates when patients were retreated with combination therapy.38
In fact, Ogawa and colleagues postulated that 4 weeks of RBV monotherapy prior to starting IFN/RBV combination therapy, stimulates the host immune system and promotes HCV gene mutations resulting in improved IFN efficacy.2009
Although the therapeutic mechanisms of RBV in patients with HCV remain unclear, the mechanisms by which RBV can induce dose-limiting haemolytic anaemia are better understood. After entering the circulation, a significant portion of RBV is transported into RBCs and metabolised into various phosphorylated derivatives.17
Because of the lack of phosphatase activity in RBCs, these phosphorylated metabolites of RBV are trapped intracellularly and accumulate over time, leading to depletion of intracellular adenosine triphosphate, impaired adenosine triphosphate–dependent oxidative respiration and impaired membrane integrity, culminating in haemolysis.40
Anaemia is a common side effect of RBV therapy. Most patients experience a rapid decline of 2–3 g/dL in haemoglobin during the first 4 weeks of initiating RBV therapy.3, 4, 30
and approximately 50% of patients on combination PIFN/RBV experience a haemoglobin decline of ≥4 g/dL.41
RBV-associated haemolytic anaemia is the primary reason for dose reductions and treatment termination in patients taking PIFN/RBV.42
The addition of either BOC or TVR to PIFN/RBV in the treatment of patients with G1 HCV increases the incidence of anaemia. In clinical trials of BOC triple therapy vs. a control group treated with PIFN/RBV, 49% of patients experienced anaemia, defined as a haemoglobin level <10 g/dL, and 26% of patients required RBV dose reduction due to anaemia vs. 29% and 13%, respectively, in controls. Erythropoietin alpha (EPO) was administered to patients (at the investigators discretion) in 43% of patients on BOC triple therapy vs. 24% of controls respectively. In patients on BOC triple therapy, 3% required blood transfusions and approximately 3% discontinued therapy early due to anaemia vs. <1% and <1% in controls respectively.13, 14
In clinical trials of TVR triple therapy vs. a control group treated with PIFN/RBV controls, 32% of patients experienced anaemia and 22% of patient's required RBV dose reduction due to anaemia vs. 15% and 9% in controls respectively. EPO use was prohibited in TVR-based studies. In patients on TVR triple therapy 4.6% required blood transfusions and 2% discontinued therapy early due to anaemia vs. 1.6% and 0.5% in controls respectively.11, 12
Studies have shown that G1 patients with inosine triphosphatase (ITPA) deficiency - a benign inherited enzymopathy in which inosine triphosphate accumulates in red blood cells, are protected from RBV-associated haemolytic anaemia. These patients are less likely to require RBV dose reductions.43, 44
Our study was conducted prior to the discovery of the significance of ITPA deficiency. It would be warranted to test patients enrolled in future trials of TBV or other RBV prodrugs for ITPA deficiency.
In contrast to RBV, administration of TBV, results in high hepatic RBV levels and limits RBV metabolite accumulation in RBCs. Indeed, pharmacokinetic studies in nonhuman primates revealed that TBV-derived RBV is concentrated in the liver in an amount that is 38% higher than that seen after administration of RBV.16
Furthermore, phosphorylated TBV metabolites were not detected in monkey RBCs after single and multiple TBV doses, suggesting that TBV cannot enter RBCs until it is converted to RBV.19
These preclinical results are supported by data from two phase 3 studies, - (Viramidines's Safety and Efficacy vs. Ribavirin) VISER 1 and VISER 2, which demonstrated that TBV was significantly less likely than RBV to cause anaemia (5%–6% vs. 22%–24%).21, 45
Although both studies showed that TBV was associated with lower rates of anaemia, at a fixed- dose of 600 mg twice daily, (as was administered in our study,) SVR rates were lower (38%–40%) with TBV/PIFN than with PIFN/RBV (52%–55%).21, 45
However, there was a trend towards greater efficacy among patients with higher exposure to TBV on the basis of body weight, and the sharpest decline in viral load occurred at Weeks 4 through 6,21
presumably when TBV activity reached steady state. In fact, patients from North America and Europe met non-inferiority for both the total as well as for the subset of patients weighing <75 kg with SVR rates of 51 vs. 56% and 62 vs. 60% respectively.21
Indeed, results of a randomised active-controlled, parallel-group study of 278 treatment-naïve G1 patients confirmed that patients treated with weight-based taribavirin and PIFN have equal efficacy yet less anaemia compared with those treated with weight-based ribavirin and PIFN.46
Specifically while there were no statistical differences in SVR rates, the incidence of anaemia was significantly lower (P
< 0.05) in patients receiving both 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7%, respectively) compared with RBV (32.9%). It was concluded from this trial that the 25 mg/kg/day dose of TBV resulted in the optimal combination of treatment efficacy and safety. Since our study was completed prior to the publication of these results, a larger trial pre-dosing TBV at 25mg/kg/day is warranted. In addition to the small sample size and lack of weight-based TBV, as TBV is converted to RBV by adenosine deaminase (ADA), polymorphisms of ADA could develop, further contributing to the lack of statistically significant results found in our study.
While our study was not designed to address the incidence of anaemia in TBV compared with RBV, the rate of anaemia in both the pre-dosed TBV arm and the standard start TBV arm had extremely low anaemia rates −4.3% and 5% respectively. Furthermore, no patient underwent TBV dose reductions or terminations, or required a blood transfusion. The use of EPO was prohibited in the current clinical trial. The EPO has been observed to improve quality of life and adherence to PIFN/RBV treatment while lessening the need for RBV dose reductions in patients developing anaemia on combination therapy.8
Still, other studies have yielded conflicting results as to the impact of EPO on SVR.47, 48
It should be underscored that EPO is not approved by the FDA for use in combination with PIFN/RBV. Furthermore, EPO has been associated with its own unique adverse events, and the addition of EPO to treatment regimens increases both the complexity and cost of treating patients with HCV.
For patients with G1 HCV receiving triple combination therapy with a protease inhibitor plus PIFN/RBV, the protease inhibitor cannot be dose reduced or used without RBV. Thus, if RBV requires permanent discontinuation, BOC or TVR would also need to be permanently discontinued due to the risk of developing viral rebound and/or drug resistance. Given the added concerns of anaemia developing during triple combination therapy, studies are needed to determine the safety and efficacy of TBV instead of RBV as a component of triple therapy.