Pritelivir for recurrent aciclovir-resistant herpes simplex virus 2 infections in immunocompromised patients

Abstract

Because of prolonged viral shedding and aciclovir exposure, recurrences of aciclovir-resistant herpes simplex virus (HSV) infections are increasingly reported in immunocompromised patients, especially in HSCT recipients.1–3 We present herein two HSCT recipients receiving repeated courses of the novel helicase-primase inhibitor pritelivir for recurrent genital aciclovir-resistant HSV-2 infections. The first patient received HSCT for a sickle-cell disease. Three months later, while on sirolimus-based immunosuppressive therapy and valaciclovir prophylaxis, she developed widespread painful genital and anal ulcerations, with positive HSV-2 PCR of a local swab (Table 1). Genotypic resistance testing revealed a L228Stop frameshift mutation in HSV thymidine kinase (TK) (encoded by the UL23 gene), associated with high-level resistance to aciclovir. A 2 week course of foscarnet (40 mg/kg/8 h) provided no clinical benefit and had to be stopped because of severe electrolyte disturbances. Pritelivir was obtained through the Expanded Access Program supported by AiCuris [loading dose of 400 mg on Day 1, then 100 mg once daily; in the case of a partial response at Day 28, pritelivir can be administered for an additional 14 days (maximum total treatment duration = 42 days)]. In the patient, pritelivir resulted in both lesion healing and virological control. Pritelivir was well tolerated and stopped on Day 42 after reaching almost complete resolution of HSV-2 infection. A first relapse occurred 4 weeks after pritelivir discontinuation. Foscarnet was reintroduced, but had to be stopped because of toxicity, without clinical improvement of lesions. Complete resolution of genital lesions was achieved with a 42 day course of pritelivir. The same evolution was observed during the next relapse, which occurred 2 weeks after the discontinuation of the second course of pritelivir. No pritelivir resistance-associated mutation (RAM) was detected during these relapses. Clinical and virological characteristics of HSV-2 infections under successive courses of prophylactic and curative antiviral treatment ND, not done. UL23, UL30, UL5 and UL52 genes encode HSV-2 TK, DNA polymerase, helicase and primase, respectively, and were sequenced as previously described.3,9 The second patient received HSCT for AML. During the previous 15 years, she received iterative courses of valaciclovir for recurrent HSV genital infections. Six months after HSCT, while on ciclosporin, steroids, vedolizumab and ruxolitinib for graft-versus-host-disease management, and valaciclovir prophylaxis, she developed aciclovir-resistant HSV-2 infection (L263Stop frameshift mutation in the UL23 gene), which was successfully treated with foscavir. Two months later, following a relapse of leukaemia treated with cytarabine and gemtuzumab ozogamicin, she presented with a recurrence of aciclovir-resistant HSV-2 genital infection due to another frameshift mutation in TK (D229Stop). Because of failure of a 3 week course of foscavir, she was treated with pritelivir for 28 days, with good efficacy and tolerance. During the subsequent 7 months, she presented with three successive aciclovir-resistant HSV-2 genital recurrences, while on valaciclovir prophylaxis. Different patterns of aciclovir resistance were evidenced, but no pritelivir RAM was detected. The first two episodes were self-limited and resolved spontaneously, but the third one required a new 28 day course of pritelivir. The emergence of HSV resistance to aciclovir has increasingly been reported among immunocompromised patients. In a surveillance study conducted in 3357 French patients with HSV infection in 1999–2002, aciclovir-resistant viruses were isolated in 0.35% and 3.5% of immunocompetent and immunocompromised subjects, respectively, with the highest rate in HSCT recipients (10.9%).1 More recently in the UK, 17% of HSV-1 infections diagnosed in 532 HSCT recipients were due to aciclovir-resistant strains.2 This high prevalence of RAMs has been attributed to a prolonged T cell immunodeficiency alongside faster viral replication and greater selection pressure from prolonged aciclovir/valaciclovir-based prophylaxis. As observed in 95% of aciclovir-resistant HSV isolates in immunocompromised patients,3 the mutations identified in our patients involved TK, resulting in the synthesis of a non-functional truncated TK. Indeed, because TK, unlike DNA polymerase, is not essential for viral replication in dividing cells, there is a higher probability of emergence of an aciclovir-resistant strain by mutation in the UL23 gene than by mutation in the UL30 gene (encoding the viral DNA polymerase). In the two patients reported here, early relapses might have been favoured by severe immunodeficiency, persistent selection pressure by valaciclovir prophylaxis (both patients) and incomplete healing of the lesions at the end of the first pritelivir course (patient 1). Mutations in the UL23 gene confer cross-resistance to all approved nucleoside analogues for HSV (aciclovir, penciclovir) as they all require viral-mediated mono-phosphorylation. Pritelivir is an interesting drug against aciclovir-resistant HSV as it targets another viral-specific enzyme required during DNA replication, the helicase-primase complex. Among healthy adults with frequent HSV-2 recurrence, pritelivir reduced the rate of genital HSV shedding, with higher efficacy than valaciclovir.4,5 Our case reports confirm that pritelivir also appears to resolve aciclovir-resistant HSV infections in immunocompromised patients, as recently described in another HSCT recipient.6 Pritelivir was well tolerated, probably because there is no eukaryotic equivalent to the helicase-primase complex. Moreover, no resistance to pritelivir emerged despite prolonged viral shedding and longer cumulative drug exposure than in immunocompetent patients included in the Phase 2 trials,7 suggesting that pritelivir seems to have a high genetic barrier to resistance. Pritelivir is currently being evaluated as a time-limited therapeutic option (28 to 42 day courses) for the treatment of HSV mucocutaneous infections in immunocompromised individuals (ClinicalTrials.gov NCT03073967). However, because of its high efficacy and good safety profile, our observations raise the question of its potential interest as long-term prophylaxis in immunocompromised patients with aciclovir-resistant HSV recurrences because of poor outcomes of HSV in this population8 and the absence of alternative antiviral options with oral administration to prevent recurrences. This study was carried out as part of our routine work. No external funding was received for the conduct of this study. A.S. has received honoraria from Gilead for participation in a conference. F.L. has received honoraria from Gilead and F2G. D.B. has received honoraria from bioMérieux, Qiagen, Roche Diagnostics and DiaSorin Molecular for consultant activity or participation in conferences. P.F. has received honoraria and travel grants from ViiV Healthcare, Bristol-Myers Squibb, Janssen Cilag, Gilead Sciences, Pfizer, Medtronic and MSD France for participation in advisory boards, educational programmes and conferences. All other authors: none to declare.

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