Therapeutic Potential of and Treatment with Boceprevir/Telaprevir-Based Triple-Therapy in HIV/Chronic Hepatitis C Co-Infected Patients in a Real-World Setting

Abstract

The aim of this study was to assess the therapeutic potential of telaprevir (TPV)/boceprevir (BOC)-based triple-therapy in a complete cohort of HIV/chronic hepatitis C co-infected patients (HIV/HCV). Moreover, a case series of four HIV/HCV genotype (HCV-GT)1 patients with rapid virologic response (RVR), who received only 28 weeks of BOC-based triple-therapy (BOCW28), was reported. 290/440 HIV-positive patients with positive HCV serology had at least one visit during the past 2 years, 142/290 had target detectable HCV-RNA with 64% (82/142) carrying HCV-GT1. While 18 HIV/HCV-GT1 displayed contraindications, 45% (64/142) of HIV/HCV were eligible for triple-therapy. Insufficiently controlled HIV-infection despite combined antiretroviral therapy (cART) (HIV-RNA <50 copies/mL: 73% vs. 22%; p<0.001) and liver cirrhosis (31% vs. 8%; p=0.025) were overrepresented among patients with contraindications for triple-therapy. Low treatment uptake rates (39% (25/64)) during the first 2 years of triple-therapy availability suggest that its benefit in HIV/HCV co-infected patients might fall short of expectations. Modification of cART or TPV dose adjustment would have been necessary in 61% and 84% of HIV/HCV-GT1 on cART eligible for triple-therapy using TPV and BOC, respectively, suggesting that drug–drug interactions with cART complicate management in the majority of patients. All four BOCW28 patients achieved a sustained virologic response. Prospective studies are necessary to validate our observations on the shortening of treatment duration in HIV/HCV-GT1 with RVR.

Introduction

Chronic liver disease, which is predominately caused by chronic hepatitis C (CHC), is the second leading cause of death in patients infected with human immunodeficiency virus (HIV).¹ When compared to hepatitis C virus (HCV) monoinfection, HIV/HCV co-infection, which is observed in 25–30% of European and US-American HIV-positive patients,² was found to be associated with higher rates of liver fibrosis progression,³ markedly higher risks of cirrhosis and end-stage liver disease,⁴ and increased health-care utilization.⁵ In addition, an epidemic of acute hepatitis C (AHC), shown by a 14-fold increased incidence rate in the last 13 years, has been reported among HIV-positive men who have sex with men (MSM).^6,7 This ongoing epidemic has resulted in increasing disease awareness and intensified screening for HCV co-infection among HIV-positive patients.⁸ This may lead to an additional increase in the prevalence of HIV/HCV co-infection in the near future, as rates of spontaneous clearance among HIV-positive individuals are only about 15%.⁹ Thus, treatment of both viremic acute HCV infection and chronic hepatitis C is of high priority in HIV-positive patients.

Throughout the last decade, the efficacy of CHC therapy in HIV-positive patients has improved as a result of the individualization of treatment and improvements in the management of treatment-associated side effects. However, the efficacy of dual-therapy with pegylated interferon plus ribavirin (PEGIFN+RBV) remains moderate, especially in HIV-positive patients co-infected with the highly prevalent HCV-Genotype (HCV-GT)1.

In a recent large, multicenter study on PEGIFN+RBV therapy in this subgroup of patients, rates of sustained virologic response (SVR) observed were as low as 21%.¹⁰ The HCV NS3/4A protease inhibitors boceprevir (BOC) and telaprevir (TPV), in combination with PEGIFN+RBV, were recently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of chronic HCV-GT1 infection.^11

–14 The approval of these first-generation direct-acting antiviral agents (DAAs) has ushered in a new era in the treatment of HIV/HCV-GT1 co-infected patients. First results of phase IIa studies of triple-therapy with TPV¹⁵ and BOC,¹⁶ in combination with PEGIFN+RBV in HIV-positive individuals, have recently been published. Significantly improved efficacy was observed in patients treated with DAA-based triple-therapy when compared to dual-therapy plus placebo with SVR rates of 74% vs. 45% and 63% vs. 29% in the TPV and BOC study, respectively.

