Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences A Randomized Clinical Trial

Importance Current therapy of herpes infections relies on nucleoside analogues. Pritelivir is a well-tolerated novel herpes simplex virus (HSV) helicase-primase inhibitor that reduced genital shedding and lesions. Objective To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection. Design, Setting, and Participants A phase 2, randomized, double-blind, crossover clinical trial at clinical research centers in 4 US cities (October 2012-July 2013) compared daily oral doses of 100 mg of pritelivir with 500 mg of valacyclovir. The planned sample size was 98 adults, allowing for detection of a 50% reduction in viral shedding between the study treatments. Healthy adults with 4 to 9 annual genital HSV-2 recurrences were eligible. Ninety-one participants were randomized: 45 to receive pritelivir and 46 to receive valacyclovir first when the US Food and Drug Administration placed the trial on clinical hold based on findings in a concurrent nonclinical toxicity study, and the sponsor terminated the study. Interventions Participants took the first drug for 28 days followed by 28 days of washout before taking the second drug for 28 days. Throughout treatment, the participants collected genital swabs 4 times daily for testing by HSV polymerase chain reaction assays. Main Outcomes and Measures The primary end point was within-participant genital HSV shedding while receiving pritelivir compared with valacyclovir. Secondary end points included the quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes. Results Of the 91 randomized participants (median age, 48 years; 57 women [63%]), 56 had completed both treatment periods at the time of the study’s termination. In intent-to-treat analyses, HSV shedding was detected in 2.4% (173 of 7276 ) of swabs during pritelivir treatment compared with 5.3% (392 of 7453) during valacyclovir treatment (relative risk [RR], 0.42; 95% CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, −0.1; 95% CI, −0.6 to 0.5; P = .83). Genital lesions were present on 1.9% of days in the pritelivir group vs 3.9% in the valacyclovir group (RR, 0.40; 95% CI, 0.17-0.96; P = .04). The frequency of shedding episodes did not differ by group, with 1.3 per person-month for pritelivir and 1.6 per person-month for valacyclovir (RR, 0.80; 95% CI, 0.52 to 1.22; P = .29). Treatment-emergent adverse events occurred in 62.3% of participants in the pritelivir group and 69.2% of participants in the valacyclovir group. Conclusions and Relevance Among adults with frequently recurring genital HSV-2, the use of pritelivir compared with valacyclovir resulted in a lower percentage of swabs with HSV detection over 28 days. Further research is needed to assess longer-term efficacy and safety

AIC649 Induces a Bi-Phasic Treatment Response in the Woodchuck Model of Chronic Hepatitis B.

AIC649 has been shown to directly address the antigen presenting cell arm of the host immune defense leading to a regulated cytokine release and activation of T cell responses. In the present study we analyzed the antiviral efficacy of AIC649 as well as its potential to induce functional cure in animal models for chronic hepatitis B. Hepatitis B virus transgenic mice and chronically woodchuck hepatitis virus (WHV) infected woodchucks were treated with AIC649, respectively. In the mouse system AIC649 decreased the hepatitis B virus titer as effective as the "gold standard", Tenofovir. Interestingly, AIC649-treated chronically WHV infected woodchucks displayed a bi-phasic pattern of response: The marker for functional cure--hepatitis surface antigen--first increased but subsequently decreased even after cessation of treatment to significantly reduced levels. We hypothesize that the observed bi-phasic response pattern to AIC649 treatment reflects a physiologically "concerted", reconstituted immune response against WHV and therefore may indicate a potential for inducing functional cure in HBV-infected patients

Effects of therapy using a helicase-primase inhibitor (HPI) in mice infected with deliberate mixtures of wild-type HSV-1 and an HPI-resistant UL5 mutant

Point mutations in the HSV-1 UL5 (helicase) gene confer resistance to helicase-primase inhibitors (HPIs), e.g. BAY 57-1293. Such mutations normally occur at a frequency of < or =10(-6)PFU. However, individual HSV-1 laboratory strains and some clinical isolates contained resistance mutations (e.g. UL5: Lys356Asn) at 10(-4)PFU. To address the possibility that pre-existing mutants at high frequency might have an impact on therapy using HPIs, deliberate mixtures were prepared to contain the SC16 UL5: Lys356Asn mutant in SC16 wild-type in the proportion of 1/500 or 1/50PFU. Mice were infected in the neck-skin with 5x10(4)PFU/mouse of wt alone, mutant alone, or the respective mixture. The mutant could not be detected in infectious virus yields from mice inoculated with the 1/500 mixture. However, resistant mutant was recovered from some treated mice inoculated with the 1/50 mixture. All mice inoculated with mixtures remained responsive to BAY 57-1293-therapy with no increase in clinical signs compared to treatment of wt-infected mice

AIC649 induces a bi-phasic treatment effect on viremia levels in chronic WHV carrier woodchucks.

