The Era of Direct-acting Antivirals Has Begun

The Beginning of the End for HCV?

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.


Semin Liver Dis. 2011;31(4):399-409. 

In This Article

Nucleoside and Nucleotide NS5B Polymerase Inhibitors

The nucleoside and nucleotide analog inhibitors of the HCV polymerase target the catalytic site of the enzyme. When they incorporate in the RNA chain in lieu of the natural substrate, they cause RNA chain termination. Nucleoside analogs must be phosphorylated three times by cellular kinases to become active as the triphosphate form. Nucleotide analogs are already in the active form. Because the NS5B target is highly conserved between HCV genotypes, polymerase inhibitors usually have pangenotypic activity (Fig. 1).

Figure 1.

Characteristics of the five classes of direct-acting antivirals (DAAs). *Varies with the generation. **Palm II are effective against multiple genotypes. (DAA, direct acting antiviral; NS3/4A, nonstructural 3/4A protein; PI, protease inhibitor; NS5A, nonstructural 5A protein; NS5B, nonstructural 5B protein; Nuc, nucleoside.)

PSI-352938 (PSI-938)

PSI-938 is a purine (guanosine) nucleotide analog polymerase inhibitor of HCV. In earlier phases of development, PSI-938 was shown to have pangenotypic coverage, high liver to plasma ratios, residual activity against S282T variants (substitution selected by and associated with resistance to the 2'-methyl nucleosides), and low risk of drug-drug interactions. The 14-day results of a phase II study, the NUCLEAR study, were recently presented.[31] The NUCLEAR study compared different combinations of once daily PSI-938 plus PSI-7977 (a second polymerase inhibitor) to PSI-938 monotherapy for 14 days in treatment naïve patients with HCV genotype 1. It is the first to evaluate the combination of two nucleotide analogs for the treatment of HCV infection. Of the 24 patients who received combination treatment, 22 (92%) achieved HCV RNA <15 IU after 14 days of treatment. The two drugs are known to have complementary resistant profiles and not surprisingly, no viral breakthroughs were observed. Treatment was well tolerated. An interferon-free combination trial of PSI-938 and PSI-7977, the QUANTUM trial, has been initiated. PSI-938 was granted the fast track designation by the FDA for treatment of chronic HCV infection in August 2011.


PSI-7977 is a pyrimidine (uridine) nucleotide analog active against all HCV genotypes. The dramatic results of the phase 2b study PROTON assessing safety and efficacy of PSI-7977 in combination with pegIFN/RBV against HCV genotypes 2 and 3 were presented earlier in 2011.[32] PROTON enrolled 25 treatment-naïve patients. One patient was lost to follow-up early in the study. Among the 24 patients who completed 12 weeks of triple therapy, 24 (100%) achieved SVR. These results suggest that therapy can be significantly shortened in patients infected with HCV genotypes 2 and 3 without compromising the chances of response. A phase II study in patients with HCV genotype 2 and 3 is ongoing to explore the use of PSI-7977 in monotherapy for 12 weeks versus PSI-7977 in combination with peg/RBV for 8 weeks.


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