However, in addition to psychosocial factors,^17
–19 several medical conditions may significantly limit treatment uptake with triple-therapy in a real-life cohort of HIV/HCV co-infected patients. As PEGIFN+RBV is the backbone of triple-therapy, similar contraindications apply for dual-therapy and triple-therapy. In addition, recent data derived from the Austrian²⁰ and French²¹ early access programs suggest that in cirrhotic patients with thrombocytopenia, hypoalbuminemia, or clinically significant portal hypertension, the high risk of severe adverse events may outweigh the potential benefit of triple-therapy. Triple-therapy with BOC or TPV is restricted to patients with HIV/HCV-GT1 co-infection. Furthermore, drug–drug interactions (DDIs) with both combined antiretroviral therapy (cART) and other concomitant medication may complicate management in a high proportion of patients. Thus, while more effective antiviral therapy for HIV/HCV-co-infected patients is urgently needed, treatment uptake rates might be heavily impaired in this patient population.

The aim of this study was to assess the therapeutic potential of DAA-based triple-therapy, the necessity of a cART switch prior to treatment initiation, and the treatment uptake rates in a complete cohort of HIV/HCV co-infected patients during the first 2 years of triple-therapy availability. In addition, a case series of patients with CHC and rapid virologic response (RVR) who received only 28 weeks of BOC-based triple-therapy will be reported.

Patients and Methods

Study population

440 HIV-positive patients with positive HCV serology diagnosed at the Medical University of Vienna from June 2005 to July 2013 were included in this retrospective analysis. As the aim of this study was to assess the potential of DAA-based triple-therapy in a complete cohort of HIV/HCV co-infected patients, no other inclusion or exclusion criteria were specified.

Laboratory assessments and interleukin 28B rs12979860 SNP (IL28B) testing

HCV-GT as well as serum HCV-RNA and HIV-RNA levels were determined using commercially available assays [VERSANT HCV Genotype 2.0 Assay (LiPA) (Siemens, Vienna, Austria) and COBAS AmpliPrep/TaqMan HCV/HIV Test (Roche, Vienna, Austria)]. HIV-RNA suppression was defined as HIV-RNA serum levels <50 copies mL⁻¹. Serum CD4+T-lymphocyte count was determined using standard flow cytometry. The IL28B rs12979860 SNP was analyzed as described previously using the StepOnePlus Real Time PCR System (Applied Biosystems, Carlsbad, CA, USA) and a Custom TaqMan SNP Genotyping Assay.²²

Assessment of liver fibrosis and hepatic venous pressure gradient (HVPG) measurement

Liver biopsies were scored according to the METAVIR classification.²³ Measurement of liver stiffness was performed by transient elastography using FibroScan^® (Echosens, Paris, France) as previously described.²⁴ Significant liver fibrosis was defined as METAVIR ≥F2, liver stiffness >7.1 kPa,²⁵ or aspartate transaminase (AST) to platelet ratio index (APRI) >1.²⁶ The presence of either METAVIR F4, liver stiffness >12.5 kPa,²⁵ or APRI >2²⁶ was denoted as liver cirrhosis. If available, liver biopsies were used for the grading of liver fibrosis. Otherwise, liver fibrosis was graded based on liver stiffness or APRI. HVPG measurement was performed as described previously.²⁷

Contraindications for DAA-based triple-therapy

The presence of one of the following patient characteristics was considered a contraindication for DAA-based triple-therapy: hemoglobin <8 g dL⁻¹; platelet count <50 G L⁻¹; white blood cell count <2 G L⁻¹; CD4+T-lymphocyte count <200 cells μL⁻¹; liver cirrhosis and either platelet count <100 G L⁻¹,²⁸ or serum albumin levels <35 g dL⁻¹,²⁸ or HVPG >10 mmHg.²⁰

DDIs of cART and DAAs

Based on The University of Liverpool database,²⁹ coadministration of the following antiretrovirals and TPV was considered safe: ritonavir boosted atazanavir (ATV/r), tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), lamivudine (LAM), etravirine, rilpivirine, raltegravir (RAL), and efavirenz (EFV) with TPV dose adjustment. BOC may be safely coadministered with TDF, FTC, LAM, abacavir, etravirine, and RAL.

