Antiretroviral therapy and liver disease progression in HIV and hepatitis C co-infected patients: a systematic review and meta-analysis
Llewellyn et al. Hepatology, Medicine and Policy
Antiretroviral therapy and liver disease progression in HIV and hepatitis C co-infected patients: a systematic review and meta-analysis
Alexis Llewellyn 0 1
Mark Simmonds 0 1
Will L Irving 1 2
Ginny Brunton 1 3
Amanda J Sowden 0 1
0 Centre for Reviews and Dissemination, University of York , York , UK
1 Abbreviations: ARV, Antiretroviral therapy; cART, Combination antiretroviral therapy; HCV , Hepatitis C virus; HR, Hazard ratio; IDU, Injection drug use; MD, Mean difference; OR, Odds ratio; RR, Relative risk
2 Faculty of Medicine & Health Sciences, University of Nottingham , Nottingham , UK
3 UCL Institute of Education, University of London , London , UK
Background: HIV co-infection exacerbates hepatitis C disease, increasing the risk of cirrhosis and hepatitis C-related mortality. Combination antiretroviral therapy (cART) is the current standard treatment for co-infected individuals, but the impact of cART and antiretroviral (ARV) monotherapy on liver disease in this population is unclear. We aimed to assess the effect of cART and ARV monotherapy on liver disease progression and liver-related mortality in individuals co-infected with HIV and chronic hepatitis C. Methods: A systematic review with meta-analyses was conducted. MEDLINE and EMBASE bibliographic databases were searched up to September 2015. Study quality was assessed using a modified Newcastle-Ottawa scale. Results were synthesised narratively and by meta-analysis. Results: Fourteen observational studies were included. In analyses that adjusted for potential confounders, risk of liver-related mortality was significantly lower in patients receiving cART (hazard ratio/odds ratio 0.31, 95 % CI 0.14 to 0.70). Results were similar in unadjusted analyses (relative risk 0.40, 95 % CI 0.29 to 0.55). For outcomes where metaanalysis could not be performed, results were less consistent. Some studies found cART was associated with lower incidence of, or slower progression of liver disease, fibrosis and cirrhosis, while others showed no evidence of benefit. We found no evidence of liver-related harm from cART or ARV monotherapy compared with no HIV therapy. Conclusions: cART was associated with significantly lower liver-related mortality in patients co-infected with HIV and HCV. Evidence of a positive association between cART and/or ARV monotherapy and liver-disease progression was less clear, but there was no evidence to suggest that the absence of antiretroviral therapy was preferable.
Systematic review; Meta-analysis; Anti-retroviral agents; Hepatitis C; HIV
Hepatitis C is an infectious liver disease caused by the
hepatitis C virus (HCV). Hepatitis C infections occur if
the virus is able to enter the blood stream and reach the
liver. Co-infection with hepatitis C virus (HCV) and
human immunodeficiency virus (HIV) is common due to
similar modes of transmission. There are an estimated 7
million individuals worldwide co-infected with HCV and
]. Chronic HCV infection affects approximately
6.2 % of HIV positive individuals, with greater rates in
intravenous drug users [
]. HIV co-infection exacerbates
HCV disease, increasing the risk of cirrhosis and
HCVrelated mortality [
In high-income countries, the widespread use of
monotherapy with an antiretroviral drug (or ARV
monotherapy) in the late 80s, followed by combination
antiretroviral therapy (cART) since 1996 has resulted in
HIV-infected patients living longer, and chronic HCV
infection is now the second most common cause of
death, after AIDS-related complications, among
HIVinfected individuals in areas where cART is available [
The effect of cART on the clinical course of HCV
infection is not clear. It has been suggested that the HIV viral
] and immune reconstitution possible with
cART are critical factors that slow down the rate of
HCV fibrosis progression [
]. However, some studies
have reported that cART may adversely affect hepatitis
C-related outcomes by increasing HCV viral load, liver
toxicity and fibrosis progression [
Today, most individuals infected with HCV in
highincome countries acquire the virus through unsterile drug
injecting practices. However, before the introduction of
effective blood donor screening, individuals became infected
through blood transfusion or therapy with medical
products manufactured from donated human blood. It is
estimated that blood transfusion resulted in approximately
23,500 HCV transmissions during the 1970s and 1980s in
] and around 28,000 in the UK, [
] before an
effective blood donor screening test was introduced in the
UK in 1991. More than 4,600 patients with bleeding
disorders were also infected via treatment with
HCVcontaminated plasma products. Since 2004, those
surviving patients who acquired chronic HCV infection through
NHS contaminated blood or blood products before donor
screening tests or virus inactivation methods were
available have received financial help via a UK wide ex-gratia
scheme established by the Department of Health [
We report the findings from a systematic review that
was commissioned by the Department of Health, England
]. cART is the current standard treatment for this
patient group but its impact on liver disease progression and
liver related mortality is unclear. Evidence of harm
associated with cART and/or ARV monotherapy may have
implications for compensation policies for people who
acquired HCV through contaminated blood products
prior to 1991. The findings from an earlier review
examining the association between cART and ARV monotherapy
and liver disease outcomes were inconclusive [
publication of the review in 2007 new primary studies
have become available and an up-to-date review of the
available evidence is needed.
