Digestive and Liver Disease 46 (2014) S206–S211
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Review Article
Efficacy of sofosbuvir-based therapies in HIV/HCV infected patients and persons who inject drugs Massimo Puoti ∗ , Claudia Panzeri, Roberto Rossotti, Chiara Baiguera Division of Infectious Diseases, AO Ospedale Niguarda Ca’ Granda, Milano, Italy
a r t i c l e
i n f o
Article history: Received 8 August 2014 Accepted 30 September 2014 Available online 7 November 2014 Keywords: Hepatitis C virus Human immune deficiency virus Injection drugs users Sofosbuvir
a b s t r a c t In the era of Directly Acting anti HCV Antivirals treatment of hepatitis C is successful in the majority of persons treated. However, treatment of persons with HIV or who inject drugs remains challenging because of special issues: drug–drug interactions with antiretroviral, psychiatric and drug substitution therapies, treatment adherence, impact of treatment on HIV disease course or on risk of bacterial infections. Sofosbuvir induced sustained virologic response in 91% of 23 HIV/HCV coinfected persons treated in combination with ribavirin and pegylated interferon, in 83% of 497 treated in combination with ribavirin and in all 50 patients infected with HCV GT1 treated in combination with ledipasvir and ribavirin. The rates of efficacy in HCV–HIV coinfected were almost the same as those observed in HCV monoinfected suggesting that the efficacy of sofosbuvir is not reduced by HIV coinfection. There are no data on the efficacy of sofosbuvir in injection drugs users. The pangenotypic activity, the high barrier to resistance, the modest potential for drug–drug interactions makes sofosbuvir a reference drug for the treatment of these two special populations. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction According to recent estimates, more than 185 million people around the world are infected with the hepatitis C virus (HCV), 350 000 of whom die each year [1]. HCV is transmitted primarily as a result of direct, through-the-skin exposure to infected blood [1]. Certain groups are at higher risk of HCV infection, and People Who Inject Drugs (PWID) are an important risk category. In middleand high-income countries, most HCV infections occur among people who use unsterile equipment to inject drugs and contaminated drug solutions [1,2]. Of the estimated 16 million people in 148 countries who actively inject drugs, 10 million are infected with HCV [2]. Human immunodeficiency virus (HIV) and HCV have common routes of transmission, and it is estimated that, globally, 4–5 million persons out of the 185 million infected by HCV are also coinfected by HIV [3]. Sexual transmission of HCV is also common in Persons Living with HIV (PLHIV), particularly in men who have sex with men (MSM) [4]. In several recent outbreaks of HCV infection among HIV infected MSM in Europe, Australia and
∗ Corresponding author at: Division of Infectious Diseases, Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy. Tel.: +39 0264442189; fax: +39 02 64442681. E-mail address: [email protected] (M. Puoti).
the US, transmission has been linked to sexual exposure as well as, potentially, to underreported use of non-injecting recreational drugs [4]. These two groups have a high rate of acquisition of HCV: in the first year of injection drug use more than 50% of the subjects acquire HCV and the rate of HCV infection in PLHIV is 1000 higher than that of the general population [2]. So they are an important epidemiological reservoir for the persistence of the virus in the general population. Thus elimination of HCV infection in these subjects may not only improve individual health status but also may also decrease circulation of HCV infection [2]. In the era of Directly Acting anti HCV Antivirals (DAAs) treatment of Hepatitis C has become successful in the majority of persons treated [5]. However, treatment of PLHIV and PWID remains challenging because of special issues: drug–drug interactions with antiretroviral, psychiatric and opiate substitution therapies, treatment adherence, impact of treatment on HIV disease course or on risk of bacterial infections [2,5]. Sofosbuvir (SOF) is a pyrimidine nucleotide analogue that inhibits HCV NS5B RNA dependent RNA polymerase that is essential for viral replication and is relatively conserved across HCV genotypes and HCV quasispecies [5–7]. Thus sofosbuvir has pangenotypic activity and a high barrier to resistance [7]. Sofosbuvir in combination with ribavirin with or without pegylated interferon, and in combination with other anti HCV DAAs achieves high response rates in the treatment of hepatitis C [7].
