Professional Documents
Culture Documents
Review Article
a r t i c l e
i n f o
Article history:
Received 8 August 2014
Accepted 30 September 2014
Available online 7 November 2014
Keywords:
Hepatitis C virus
Human immune deciency virus
Injection drugs users
Sofosbuvir
a b s t r a c t
In the era of Directly Acting anti HCV Antivirals treatment of hepatitis C is successful in the majority
of persons treated. However, treatment of persons with HIV or who inject drugs remains challenging
because of special issues: drugdrug interactions with antiretroviral, psychiatric and drug substitution
therapies, treatment adherence, impact of treatment on HIV disease course or on risk of bacterial infections. Sofosbuvir induced sustained virologic response in 91% of 23 HIV/HCV coinfected persons treated in
combination with ribavirin and pegylated interferon, in 83% of 497 treated in combination with ribavirin
and in all 50 patients infected with HCV GT1 treated in combination with ledipasvir and ribavirin. The
rates of efcacy in HCVHIV coinfected were almost the same as those observed in HCV monoinfected
suggesting that the efcacy of sofosbuvir is not reduced by HIV coinfection. There are no data on the
efcacy of sofosbuvir in injection drugs users. The pangenotypic activity, the high barrier to resistance,
the modest potential for drugdrug interactions makes sofosbuvir a reference drug for the treatment of
these two special populations.
2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction
According to recent estimates, more than 185 million people
around the world are infected with the hepatitis C virus (HCV),
350 000 of whom die each year [1]. HCV is transmitted primarily
as a result of direct, through-the-skin exposure to infected blood
[1]. Certain groups are at higher risk of HCV infection, and People
Who Inject Drugs (PWID) are an important risk category. In middleand high-income countries, most HCV infections occur among people who use unsterile equipment to inject drugs and contaminated
drug solutions [1,2]. Of the estimated 16 million people in 148
countries who actively inject drugs, 10 million are infected with
HCV [2].
Human immunodeciency virus (HIV) and HCV have common
routes of transmission, and it is estimated that, globally, 45 million persons out of the 185 million infected by HCV are also
coinfected by HIV [3]. Sexual transmission of HCV is also common in Persons Living with HIV (PLHIV), particularly in men who
have sex with men (MSM) [4]. In several recent outbreaks of
HCV infection among HIV infected MSM in Europe, Australia and
http://dx.doi.org/10.1016/j.dld.2014.09.027
1590-8658/ 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
S207
S208
was less than 80% only in HCV GT1 nave cirrhotics treated for 24
weeks, in HCV GT3 naves treated for 12 weeks and in HCV GT3
experienced cirrhotics even if treated for 24 weeks. Therefore, prolongation of treatment to 24 weeks seems to be required in nave
patients infected by HCV GT3 and something should be added to
optimize the efcacy of SOF + RBV treatment administered for 24
weeks in patients infected by HCV GT1, especially if cirrhotics, and
in experienced cirrhotics with HCV GT3 infection.
In conclusion the two studies demonstrated a good tolerability,
and estimates of efcacy greater than 80% in a large and heterogeneous population of more than 450 patients treated with sofosbuvir
and ribavirin.
Hepatitis C is a heterogeneous disease so HCV genotype, exposure to previous treatment with peginterferon and ribavirin and
the presence of cirrhosis are strongly related to response to antiviral treatment also in PLHIV. The heterogeneity of this large study
population permits a series of indications for clinical practice to
be derived from these two studies. The robust demonstration of an
efcacy greater than 85% in most of the subgroups of PLHIV enrolled
in these two studies, the inclusion of a large number of patients
intolerant to peginterferon and the possibility of maintaining most
of the concurrent cART regimen due to lack of interactions with
almost all antiretrovirals suggest that treatment with SOF + RBV
could be a rst line choice for the treatment of Hepatitis C in the
following subgroup of PLHIV:
nave infected by HCV GT2 with a treatment duration of 12 weeks.
nave infected by HCV GT3 and experienced with HCV GT2 with
or without cirrhosis and experienced HCV GT3 without cirrhosis
with a treatment duration of 24 weeks.
In patients with HCV GT1 especially without cirrhosis, the rates of
SVR are similar to those obtained with INF based triple therapies,
however, higher rates of SVR have been obtained by combining
sofosbuvir with other DAAs in HIV uninfected patients.
