Response-Guided Boceprevir-based Triple Therapy in HIV/HCV-coinfected Patients: The HIVCOBOC-RGT Study
Response-Guided Boceprevir-based Triple Therapy in HIV/HCV-coinfected Patients: The HIVCOBOC-RGT Study
Mattias Mandorfer 1 2 3
Sebastian Steiner 1 2 3
Philipp Schwabl 1 2 3
Berit A. Payer 1 2 3
Maximilian C. Aichelburg 0 1 2
Gerold Lang 0 1 2
Katharina Grabmeier-Pfistershammer 0 1 2
Michael Trauner 2 3
Markus Peck-Radosavljevic 1 2 3
Thomas Reiberger () 1 2 3
0 Division of Immunology , Allergy and Infectious Diseases , Department of Dermatology, Medical University of Vienna , Austria
1 Vienna HIV & Liver Study Group
2 Received 13 July 2014; accepted 29 August 2014; electronically published 11 September 2014. atology, Department of Internal Medicine III, Medical University of Vienna , Waeh- ringer Guertel 18-20, 1090 Vienna , Austria
3 Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna
Background. The HIVCOBOC-RGT study (NCT01925183) was the first study to evaluate response-guided shortening of the duration of boceprevir (BOC)-based triple therapy in human immunodeficiency virus (HIV)/ hepatitis C virus genotype 1-coinfected patients (HIV/HCV-GT1). Methods. After 4 weeks of pegylated interferon-α-2a/ribavirin (PEGIFN/RBV) lead-in, patients with targetnot-detectable HCV-RNA at week 8 (rapid virologic response; LI4W-W8UTND) received 24 weeks of BOC/PEGIFN/RBV (total: 28 weeks [W28]). Patients with target-detectable HCV-RNA at week 8 received 44 weeks of BOC/PEGIFN/RBV (total: 48 weeks [W48]). Results. Fourteen patients (67%) had LI4W-W8UTND and were eligible for the shortened W28 arm, while 7 (33%) patients were allocated to the W48 arm. No breakthrough or relapse occurred in the W28 arm, resulting in a sustained virologic response (SVR12TND) rate of 100% (12/12). In the W48 arm, the SVR12TND was 50% (3/ 6), with 3 patients meeting the futility rule at treatment week 12. The preliminary overall SVR12TND rate was 83% (15/18). Serious adverse events were observed in 5 (24%) patients, with 2 (10%) patients requiring surgical treatment of abscesses. Conclusions. The majority of HIV/HCV-GT1 were eligible for response-guided shortening of treatment duration to W28 and all of these patients had a SVR12TND. If second-generation direct-acting antivirals are not available, W28 of BOC-based triple therapy may be recommended.
antiviral agents; boceprevir; hepatitis C; HIV; response-guided therapy
Liver disease is the second leading cause of death in
patients infected with human immunodeficiency virus
]. When compared to hepatitis C virus (HCV)
monoinfection, HIV/HCV coinfection, observed in
25%–30% of European and US-American HIV-positive
], was found to be associated with high rates
of liver fibrosis progression [
] and markedly higher
risks of cirrhosis and end-stage liver disease . As
successful treatment of chronic hepatitis C is associated
with a reduced risk for hepatic decompensation,
liverrelated, nonliver-related, and overall mortality [
HIV/HCV-coinfected patients, optimizing antiviral
therapy is of highest priority.
Throughout the last decade, the efficacy of
dualtherapy with pegylated interferon plus ribavirin
(PEGIFN/RBV) in HIV-positive patients has improved
as a result of the individualization of treatment by
response-guided therapy (RGT) [
especially in patients coinfected with the highly prevalent
HCV-genotype (HCV-GT)1, efficacy of PEGIFN/RBV
remained unsatisfactory, as underlined by a recent
large, multicenter study with sustained virologic
response (SVR24TND) rates as low as 21% [
The approval of first-generation direct-acting
antiviral agents (DAAs), telaprevir (TVR) and boceprevir
(BOC), has ushered in a new era in the treatment of HCV-GT1–
infected patients [
]. Recently published phase IIa studies of
triple therapy with TVR [
] and BOC [
] in combination
with PEGIFN/RBV in treatment-naive HIV-positive
individuals demonstrated substantially improved efficacy. While
BOCbased triple therapy was found to be associated with additional
side effects, as well as with an increase in the frequency and
severity of established dual-therapy side effects [
HCV-monoinfected patients, evidence from HIV-positive
patients is very limited.