http://dx.doi.org/10.1016/j.dld.2014.09.027 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
M. Puoti et al. / Digestive and Liver Disease 46 (2014) S206–S211
This article reviews the rationale for treatment of hepatitis C and the efficacy and tolerability of sofosbuvir in these two groups. 2. Rationale for treatment of hepatitis C in PLHIV Since the introduction of combination antiretroviral therapy (cART), liver disease has become a major cause of morbidity and mortality in HIV-infected persons and is currently one of the most frequent causes of non-HIV-related death among HIV-infected persons [3]. Whether HCV has a negative impact on the progression of HIV infection has been extensively debated. However, there is increasing evidence that HCV coinfection has a harmful effect on the progression of HIV infection, impairing virological and immunological response to cART, and on comorbid conditions such as renal, bone and cardiovascular diseases, and may increase the risk of mortality despite the use of cART [8]. Sustained viral response (SVR) (equivalent to eradication of HCV) after administering anti-HCV therapy is associated with improved survival and reduced liver decompensation in patients with chronic hepatitis C with or without HIV infection. In HIV/HCV coinfection, SVR may also decrease the progression of HIV infection and mortality not related to liver disease [9]. One of the major issues in the treatment of Hepatitis C in PLHIV are the potential interactions between anti HCV and anti HIV antivirals. Sofosbuvir is a substrate for P glycoprotein (P-gp) and Breast Cancer Resistant Protein [7]. Thus it is expected that sofosbuvir concentrations may be reduced by co-administration with potent P-gp inducers. Sofosbuvir is prodrug that undergoes extensive intracellular hepatic metabolism to a pharmacologically active uridine triphosphate form (GS-461203). Dephosphorylation results in the formation of GS-331007 that is the predominant circulating metabolite without anti HCV activity in vitro. Renal clearance is the major elimination pathway for GS-331007 thus no interactions are expected at the level of hepatic cytochromes [7]. For these reasons Tipranavir is the only antiretroviral that may significantly modify sofosbuvir concentrations [7]. In healthy volunteers no clinically significant drug interactions were found between SOF and efavirenz, emtricitabine, raltegravir, darunavir/ritonavir and tenofovir [10]. Thus SOF apparently has no potentially significant drug–drug interactions with most of the antiretrovirals. 3. Sofosbuvir in combination with pegylated interferon and ribavirin in PLHIV A single-centre, open-label, single-arm trial assessed the efficacy and safety of a 12 week course of sofosbuvir 400 mg daily in combination with pegylated interferon alfa 2a 180 mcg per week and weight-based ribavirin 1000–1200 mg [11]. The study included 23 subjects on stable antiretroviral therapy for more than 8 weeks, with CD4 counts > 200/mmc and without cirrhosis. Fifteen subjects were infected with HCV genotype 1a, 4 with HCV genotype 1b, 1 with HCV genotype 2, 2 with HCV genotype 3 and 1 with HCV genotype 4. Most of the patients (18/23) were male, 8 were black and only 5 had the favourable IL28b genotype CC. Mean CD4 cell count was 562 cells/mmc and all patients were on treatment with tenofovir and emtricitabine in combination with: efavirenz in 7, atazanavir/ritonavir in 5, raltegravir in 6, darunavir/ritonavir in 4 and rilpivirine in 1. Twenty two had HCVRNA 500/mmc and 37 had been on a stable cART for at least 8 weeks with tenofovir/emtricitabine plus rilpivirine (11/37) and/or, raltegravir (13/37) and/or efavirenz (16/37). Forty-two were African American, 42 infected with HCV GT1a and 13 had liver fibrosis METAVIR F3 stage. Only 34 patients reached the 16th week of the study and all 34 showed SVR4. SVR12 was observed in all 10 patients not under cART who reached the 24th week of the study. The fitted HCV viral kinetic model showed a similar decline in both the group undergoing cART and the group without cART. Only one patient who skipped cART for 4 days showed an HIV breakthrough but HIV replication was re-suppressed with the same regimen. The tolerability was very good, only one patient showed a grade 3 event (pneumonia) and three patients grade ≥3 lab abnormalities (1 elevated AST, 1 neutropenia and 1 grade 4 CPK elevation). If confirmed by further data analysis these preliminary results suggest that an interferon and ribavirin free fixed dose combination of sofosbuvir and Ledipasvir is equally effective in PLHIV as in HCV mono-infected and that it could become the first line option in PLHIV with HCV Genotype 1 coinfection.
