MAJOR ARTICLE
HIV/AIDS
Interferon-Ribavirin in Association
with Stavudine Has No Impact on Plasma
Human Immunodeficiency Virus (HIV) Type 1
Level in Patients Coinfected with HIV and
Hepatitis C Virus: A CORIST-ANRS HC1 Trial
Dominique Salmon-Céron,1 Régis Lassalle,4 Alain Pruvost,5 Henri Benech,5 Magali Bouvier-Alias,6
Christopher Payan,7 Cécile Goujard,8 Eric Bonnet,9 Fabien Zoulim,10 Philippe Morlat,11 Philippe Sogni,2
Sophie Pérusat,4 Jean-Marc Tréluyer,3 Geneviève Chêne,4 and the CORIST-ANRS HC1 Study Groupa
1
Department of Internal Medicine, Cochin–Saint Vincent de Paul Hospital, 2Department of Hepatology, Cochin Hospital, and 3Department of
Pharmacology, Cochin–Saint Vincent de Paul Hospital, Paris, 4INSERM Unit 330, Victor Segalen University, Bordeaux, 5CEA, Pharmacology and
Immunology Unit, DSV/DRM, CEA/Saclay, Gif-sur-Yvette, 6Department of Virology, Henri Mondor Hospital, Creteil, 7Department of Virology, Angers
Hospital, Angers, 8Department of Internal Medicine, Bicêtre Hospital, Kremlin-Bicêtre, 9Department of Infectious Diseases, Purpan Hospital,
Toulouse, 10Department of Hepatology, Lyon Hospital, Lyon, and 11Department of Internal Medicine, Saint-André Hospital, Bordeaux, France
A randomized, open-label trial was performed to study virological and intracellular interactions between
stavudine and ribavirin in 30 patients coinfected with human immunodeficiency virus (HIV) and hepatitis C
virus (HCV). Patients were randomized to receive either interferon and ribavirin or no treatment for HCV
infection for 3 months. Intracellular peripheral blood mononuclear cells’ stavudine-triphosphate (TP) concentrations were assessed. Plasma HIV RNA levels did not change significantly between baseline and month
3. There was a nonstatistically significant trend for a lower median residual concentration of intracellular
stavudine-TP in the treated group, compared with the control group. The same trend was also observed for
peak concentrations. Coprescription of ribavirin and stavudine has no short-term impact on plasma HIV RNA
level in HIV-HCV–coinfected patients treated with stavudine as a part of their antiretroviral treatment; this
coprescription can be safely used, although an in vivo interaction between ribavirin and stavudine is possible.
Hepatitis C virus (HCV) infection is one of the most
frequent viral coinfections in HIV-infected patients.
Received 14 August 2002; accepted 1 January 2003; electronically published
9 May 2003.
Presented in part: 3rd International Symposium on HCV Disease, September
2001, and 8th European Conference on Clinical Aspects and Treatment of HIV
Infection, Athens, Greece, October 2001.
Financial support: French Agency for Research on AIDS, Agence Nationale de
Recherches sur le Sida (ANRS)–Essai HC01; Bristol-Myers Squibb Laboratories;
Schering-Plough.
a
Members of the study group are listed at the end of the text.
Reprints or correspondence: Dr. Dominique Salmon-Céron, CHU COCHIN,
Assistance Publique, Hôpitaux de Paris, 27, rue du Faubourg Saint Jacques, 75014
Paris-France ([email protected])
Clinical Infectious Diseases 2003; 36:1295–304
2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3610-0014$15.00
The prevalence of HCV antibodies in patients infected
with HIV is 30% on average [1–3]. Although the prognosis for HIV-infected patients has dramatically improved in the past 5 years, since the introduction of
HAART, end-stage liver disease related to HCV infection has become one of the main causes of death among
HIV-HCV–coinfected patients [4–6]. This emphasizes
the need for an efficacious and safe treatment for HCV
infection in HIV-infected patients. However, an in vitro
antagonism has been reported between the drugs indicated for the 2 infections—that is, between ribavirin
and thymidine nucleoside analogues, such as zidovudine [7] and stavudine [8]. Indeed, in vitro, ribavirin
induces a decrease in the phosphorylation of zidovudine and stavudine [9–11]. This is a consequence of an
increased production of deoxythymidine triphosphate
HIV/AIDS • CID 2003:36 (15 May) • 1295
(dT-TP) [7, 10], which induces, by feedback, a decrease of the
thymidine kinase activity. A few observational studies described
no effect of interferon-ribavirin on plasma HIV-1 RNA level
when HIV-HCV–coinfected patients were treated with zidovudine or stavudine [12–14]. However, no formal randomized
study has been performed to date, and no measurement of
intracellular concentrations of the active triphosphorylated
principle stavudine-TP or zidovudine-TP was available.
