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Short duration pan‐genotypic therapy with glecaprevir‐pibrentasvir for six weeks among people with recent HCV infection
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Hepatology Oct 24 2019 - Marianne Martinello1,2,3, Chloe Orkin4, Graham Cooke5, Sanjay Bhagani6, Edward Gane7, Ranjababu Kulasegaram8, David Shaw9, Elise Tu1, Kathy Petoumenos1, Philippa Marks1, Jason Grebely1, Gregory J Dore1,2, Mark Nelson10*, Gail V Matthews1,2*
Among treatment‐naïve individuals with chronic HCV infection and without cirrhosis, glecaprevir‐pibrentasvir for eight weeks is recommended. The aim of this analysis was to evaluate the efficacy of glecaprevir‐pibrentasvir for six weeks in people with acute and recent HCV infection. In this open‐label single‐arm multicentre international pilot study, adults with recent HCV (duration of infection <12 months) received glecaprevir‐pibrentasvir 300mg‐120mg daily for six weeks. Primary infection was defined by first positive anti‐HCV antibody and/or HCV RNA within six months of enrolment and either acute clinical hepatitis within the past 12 months (symptomatic seroconversion illness or ALT>10xULN) or anti‐HCV antibody seroconversion within 18 months. Reinfection was defined as new positive HCV RNA within six months of enrolment and evidence of prior spontaneous or treatment‐induced clearance. The primary endpoint was sustained virologic response at 12 weeks post‐treatment (SVR12). Thirty men (median age 43 years, 90% men‐who‐have‐sex‐with‐men) received treatment, of whom 77% (n=23) were HIV‐positive, 47% (n=14) had ever injected drugs, and 13% (n=4) had HCV reinfection. The majority had HCV genotype 1 (83%, n=25), followed by genotype 4 (10%, n=3) and genotype 3 (7%, n=2). At baseline, median estimated duration of infection was 29 weeks (range 13, 52) and median HCV RNA was 6.2 log10 IU/mL (range 0.9, 7.7). SVR12 in the intention‐to‐treat and per‐protocol populations was achieved in 90% (27/30) and 96% (27/28), respectively. There was one case of relapse and two cases of non‐virological failure (death, n=1; loss to follow up, n=1). No treatment‐related serious adverse events were seen.
Glecaprevir‐pibrentasvir for six weeks was highly effective among people with acute and recent HCV infection, supporting further evaluation of shortened duration pan‐genotypic therapy in this setting. In order achieve HCV elimination targets (29), increased diagnosis and treatment of recent HCV infection will be required (30). Striving for micro-elimination in high incidence populations is an important step toward reaching HCV elimination targets. High and increasing HCV incidence among populations of PWID and HIV-positive MSM highlight the need to determine the optimal duration of therapy and choice of DAA regimen in recent infection, including for treatment of reinfection. Access to HCV care and treatment for people at high risk of onward transmission, including those with recent HCV infection, should be a priority (1). HCV treatment-as-prevention efforts should be enhanced by the immediate commencement of DAA therapy in people with recent HCV. A targeted “test and treat” (and retreat) strategy, with short duration DAA therapy among at risk populations, may be one of the most costeffective public health strategies in attempts to eliminate HCV (31).
HIV Co-infection was documented in 77% (n=23); median CD4 count was 571x106/L (range 341, 1488). All HIV-positive participants were receiving combination antiretroviral therapy (cART; n=23, 100%), with HIV RNA ≤50 copies/mL in 96% (n=22). At baseline, most (n=18, 78%) were receiving an INSTI (dolutegravir or raltegravir) plus two nucleoside reverse transcriptase inhibitors (Supplementary Table 2). Four (13%) participants required alterations to their antiretroviral regimen given potential drug interactions; all changed from a non-nucleoside reverse transcriptase inhibitor (n=2) or boosted-protease inhibitor (n=2) to an INSTI. Of the three HIV-negative MSM enrolled, one was receiving HIV pre-exposure prophylaxis.
Fourteen (47%) participants had ever injected drugs, with nine (30%) reporting injecting drug use within six months of enrolment. (Meth)amphetamine use ever and current was predominant, by both injecting (ever, 40%; current, 30%) and non-injecting (ever, 60%; current, 33%) routes of administration. Indeed, (meth)amphetamine was the only drug injected in the six months prior to enrolment (Supplementary Table 3). Among participants who reported injecting drug use, median age at first injecting was 37 years (range 19, 55). Median duration of injecting drug use prior to estimated date of HCV infection was 2.1 years (IQR 1.0, 3.6). Only two participants (7%) had ever received opioid substitution therapy (OST), with no participants on OST at enrolment.