The practicability of response-guided triple therapy with TVR
] and BOC [
] in HCV-monoinfected patients has previously
been established. Based on the results of the SPRINT-2 trial [
both the US and European label of BOC recommend a
shortening of treatment duration in treatment-naive HCV-monoinfected
patients with target-not-detectable (TND) HCV-RNA at
treatment week 8, including a 4-week PEGIFN/RBV lead-in phase
(rapid virologic response; LI4W-W8UTND). However, while
RGT is currently used to individualize the duration of dual
therapy in HIV-positive patients [
], response-guided triple therapy
has not been investigated in this special population. Thus, current
European AIDS Clinical Society (EACS) guidelines [
recommend a fixed duration of 48 weeks of TVR/BOC-based triple
therapy for HIV/HCV-GT1, similar to the 2 published studies
on triple therapy in HIV-positive patients [
]. However, a
recently published case series suggests that a total treatment
duration of 28 weeks of BOC-based triple therapy might be
sufficient in HIV/HCV-GT1 with LI4W-W8UTND .
The HIVCOBOC-RGT study evaluated the concept of
response-guided shortening of the duration of BOC-based triple
therapy in HIV/HCV-GT1.
PATIENTS AND METHODS
Study Design and Patients
Twenty-one HIV/HCV-GT1 were treated according to the
HIVCOBOC-RGT study protocol (NCT01925183). The
HIVCOBOC-RGT study was conducted at a tertiary center and
the inclusion period was 1 year. In brief, inclusion requirements
were: HIV infection with a CD4+ T-lymphocyte (CD4+) count
>200 cells/µL and HIV-RNA <50 copies/mL on combined
antiretroviral therapy (cART) with tenofovir/emtricitabine and
raltegravir. Moreover, chronic infection with HCV-GT1,
targetdetectable HCV-RNA for more than 6 months, and a valid
liver stiffness measurement or liver biopsy within 6 months
prior to the enrollment were required. Patients coinfected
with a HCV-GT other than HCV-GT1, patients with
decompensated cirrhosis, and those with chronic liver disease other
than hepatitis C were excluded. Further, ongoing alcohol
abuse (defined as average daily alcohol consumption >50 g);
ongoing intravenous drug use; or significant cardiac, pulmonary,
or renal disease were defined as exclusion criteria.
The nomenclature proposed by the Definitions/Nomenclature
Working Group of the HCV Drug Development Advisory
Group was adopted in reporting of virologic response [
Patients were treated with pegylated interferon-α-2a (180 µg) once
a week and weight-based RBV doses ranging from 1000 to 1200
mg daily. After 4 weeks of PEGIFN/RBV lead-in (LI4W-W4),
BOC was added (800 mg 3 times daily). Patients with
LI4WW8UTND received 24 weeks of BOC/PEGIFN/RBV (total: 28
weeks [W28]), while patients with target-detectable
HCVRNA at treatment week 8 (LI4W-W8) received 44 weeks of
BOC/PEGIFN/RBV (total: 48 weeks [W48]) (Figure 1).
Treatment was discontinued due to futility rules in patients with
HCV-RNA >100 IU/mL at treatment week 12 (LI4W-W12) or
target-detectable HCV-RNA at treatment week 24 (LI4W-W24).
Interleukin 28B and Liver Stiffness Measurement
The interleukin 28B (IL28B) rs12979860 single nucleotide
polymorphism (SNP) was analyzed as previously described [
Measurement of liver stiffness was performed by transient
elastography, as previously described [
]. Significant liver fibrosis
and cirrhosis were defined as liver stiffness values ≥7.2 kPa and
≥14.6 kPa, respectively [
Standard laboratory tests were used to assess hematological and
biochemical parameters. 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]). The lower limits of
quantification/detection were 15 IU/mL and 20 copies/mL for
HCV and HIV, respectively. High HCV-RNA was defined as
baseline HCV-RNA level >6 × 105 IU/mL [
Primary Efficacy and Safety Endpoints
The primary efficacy endpoint was sustained virologic response,
defined as TND HCV-RNA 12 weeks after the end of treatment
(SVR12TND), while the incidence of adverse events (AEs) and
serious adverse events (SAEs) was the primary safety endpoint.
In addition, we assessed hematologic abnormalities,
erythropoietin and granulocyte colony-stimulating factor analogue
administration, blood transfusions, and the rate of treatment
discontinuation due to AEs. Intention-to-treat analysis was
applied to assess the primary outcome, SVR12TND, as well as
Statistical analyses were performed using IBM SPSS Statistics 21
(SPSS Inc, Chicago, Illinois). Continuous variables were
reported as mean ± standard deviation or median (interquartile range),
while categorical variables were reported as number of patients
with ( proportion of patients with) the certain characteristic.