Therefore, we studied the effects of initiating treatment containing ribavirin on plasma HIV-1 RNA levels and intracellular
pharmacological parameters in a randomized, controlled trial
including HIV-HCV–coinfected patients treated with an antiretroviral regimen containing stavudine.
PATIENTS AND METHODS
Patients. Adult patients were eligible for enrollment in the
study if they tested positive for anti-HIV antibodies, tested
positive for anti-HCV antibodies by second-generation ELISA
and for HCV RNA by PCR, were aged ⭐65 years, had a CD4+
cell count of ⭓200 cells/mL and a plasma HIV-1 RNA level of
⭐3000 copies/mL for ⭓3 months before randomization, had
been receiving stable antiretroviral treatment including stavudine for ⭓3 months, had interpretable results of liver biopsy
revealing at least mild to moderate activity (according to the
METAVIR or the KNODELL scoring system), and were able to
provide written informed consent.
Patients were not eligible for inclusion if they had decompensated cirrhosis; if they had received prior treatment containing ribavirin and interferon, unless it had been stopped ⭓6
months before randomization; if they had autoimmune, tumoral, biliary, or vascular-associated liver disease; if they had
a hemoglobin level of !12 g/dL and a serum creatinine level
of 1150 mM; if they had psychiatric conditions or seizure disorders; and if they used injection drugs actively; or if they
were pregnant or displayed no evidence of use of effective
contraception.
Study design and treatment regimen. This 3-month study
was a multicenter, randomized, open-label, phase 2 trial. Two
groups of patients receiving stavudine in their usual antiretroviral treatment and having an indication of anti-HCV treatment were randomized either to immediately begin receiving
treatment with interferon-ribavirin or to postpone interferonribavirin therapy for 3 months. Seventeen hospital centers in
France participated in this trial. Patients were randomized centrally at the Central Data Center (INSERM Unit 330) following
a computer-generated random-number list to 1 of the 2 treatment groups. The randomization was stratified according to
the clinical center. At the end of the study, treated patients
could continue to receive interferon-ribavirin therapy, and pa-
1296 • CID 2003:36 (15 May) • HIV/AIDS
tients included in the control group could initiate this treatment. The study was approved by the ethics committee of the
Cochin Hospital and the Institutional Review Board of the
Agence Nationale de Recherches sur le SIDA (ANRS; Paris,
France).
Ribavirin (Rebetol; Schering-Plough) was provided orally
twice per day at a total dosage of 1000 mg (for patients with
a body weight of !75 kg) or 1200 mg (for those with a body
weight of ⭓75 kg) per day, and interferon (Introna; ScheringPlough) was provided subcutaneously at 3 MU 3 times per
week. During follow-up, adverse events were graded in severity
from 1 to 4, in accordance with the grading scheme used in
the studies sponsored by the ANRS [15]. For severe adverse
events other than anemia, the dosage of interferon was reduced
to 1.5 MU 3 times per week. The dosage of ribavirin was
reduced to 600 mg per day for patients whose hemoglobin
concentration decreased to !10 g/dL, and it was discontinued
if the concentration decreased to !8.5 g/dL.