6. Treatment of hepatitis C in PWID PWID are often infected at a young age, which could imply a slow development of cirrhosis. On the other hand, more than 75% of PWID are males and unhealthy behaviour, including high alcohol consumption, may be frequent [26]. Thus progression to cirrhosis in the long term may occur in a significant proportion of PWID. A study on liver histology at autopsy of 102 PWID in Norway showed that about 1/3 of Injection Drugs Users (IDU) chronically infected with HCV progressed to advanced liver fibrosis within three decades after exposure [27]. However, the all-cause mortality in PWID is high and in the first three decades after HCV infection competitive causes of mortality may reduce survival of PWID. Recently, a cohort study on 523 drug users followed for 33 years in Norway showed no difference between HCV RNA positive and HCV RNA negative individuals in the first three decades after HCV infection. However, among PWID with chronic HCV infection who survived till the age of 50, HCV infection emerged as the main cause of death. [28] Thus, from the point of view of individual health, HCV infection may reduce life expectancy only if the individual survives for more than 20 years after infection and injection drug use initiation. Injection drug use is the primary mode of transmission of HCV in developed countries [29], with 15–90% of injecting drug users testing positive for HCV antibodies [30]. Current interventions for reducing HCV transmission focus on reducing the frequency of injecting and syringe sharing/unsafe injection [29]. These may have reduced HCV transmission in some settings [31], but there is no evidence for substantial reductions in HCV prevalence. A simplified HCV transmission model provided evidence that antiviral treatment at achievable rates may be an effective primary
prevention tool for substantially reducing the prevalence of HCV infection, despite the persistent risk of re-infection. Higher SVR with improved and accessible treatment regimens increases the impact of treatment [32]. To date, uptake of therapy remains low among PWID, and is rarely encouraged [33]. Many factors contribute to the low treatment rates in IDU including concerns about re-infection, the low priority of injectors for scarce treatment resources and the lack of evidence showing unequivocal benefits [2]. Nonetheless, the available evidence suggests that IDU can be treated successfully with peginterferon and ribavirin, especially when innovative approaches to delivering therapy are used [2]. However, with peginterferon based therapies low treatment willingness, and high psychiatric comorbidity may contribute to low treatment rates [2]. A study showed that treating chronic HCV infection in injectors and ex- or non-injectors is cost-effective, but treating injectors may be more cost-effective when the chronic HCV prevalence among IDU is below 60% [34]. However, the results of these models should be confirmed by empirical studies examining the treatment of IDUs and measuring the effects on prevalence. Nevertheless, antiHCV treatment is supported by international recommendations which suggest that treatment among PWID is feasible and provide a framework for HCV assessment, management, and treatment [2]. Further research is needed to evaluate strategies to enhance assessment, adherence, and SVR among PWID, particularly as new treatments for HCV infection become available. In PWID the distribution of HCV genotypes is more heterogeneous than in the general population [30] so different schedules of antiviral treatment are needed. In addition, many PWID are on opiate substitution therapy, assume other drugs for psychiatric comorbidities or illicit drugs [2]. So drug–drug interactions may be a concern when treating HCV with drugs which can potentially interfere with the metabolism of opiates, psychiatric and illicit drugs [2]. Sofosbuvir with its pangenotypic activity, its low potential for drug–drug interaction and its possibility for use without interferon could be the reference antiviral for the treatment of PWID. No patient actively injecting drugs was enrolled in registration studies with sofosbuvir, therefore, studies on this population are still warranted. However, sofosbuvir efficacy and tolerability have been demonstrated in 53 patients with contraindications to interferon due to psychiatric comorbidities [16]. 