Student 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 Fisher exact test. A P value ≤ .05 was
considered as statistically significant.
Sensitivity and specificity were calculated using the MedCalc
MedCalc Software, Ostend, Belgium).
Ethics and Clinical Trial Registration
This study was conducted with written informed consent from
each participant and was approved by the local ethics
committee of the Medical University of Vienna (number: 2055/2012).
The “Individualized Triple-therapy Using Boceprevir in
HIVpositive Patients With Hepatitis C (HIVCOBOC-RGT)” study
was registered at EudraCT (number: 2012-005591-33) and
ClinicalTrials.gov (identifier: NCT01925183).
Study Population and Patient Characteristics
All patients screened and eligible for this study were included.
Two patients were screened but ineligible, as cART could not
be changed to tenofovir/emtricitabine and raltegravir in these
patients. The majority of patients were male (76%) with a
mean age of 39.1 ± 8.9 years. All patients were on cART
(tenofovir/emtricitabine plus raltegravir) with a mean CD4+ count of
545 ± 193 cells/µL (Table 1). Seventy-one percent were
treatment-naive, while 29% of patients had a relapse after a prior
course of dual therapy. No prior partial or null responders
were included in this study. None of the patients had previously
received TVR/BOC-based triple therapy or any other
DAAbased treatment. The majority of patients were infected with
subtype 1a (86%), while 14% had subtype 1b. The mean
HCV-RNA level was 6.64 ± 0.71 log IU/mL, with 86% of
patients having high HCV-RNA. The distribution of IL28B
rs12979860 SNP genotypes was: C/C, 29%; C/T, 48%; and
T/T, 24%. Thirty-eight percent of patients had significant liver
fibrosis, while no patient had cirrhosis.
Rates of LI4W-W8UTND, SVR12TND and their Predictors
While information on LI4W-W8UTND was available in all
patients, patients who are still on treatment or in the follow-up
period were not considered for the SVR12TND analysis.
Fourteen patients (67%) had LI4W-W8UTND and were
eligible for the shortened W28 arm, while 7 (33%) patients were
allocated to the W48 arm (Figure 1).
All patients (100% [12/12]) in the W28 arm achieved a
SVR12TND. In the W48 arm, the SVR12TND rate was (50%
[3/6]), as 3 patients met the treatment-week 12 futility rule,
resulting in an overall SVR12TND rate of 83% (15/18) (Table 1,
Supplementary Figure 1).
None of the baseline characteristics was predictive of
LI4WW8UTND or SVR12TND. However, LI4W-W8UTND was
associated with a higher rate of SVR12TND (W28: 100% vs W48: 50%;
P = .025), although treatment duration was shortened to W28 in
these patients (Table 1).
None of the patients had TND HCV-RNA at the end of the
PEGIFN/RBV lead-in phase (LI4W-W4UTND), as HCV-RNA
was quantifiable in all patients (LI4W-W4Q). HCV-RNA levels
at the end of the PEGIFN/RBV lead-in phase (treatment week 4;
LI4W-W4) were lower in patients with (2.79 ± 1.52 log IU/mL),
when compared to patients without LI4W-W8UTND (5.98 ±
1.48 log IU/mL; P < .001) (Table 1, Supplementary Figure 1).
Moreover, a more pronounced viral load decline at LI4W-W4
was observed among patients who achieved LI4W-W8UTND
(LI4W-W8UTND: −3.78 ± 1.35 vs No-LI4W-W8UTND: −0.795 ±
1.107 log IU/mL; P < .001). None of the 5 patients with a viral
load decline at LI4W-W4 of less than −1.74 log IU/mL
(LIW4W4Q[<−1.74]) had LI4W-W8UTND (sensitivity: 71%;
specificity: 100%) (Table 2). In contrast, all of the 11 patients with a
viral load decline at LI4W-W4 above −2.55 log IU/mL
(LI4WW4Q[>−2.55]) had LI4W-W8UTND (sensitivity: 79%; specificity:
100%). Among 5 patients with a viral load decline of −1.74 to
−2.55 log IU/mL, 3 (60%) patients had LI4W-W8UTND.
Safety and Tolerability
All patients had at least 1 AE, while SAEs occurred in 5 (24%)
patients. Two patients (10%) were hospitalized due to surgical
treatment of abscesses. Another AE related to bacterial
infections was cellulitis in 3 cases (14%). These patients were treated
with oral antibiotics as outpatients and their AEs were classified
as nonserious. Moreover, the following SAEs were observed:
Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus; LI4W-W4, treatment week 4; LI4W-W8UTND, target-not-detectable HCV-RNA at treatment
week 8; n.s., not statistically significant; SNP, single nucleotide polymorphism; SVR12TND, sustained virologic response; W28, 28 weeks of treatment duration; W48,
48 weeks of treatment duration.
a Available in 18 patients.