Follow-up. Clinical, laboratory, and virological data were
collected at a screening visit ⭐14 days before randomization,
on the day of randomization (baseline), each week during the
first month, and then monthly until month 3. Routine followup included complete physical examination, peripheral blood
cell counts, biochemical profile, and liver function tests. Intracellular stavudine-TP concentrations were measured at
baseline and at months 1 and 3. Measurement was performed
before (trough) and 3 h after (peak) stavudine intake. HIV1 RNA levels, CD4+ cell counts, and HCV RNA levels were
also recorded 12 months after randomization.
Laboratory measurements.
The plasma level of HIV-1
RNA was determined with an ultrasensitive PCR assay (Ultrasensitive Simplicor HIV-1 Monitor 1.5; Roche Molecular Systems) with a lower limit of quantification of 50 copies/mL [16].
Qualitative HCV RNA was detected using a PCR assay (Amplicor 2.0 HCV Monitor; Roche Diagnostics Systems). Quantification of HCV RNA was performed using a branched-chain
DNA assay (bDNA3.0; Bayer Diagnostics), with a limit of detection of 615 HCV RNA copies/mL. HCV genotypes were
determined by the INNO-LIPA test (Immunogenetics; HCVII).
Measurements of intracellular stavudine-TP concentrations
in PBMCs were performed in accordance with a previously
developed and validated liquid chromatography tandem mass
spectrometry method [17, 18]. In brief, ⭐4 h after blood samples (∼7 mL) were obtained, PBMCs were prepared by centrifugation with Ficoll Histopaque 1077, counted (Mallassez
cell), and immediately stored at a temperature of at least ⫺20C
pending analysis. PBMCs were lysed in 500 mL Tris HCl (0.05
M; pH, 7.4), and, after methanol evaporation, a 40-mL fraction of the remaining solution was injected into the liquid
chromatography tandem to mass spectrometry (LC-MS-MS)
system.
The chromatography was achieved on a Supelcogel octadecylpolymer (ODP)–50, 5-mm, 150 ⫻ 2.1–mm inner diameter
(Supelco) column by using a mobile phase comprising 1,5dimethylhexylamine 99% (Sigma-Aldrich), formate ammonium, and gradient-grade acetonitrile (Merck). The mass spectrometry detection was achieved in the negative electrospray
mode. Final results were provided in fentomoles per 106
PBMCs. In addition, the mass spectrometric signal corresponding to dT-TP was recorded in accordance with a previously
described method [19]. Measurements of plasma levels of antiretroviral drugs were performed by high-performance liquid
chromatography using validated methods.
Trough plasma concentrations of ribavirin were also measured by high-performance liquid chromatography. In brief,
the method involved a solid-phase extraction of ribavirin and
the internal standard (3 methylcytidine methosulfate) on Bond
Elut phenyl boronic acid column by using a 100-mL plasma
sample. One hundred microliters of the eluate (phosphoric
acid, 0.1 M) were separated on a Satisfaction C8 Plus 5 mm,
250 ⫻ 3 mm (Cluzeau) by using water with trifluoroacetic acid
0.01% and were quantified at 215 nm.
End points. The primary end point of the study was the
difference of plasma HIV-1 RNA level between baseline and
month 3. The first secondary end point was the difference in
intracellular concentrations of stavudine-TP between baseline
and month 3. Ratios of chromatographic peak area stavudineTP/dT-TP were also calculated. Other end points included
CD4+ cell count, clinical and laboratory toxicity of interferonribavirin, evolution of HCV RNA, and alanine aminotransferase
(ALT) levels up to month 3.
Statistical analysis. The sample size was calculated to have
a power of 90% to show a difference of ⭓0.5 log10 in HIV-1
RNA levels between the groups at month 3, with a 0.5-log10
SD, yielding a total of 18 patients to be included in each group.
Knowing that a difference 10.5 log10 would be clinically interesting, a 95% CI of the difference was built and used a bootstrapping method, the result of the limited number of patients
to be included in the study. In accordance with the intent-totreat principle, all patients were kept in their initial arm of
randomization.
The difference in the HCV RNA level between baseline and
month 3 was compared between groups by Student t test. Hemoglobin (g/dL), stavudine-TP (fmol/106 cells), and ribavirin
(mg/L) concentrations were compared at each follow-up visit
with a Wilcoxon test. Correlations were calculated by Spearman’s test. Two-sided P values were reported for statistical tests
with a p 0.05. Analyses were performed with SAS software,
version 8.00 (SAS Institute).