We followed the general principles recommended in
Centre for Reviews and Dissemination (CRD) Guidance
for Undertaking Reviews in Health Care, [
] and the
reporting guidance of the PRISMA and MOOSE
MEDLINE and EMBASE electronic databases were
searched up to September 2015 for studies published in
English. We applied no date restrictions or study design
filters. Search terms included “hepatitis C”, “HIV”,
“antiretroviral therapy”, and “liver disease”. The reference lists
of relevant published reviews were checked for additional
]. A full search strategy is reported in
the Additional file 1.
Studies evaluating the effect of cART and/or ARV
monotherapy in individuals co-infected with HIV and
HCV were eligible for inclusion. Studies had to include a
comparison group of participants who did not receive
the intervention. Studies that measured treatment
exposure and outcome at the same point in time were
excluded because they were not considered suitable for
measuring disease progression.
The two outcomes of interest were liver-related
mortality and liver disease progression, and the latter includes
progression to/of fibrosis and cirrhosis; decompensated
liver disease; end-stage liver disease; and hepatocellular
carcinoma. Outcomes had to be measured using liver
biopsy or a validated non-invasive method. Studies
examining HCV viral load or transaminase/aminotransferase only
were excluded. Data had to be presented as, or allow
calculation of, relative risks (RR), odds ratios (OR), hazard
ratios (HR), or mean differences (MD).
Titles and abstracts were screened by a single reviewer,
and full papers were assessed by two reviewers
independently, with disagreements resolved through discussion.
Data extraction and risk of bias
Relevant study details and patient characteristics (e.g., age,
sex, baseline liver disease severity, mode of HCV/HIV
infection; HIV/HCV treatment regimens and history;
concomitant treatments) and outcomes were extracted into
standardised forms. Where outcomes were reported with
different levels of adjustment (e.g., adjusting for age and
sex only versus age, sex and time-dependent covariates),
data with the greatest number of adjustments were
preferred. Risk of bias was evaluated using a modified version
of the Newcastle-Ottawa quality assessment tool [
Three main domains were considered: participant
selection, confounding, and outcome measurement. Further
details are reported in the Supporting Information. Data were
extracted by a single reviewer and checked by a second,
with disagreements resolved through discussion. Where
relevant, study authors were contacted for missing data.
Results for liver-related mortality and liver disease
progression were pooled in a meta-analysis if at least two
studies reported that outcome, and if data were reported
consistently enough for analysis to be feasible. Otherwise,
results were synthesised narratively. Where meta-analyses
were performed, studies were pooled using standard
random-effects DerSimonian-Laird meta-analyses [
Heterogeneity was assessed through visual inspection of
forest plots and using I2 [
]. When pooling adjusted odds,
hazard or risk ratios these were assumed to be equivalent
regardless of the specific statistic reported or which
covariates were used in adjusted models. Adjusted and
unadjusted ratios were pooled using the inverse variance
method. Meta-analyses were conducted using R software.
Where participants from several studies were recruited
from the same cohorts and significant overlap was
suspected, data from only one study with the most reliable
reporting were included in the main analyses. The
impact of suspected overlap in participants across studies
was explored in sensitivity analyses, as was the use of
composite outcomes (one study reported end-stage liver
disease, hepatocellular carcinoma or death only as a
composite outcome [
Where possible, pre-planned subgroup analyses
including only studies with a large proportion of patients
with haemophilia were conducted. Meta-regression
analyses or other subgroup analyses were considered
inappropriate due to the small number of studies.