Estimate of the efficacy of DAA-based triple-therapy

In phase IIa studies of triple-therapy with TPV¹⁵ and BOC¹⁶ in combination with PEGIFN+RBV in HIV-positive individuals, SVR rates were 74% (28/38) and 63% (40/64) in the TPV and BOC study, respectively. Pooling these two studies, the expected SVR rate in HIV/HCV-GT1 co-infected patients treated with DAA-based triple-therapy is 67% (68/102).

BOC-based triple-therapy

The reported treatment schedule was not based on a prespecified protocol. Thus, our observations should be considered as a case series.

As recommended by the current European AIDS Clinical Society (EACS) guidelines,³⁰ patients with CHC were treated with pegylated interferon-α-2a (180 μg) once a week and weight-based ribavirin doses ranging from 1000–1200 mg daily. After a lead-in phase of 4 weeks, BOC was added at a dose of 800 mg TID. Although the intended treatment duration was 48 weeks, treatment was discontinued at treatment week 28 due to adverse events. RVR was defined as target not detectable (TND)³¹ HCV-RNA at treatment week 8. SVR12 and SVR24 were defined as TND HCV-RNA 12 and 24 weeks after the end of treatment, respectively.

Statistical analyses

Statistical analyses were performed using IBM SPSS Statistics 21 (SPSS Inc., Armonk, NY, USA). Continuous variables were reported as median (interquartile range), while categorical variables were reported as number (proportion) of patients with the certain characteristic. Student's t-test was used for group comparisons of continuous variables when applicable. Otherwise, Mann-Whitney U test was applied. Group comparisons of categorical variables were performed using either Pearson's chi-squared or Fisher's exact test. A p value≤0.05 was considered statistically significant.

Ethics

This study was conducted in accordance with the Declaration of Helsinki as approved by the local ethics committee of the Medical University of Vienna (EK Nr. 1699/2013).

Results

Potential of triple-therapy

A total of 440 HIV-positive patients had a positive HCV serology (Fig. 1.) 290 of the HIV-positive patients with positive HCV serology had at least one visit to the outpatient clinic over the past 2 years. 142 out of 290 patients had target detectable (TD) HCV-RNA, of which 82 patients (64%) carried HCV-GT1. HCV-GT2, 3, and 4 were observed in 2 (2%), 33 (26%), and 11 patients (9%), respectively.

FIG. 1.

(A) Flow chart displaying the number of patients excluded in each step. (B) Illustration of the stepwise reduction of the number of patients eligible for DAA-based triple therapy. DAA, direct-acting antiviral agent; GT, genotype; HCV, hepatitis C virus.

Among 82 HIV/HCV-GT1-co-infected patients, 18 patients displayed contraindications for triple-therapy: anemia, thrombocytopenia <50 G L⁻¹, and leukopenia were each observed once. Seventeen patients displayed a low CD4+T-lymphocyte count, and three patients had both liver cirrhosis and thrombocytopenia <100 G L⁻¹. Thus, 64 (45%) out of 142 HIV/HCV co-infected patients were eligible for treatment with triple-therapy. Based on the previously described estimated SVR rate of 67%, triple-therapy may be successful in 43 of these patients. Thus, triple-therapy has the potential to cure HCV-infection in 29% (43/142) of all HIV-positive patients with detectable HCV-RNA attached to the center.

During the first 2 years of triple-therapy availability, triple-therapy was initiated in 25 (39%) out of 64 HIV/HCV-GT1 patients eligible for triple-therapy, equaling to 18% (25/142) of all HIV/HCV co-infected patients.

Characteristics of HIV/HCV-GT1 co-infected patients and comparison of subgroups of patients with and without contraindications for triple-therapy

The majority of patients was male (54%) and had a history of intravenous drug use (78%) (Table 1).

Table 1.