RESULTS
Characteristics of the patients at baseline and follow-up.
There were 31 patients enrolled from November 1999 through
November 2000. One patient withdrew between screening and
day 0 because of changes of antiretroviral treatment and was
not included in the analysis. Thirty patients were included
in the final analysis: 18 were assigned to interferon-ribavirin
group, and 12 were assigned to the control group. The 2 groups
were similar at baseline with regard to clinical and laboratory
characteristics (table 1). A majority of the patients were injection drug users (67%). At baseline, 27 patients received HAART,
and 3 received a dual therapy of nucleoside analogues. Besides
stavudine, the most frequently prescribed drugs were lamivudine (20 patients), didanosine (9 patients), nelfinavir (6 patients), indinavir (7 patients), efavirenz (8 patients), and nevirapine (4 patients). At entry to the study, 67% of the patients
had HIV-1 RNA levels of !50 copies/mL.
Two patients in the interferon-ribavirin arm prematurely
discontinued the study treatment because of adverse events that
occurred between baseline and week 2 (depression, asthenia,
irritability, and anxiety for one patient, and depression, asthenia
and nausea for the other; the latter patient also withdrew his
participation from the study). No patient was lost to followup until month 3.
Evolution of HIV-1 RNA level and CD4+ cell count up to
month 3. There was no significant variation in the plasma
level of HIV RNA after 3 months of treatment as compared
with baseline values in either group (figure 1). The mean difference (month 3 minus baseline) in the plasma HIV-1 RNA
level was ⫺0.03 log10 copies/mL in the interferon-ribavirin
group versus +0.15 log10 copies/mL in the control group
(P p .08). This yielded a mean difference between groups of
⫺0.18 log10 copies/mL (95% CI, ⫺0.43 to 0.07). Only one
patient in each group had an increase in the HIV-1 RNA level
of 10.50 log10 copies/mL. At month 3, 14 (82%) of 17 patients
randomized to the HCV treatment group and 7 (58%) of 12
randomized to the control group had an HIV-1 RNA level of
!50 copies/mL (P p .22).
In the treated group, the mean CD4+ cell count decreased
between day 0 and month 3 by 66 cells/mL, and it increased
by 80 cells/mL in the control group (P p .10). The percentage
of CD4+ cells remained stable in both groups (figure 2).
Evolution of HCV RNA level up to month 3. Of the 18
treated subjects, 7 (39%) had an undetectable HCV level after
3 months of interferon-ribavirin therapy. The mean HCV RNA
level changed by ⫺1.82 log10 copies/mL in the treated group;
it remained stable (+0.07 log10 copies/mL) in the control group
(P ! .001). The percentage of patients with a normal ALT level
increased in the treated group, from 33% at baseline to 65%
HIV/AIDS • CID 2003:36 (15 May) • 1297
Table 1. Baseline characteristics of patients in the Coinfected-Ribavirin Stavudine
(CORIST)–Agence Nationale de Recherche sur le SIDA (ANRS) HC1 trial.
Characteristic
Interferon-ribavirin
group
(n p 18)
Control group
(n p 12)
Clinical parameters
Age, median years (range)
37 (28–45)
36 (31–43)
Male sex
13 (72.2)
5 (41.7)
Injection drug use
14 (77.8)
6 (50.0)
Heterosexual sex
2 (11.1)
4 (33.3)
Hemophilia
2 (11.1)
1 (8.3)
Unknown
0 (0.0)
1 (8.3)
B
3 (16.7)
5 (41.7)
C
5 (27.8)
0 (0)
Transmission category for HIV infection
HIV infection clinical stage
Antiretroviral treatment received
NRTI + PI
7 (38.9)
8 (66.7)
10 (55.6)
2 (16.7)
1 (5.6)
2 (16.7)
CD4+ cell count, mean cells/mm3 SD
589 301
584 278
HIV-RNA level, mean log10 copies/mL SD
2.0 0.6
2.1 0.7
Hemoglobin level, mean g/dL SD
15.0 1.3
14.2 1.5
6.0 (4.4–6.9)
6.1 (4.2–6.5)
NRTI + NNRTI
NRTI dual therapy
Laboratory parameters
HCV-RNA level
Median log10 copies/mL (range)
!1.7 log10 copies/mL
12 (66.7)
8 (66.7)
HCV genotype
1a
10 (55.6)
5 (41.7)
3
6 (33.3)
5 (41.7)
4
2 (11.1)
2 (16.7)
NOTE. Data are no. (%) of patients, unless otherwise indicated. HCV, hepatitis C virus; NNRTI,
nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor.