7. Conclusions The pangenotypic activity, the high barrier to resistance, the modest potential for drug–drug interactions make sofosbuvir a reference drug for the treatment of PLHIV and PWID. Data on the efficacy and tolerability of sofosbuvir in PLHIV are robust because 497 PLHIV were enrolled in the registration studies PHOTON I and PHOTON II. The efficacy and tolerability of sofosbuvir in PLHIV are equal or better to those observed in HCV mono-infected. Sofosbuvir in combination with ribavirin is the standard reference combination for the treatment of Hepatitis C genotype 2 and 3 in PLHIV, and probably the sofosbuvir and ledipasvir fixed dose combination will become the first line option in patients infected by HCV GT1. Other potential uses of sofosbuvir in combination with Simeprevir or Daclatasvir are promising but the data on use of these combos in PLHIV are still lacking. Sofosbuvir also has a great potential for use in PWID, however, data in this population are still needed. Conflict of interest MP has served as member of temporary advisory boards and/or speaker in own events and/or in courses for Internal personnel and/or has received research grants from the following companies: Abbvie, Astellas, Bristol Myers Squibb, Boehringer Ingelheim,
M. Puoti et al. / Digestive and Liver Disease 46 (2014) S206–S211
Gilead Sciences, Glaxo Smith Kline, Janssen, Novartis, Merck Sharp and Dohme, Pfizer, Vertex, ViiV. CP, RR and CB have no financial disclosures. This article is part of a supplement supported by an unrestricted educational grant from Gilead Sciences Europe Ltd. Gilead has had no editorial control or involvement in the content of this article. The views and opinions within this supplement are those of the authors and not necessarily those of Gilead. References [1] Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infectious Diseases 2005;5:558–67. [2] Robaeys G, Grebely J, Mauss S, et al. Recommendations for the management of hepatitis C virus infection among people who inject drugs. Clinical Infectious Diseases 2013;57:S129–37. [3] Puoti M, Moioli MC, Travi G, et al. The burden of liver disease in human immunodeficiency virus-infected patients. Seminars in Liver Disease 2012;32:103–13. [4] van de Laar TJ, Matthews GV, Prins M, et al. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 2010;24:1799–812. [5] Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterology 2014;146:1176–92. [6] Lam AM, Murakami E, Espiritu C, et al. PSI-7851, a pronucleotide of beta-D2 -deoxy-2 -fluoro-2 -C-methyluridine monophosphate, is a potent and pangenotype inhibitor of hepatitis C virus replication. Antimicrobial Agents and Chemotherapy 2010;54:3187–96. [7] Keating GM. Sofosbuvir a review of its use in patients with chronic hepatitis C. Drugs 2014;74:1127–46. [8] Puoti M, Rossotti R, Travi G, et al. Optimizing treatment in HIV/HCV coinfection. Digestive and Liver Disease 2013;45:S355–62. [9] Berenguer J, Rodríguez E, Miralles P, et al. Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus. Clinical Infectious Diseases 2012;55:728–36. [10] Kirby B, Mathias A, Rossi S, et al. No clinically significant pharmacokinetic drug interactions between sofosbuvir (GS-7977) and HIV antiretrovirals Atripla, rilpivirine, darunavir/ritonavir, or raltegravir in healthy volunteers. Hepatology 2012;56:1067A. [11] Rodriguez-Torres M, Rodriguez-Orengo J, Gaggar A, et al. Sofosbuvir and peginterferon alfa-2a/ribavirin for treatment-naıve genotype 1–4 HCV infected patients who are HIV coinfected with HIV. In: Infectious diseases week. 2013. Abstract 714. [12] Gatti F, Nasta P, Matti A, et al. Treating hepatitis C virus in HIV patients: are side effects a real obstacle. AIDS Reviews 2007;9:16–24. [13] Grint D, Peters L, Schwarze-Zander C, et al. Temporal changes and regional differences in treatment uptake of hepatitis C therapy in EuroSIDA. HIV Medicine 2013;14:614–23. [14] Sulkowski MS, Naggie S, Lalezari J, et al. Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection. Journal of the American Medical Association 2014;312:353–61. [15] Molina JM, Orkin C, Iser DM, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotypes 1, 2, 3 and 4 infection in patients co-infected with HIV (PHOTON-2). In: AIDS 2014, 20th international AIDS conference. 2014. Abstract MOAB0105LB.
