Reply to Padmanabhan and Dixit: Hepatitis C virus entry inhibitors for optimally boosting direct-acting antiviral-based treatments

Abstract

We thank Padmanabhan and Dixit for their comments (1) on our paper (2). They pointed out that entry inhibitors might form potent partners for optimal drug combinations. They analyzed previously published data on 10 hepatitis C virus (HCV) entry inhibitors that are under clinical or preclinical development and found some of these HCV entry inhibitors showed high instantaneous inhibitory potentials (IIPs) (3) compared with IIPs of direct-acting antivirals (DAAs). To analyze further the utility of combining entry inhibitors with other DAAs and to extend our original results (2), we quantified the anti-HCV effect of four different classes of entry inhibitors [AR4A (anti-HCV E2 antibody) (4), BLT-1 [scavenger receptor class B type 1 (SR-BI) inhibitor] (5), erlotinib (EGF receptor inhibitor) (6), and dasatinib (EphA2 inhibitor) (6)] singly and in combination with six DAAs studied by Padmanabhan and Dixit (1) in the HCV infectious cell culture system ( Fig. 1 A and B). Single treatment of these entry inhibitors exhibited a dose-dependent reduction in HCV RNA levels. Using the median effect (1-3), we estimated IC 50 , the half-maximum inhibitory concentration, and m, the slope parameter, for each drug from its dose-response curve (Table 1), which enables us to calculate IIP = log½1 + ðD=IC 50 Þ m at D = 100 × IC 50 (i.e., IIP 100 ) (Fig. 1C). We found BLT-1 shows the highest IIP 100 among the entry inhibitors, which is equivalent in value to DAAs. In addition, applying Bliss independence (7), we quantified the upper limits of anti-HCV activity for triple-drug treatments at D = 100 × IC 50 (IIP Bcom 100 ) (Fig. 1D). These data clearly showed that HCV entry inhibitors augmented the antiviral effect of double DAA-based treatments. Interestingly, augmentation of antiviral effects by addition of entry inhibitors largely depended on the entry inhibitor used: Triple-drug treatments, including BLT-1, showed an especially high IIP Bcom 100 , which is comparable to the IIP Bcom 100 of triple DAA-based treatments, among the tested entry inhibitors.Entry inhibitors are primarily aimed at preventing viral infection. However, because they are effective in eliminating HCV from already established infection in human liver chimeric mice and chimpanzees, HCV entry inhibitors can be candidates for an additional choice of anti-HCV treatment (8-11). In particular, host-targeting agents such as BLT-1, erlotinib, and dasatinib show less opportunity for emergence of drug-resistant virus. The results of Padmanabhan and Dixit (1), which are further supported by the work reported here, show that entry inhibitors can be combined with other classes of DAAs to provide potentially potent anti-HCV treatment that may be especially effective for difficult-totreat patients.

Building a mechanistic mathematical model of hepatitis C virus entry

“…Whereas, when targeted simultaneously a >50% inhibitory effect can be achieved by blocking 50% of each receptor. This may inform the use of entry inhibitors in combination therapy [16,17].…”

“…A deeper understanding of E2 function and its interactions with SR-B1 and CD81 is likely to aid the design of candidate B-cell targeted vaccines. Moreover, an appreciation of pinch points in the HCV entry pathway may guide the use of entry inhibitor drugs in combination with direct-acting antivirals [16,17].…”

Mutational pathway maps and founder effects define the within-host spectrum of hepatitis C virus mutants resistant to drugs

“…At the same time, the demand for DAAs is set to rise sharply with growing evidence of their success in the real world [39] and with >98% of the ~150 million chronic hepatitis C patients worldwide yet to receive DAA-based treatments [40, 41]. Efforts are therefore underway to develop rational strategies to identify the best combinations of the available DAAs, which would ensure cure while minimizing the treatment duration, cost, and side effects [2–7, 42, 43]. Our study informs these timely efforts.…”

Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon‐free treatment era

“…An interferon‐free treatment era is thus around the corner. Significant efforts are now being made to optimize treatments with DAAs so that cure can be achieved with the least drug exposure and in the shortest possible time . Interferon, we believe, may have a new role here.…”