Clinical experience with dolutegravir/abacavir/lamivudine in HIV–HCV co-infected patients treated with a sofosbuvir-based regimen—safety and efficacy

Abstract

Background: There is no known reason to suspect an adverse drug interaction between dolutegravir-based antiretroviral therapy and sofosbuvir, simeprevir, or ledipasvir. There is a paucity of clinical data for this combination.

Methods: Prospective, open-label study of patients with HIV well controlled on dolutegravir, abacavir, and lamivudine, who were co-infected with HCV genotype 1, and required therapy with simeprevir plus sofosbuvir or sofosbuvir/ledipasvir single-tablet regimen (STR) for 12 weeks. The two primary endpoints were percentage of patients achieving sustained virologic response (SVR) at 12 weeks post-treatment and percentage of patients with a HIV-1 viral load <50 copies/ml at end of the combination therapy.

Results: Twenty-eight subjects were enrolled from August 2014 to September 2015. Thirteen patients were treated with simprevir plus sofosbuvir, and 15 subjects were treated with sofosbuvir/ledipasvir. 23 genotype 1a, and 5 genotype 1b were included. Nineteen were treatment naïve, and 2 patients had compensated cirrhosis. The mean age was 59 years (95% CI 58.21–59.78 years). The mean age was 59 years (95% CI: 58.21–59.78 years), and 25 patients were black. Out of the 28 patients who completed this study, SVR 12 was achieved in 27 of 28 patients (96%, 95% CI 89.6–100.0%), and all patients had an HIV virus load <50 copies/ml at week 12 of therapy, for an intent-to-treat rate of 100%. No patients ended therapy secondary to adverse events.

Conclusion: Our study suggests a good safety and efficacy for the combination of a dolutegravir, abacavir, and lamivudine with sofosbuvir-based DAA therapy.

Keywords:

• Sofobuvir
• Simeprevir
• Ledipasvir
• HIV–HCV
• Coinfection
• Antiretroviral therapy

Introduction

In the United States, roughly 25% of human immunodeficiency virus (HIV)-positive individuals are co-infected with hepatitis C virus (HCV).^1,2 While mortality related to HIV has declined since the introduction of highly effective antiretroviral therapy (ART) in the mid-1990s, HCV-related liver disease has become a leading cause of morbidity and mortality in co-infected persons. It has been shown that HIV hastens the effects of HCV, leading to an earlier onset of advanced liver disease and cirrhosis as well as increased mortality due to liver decompensation.^1–3

The current panel recommendations advise initiation of ART in all HIV/HCV-coinfected patients, as ART may slow the rate of progression of liver fibrosis and dysfunction.^4,5 Current HIV treatment guidelines encourage the use of integrase inhibitor-based regimens, such as dolutegravir, in monoinfected and HCV-coinfected persons. However, concurrent treatment of HIV and HCV can be complicated by drug–drug interactions between antiretroviral drugs and direct-acting antivirals (DAAs) for HCV, overlapping toxicities, and increasing pill burden.^4–6 Due to uncertainty of potential adverse events with coadministration of ART with DAAs, HIV—HCV co-infected patients are often required to change their ART regimen before initiating DAAs. The switching of ART can be difficult for the patients whom have achieve good immune reconstitution with their ART and for the providers who may be treating treatment-experienced patients with variant resistance profiles. Therefore, there is a need for more information regarding the use of DAAs with concomitant ART in HIV–HCV coinfection.

Sofosbuvir, an NS5B polymerase inhibitor, is used in combination with the protease inhibitors simeprevir or the NS5A polymerase inhibitors ledipasvir for the treatment of HCV genotype 1 in mono- or co-infected patients.^6–9 After 12 weeks of simeprevir plus sofosbuvir, 97% of treatment-naïve monoinfected patients experienced sustained virologic response (SVR) vs. 79% of HIV–HCV co-infected patients.⁸ In contrast, SVR12 rates for sofosbuvir/ledipasvir single tablet regimen (STR) were similar in HCV monoinfected and HIV/HCV-coinfected persons.⁹

While there is no known reason to suspect an adverse drug–drug interaction between dolutegravir and sofosbuvir administered with simepravir or sofosbuvir/ledipasvir STR, there is a lack of published data pertaining to the use of dolutegravir combined with sofosbuvir-based HCV therapy. The goal of our study was to acquire more information pertaining to the clinical use, safety, and efficacy of sofosbuvir-based regimens and dolutegravir/abacavir/lamivudine STR to treat HIV–HCV coninfected persons.