a
1a, 1b, and 1a/1b.
at month 3, whereas it remained stable in the control group,
at 25% both at baseline and month 3 (figure 3).
Intracellular stavudine-TP concentrations. Five patients
could not be included in this analysis because cell samples had
been accidentally thawed, making them unfit for study. For the
25 analyzed patients, an important range of concentrations was
observed at each sampling time. A decrease in the median
peak and trough stavudine-TP concentrations was recorded
after the initiation of interferon-ribavirin therapy (table 2).
However, median stavudine-TP concentrations increased in
the control group between baseline and month 1, and they
were then were stable from month 1 to month 3. A further
analysis of intracellular stavudine-TP concentrations was subsequently performed after exclusion by a blinded pharmacologist of stavudine-TP samples corresponding to plasma
stavudine concentrations of !0.3 mg/L, suggesting a lack of
1298 • CID 2003:36 (15 May) • HIV/AIDS
stavudine intake 3 h before the measurements. In this analysis,
the same trends were observed (data not shown).
The ratios of peak concentrations of stavudine-TP to dT-TP
were similar at trough baseline concentration in the 2 groups
(median, 0.17 and 0.15 in the treated and control groups, respectively). This ratio decreased in the treated group between
baseline (median, 0.17) and month 3 (median, 0.16) versus
month 3 (median, 0.07); it remained constant in the control
group at month 1 and month 3 (median, 0.15). Plasma concentrations of stavudine were similar between both groups, with
no significant change observed over time.
Adverse events. Most adverse events were mild to moderate. Complaints of flulike symptoms were the most frequently
identified adverse events in 15 treated patients (83%). No such
adverse events were reported in the control group. The median
hemoglobin level decreased by ⫺2.1 g/dL in the treated group
Figure 1. Plasma HIV RNA level from baseline to month 3 in the Coinfected-Ribavirin Stavudine (CORIST)–Agence Nationale de Recherche sur le
SIDA (ANRS) HC1 trial. IFN-RIB, interferon-ribavirin.
and remained stable (⫺0.1 g/dL) in the control group.
Relationships between ribavirin concentrations and efficacy
or toxicity. Plasma and intraerythrocytic trough concentrations of ribavirin were measured at month 1 and month 3.
Intraerythrocytic and plasma concentrations obtained at month
1 and month 3 were correlated (r 2 p 0.48 [P p .01] and
r 2 p 0.37 [P p .01], respectively). Plasma ribavirin concentrations at month 3 were significantly correlated with a decrease
in the HCV RNA level between baseline and month 3 (r 2 p
0.36; P p .02; figure 4). Plasma ribavirin concentrations measured at month 3 were significantly higher in patients with a
decrease in the HCV RNA level of ⭓2 log10 copies/mL (n p
7), compared with patients who had a decrease in the HCV
RNA level of !2 log10 copies/mL (n p 9 ) (2.1 mg/L vs. 1.2 mg/
L; P p .03). High plasma ribavirin concentrations were also
associated with toxicity, as assessed by a decrease in the hemoglobin level. Between baseline and month 3, the median
hemoglobin level decreased by 2.1 g/dL for patients with ribavirin concentrations of 11.58 mg/L (n p 8 ) at month 3 and
by 1.3 g/dL for those with ribavirin concentrations of ⭐1.58
mg/L at month 3 (n p 8; P p .04). No significant relationship
was observed between ribavirin concentrations and ALT levels.