Characteristics of HIV/HCV-GT1 Co-Infected Patients and Comparison of Subgroups of Patients With and Without Contraindications for DAA-Based Triple-Therapy

Patient characteristics	HIV/HCV-GT1 co-infected patients, N=82	Subgroup without contraindications, N=64	Subgroup with contraindication, N=18	p Value
Epidemiological characteristics
Sex
Male	54% (44/82)	55% (35/64)	50% (9/18)	0.725
Female	46% (38/82)	45% (29/64)	50% (9/18)
Age (years)	39.5±9.9	39.7±10.1	38.9±9.4	0.789
Transmission
IVDU	78% (64/82)	80% (51/64)	72% (13/18)	0.2
Blood products	5% (4/82)	6% (4/64)	0% (0/18)
MSM	4% (3/82)	5% (3/64)	0% (0/18)
Heterosexual	11% (9/82)	8% (5/64)	22% (4/18)
Unknown	2% (2/82)	2% (1/64)	6% (1/18)
Blood draw
Hemoglobin (g dL⁻¹)	13.4±1.9	13.5±1.7	13±2.6	0.34
Platelet count (G L⁻¹)	204±74.1	211±70	174±85	0.074
White blood cell count (G L⁻¹)	6.12±2.34	6.21±2.38	5.8±2.2	0.501
Albumin (g dL⁻¹)	40.8±6.6	41.1±6.7	39.4±6.1	0.366
Creatinine (mg dL⁻¹)	0.84 (0.18)	0.84 (0.16)	0.77 (0.27)	0.153
INR	1.01±0.12	1.04±0.15	0.998±0.112	0.39
Bilirubin (mg dL⁻¹)	0.55 (0.41)	0.55 (0.41)	0.595 (0.708)	0.354
AST (U L⁻¹)	48.5 (36.5)	49 (37.3)	41.5 (49.5)	0.71
ALT (U L⁻¹)	58.2±48.2	59.2±50.3	54.1±39.9	0.373
GGT (U L⁻¹)	76 (92.75)	72 (87.8)	113 (133)	0.045
HIV infection parameters
CD4+T-lymphocyte count (cells μL⁻¹)	448±265	531±237	151±77	<0.001
cART	98% (80/82)	97% (62/64)	100% (18/18)	1
PI	66% (53/80)	63% (39/62)	78% (14/18)	0.24
N(t)RTI	96% (77/80)	97% (60/62)	94% (17/18)	0.54
NNRTI	24% (19/80)	21% (13/62)	33% (6/18)	0.217
II	20% (16/80)	21% (13/62)	17% (3/18)	0.755
HIV-RNA <50 copies mL⁻¹	61% (49/80)	73% (45/62)	22% (4/18)	<0.001
HIV-RNA <400 copies mL⁻¹	74% (59/80)	84% (52/62)	39% (7/18)	<0.001
Compatible with TPV		39% (24/62)
Compatible with BOC		18% (11/62)
HCV infection parameters
Treatment-naive	83% (68/82)	78% (50/64)	100% (18/18)	0.032
HCV-RNA (log IU mL⁻¹)	6.44 (1.05)	6.45 (1.01)	6.37 (1.81)	0.775
HCV-GT
1a	76% (44/58)	74% (35/47)	82% (9/11)	0.717
1b	24% (14/58)	26% (12/47)	18% (2/11)
IL28B non-C/C	69% (38/55)	68% (32/47)	75% (6/8)	1
Significant liver fibrosis	49% (39/79)	52% (33/63)	38% (6/16)	0.288
Liver cirrhosis	13% (10/79)	8% (5/63)	31% (5/16)	0.025
Contraindications
Any	22% (18/82)		100% (18/18)
Hemoglobin <8 g dL⁻¹	1% (1/82)		6% (1/18)
Platelet count <50 G L⁻¹	1% (1/82)		6% (1/18)
White blood cell count <2 G L⁻¹	1% (1/82)		6% (1/18)
CD4+T-lymphocyte count <200 cells μL⁻¹	21% (17/82)		94% (17/18)
Liver cirrhosis and
platelet count <100 G L⁻¹	4% (3/82)		17% (3/18)
albumin <35 g dL⁻¹	0% (0/64)		0% (0/18)
HVPG >10 mmHg	0% (0/64)		0% (0/18)