Methods

Patients

Eligible patients were HIV-positive adults who were coninfected with HCV genotype 1. Treatment-naïve and -experienced patients who previously failed with pegylated interferon and ribavirin were included. Patients were negative for HLA-B*5701 allele and stable on an antiretroviral regimen consistent of dolutegravir, abacavir, and lamivudine for at least 8 weeks. They had undetectable HIV-1 RNA viral load (<50 copies/ml) at screening and no viral load greater than 200 copies/ml in the previous 12 weeks before enrolling in the study. The required CD4 count at screening was greater than 200 cells/mm³, with no CD4 count less than 200 in preceding 12 weeks. Women of child-bearing potential had a negative serum pregnancy test at screening and prior to initiating study medications at day 1.

The exclusion criteria included: history of integrase inhibitor resistance or failure, history or presence of allergy to the study drugs or their components, an absolute neutrophil count under 1200/mm³ for blacks and under 1500/mm³ for all other ethnicities, platelet count under 90,000 mm³, a hemoglobin less than 11 gm/dl in women or less than 12 gm/dl in men, Glomerular filtration rate less than 50 ml/min via Cockroft–Gault Method, alanine aminotransferase ≥5 times the upper limit of normal, alanine aminotransferase ≥3 times the upper limit of normal with a bilirubin ≥1.5 times the upper limit of normal. Patients previously treated with DAA therapy as well as those with hepatocellular carcinoma, an alpha-fetoprotein greater than 100 ng/mL, hepatitis B infection, or evidence of decompensated liver disease (Child-Pugh Class B or C) were also excluded. The permitted DAA regimens included: sofosbuvir plus simepravir or sofobuvir/ledipasvir STR.

Study design

This was a prospective, open-label pilot study of adult HIV-positive patients who were well-controlled on the integrase-based regimen of dolutegravir 50 mg and abacavir 600 mg/ lamivudine 300 mg. The patients were co-infected with HCV genotype 1 and required treatment with sofosbuvir 400 mg and simeprevir 150 mg once daily or sofosbuvir 400 mg/ledipasvir 90 mg for 12 weeks. The objective of our study was to evaluate the safety and efficacy of sofosbuvir plus simeprevir or ledipasvir in HIV-infected patients controlled on dolutegravrir and abacavir/lamivudine.

Study endpoints

The primary efficacy endpoints were percentage of patients achieving SVR at week 12 post-treatment (quantified as HCV RNA less than <25 IU/mL) and the percentage of patients who maintained HIV suppression after 12 weeks of combination therapy (defined as HIV viral load < 50 copies/mL). Whereas, the primary safety endpoint was the percentage of patients with grade II or higher adverse events.

Efficacy and safety assessments

Plasma HCV RNA levels were measured with COBAS TaqMan HCV RNA assay version 2.0, with a lower limit of quantification of 25 IU/mL and a lower limit of detection of 10 IU/mL. The HCV RNA levels will be measured at baseline, weeks 4 and 8, end of treatment at week 12, and post-treatment weeks 2, 4, and 12. Virologic response was defined as an undetectable RNA viral load during the treatment and post-therapy period.

All adverse events reported by the patient or observed by the investigator were individually listed in the case report form. The signs and symptoms, date of onset, duration, measures taken, and follow-up procedures were reported. The adverse event’s relationship to the study drugs was categorized as either “definite,” “probable,” “possible,” or “definitely not”; and the severity was graded using the AIDS Clinical Trial Group criteria.

Statistical analyses

A descriptive analysis was performed, denoting patients’ demographics including age, race, and sex as well as laboratory data, comorbidities, concomitant mediations, and response to antiviral and HCV treatment.

Results

Study population

Twenty-eight subjects were enrolled from August 2014 to September 2015 and followed through the completion of this study in February 2016. Of the 28 individuals enrolled, 13 patients were treated with simprevir plus sofosbuvir while 15 subjects were treated with sofosbuvir/ledipasvir STR. Sixteen were males. The predominance was of black ethnicity (25/28), and the mean age was 59 (95%CI 58.21–59.78 years). The mean CD4 count was 631 cells/mm³ (95% CI: 492–796 cell/mm³). The mean HCV RNA viral load was 4,030,434 IU/ml (95% CI: 2,348,658–5,712,211 IU/ml) with 23/28 patients having genotype 1a and the remaining five patients having genotype 1b. Nineteen were treatment naïve, and two patients had compensated cirrhosis.