One patient underwent appendectomy for acute appendicitis
during the follow-up period, 1 patient was hospitalized due to
general disability, and 1 patient was hospitalized due to a
preexisting medical condition.
Except for the 2 previously mentioned patients requiring
surgical treatment of abscesses, no treatment discontinuations due
to AEs occurred. One of these patients had a SVR12TND. In the
other patient, the SAE occurred simultaneously to LI4W-W12
and the patient met the LI4W-W12 futility rule at the time of
Grade 3/4 hematologic abnormalities were observed in 5
(24%) patients, while 9 (43%) patients developed a CD4+ count
<200 cells/µL. PEGIFN and RBV dose reductions were necessary
in 1 (5%) and 10 (48%) patients, respectively. Erythropoietin
and granulocyte colony-stimulating factor analogues were
administered in 7 (33%) and 6 (29%) patients, respectively, and
2 (10%) patients received blood transfusions.
As response-guided TVR/BOC-based triple therapy has not
been investigated in HIV-positive patients, current EACS
] recommend a fixed duration of W48 of
TVR/BOCbased triple therapy [
]. However, this may be a pragmatic
recommendation arising from the absence of studies
investigating individualized treatment. Previous studies on triple therapy
in HIV-positive restricted to treatment-naive patients reported
SVR12TND rates ranging of 63%  and 74% [
], which are
very similar to the rates observed in treatment-naive,
HIVnegative patients [
]. Thus, DAAs may allow overcoming
the diminishing effect of HIV coinfection on virologic response
to interferon-based therapies, challenging the therapeutic
paradigm of extended therapy duration in this special population
In our study, the majority of HIV/HCV-GT1 achieved
LI4WW8UTND and were eligible for response-guided shortening
of treatment duration to W28. All of these patients had an
SVR12TND, although this treatment arm comprised a
substantial proportion of patients with negative baseline predictors of
response to triple therapy [
], including a significant
proportion of treatment-experienced patients, as well as patients
with HCV-subtype 1a, high HCV-RNA, IL28B non-C/C
genotype, and significant liver fibrosis. Thus, if second-generation
DAAs are not available, W28 of BOC-based triple therapy
may be recommended for HIV/HCV-GT1 with LI4W-W8UTND.
Previous studies demonstrated excellent efficacy of dual
therapy in patients with TND HCV-RNA at W4 (W4UTND)
]. Thus, in this subgroup, which accounts for about a
quarter of HIV/HCV-GT1, the additional benefit of DAAs in
terms of efficacy appears negligible. Interestingly, a recent
meta-analysis suggests that in HCV-monoinfected patients
with W4UTND, dual therapy may be even more effective .
Nevertheless, the use of BOC-based response-guided triple
therapy allows for substantial shortening of treatment duration
when compared to dual therapy, as a treatment duration of W48
is recommended in HIV/HCV-GT1 with W4UTND [
However, it is unclear whether the benefits of shortening treatment
duration to W28 outweigh the additional, BOC-related side
] in these patients.
Nevertheless, in patients without LI4W-W4UTND but with
LI4W-W8UTND (who accounted for 67% of our study population),
response-guided shortening of the duration of BOC-based
triple therapy may reduce the strain associated with antiviral
], as treatment regimens such as 72 weeks of dual
therapy or W48 of TVR/BOC-based triple therapy are
recommended in this subgroup [
]. However, our study did not have
sufficient statistical power to detect clinically relevant
differences in safety and tolerability between the treatment arms.
Interestingly, while none of the baseline characteristics was
associated with LI4W-W8UTND, we observed a significant
difference in viral load decline at LI4W-W4 between patients with
LI4W-W8UTND, and without. All patients with LI4W-W4Q
[>−2.55] had LI4W-W8UTND. This value is very similar to a
previously established cut-off for the identification of
HIV/HCVGT1 with a good responsiveness to dual therapy [
the utility of a lead-in phase for assigning patients to dual
therapy or TVR/BOC-based triple therapy should be emphasized,
and viral kinetics during the lead-in phase may allow for early
identification patients eligible for response-guided shortening
of treatment duration to W28.
Importantly, none of the patients in our study had
LI4WW4UTND, which might be attributed to the high prevalence of
negative baseline characteristics. This suggests that no
easy-totreat patients with a presumably high responsiveness to
interferon-based therapies were included.