ALT, alanine transaminase; AST, aspartate transaminase; BOC, bocecprevir; cART, combined antiretroviral therapy; DAA, direct-acting antiviral agent; GGT, gamma-glutamyl transpeptidase; GT, genotype; HCV, hepatitis C virus; HVPG, hepatic venous pressure gradient; II, integrase inhibitors; IL28B, interleukin 28B rs12979860 SNP; INR, international normalized ratio; IVDU, intravenous drug abuse; MSM, men who have sex with men; NNRTI, non-nucleoside reverse-transcriptase inhibitors; N(t)RTIs, nucleos(t)idic reverse transcriptase inhibitors; PI, protease inhibitor; TPV, telaprevir.

Definitions: Liver biopsies were scored according to the METAVIR classification.²³ Measurement of liver stiffness was performed by transient elastography using FibroScan® (Echosens, Paris, France) as previously described.²⁴ Significant liver fibrosis was defined as METAVIR ≥F2, liver stiffness >7.1 kPa,²⁵ or aspartate transaminase (AST) to platelet ratio index (APRI) >1.²⁶ The presence of either METAVIR F4, liver stiffness >12.5 kPa,²⁵ or APRI >2²⁶ was denoted as liver cirrhosis. If available, liver biopsies were used for the grading of liver fibrosis. Otherwise, liver fibrosis was graded based on liver stiffness or APRI. HVPG measurement was performed as described previously.²⁷

Statistics: Continuous variables were reported as median (interquartile range), while categorical variables were reported as number (proportion) of patients with the certain characteristic. Student's t-test was used for group comparisons of continuous variables when applicable. Otherwise, Mann-Whitney U test was applied. Group comparisons of categorical variables were performed using either Pearson's chi-squared or Fisher's exact test. A p value≤0.05 was considered statistically significant.

There was a trend toward a lower platelet count among patients with a contraindication for triple-therapy (174±85 vs. 211±70; p=0.074). The mean CD4+T-lymphocyte count was 448±265 cells μL⁻¹ and 97% of patients were on cART. Of these, 66% were receiving HIV PIs, 96% nucleos(t)idic reverse transcriptase inhibitors (N(t)RTIs), 24% non-nucleoside reverse-transcriptase inhibitors (NNRTIs), 20% integrase inhibitors (IIs), and 61% had suppressed HIV-RNA.

Higher CD4+T-lymphocyte counts (531±237 vs. 151±77 cells μL⁻¹; p<0.001) and a higher proportion of patients with HIV-RNA <50 copies mL⁻¹ (73% vs. 22%; p<0.001) and <400 copies mL⁻¹ (84% vs. 39%; p<0.001) while on cART were observed among patients without contraindications for triple-therapy.

The majority of patients (83%) was treatment-naïve and harbored the IL28B non-C/C genotype (69%). Significant liver fibrosis and liver cirrhosis were observed in 49% and 13% of patients, respectively. The proportion of treatment-naïve patients (100% vs. 78%; p=0.032) and patients with liver cirrhosis (31% vs. 8%; p=0.025) was higher in patients with a contraindication for triple-therapy than in patients without contraindications.

Necessity of a cART switch prior to the initiation of triple-therapy

Based on the above-mentioned criteria, cART switch or TPV dose modification would have been necessary in 38 (61%) and 52 (84%) of 62 patients on cART eligible for triple-therapy using TPV and BOC, respectively. If the DAA would have been chosen based on the DDI profile, changes of cART or TPV dose modification would have been performed in 37 (60%) of patients prior to the initiation of triple-therapy.

Case series of patients with CHC and RVR who received only 28 weeks of BOC-based triple-therapy

In all four CHC patients, a cART switch to TDF/FTC/RAL prior to the initiation of triple-therapy was necessary (Table 2). Median CD4+T-lymphocyte counts were 960, 293, 663, and 499 cells μL⁻¹ and none of the patients was treatment-naïve. HCV-GT1a was observed in three patients and one patient (Patient A) was infected with HCV-GT1b. While one patient was IL28B C/T (Patient C), three patients were harboring the IL28B C/C genotype. The baseline liver stiffness values were 4.7, 13, 5.4, and 5.7 kPa.