Efficacy and safety

Out of the 28 patients who completed this study, SVR 12 was achieved in 27 of 28 patients (96%, 95% CI 89.6–100.0%). A listing of the adverse events, grade of intensity, and relation to medications are summarized in Table 1. All of the noted adverse events were non-life threatening, with 12 grade 2 or 3 adverse events noted during the study period. Of the reported adverse events, only one reported incidence of severe fatigue was thought to be related to study medication. Nonetheless, no patient withdrew from the study due to adverse events.

Table 1 Adverse events

Adverse events	N(%)
Arthralgias	6(30)
Respiratory tract infection	7(35)
Shortness of breath	2(10)
Nausea	2(10)
Others^a	3(15)

^a 1 oral thrush, 1 ulcer lower lip, and 1 corneal abrasion.

HIV-1 suppression

All 28 patients who finished this study maintained a HIV virus load <50 copies/ml at week 12 of therapy, for an intent-to-treat rate of 100%.

Discussion

The Department of Health and Human Services’ guidelines for initiating antiretrovirals in adolescents and adults recommends the usage of integrase- or protease inhibitor-based regimens.⁴ These recommendations are based on data noting the bioavailability, tolerability, and durable virologic efficacy of these regimens.⁴ Of the six advised treatment options, five are integrase-based, with two preferred regimens containing dolutegravir.⁴ However, on review of the coinfection trials for sofobuvir regimens, the majority of enrolled patients were not receiving dolutegravir as part of their ART.

Amongst the major coinfection clinical studies, only a few of these trials included an integrase-based ART regimen.^5,6,10,11 In ION, 146 of 335 HIV-positive subjects coninfected with genotype 1 or 4 received the integrase inhibitor, raltegravir, and tenofovir-emtricitabine with ledipasvir-sofosbuvir STR.¹² The ASTRAL-5 trial enlisted 106 HIV-positive chronic hepatitis C patients of all genotypes, with the majority being genotype 1a (62%). A variety of antiretroviral regimens were included, but usage of integrase inhibitors only represented 34%. Furthermore, the integrase inhibitors utilized were raltegravir and elvitegravir.¹³ In the TURQUOISE-1 trial, 63 HIV–HCV co-infected patients who were treatment-naive or -experienced with peginterferon plus ribavirin and stable on atazanavir- or raltegravir-based ART. Of the 63 enrolled patients, 35 were taking a raltegravir-inclusive antiretroviral regimen.¹⁴ The ALLY-2 coinfection trial is the only study to date that has involved a sofosbuvir-focused DAA and integrase inhibitor dolutegravir [7 patients].^11,15

The current treatment guidelines for HIV/HCV-coinfected patients encourages the use of dolutegravir with sofosbuvir-based DAA due to the perceived minimal adverse interactions with concomitant use of these agents.⁶ We desired to collect additional real life data in efforts to better document any potential adverse events that could occur as well as further assess the safety and efficacy of this combination. There were no grade 3 or 4 adverse events noted to be associated with therapy, and only one patient relapsed during the study period. The patient that relapsed was noncirrhotic, treatment-naïve with genotype 1a and baseline HCV viral load of 643,600 IU/ml, and a CD4 count of 642. The patient was started on sofosbuvir and simeprevir; and at week 4 and 12 of therapy, the HCV viral was undetectable. However, virologic suppression was not sustained at week 4 post completion of therapy. Despite failure with simeprevir and sofobuvir, the relapser was retreated with sofosbuvir/ledipasvir STR plus weight-based ribavirin for 12 weeks and achieved SVR12.

Furthermore, sofosbuvir-based DAAs did not seem to compromise HIV control. All participants in this study including the one patient who relapsed maintained HIV viral suppression. Baseline HCV viral load and age did not seem to have an effect on SVR12 rates.

We conclude that treatment with dolutegravir-based ART and sofosbuvir-focused DAA was safe and well tolerated. However, due to the small numbers, definitive data on the response rates in cirrhotics and treatment-experienced patients cannot be provided.

Contributors

TMJ and SB are infectious disease fellows involved in the development of the protocol and participated in drafting and editing the manuscript. RS is an associate facility member involved in the development of the protocol, oversaw data collection, and participated in drafting this manuscript. JS is the director of infectious disease, served as the lead clinical investigator on the protocol, and participated in drafting and editing the manuscript. JPF assisted in designing the experiment, analyzing the data, and participated in drafting and editing the manuscript. PPS, HG, and RH performed the data collection and assisted in the drafting and editing of the manuscript. All authors read and approved the final manuscript.