The number of HCV GT4 nave patients is not sufcient to draw a
rm conclusion, however, the lower limit of the condence interval
of the estimate of SVR12 in 31 patients was 79%.
Although there are no studies comparing the efcacy of SOF and
RBV in persons with and without HIV coinfection and there is no
meta-analysis based on individual patients data, it could be possible to compare the efcacy of SOF and RBV observed in patients with
and without HIV coinfection by analysing the data from different
studies. Fig. 2 shows the comparison between the data from HIV
uninfected subjects obtained in registration studies and reported
in the SOF summary of product characteristics [16] with those
observed in PLHIV in the PHOTON I and PHOTON II studies.
The rates of efcacy in PLHIV are almost the same across all
subgroups and thus these data suggest that the efcacy of SOF and
RBV is not reduced by HIV coinfection. Thus, in the sofosbuvir era,
PLHIV are no longer a special population with an unmet need.
5. Sofosbuvir in combination with other DAAs in PLHIV
The use of sofosbuvir in combination with a second DAA has
been extremely successful in HCV mono-infected persons with HCV
genotype 1. Two small pilot studies [17,18] showed SVR12 rates
higher than 95% when sofosbuvir was combined with daclatasvir
(a NS5A inhibitor) and with simeprevir (a second wave protease inhibitor) in small study population. The combination with
simeprevir was able to induce the same SVR rates also in patients
with cirrhosis.
An efcacy higher than 95% was also obtained in large phase III
studies assessing the efcacy of sofosbuvir co-formulated with ledipasvir (a NS5A inhibitor) in a xed drug combination in a large study
S209
Fig. 1. Cumulative estimates with 95% condence intervals of the percentage of Sustained Virologic Response 12 weeks after discontinuing sofosbuvir and ribavirin (SVR12)
in 497 HIV/HCV coinfected patients stratied according to: Hepatitis C Virus Genotype (HCV G) previous treatment with pegylated interferon and ribavirin, naves and
experienced (exp) presence of cirrhosis, and duration of treatment.
Fig. 2. Estimates of the percentage of Sustained Virologic Response 12 weeks after discontinuing sofosbuvir and ribavirin (SVR12) in 497 HIV/HCV coinfected patients and in
767 HCV monoinfected patients stratied according to the presence of cirrhosis (cirr.) and previous treatment with pegylated interferon and ribavirin naves and experienced
(exp).
S210
daclatasvir or simeprevir in PLHIV, there are no data on the efcacy and tolerability of these combinations in this group of patients.
Simeprevir has a moderate potential for drugdrug interactions
with anti-HIV protease inhibitors, efavirenz and nevirapine [24]
and the daclatasvir dosage should be adjusted when used with
efavirenz or ritonavir boosted anti HIV protease inhibitors [24].
Thus, the concurrent cART should be adjusted in a relevant proportion of patients who are candidates for simeprevir or daclatasvir
administration. Preliminary results have recently been reported for
ERADICATE, an NIH funded study on the efcacy of ledipasvir and
sofosbuvir xed dose combination administered for 12 weeks without ribavirin in PLHIV [25]. Fifty HIV/HCV coinfected patients with
HCV GT1, without cirrhosis were enrolled: 13 patients were not
on concurrent cART but had stable CD4 and HIV RNA < 500 cp/mL
or had CD4 > 500/mmc and 37 had been on a stable cART for at
least 8 weeks with tenofovir/emtricitabine plus rilpivirine (11/37)
and/or, raltegravir (13/37) and/or efavirenz (16/37). Forty-two
were African American, 42 infected with HCV GT1a and 13 had
liver brosis METAVIR F3 stage. Only 34 patients reached the 16th
week of the study and all 34 showed SVR4. SVR12 was observed
in all 10 patients not under cART who reached the 24th week of
the study. The tted HCV viral kinetic model showed a similar
decline in both the group undergoing cART and the group without cART. Only one patient who skipped cART for 4 days showed
an HIV breakthrough but HIV replication was re-suppressed with
the same regimen. The tolerability was very good, only one patient
showed a grade 3 event (pneumonia) and three patients grade 3
lab abnormalities (1 elevated AST, 1 neutropenia and 1 grade 4
CPK elevation).
If conrmed by further data analysis these preliminary results
suggest that an interferon and ribavirin free xed dose combination of sofosbuvir and Ledipasvir is equally effective in PLHIV as in
HCV mono-infected and that it could become the rst line option
in PLHIV with HCV Genotype 1 coinfection.
S211