Virological failure, confirmed as relapse on sequencing, was observed in one (3%) participant with acute genotype 1a HCV infection (Figure 5; Supplementary Figure 3). The participant was a 50-year-old male with HIV infection, who was diagnosed with primary acute HCV in the setting of asymptomatic seroconversion. At screening and baseline, estimated duration of HCV infection was 18 and 24 weeks, respectively, with a narrow seroconversion window as the last negative anti-HCV Ab was only five weeks prior to the first positive anti-HCV Ab. Baseline HCV RNA was 7.7 log10 IU/mL. The participant was adherent to treatment, and HCV RNA declined rapidly (week 2, HCV RNA 38 IU/mL [1.6 log10 IU/mL]; week 4, HCV RNA <10 IU/mL [target detected, not quantifiable]; week 6, HCV RNA target not detected). Recurrence of HCV viraemia was identified at week 12 post treatment (post treatment week 4, HCV RNA <10 IU/mL [target detected, not quantifiable]; post-treatment week 12, HCV RNA 7.5 log10 IU/mL). No significant NS3 or NS5a resistance-associated polymorphisms were detected at baseline or post-treatment week 12. The participant received retreatment with sofosbuvir-velpatasvir-voxilaprevir for 12 weeks and achieved SVR12.
No cases reinfection have been identified among those participants remaining in follow up at post treatment week 24; follow up will continue for up to five years post treatment.
Glecaprevir-pibrentasvir for six weeks was highly effective, safe and well-tolerated among people with acute and recent HCV infection (SVR12 ITT 90%, SVR12 PP 96%), including among people with HIV coinfection and high baseline HCV RNA (>6 log10 IU/mL). Treatment resulted in rapid HCV RNA suppression and normalisation of liver enzymes. No treatment-related serious adverse events were reported.
In line with high efficacy observed in this study, other studies of shortened duration dual and triple class DAA regimens have demonstrated promising results in recent HCV infection (2). Among people with acute and recent HCV genotypes 1 and 4 infection, high efficacy was reported with six weeks of sofosbuvir-ledipasvir (n=20, SVR12 ITT 100%; HCV mono-infection only) (14), and eight weeks of grazoprevir-elbasvir (n=80, SVR12 ITT 94%, SVR12 PP 99%) (6), paritaprevir-ritonavir-ombitasvir and dasabuvir (n=30, SVR12 ITT 97%, SVR12 PP 100%) (15), and sofosbuvir-ledipasvir (n=27, SVR12 ITT 100%) (16). Lower SVR (n=26, SVR12 ITT 77%, PP 87%) was demonstrated with six weeks of sofosbuvir-ledipasvir among HIV-positive MSM (17). TARGET3D Cohort Two has demonstrated high efficacy with glecaprevir-pibrentasvir for six weeks, and importantly, was the first study to evaluate a short duration pan-genotypic DAA regimen in this population. While small sample sizes and differences in study design make comparisons between studies problematic, there is a growing body of evidence supporting shortened duration therapy in acute HCV infection.
Evaluation of factors that impact the effectiveness of short duration therapy in acute HCV is difficult given low rates of treatment failure seen across studies. Baseline HCV RNA may impact efficacy with short (≤6 weeks) duration DAA therapy, with higher baseline HCV RNA associated with post-treatment relapse in studies of both acute (17, 18) and chronic (19, 20) HCV infection. In this study, one case of post-treatment relapse was seen in a participant with genotype 1a HCV infection, well-controlled HIV infection, and very high baseline HCV RNA (7.7 log10). In the aforementioned study among HIV-positive MSM who received sofosbuvir-ledipasvir for six weeks, three cases of relapse also occurred in participants with high baseline HCV RNA (>6.9 log10 IU/mL) (17).
To robustly evaluate the efficacy of short duration (≤6 weeks) DAA therapy, optimal DAA regimen choice is essential, with mathematical modelling showing that induction of a rapid second-phase viral decline should permit shorter treatment durations (21); this rapid second-phase viral decline occurs following administration of HCV NS3/4A protease inhibitors and NS5A inhibitors, but not nucleoside analogues (21- 23). As such, use of glecaprevir-pibrentasvir, a potent pan-genotypic DAA regimen containing an HCV NS3/4A protease inhibitor and NS5A inhibitor, is ideal.

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