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Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Review Article
Efficacy of sofosbuvir-based therapies in HIV/HCV infected patients and persons who inject drugs Massimo Puoti ∗ , Claudia Panzeri, Roberto Rossotti, Chiara Baiguera Division of Infectious Diseases, AO Ospedale Niguarda Ca’ Granda, Milano, Italy
a r t i c l e
i n f o
Article history: Received 8 August 2014 Accepted 30 September 2014 Available online 7 November 2014 Keywords: Hepatitis C virus Human immune deficiency virus Injection drugs users Sofosbuvir
a b s t r a c t In the era of Directly Acting anti HCV Antivirals treatment of hepatitis C is successful in the majority of persons treated. However, treatment of persons with HIV or who inject drugs remains challenging because of special issues: drug–drug interactions with antiretroviral, psychiatric and drug substitution therapies, treatment adherence, impact of treatment on HIV disease course or on risk of bacterial infections. Sofosbuvir induced sustained virologic response in 91% of 23 HIV/HCV coinfected persons treated in combination with ribavirin and pegylated interferon, in 83% of 497 treated in combination with ribavirin and in all 50 patients infected with HCV GT1 treated in combination with ledipasvir and ribavirin. The rates of efficacy in HCV–HIV coinfected were almost the same as those observed in HCV monoinfected suggesting that the efficacy of sofosbuvir is not reduced by HIV coinfection. There are no data on the efficacy of sofosbuvir in injection drugs users. The pangenotypic activity, the high barrier to resistance, the modest potential for drug–drug interactions makes sofosbuvir a reference drug for the treatment of these two special populations. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction According to recent estimates, more than 185 million people around the world are infected with the hepatitis C virus (HCV), 350 000 of whom die each year [1]. HCV is transmitted primarily as a result of direct, through-the-skin exposure to infected blood [1]. Certain groups are at higher risk of HCV infection, and People Who Inject Drugs (PWID) are an important risk category. In middleand high-income countries, most HCV infections occur among people who use unsterile equipment to inject drugs and contaminated drug solutions [1,2]. Of the estimated 16 million people in 148 countries who actively inject drugs, 10 million are infected with HCV [2]. Human immunodeficiency virus (HIV) and HCV have common routes of transmission, and it is estimated that, globally, 4–5 million persons out of the 185 million infected by HCV are also coinfected by HIV [3]. Sexual transmission of HCV is also common in Persons Living with HIV (PLHIV), particularly in men who have sex with men (MSM) [4]. In several recent outbreaks of HCV infection among HIV infected MSM in Europe, Australia and
∗ Corresponding author at: Division of Infectious Diseases, Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy. Tel.: +39 0264442189; fax: +39 02 64442681. E-mail address: [email protected] (M. Puoti).
the US, transmission has been linked to sexual exposure as well as, potentially, to underreported use of non-injecting recreational drugs [4]. These two groups have a high rate of acquisition of HCV: in the first year of injection drug use more than 50% of the subjects acquire HCV and the rate of HCV infection in PLHIV is 1000 higher than that of the general population [2]. So they are an important epidemiological reservoir for the persistence of the virus in the general population. Thus elimination of HCV infection in these subjects may not only improve individual health status but also may also decrease circulation of HCV infection [2]. In the era of Directly Acting anti HCV Antivirals (DAAs) treatment of Hepatitis C has become successful in the majority of persons treated [5]. However, treatment of PLHIV and PWID remains challenging because of special issues: drug–drug interactions with antiretroviral, psychiatric and opiate substitution therapies, treatment adherence, impact of treatment on HIV disease course or on risk of bacterial infections [2,5]. Sofosbuvir (SOF) is a pyrimidine nucleotide analogue that inhibits HCV NS5B RNA dependent RNA polymerase that is essential for viral replication and is relatively conserved across HCV genotypes and HCV quasispecies [5–7]. Thus sofosbuvir has pangenotypic activity and a high barrier to resistance [7]. Sofosbuvir in combination with ribavirin with or without pegylated interferon, and in combination with other anti HCV DAAs achieves high response rates in the treatment of hepatitis C [7].