Table 2.

Baseline Characteristics and Outcome of Patients with CHC with RVR and 28 Weeks of BOC-Based Triple-Therapy

Patient characteristics	Patient A	Patient B	Patient C	Patient D
HIV infection parameters
CD4+T-lymphocyte count (cells μL⁻¹)	960	293	663	499
cART	TDF/FTC/RAL	TDF/FTC/RAL	TDF/FTC/RAL	TDF/FTC/RAL
HCV infection parameters
Treatment-naive	no	no	no	no
HCV-GT	1b	1a	1a	1a
HCV-RNA (log IU mL⁻¹)	7.46	6.79	6.42	6.89
IL28B	C/C	C/C	C/T	C/C
Liver stiffness (kPa)	4.7	13	5.4	5.7
Virologic response
W4 HCV-RNA (log IU mL⁻¹)	5.72	1.92	2.03	1.9
W8 HCV-RNA	TND	TND	TND	TND
W12 HCV-RNA	TND	TND	TND	TND
W28 HCV-RNA	TND	TND	TND	TND
FU12 HCV-RNA	TND	TND	TND	TND
FU24 HCV-RNA	TND	TND	TND	TND

BOC, boceprevir; cART, combined antiretroviral therapy; CHC, chronic hepatitis C; FTC, emtricitabine; FU, follow-up week; GT, genotype; HCV, hepatitis C virus; IL28B, interleukin 28B rs12979860 SNP; RAL, raltegravir; RVR, rapid virologic response; TDF, tenofovir disoproxil fumarate; TND, target not detectable; W, treatment week.

All patients had TD HCV-RNA at treatment week 4, with HCV-RNA levels of 5.72, 1.92, 2.03, and 1.9 log IU mL⁻¹, and were TND at treatment week 8. HCV treatment was discontinued at treatment week 28 in three patients because of adverse events. Patient A had an abscess in the gastrocnemius muscle requiring surgery. Patient B and C suffered from anemia, fatigue, and depression, while in patient D, nausea and vomiting were the treatment-limiting adverse events.

Neutropenia and anemia was treated with granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) analogues in three patients, while patient D did not require hematologic growth factors. RBV dose reductions were performed in patient B and C, while the dose of PEGIFN was reduced in patient A. All four patients had a SVR12 and SVR24.

Discussion

Among 440 HIV-positive patients with positive HCV serology, only 290 had at least one visit at the outpatient clinic over the past 2 years, although intended visits were scheduled in 3-month intervals. Thus, low adherence to clinical visits and poor compliance to cART are major limiting factors for treatment uptake in our cohort of HIV/HCV co-infected patients. In addition, currently available DAAs are restricted to HCV-GT1. Only 64 (45%) HIV/HCV co-infected patients were eligible for treatment with triple-therapy, resulting in a potential to cure HCV infection in 43 (29%) of all 142 HIV/HCV co-infected patients cared for at the center. However, this may still be an overoptimistic estimation, since it does not take the proportion of patients refusing CHC therapy into account. While this proportion is unknown for triple-therapy, a refusal rate of 23% among eligible HIV/HCV co-infected patients has been reported for dual-therapy.³² As triple therapy was only initiated in 25 (39%) of 64 eligible patients, considerably high refusal rates may be assumed. These observations confirm a previous prediction based on a Spanish cohort of HIV/HCV co-infected patients that the benefit of DAA-based triple-therapy might be lower than initially expected.³³