Long-term follow-up up to month 12. Follow-up data were
recorded until 12 months for 13 of 18 patients in the interferonribavirin group and for 10 of 12 patients in the control group.
In the first group, anti-HCV treatment was stopped before
month 12 for 5 of 13 patients and stavudine was stopped for
2 patients. In the control group, 7 of 10 patients initiated antiHCV treatment, and 3 stopped stavudine therapy. The mean
difference (month 12 value minus baseline value) in the plasma
HIV-1 RNA level was +0.08 log10 copies/mL in the interferonribavirin group and +0.03 log10 copies/mL in the control group
(P p .36). At month 12, a total of 2 (15%) of 13 patients in
the immediately treated group and 1 (10%) of 10 in the control
group had an increase in the HIV RNA level of 10.50 log10
copies/mL, and 8 (62%) of 13 patients and 7 (70%) of 10
patients had undetectable HIV-1 RNA levels, respectively. The
mean CD4+ cell count at month 12 was 670 cells/mm3 in the
treated group and 572 cells/mm3 in the control group (P p
.45). With regard to the HCV RNA level at month 12, among
10 patients in the immediately treated group with available data
at month 12, a total of 4 had undetectable HCV RNA.
DISCUSSION
This study provides evidence that the concomitant use of ribavirin with thymidine nucleoside analogues does not induce
major changes in the plasma HIV RNA level in the short term
as a consequence of a decrease in intracellular concentrations
HIV/AIDS • CID 2003:36 (15 May) • 1299
Figure 2. Top, Absolute CD4+ cell count at each evaluation from baseline to month 3 in the Coinfected-Ribavirin Stavudine (CORIST)–Agence
Nationale de Recherche sur le SIDA (ANRS) HC1 trial. Bottom, Mean percentage of CD4+ cells at each evaluation from baseline to month 3 in the
CORIST-ANRS HC1 trial. IFN-RIB, interferon-ribavirin.
of the active form of the drug in HIV-HCV–coinfected patients
treated with stavudine as a part of their antiretroviral treatment.
A trend toward a decrease in the intracellular stavudine-TP
concentrations in patients treated with IFN-a-2b and ribavirin
was observed, which possibly reflects a true metabolic effect,
because this decrease was observed for all the measurements
performed after the introduction of ribavirin, and it was observed for trough as well as for peak concentrations. However,
1300 • CID 2003:36 (15 May) • HIV/AIDS
the interpretation of this trend is difficult because of a large
inter- and intrapatient variability in the stavudine-TP concentrations and because of an unexplained increase in the stavudine-TP concentrations in the control group between baseline
and month 1.
The variability observed in the intracellular measurements
has 3 components: LC-MS-MS analysis, PBMC preparation and
enumeration, and intrinsic metabolism of nucleosides ana-
Figure 3. Mean hepatitis C virus (HCV) RNA level from baseline to month 3 in the Coinfected-Ribavirin Stavudine (CORIST)–Agence Nationale de
Recherche sur le SIDA (ANRS) HC1 trial. IFN-RIB, interferon-ribavirin.
logues. The precision of the LC-MS-MS technique has been
evaluated at !10% [19], which is much lower than that recorded
here. In contrast, the variability of intracellular nucleoside reverse-transcriptase inhibitors’ (NRTIs’) intrinsic metabolism is
unknown. We believe that variability of PBMC preparation and
enumeration were responsible for a large part of the total
variability observed in this study. When sources of variation
are minimal (same operator, same PBMC sample, and same
day), the coefficient of variation has been estimated to be 7.6%
(A. Pruvost, personal communication). We acknowledge that
sources of variation could be more important in a multisite
study and that every effort should be made to standardize and
simplify the PBMC collection and counting.
Indeed, the possibility of measuring intracellular NRTIs’
phosphate could be very useful in other situations, either to
evaluate intracellular interactions between ribavirin and other
triphosphorylated forms of NRTIs, or to study the relationship
between NRTIs and TP concentrations and both the toxicity
and the efficacy of these drugs, which are currently largely
unknown.
