Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study

doi:10.1016/S0140-6736(14)62483-1

The Lancet

Volume 385, Issue 9973, 21–27 March 2015, Pages 1098-1106

https://doi.org/10.1016/S0140-6736(14)62483-1 Get rights and content

Summary

Background

Although interferon-free regimens are approved for patients co-infected with HIV and genotype-2 or genotype-3 hepatitis C virus (HCV), interferon-based regimens are still an option for those co-infected with HIV and HCV genotypes 1 or 4. These regimens are limited by clinically significant toxic effects and drug interactions with antiretroviral therapy. We aimed to assess the efficacy and safety of an interferon-free, all-oral regimen of sofosbuvir plus ribavirin in patients with HIV and HCV co-infection.

Methods

We did this open-label, non-randomised, uncontrolled, phase 3 study at 45 sites in seven European countries and Australia. We enrolled patients (aged ≥18 years) co-infected with stable HIV and chronic HCV genotypes 1–4, including those with compensated cirrhosis. Once-daily sofosbuvir (400 mg) plus twice-daily ribavirin (1000 mg in patients with bodyweights <75 kg and 1200 mg in those with weights ≥75 kg) was given for 24 weeks to all patients except treatment-naive patients with genotype-2 HCV, who received a 12-week regimen. The primary efficacy endpoint was sustained virological response 12 weeks after treatment. We did analysis by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01783678.

Findings

Between Feb 7, 2013, and July 29, 2013, we enrolled 275 eligible patients, of whom 262 (95%) completed treatment; 274 patients were included in the final analysis. Overall rates of sustained virological response 12 weeks after treatment were 85% (95% CI 77–91) in patients with genotype-1 HCV, 88% (69–98) in patients with genotype-2 HCV, 89% (81–94) in patients with genotype-3 HCV, and 84% (66–95) in patients with genotype-4 HCV. Response rates in treatment-naive patients with HCV genotypes 2 or 3 (89% [95% CI 67–99] and 91% [81–97], respectively) were similar to those in treatment-experienced patients infected with those genotypes (83% [36–100] and 86% [73–94], respectively). There was no emergence of sofosbuvir-resistance mutations in patients with HCV viral relapse. Six (2%) patients discontinued treatment because of adverse events. The most common adverse events were fatigue, insomnia, asthenia, and headache. Four (1%) patients had serious adverse events regarded as related to study treatment. Additionally, four (1%) patients receiving antiretroviral treatment had a transient HIV viral breakthrough; however, none required changes in antiretroviral regimen.

Interpretation

Sofosbuvir and ribavirin provided high rates of sustained virological response after 12 weeks of treatment in treatment-naive and treatment-experienced patients co-infected with HIV and HCV genotypes 1–4. The characteristics of this interferon-free combination regimen make sofosbuvir plus ribavirin a useful treatment option for this patient population.

Funding

Gilead Sciences.

Introduction

In Europe, 25% of patients with HIV are co-infected with hepatitis C virus (HCV).¹ HIV exacerbates the morbidity of patients with HCV, even in those receiving highly active antiretroviral therapy.2, 3, 4 Patients co-infected with HCV and HIV have higher rates of liver failure and liver-related death than do those with HCV monoinfection.2, 3, 4 As such, mortality in co-infected patients remains unchanged from before the introduction of combination antiretroviral therapy in 1996.⁵ Eradication of HCV in patients with HCV and HIV co-infection is associated with a reduction in liver-related events and in HIV progression and mortality not related to liver disease.⁶

Sofosbuvir is an oral nucleotide analogue inhibitor of the HCV non-structural 5B polymerase that has been approved for treatment of HCV genotypes 1–4.⁷ Sofosbuvir in combination with peginterferon and ribavirin is effective for treatment of HCV genotypes 1, 4, 5, and 6, and sofosbuvir with ribavirin produces high rates of sustained virological response in patients with HCV genotypes 2 and 3.8, 9, 10, 11 The PHOTON-1 study¹² reported high rates (67–94%) of sustained virological response after administration of sofosbuvir plus ribavirin to treatment-naive patients with HCV genotypes 1–3 and to treatment-experienced patients with HCV genotypes 2 and 3 co-infected with HIV and HCV. These findings have been used by the American Association for the Study of Liver Disease and the Infectious Diseases Society of America in jointly issued treatment guidelines.¹³ Ledipasvir in combination with sofosbuvir as a single-tablet regimen was approved in the USA for patients with HCV genotype 1 and in Europe for patients with genotypes 1 and 4, including for those with HIV co-infection.¹⁴ Other drugs in combination with sofosbuvir, such as daclatasvir and simeprevir, have been approved in some countries, although not specifically for use in patients with HIV and HCV co-infection.

We assessed the efficacy of sofosbuvir and ribavirin in patients co-infected with HCV and HIV. With this study, we aimed to expand on the results of PHOTON-1 by including patients with HCV genotype 4, and to verify the benefit associated with a longer treatment duration for patients with HCV genotype 3 than for those with genotype-2 infection, irrespective of previous treatment.