A higher proportion of patients with insufficiently controlled HIV infection and a lower mean CD4+T-lymphocyte count was observed among patients with a contraindication for triple-therapy. Moreover, low CD4+T-lymphocyte count was the most common contraindication for triple-therapy in our cohort. Thus, the central role of cART in the management of HIV/HCV co-infected patients should be considered. DDIs significantly limit access to DAA-based triple-therapy, in particular when HIV protease inhibitors (PIs) are used. In our cohort, 39 (63%) of 62 patients on cART who were eligible for DAA-based triple-therapy were on HIV PI-based cART regimens. In contrast, Marks and co-workers³⁴ recently reported considerably lower rates of HIV PI use in their cohort of HIV/HCV-GT1 co-infected patients. While BOC should not be administered with any HIV PI, TPV can be used with atazanavir. When the necessity of a dose modification of TPV administered with EFV and other relevant DDIs is considered, cART switch or TPV dose modification would have been necessary in 38 (60%) and 52 (83%) of 63 patients on cART eligible for triple-therapy, using TPV and BOC, respectively. Choosing DAA based on DDI profile would most likely not have reduced the necessity of cART changes. Thus, the impact of DDIs with cART varies throughout different cohorts of HIV/HCV-GT1 co-infected patients and may significantly depend on local cART practice. Nevertheless, DDIs with cART complicate patient management in the majority of patients and require considerable expertise in the treatment of both HIV and HCV infection.

Interestingly, all patients with a contraindication were naïve to dual-therapy. This might be explained by the similarity of contraindications for dual-therapy and triple-therapy. Together with the fact that a high proportion of patients with contraindications have liver cirrhosis, it might be concluded that a relevant proportion of patients will not benefit from triple-therapy, even among HIV/HCV-GT1 co-infected patients attached to an outpatient clinic.

Response-guided therapy of CHC with triple-therapy is the standard of care in HCV-GT1-monoinfected patients. Based on the results of the SPRINT-2 trial, both US and European label of BOC recommend a shortening of treatment duration in treatment-naïve patients with TND HCV-RNA at treatment week 8.¹³ In patients with prior relapse or partial response, the FDA recommends a shortening of treatment duration to 36 weeks based on the RESPOND-2 trial.¹⁴ While the concept of response-guided therapy has been established for dual-therapy in HIV/HCV co-infected patients,³⁵ the two studies of triple-therapy with TPV¹⁵ and BOC¹⁶ to date used a 48-week treatment duration.

None of our four CHC patients with 28 weeks of BOC-based triple-therapy was treatment-naïve and every patient displayed at least one unfavorable baseline characteristic such as HCV-GT1a, high HCV-RNA, IL28B non-C/C, or advanced liver fibrosis.^35
–37 While none of our patients displayed TND HCV-RNA at week 4 of lead-in, all patients had a RVR. Although BOC-based triple-therapy had to be discontinued due to adverse events at treatment week 28, all four patients had SVR12. Thus, our findings, together with the evidence derived from studies in HCV-monoinfected patients, suggest that 28 weeks of BOC-based triple-therapy may be sufficient for HIV/HCV-GT1-co-infected patients with RVR. Prospective trials, such as the HIVCOBOC-RGT trial (NCT01925183) are highly encouraged to confirm our observations.

In conclusion, our study demonstrates that in HIV/HCV co-infected patients, treatment uptake with triple-therapy is limited by low adherence to clinical visits and poor compliance to cART, as well as the restriction to HCV-GT1. Insufficiently controlled HIV infection and liver cirrhosis were overrepresented among patients with contraindications for triple-therapy and DDIs with cART complicate patient management in the majority of patients. The low rates of treatment uptake during the first 2 years of triple-therapy availability suggest that its benefit among HIV/HCV co-infected patients might fall short of expectations. Prospective studies are necessary to validate our observations on the shortening of treatment duration in patients with HIV/HCV-GT and RVR.

Footnotes

Acknowledgments

Contributions: Study concept and design (MM, BAP, AN, MT, MP, and TR); acquisition of data (MM, BAP, AN, GL, MCA, RS, CB, AR, and TR); analysis and interpretation of data (MM and TR); drafting of the article (MM and TR), critical revision of the article for important intellectual content (MM, BAP, AN, GL, MCA, RS, CB, AR, MT, MP, and TR)

Funding: No funding specific to this study was received.

Author Disclosure Statement

MM, BAP, RS, MT, MP, and TR received travel support from Roche. BAP and TR received speaking fees from Roche. CB received consulting fees from Roche. MP received consulting fees and a grant from Roche. MM, MCA, and TR received travel support from MSD. CB received consulting fees from MSD. MT and MP received grants from MSD. BAP and MCA received travel support from Janssen. MM, CB, and MP received consulting fees from Janssen. For the remaining authors, none were declared.

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