Because zidovudine and stavudine have the same mechanism
of action and probably the same type of interaction with ribavirin, our choice was directed toward stavudine for the sake
of simplicity in a trial of limited size. We believe that the results
obtained with stavudine-ribavirin might be extrapolated to zidovudine-ribavirin, because zidovudine has the same intracellular anabolic pathway (via thymidine kinase) as stavudine.
Nevertheless, the magnitude of the effect could be different
between zidovudine and stavudine because the enzymatic affinity of zidovudine for ribavirin is 600-fold higher than the
enzymatic affinity of stavudine for ribavirin [8, 9].
The ratio of the chromatographic peak concentrations of
stavudine-TP to dT-TP is PBMC-count independent, and its
evolution can be observed in both groups, regardless of the
treatment received. At the trough concentration, the ratio of
stavudine-TP to dT-TP was similar in the 2 groups at baseline
and remained stable in the control group at month 1 and month
3, allowing for an a posteriori verification of the relevance of
this parameter. In the treated group, the ratio of stavudine-TP
to dT-TP remained constant between baseline and month 1
and decreased between month 1 and month 3 (2-fold decrease).
Taking into account the continuous decrease in the stavudineTP concentrations (∼4-fold) in the treated group, this indicates that the dT-TP concentration would have transiently
decreased between day 0 and month 1, which contradicts in
vitro data [7, 10]. This discrepancy is possibly related to the
very different time course of the 2 kinds of studies, with in
vitro experiments being performed over the very short term
HIV/AIDS • CID 2003:36 (15 May) • 1301
Table 2. Intracellular concentrations of triphosphorylated stavudine (stavudineTP) in the Coinfected-Ribavirin Stavudine (CORIST)–Agence Nationale de Recherche sur le SIDA (ANRS) HC1 trial.
Interferon-ribavirin group
Status
Control group
No. of
patients
Stavudine-TP
concentration, median
fmol/106 cells (range)
No. of
patients
Stavudine-TP
concentration, median
fmol/106 cells (range)
Trough
Day 0
1
13.7 (1.0–197.9)
10
7.7 (1.0–32.2)
Month 1
14
6.2 (0.5–78.2)
9
14.9 (0.8–51.2)
Month 3
15
3.6 (0.9–89.1)
10
11.3 (1.5–57.7)
Peak
Day 0
15
26.4 (0.9–47.9)
9
11.6 (1.3–44.7)
Month 1
14
14.7 (1.1–148.3)
9
22.5 (1.7–72.1)
Month 3
15
16.8 (2.5–64.5)
9
24.5 (2.8–105.7)
NOTE. The peak values were measured ∼12 h (range, 10–14 h) after the last stavudine intake.
Trough values were measured 3 h after the last stavudine intake.
(24–48 h). This indicates that different mechanisms of regulation can be involved.
This study also provides results concerning the correlation
between trough plasma concentrations of ribavirin and an antiviral effect that are consistent with recent results about ribavirin dosage and antiviral effect. According to our results, an
r2 of 0.36 means that 36% of the variability of the HCV response
could be explained by ribavirin concentrations. Moreover, we
clearly demonstrated a relationship between ribavirin and hemoglobin plasma concentrations. The large interindividual variability in ribavirin plasma levels observed in this study, despite
a dose adaptation to weight, might argue for the clinical usefulness of therapeutic drug monitoring of ribavirin.
The tolerance and efficacy of interferon-ribavirin association
Figure 4. Relationship between the difference in the hepatitis C virus (HCV) RNA (month 3 [M3] value minus baseline value) and plasma ribavirin
concentration at M3 in the Coinfected-Ribavirin Stavudine (CORIST)–Agence Nationale de Recherche sur le SIDA (ANRS) HC1 trial.
1302 • CID 2003:36 (15 May) • HIV/AIDS
in HIV-HCV–coinfected patients were also described. After 3
and 12 months of dual anti-HCV therapy, 39% and then 40%,
respectively, of the treated patients had undetectable HCV
loads. These results are consistent with those reported in HCVmonoinfected patients, whose rate of HCV clearance after 3
months of interferon-ribavirin therapy ranges from 30% [20]
to 50% [19]. As in HCV-monoinfected patients in whom the
response rate has been improved by administration of pegylated
interferon combined with ribavirin [21], preliminary results
have showed the same trend in HIV-HCV–coinfected patients
[22], despite a high rate of discontinuation of therapy for adverse events.