Information on safety of BOC-based triple therapy in
HIVpositive patients is very limited. In our study, hematologic side
effects were generally well managed by dose reduction of
PEGIFN or RBV and the use of hematologic growth factors.
Blood transfusions were necessary in only 2 patients and no
treatment discontinuation due to hematologic side effects was
observed. However, we observed SAEs related to bacterial
infections, requiring treatment discontinuation in 2 out of 21
patients. In addition, 3 cases of nonserious AEs due to bacterial
infection were documented in our study. Importantly, all of
the patients in our study had preserved immune status and
suppressed HIV-RNA, and did not have liver cirrhosis. In the
ANRS-HC27 BocepreVIH study [
] investigating BOC-based
triple therapy in HIV-positive treatment-experienced patients,
treatment discontinuation due to bacterial infections occurred
only in 3 out of 64 patients, although 17% of patients included
in this study had cirrhosis. However, similar to our study, SAEs
related to bacterial infections (abscess/cellulitis, pneumonia,
and sepsis) in patients without cirrhosis were reported. Thus,
in HIV-positive patients, there might be high susceptibility
for severe infectious complications during BOC-based triple
therapy, which is not limited to patients with cirrhosis and
additional risk factors [
]. As bacterial infections may occur at
any time point during antiviral therapy , the cumulative risk
might rise with longer treatment durations. This provides an
additional argument in favor of response-guided shortening
of therapy duration.
Our findings, although limited by the small number of
patients included in this study, provide important evidence for
the individualization of triple therapy in HIV/HCV-GT1. As
the availability of second-generation DAAs and
interferonfree regimens is steadily increasing, it must be assumed that
further prospective studies on triple therapy in HIV/HCV-GT1
will be rare. However, second-generation DAAs are not widely
available and health insurance coverage of these upcoming
regimens is limited, so triple therapy will continue to play a central
This is the first study to validate the concept of
responseguided shortening of the duration of BOC-based triple therapy
in HIV/hepatitis C genotype 1-coinfected patients (HIV/
HCV-GT1). In summary, the majority of HIV/HCV-GT1
were eligible for response-guided shortening of treatment
duration to 28 weeks (W28), and all of these patients had a
sustained virologic response (SVR12TND). We observed 2 SAEs
related to bacterial infections despite preserved immune status
and the absence of cirrhosis. If second-generation
directacting antivirals are not available, W28 of BOC-based triple
therapy should be recommended for HIV/HCV-GT1 with
Supplementary materials are available at The Journal of Infectious Diseases
online (http://jid.oxfordjournals.org). Supplementary materials consist of
data provided by the author that are published to benefit the reader. The
posted materials are not copyedited. The contents of all supplementary
data are the sole responsibility of the authors. Questions or messages
regarding errors should be addressed to the author.
Acknowledgments. Study concept and design (M. M., M. P. and T. R.),
acquisition of data (M. M., S. S., S. P., B. A. P., M. C. A., G. L., K. G. and
T. R.), statistical analysis (M. M.), interpretation of data (M. M., S. S.,
S. P., B. A. P., M. C. A., G. L., K. G., M. T., M. P. and T. R.), drafting of
the manuscript (M. M. and T. R.), critical revision for important intellectual
content and approval of the final version of the manuscript (M. M., S. S.,
S. P., B. A. P., M. C. A., G. L., K. G., M. T., M. P. and T. R.).
Financial support. This work was supported by MSD Sharp & Dohme
Potential conflicts of interest. M. M. received honoraria for consulting
from Janssen; payments for lectures from Boehringer Ingelheim,
BristolMyers Squibb, Janssen, and Roche; as well as travel support from MSD
and Roche. P. S. received payments for lectures from Roche and travel
support from Janssen and Roche. B. A. P. received honoraria for consulting
from MSD, payments for lectures from Roche, and travel support from
Janssen and Roche. M. C. A. received honoraria for board membership and
consulting from Gilead and MSD; and travel support from AbbVie, Gilead, and
MSD. K. G. received honoraria for consultancy from Gilead; payments for
lectures from Bristol-Myers Squibb and ViiV; as well as travel support from
Bristol-Myers Squibb, Gilead, and GlaxoSmithKline. M. T. received
payments for lectures from Gilead, MSD, and Roche; and travel support from
Gilead. M. P. received grants from Gilead, MSD, and Roche; honoraria for
board membership and consultancy from AbbVie, Bristol-Myers Squibb,
Gilead, Janssen, and MSD; as well as payments for lectures from Gilead,
MSD, and Roche. T. R. received travel support from MSD and Roche as
well as payments for lectures from Roche. All other authors report no
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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