http://dx.doi.org/10.1016/j.dld.2014.09.027 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
M. Puoti et al. / Digestive and Liver Disease 46 (2014) S206–S211
This article reviews the rationale for treatment of hepatitis C and the efficacy and tolerability of sofosbuvir in these two groups. 2. Rationale for treatment of hepatitis C in PLHIV Since the introduction of combination antiretroviral therapy (cART), liver disease has become a major cause of morbidity and mortality in HIV-infected persons and is currently one of the most frequent causes of non-HIV-related death among HIV-infected persons [3]. Whether HCV has a negative impact on the progression of HIV infection has been extensively debated. However, there is increasing evidence that HCV coinfection has a harmful effect on the progression of HIV infection, impairing virological and immunological response to cART, and on comorbid conditions such as renal, bone and cardiovascular diseases, and may increase the risk of mortality despite the use of cART [8]. Sustained viral response (SVR) (equivalent to eradication of HCV) after administering anti-HCV therapy is associated with improved survival and reduced liver decompensation in patients with chronic hepatitis C with or without HIV infection. In HIV/HCV coinfection, SVR may also decrease the progression of HIV infection and mortality not related to liver disease [9]. One of the major issues in the treatment of Hepatitis C in PLHIV are the potential interactions between anti HCV and anti HIV antivirals. Sofosbuvir is a substrate for P glycoprotein (P-gp) and Breast Cancer Resistant Protein [7]. Thus it is expected that sofosbuvir concentrations may be reduced by co-administration with potent P-gp inducers. Sofosbuvir is prodrug that undergoes extensive intracellular hepatic metabolism to a pharmacologically active uridine triphosphate form (GS-461203). Dephosphorylation results in the formation of GS-331007 that is the predominant circulating metabolite without anti HCV activity in vitro. Renal clearance is the major elimination pathway for GS-331007 thus no interactions are expected at the level of hepatic cytochromes [7]. For these reasons Tipranavir is the only antiretroviral that may significantly modify sofosbuvir concentrations [7]. In healthy volunteers no clinically significant drug interactions were found between SOF and efavirenz, emtricitabine, raltegravir, darunavir/ritonavir and tenofovir [10]. Thus SOF apparently has no potentially significant drug–drug interactions with most of the antiretrovirals. 3. Sofosbuvir in combination with pegylated interferon and ribavirin in PLHIV A single-centre, open-label, single-arm trial assessed the efficacy and safety of a 12 week course of sofosbuvir 400 mg daily in combination with pegylated interferon alfa 2a 180 mcg per week and weight-based ribavirin 1000–1200 mg [11]. The study included 23 subjects on stable antiretroviral therapy for more than 8 weeks, with CD4 counts > 200/mmc and without cirrhosis. Fifteen subjects were infected with HCV genotype 1a, 4 with HCV genotype 1b, 1 with HCV genotype 2, 2 with HCV genotype 3 and 1 with HCV genotype 4. Most of the patients (18/23) were male, 8 were black and only 5 had the favourable IL28b genotype CC. Mean CD4 cell count was 562 cells/mmc and all patients were on treatment with tenofovir and emtricitabine in combination with: efavirenz in 7, atazanavir/ritonavir in 5, raltegravir in 6, darunavir/ritonavir in 4 and rilpivirine in 1. Twenty two had HCVRNA 500/mmc and 37 had been on a stable cART for at least 8 weeks with tenofovir/emtricitabine plus rilpivirine (11/37) and/or, raltegravir (13/37) and/or efavirenz (16/37). Forty-two were African American, 42 infected with HCV GT1a and 13 had liver fibrosis METAVIR F3 stage. Only 34 patients reached the 16th week of the study and all 34 showed SVR4. SVR12 was observed in all 10 patients not under cART who reached the 24th week of the study. The fitted HCV viral kinetic model showed a similar decline in both the group undergoing cART and the group without cART. Only one patient who skipped cART for 4 days showed an HIV breakthrough but HIV replication was re-suppressed with the same regimen. The tolerability was very good, only one patient showed a grade 3 event (pneumonia) and three patients grade ≥3 lab abnormalities (1 elevated AST, 1 neutropenia and 1 grade 4 CPK elevation). If confirmed by further data analysis these preliminary results suggest that an interferon and ribavirin free fixed dose combination of sofosbuvir and Ledipasvir is equally effective in PLHIV as in HCV mono-infected and that it could become the first line option in PLHIV with HCV Genotype 1 coinfection.