Section snippets

Study design and patients

We did this open-label, non-randomised, multicentre, uncontrolled trial at 45 clinical sites in Australia, France, Germany, Italy, Portugal, Spain, and the UK. Eligible patients were aged 18 years or older with a body-mass index of 18 kg/m² or more and chronic infection with HCV genotypes 1–4 (serum HCV RNA concentrations ≥10 000 IU/mL) and HIV-1. We included treatment-naive patients with HCV genotypes 1–4 and treatment-experienced patients with HCV genotypes 2 or 3 (appendix). Roughly 20% of

Results

Figure 1 shows the study flowchart. Between Feb 7, 2013, and July 9, 2013, we enrolled 275 eligible patients, of whom 262 (95%) completed treatment; 274 patients were included in the final analysis (figure 1, appendix). Table 1 shows demographic, disease, and baseline characteristics. Most patients were HCV treatment-naive (figure 1, table 1). Most of the treatment-experienced patients had genotype-3 HCV (figure 1, table 1). Overall, 54 (20%) patients had cirrhosis, with a higher prevalence in

Discussion

Patients in our study achieved high rates of sustained virological response 12 weeks after treatment. These findings show that an interferon-free regimen of sofosbuvir plus ribavirin for 12 or 24 weeks can be highly effective for treatment of treatment-naive or treatment-experienced patients co-infected with HIV and HCV genotypes 1–4. Results from the PHOTON-2 study are in keeping with those from the PHOTON-1 study¹² done in the USA (panel). In PHOTON-1, treatment-naive patients with HCV

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Citation Excerpt :
Asthenia and insomnia were the two side-effects reported. Such excellent tolerance of sofosbuvir/ledipasvir ± ribavirin has been reported with several published series (Sharafi et al., 2020; Liu et al., 2019), trials (Afdhal et al., 2014; Mizokami et al., 2015; Molina et al., 2015), and meta-analyses (He et al., 2016; Stokes et al., 2017). Asthenia, headache, nausea, diarrhea, insomnia, and skin lesions were common side-effects in all publications, with anemia being the most common side-effect in patients taking ribavirin; however, anemia was not present in any patients in our study.
The aim of this study was to evaluate the efficacy and safety of sofosbuvir/ledipasvir ± ribavirin in Malagasy patients with hepatitis C virus genotypes 1 and 2, in real conditions.
This was a retrospective monocentric clinical study, carried out over a period of 3 years from March 1, 2017 to February 28, 2020, in a hospital hepato-gastroenterology department.
In total, 26 patients (M/F: 11/15) with hepatitis C virus genotype 1 (n = 13) or genotype 2 (n = 13), were treated with sofosbuvir/ledipasvir without (n = 21) or with (n = 5) ribavirin for 12 weeks. The mean age was 61.38 ± 7.09 years. Seventeen patients (65.4%) had cirrhosis. The overall sustained virological response was 96.2% (95% CI = 80.4–99.9%). There was no significant difference between the sustained virological responses of genotypes 1 and 2 (92.3% vs 100%; p = 0.31) or those of cirrhotic or non-cirrhotic patients (94.1% vs 100%; p = 0.46). A relapse was observed in one patient (5.9%) — cirrhotic and genotype 1b — under sofosbuvir/ledipasvir with ribavirin. Seven patients (26.9%) experienced mild adverse reactions, including asthenia (57.1%) and insomnia (42.9%).
Treatment with sofosbuvir/ledipasvir ± ribavirin for infection with hepatitis C virus genotype 1 has been shown to be safe and effective, even in the presence of cirrhosis. The sofosbuvir/ledipasvir combination is a good option for genotype 2 non-cirrhotic patients.
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Mathematical modeling of viral kinetics has been shown to identify patients with chronic hepatitis C virus (HCV) infection who could be cured with a shorter duration of direct-acting antiviral (DAA) treatment. However, modeling therapy duration has yet to be evaluated in recently infected individuals. The aim of this study was to retrospectively examine whether modeling can predict outcomes of six-week sofosbuvir (SOF) and weight-based ribavirin (R) therapy in individuals with recent HCV infection.
Modeling was used to estimate viral host parameters and to predict time to cure for 12 adults with recent HCV infection (<12 months of infection) who received six weeks of treatment with SOF + R.
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ArticlesSofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patients

Results

Discussion

Lancet

Lancet Infect Dis

Managing HIV/hepatitis C co-infection in the era of direct acting antivirals

BMC Med

HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis

Hepatology

Clinical progression of hepatitis C virus-related chronic liver disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy

Hepatology

HCV and HIV co-infection: mechanisms and management

Nat Rev Gastroenterol Hepatol

The prevalence of cirrhosis and hepatocellular carcinoma in patients with HIV infection

Hepatology

Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus

Clin Infect Dis

Sovaldi (sofosbuvir) tablets: US prescribing information

Sofosbuvir for previously untreated chronic hepatitis C infection

N Engl J Med

Articles
Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study