<p>AIC649 (3.9 x 10⁶ Units (ELISA-based titer)) or vehicle were administered i.m. twice weekly for 8 weeks (marked “Treatment”). At the indicated time points woodchucks were bled and serum was subjected to determination of WHV viral load. Values were normalized to individual baseline at day 0 and are given in %. n = 5 / group. Dotted lines: 100%, 50%, or 10% level. (A) Serum WHV DNA concentrations of individual woodchucks (identified by numbers) in the vehicle and AIC649 groups. (B) Group means of WHV DNA concentration +/- standard error of the mean (SEM). *p < 0.05.</p

AIC649 reduces the HBV titer in HBV tg mice as effective as Tenofovir.

<p>HBV tg mice were treated i.p. with AIC649 (1 x 10⁸ viral particles / dose) twice weekly for 9 times in total. Tenofovir was administered twice daily by oral gavage at a total concentration of 100 mg/day. Negative control: Tenofovir vehicle, administration analogous to Tenofovir. Mice were sacrificed at the indicated time points and plasma samples were subjected to HBV DNA determination. HBV titers are expressed in % of the respective negative vehicle group +/- SD. * p < 0.05, ** p < 0.01 (vs respective treatment on day 0).</p

AIC649 treatment induces cell-mediated immune responses in chronic WHV carrier woodchucks.

<p>AIC649 (3.9 x 10⁶ Units (ELISA-based titer)) or vehicle were administered i.m. twice weekly for 8 weeks (marked “Treatment”). At the indicated time points woodchucks were bled and PBMCs were subjected to determination of T cell proliferation after stimulation, whereas whole blood was used to analyze transcript levels of cytokines. Values were normalized to individual baseline at day 0 and are given in %. n = 5 / group. Dotted lines: 100% level. (A) Percent-change in mean T cell proliferation level from baseline at day 0 for woodchucks in the vehicle and AIC649 groups, respectively, following stimulation of PBMCs with WHsAg (WHsAg stim) or WHs peptide S226-245 (WHs peptide stim). (B) Percent-change in mean IFN-γ and TNF-α transcript level from baseline at day 0 in blood of woodchucks from both groups.</p

AIC649 treatment is associated with changes in serum activities of liver enzymes in chronic WHV carrier woodchucks.

<p>AIC649 (3.9 x 10⁶ Units (ELISA-based titer)) or vehicle were administered i.m. twice weekly for 8 weeks (marked “Treatment”). At the indicated time points woodchucks were bled and serum was used to analyze levels of liver enzymes. Values were normalized to individual baseline at day 0 and are given in %. n = 5 / group. Dotted lines: 100% or 50% level. (A). Group means of AST concentration +/- SEM. (B) Group means of GGT concentration +/- SEM.</p

AIC649 induces similar cytokine release kinetics in mice and woodchucks.

<p>Three healthy BALB/c mice / time point were treated once with 1 x 10⁵ U AIC649 i.p. (A) or 2.5 x 10⁴ U AIC649 i.m. (B). Mice were sacrificed at the indicated time points and plasma samples were pooled. The pooled plasma samples were subjected to duplicate cytokine determination. Plasma samples from non-injected mice were used as controls. Given are the means +/- SD. (C): Three healthy woodchucks were treated once with 3.9 x 10⁶ U AIC649 /ml or vehicle. Blood was drawn at the indicated time points and subjected to determination of cytokine transcript levels. Results are given as mean fold change relative to pre-treatment (t = 0) levels +/- SD.</p

Inactivated ORF virus shows antifibrotic activity and inhibits human hepatitis B virus (HBV) and hepatitis C virus (HCV) replication in preclinical models.

Inactivated orf virus (iORFV), strain D1701, is a potent immune modulator in various animal species. We recently demonstrated that iORFV induces strong antiviral activity in animal models of acute and chronic viral infections. In addition, we found D1701-mediated antifibrotic effects in different rat models of liver fibrosis. In the present study, we compare iORFV derived from two different strains of ORFV, D1701 and NZ2, respectively, with respect to their antifibrotic potential as well as their potential to induce an antiviral response controlling infections with the hepatotropic pathogens hepatitis C virus (HCV) and hepatitis B virus (HBV). Both strains of ORFV showed anti-viral activity against HCV in vitro and against HBV in a transgenic mouse model without signs of necro-inflammation in vivo. Our experiments suggest that the absence of liver damage is potentially mediated by iORFV-induced downregulation of antigen cross-presentation in liver sinus endothelial cells. Furthermore, both strains showed significant anti-fibrotic activity in rat models of liver fibrosis. iORFV strain NZ2 appeared more potent compared to strain D1701 with respect to both its antiviral and antifibrotic activity on the basis of dosages estimated by titration of active virus. These results show a potential therapeutic approach against two important human liver pathogens HBV and HCV that independently addresses concomitant liver fibrosis. Further studies are required to characterize the details of the mechanisms involved in this novel therapeutic principle