6. Treatment of hepatitis C in PWID PWID are often infected at a young age, which could imply a slow development of cirrhosis. On the other hand, more than 75% of PWID are males and unhealthy behaviour, including high alcohol consumption, may be frequent [26]. Thus progression to cirrhosis in the long term may occur in a significant proportion of PWID. A study on liver histology at autopsy of 102 PWID in Norway showed that about 1/3 of Injection Drugs Users (IDU) chronically infected with HCV progressed to advanced liver fibrosis within three decades after exposure [27]. However, the all-cause mortality in PWID is high and in the first three decades after HCV infection competitive causes of mortality may reduce survival of PWID. Recently, a cohort study on 523 drug users followed for 33 years in Norway showed no difference between HCV RNA positive and HCV RNA negative individuals in the first three decades after HCV infection. However, among PWID with chronic HCV infection who survived till the age of 50, HCV infection emerged as the main cause of death. [28] Thus, from the point of view of individual health, HCV infection may reduce life expectancy only if the individual survives for more than 20 years after infection and injection drug use initiation. Injection drug use is the primary mode of transmission of HCV in developed countries [29], with 15–90% of injecting drug users testing positive for HCV antibodies [30]. Current interventions for reducing HCV transmission focus on reducing the frequency of injecting and syringe sharing/unsafe injection [29]. These may have reduced HCV transmission in some settings [31], but there is no evidence for substantial reductions in HCV prevalence. A simplified HCV transmission model provided evidence that antiviral treatment at achievable rates may be an effective primary
prevention tool for substantially reducing the prevalence of HCV infection, despite the persistent risk of re-infection. Higher SVR with improved and accessible treatment regimens increases the impact of treatment [32]. To date, uptake of therapy remains low among PWID, and is rarely encouraged [33]. Many factors contribute to the low treatment rates in IDU including concerns about re-infection, the low priority of injectors for scarce treatment resources and the lack of evidence showing unequivocal benefits [2]. Nonetheless, the available evidence suggests that IDU can be treated successfully with peginterferon and ribavirin, especially when innovative approaches to delivering therapy are used [2]. However, with peginterferon based therapies low treatment willingness, and high psychiatric comorbidity may contribute to low treatment rates [2]. A study showed that treating chronic HCV infection in injectors and ex- or non-injectors is cost-effective, but treating injectors may be more cost-effective when the chronic HCV prevalence among IDU is below 60% [34]. However, the results of these models should be confirmed by empirical studies examining the treatment of IDUs and measuring the effects on prevalence. Nevertheless, antiHCV treatment is supported by international recommendations which suggest that treatment among PWID is feasible and provide a framework for HCV assessment, management, and treatment [2]. Further research is needed to evaluate strategies to enhance assessment, adherence, and SVR among PWID, particularly as new treatments for HCV infection become available. In PWID the distribution of HCV genotypes is more heterogeneous than in the general population [30] so different schedules of antiviral treatment are needed. In addition, many PWID are on opiate substitution therapy, assume other drugs for psychiatric comorbidities or illicit drugs [2]. So drug–drug interactions may be a concern when treating HCV with drugs which can potentially interfere with the metabolism of opiates, psychiatric and illicit drugs [2]. Sofosbuvir with its pangenotypic activity, its low potential for drug–drug interaction and its possibility for use without interferon could be the reference antiviral for the treatment of PWID. No patient actively injecting drugs was enrolled in registration studies with sofosbuvir, therefore, studies on this population are still warranted. However, sofosbuvir efficacy and tolerability have been demonstrated in 53 patients with contraindications to interferon due to psychiatric comorbidities [16]. 7. Conclusions The pangenotypic activity, the high barrier to resistance, the modest potential for drug–drug interactions make sofosbuvir a reference drug for the treatment of PLHIV and PWID. Data on the efficacy and tolerability of sofosbuvir in PLHIV are robust because 497 PLHIV were enrolled in the registration studies PHOTON I and PHOTON II. The efficacy and tolerability of sofosbuvir in PLHIV are equal or better to those observed in HCV mono-infected. Sofosbuvir in combination with ribavirin is the standard reference combination for the treatment of Hepatitis C genotype 2 and 3 in PLHIV, and probably the sofosbuvir and ledipasvir fixed dose combination will become the first line option in patients infected by HCV GT1. Other potential uses of sofosbuvir in combination with Simeprevir or Daclatasvir are promising but the data on use of these combos in PLHIV are still lacking. Sofosbuvir also has a great potential for use in PWID, however, data in this population are still needed. Conflict of interest MP has served as member of temporary advisory boards and/or speaker in own events and/or in courses for Internal personnel and/or has received research grants from the following companies: Abbvie, Astellas, Bristol Myers Squibb, Boehringer Ingelheim,
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