As expected, the side effects associated with interferonribavirin dual therapy were frequently observed (78% of the
patients) and led to a treatment interruption in 11% of the
patients during the first 12 weeks. This proportion is higher
than in HCV-monoinfected patients, especially with regard to
neuropsychiatric effects. Indeed, in the 2 pivotal studies that
have assessed the efficacy of interferon-ribavirin versus interferon alone, the frequencies of interruption in the dual-therapy
group were 8% [19] and 10% [20] after 24 weeks of treatment,
and they were 21% and 27% after 48 weeks, respectively. As
in previous studies, we have observed a decrease in the CD4+cell
count in patients immediately treated with interferon-ribavirin.
This decrease in the absolute CD4+ cell count at month 3 was
moderate in these patients with a stable immunovirologic conditions who were receiving HAART, and it was probably only
transient because the median CD4+ cell count remained stable
at month 12 and was accompanied by stability of the CD4+
percentage.
In conclusion, whatever the interpretation of the pharmacological results, this study has pointed out the lack of interaction between stavudine and ribavirin on HIV replication in
vivo, which is reassuring for this coprescription in HIV-HCV–
coinfected patients. It also raises the question of the relevance
of monitoring drug concentrations, including the TP forms, in
multicenter studies for an accurate evaluation of tolerance and
efficacy. Finally, important information regarding tolerance and
efficacy of the combination therapy provides new insights into
the knowledge of treatment of HIV-HCV–coinfected patients.
STUDY GROUP MEMBERS
The following investigators with the Coinfected-Ribavirin Stavudine (CORIST)–Agence Nationale de Recherche sur le SIDA
(ANRS) HC1 Study Group referred patients in this trial:
L. Guillevin and B. Jarrousse (Hôpital Avicenne, Bobigny); C.
Leport and J. L. Vildé (Hôpital Bichat-Claude Bernard, Paris);
B. Silbermann and D. Sicard (Hôpital Cochin, Paris); R. Hor
and J. M. Molina (Hôpital Saint-Louis, Paris); D. Rey and J.
M. Lang (CHRU de Strasbourg, Strasbourg); E. Bonnet and P.
Massip (Hôpital de Purpan, Toulouse); M. Diemer and C. Caulin (Hôpital Lariboisière, Paris); P. Miailhes, F. Zoulim, and C.
Trepo (Hôpital Hôtel Dieu, Lyon); Ph. Perré, O. Aubry, and
H. Maisonneuve (CHD Les Oudaries, la Roche sur Yon); C.
Goujard and J. F. Delfraissy (Hôpital de Bicêtre, Kremlin Bicêtre); L. Piroth and H. Portier (Hôpital du Bocage, Dijon);
D. Merrien and P. Veyssier (Hôpital de Compiègne, Compiègne); A. M. Simonpoli and Ph. Vinceneux (Hôpital Louis
Mourier, Colombes); C. Bazin (Hôpital de Caen); Ph. Morlat,
M. Bonarek, and J. Beylot (Hôpital St. André, Bordeaux); L.
Benoist and M. Thomas (Hôpital Jean Verdier, Bondy); and
M. Uzan, A. Bicart-See, and St. Dizier (Hôpital Joseph Ducoing,
Toulouse).
Acknowledgments
We thank the other members of the Scientific Committee
(M. J. Commoy, C. Degott, P. Marcellin, A. Metro, C. Perronne,
G. Pialoux, G. Raguin, E. Rey, R. Salamon, B. Silbermann, and
H. Zylberberg) for helpful discussions and support during this
trial. We thank V. Calvez, C. Leport, T. Poynard, and M. Vray,
who were members of the data and safety monitoring board
of the study. We thank E. Noé, G. Palmer, C. Rancinan, and
G. Sagardoy for their contribution to the trial. We are indebted
to the patients who participated in the trial.
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