The bibliographic searches yielded a total of 1,943 unique
records. From these, 96 studies of potential relevance were
identified and 14 studies met our inclusion criteria (see
Fig. 1 for further details).
Risk of bias
As would be expected in observational studies, risk of
confounding of results due to unmeasured factors was the
most frequent quality concern in the included studies, with
ten studies classed at moderate or high risk of bias. Risk of
bias associated with participant selection was considered
unclear due to limited reporting in five studies, and low in
nine studies (where the study sample was considered
broadly representative of the population of interest, and
assessment of HIV/HCV and outcome at baseline were
considered appropriate). The risk of bias associated with
outcome measurement was considered mostly low, as ten
studies measured and reported their outcomes using
appropriate methods. Further details about quality criteria and
judgments are reported in Table 1 and Additional file 2.
Most studies were carried out in Europe, with six from
Spain, two from Italy and one in each of France,
Germany and Austria. Three studies were carried out in
the USA. Study dates ranged from 1970 to 2011 and six
studies were conducted across the pre-post cART era
(before and after 1996) [
]. Seven studies followed
patients prospectively in time [
23, 27, 29–33
] and the
Records identified through database searching to September 2015
Records after duplicates were removed
Records screened by
author and title
Full-text articles assessed for eligibility
Studies included in the review
Included in meta -analysis: 6
Included in narrative synthesis only: 8
Full-text articles excluded:
Reasons for exclusion
Ineligible population (no
separate data on
coinfected patients) : 1
No relevant data on
No comparator group: 26
No eligible liver -disease
related outcome: 30
No eligible design (e.g.
Fig. 1 Flow of studies
remaining seven studies were classed as retrospective
24–26, 28, 34–36
Many participants were current or past injection drug
users (IDU), with eight studies having IDU rates of 72 %
or above. One study focused on patients with
haemophilia exclusively [
], and another reported that 81 % of
patients had the condition [
]. The other studies failed
to report the number of patients with haemophilia.
Baseline liver damage severity varied across the studies: ten
studies included no or few patients with cirrhosis
23–28, 30, 33, 35, 36
]; four studies included only patients
with compensated cirrhosis at baseline [
29, 31, 32, 34
Where reported, cART regimens were primarily based on
protease inhibitors and non-nucleoside reverse
transcriptase inhibitors. Further study characteristics are presented
in Table 2.
Seven studies reported data on liver-related mortality,
23, 26, 27, 29, 31, 32, 34
] and ten studies reported on
liver disease progression [
24, 25, 27–30, 32, 33, 35, 36
Three studies reported separate data on both outcomes
27, 29, 32
Findings from six of the seven studies on liver-related
mortality were combined in meta-analyses [
23, 26, 27,
29, 32, 34
]. Of those, four studies presented analyses
adjusted for potential confounding factors [
23, 26, 29, 32
Figure 2 presents a forest plot of the results from these
four studies. cART use was associated with a substantial
reduction in liver-related mortality, with a hazard/odds
around one-third of that in untreated patients (HR/OR
0.31, 95 % CI 0.14 to 0.70). Heterogeneity was high
(I2 = 95 %), likely to be due to the discordant result
between two studies [
]. One showed a much
larger benefit; most participants in this study had
haemophilia, whereas in the other studies a large
majority of patients had a history of IDU.
All six studies included in the meta-analysis presented
numbers of patients with and without liver-related
mortality from which unadjusted relative risks could be
calculated. Figure 3 presents a forest plot of the results.
cART is associated with a statistically significant lower
risk of liver-related mortality (RR 0.40, 95 % CI 0.29 to
0.55). Moderate heterogeneity was found (I2 = 24 %).
Figure 4 presents the forest plot for the two studies
which included primarily patients with haemophilia.
cART is associated with a reduced risk of liver related
mortality (RR 0.28, 95 % CI 0.09 to 0.83), but there is
too little data to accurately estimate the effect, or to
determine if the effect differs from patients with a history
The number of liver-related deaths per group was not
reported in one [
] of the two studies, but it appears
that at least 63 % of the events reported across the two
study groups were liver-related deaths. Removing this
study from the analyses had only a limited effect on the
pooled estimates (RR 0.35, 95 % CI 0.21 to 0.57).
Results from one study [
] were not included in the
main analyses to avoid the risk of possible double
counting with participants from another related study [
This study found that the risk of liver-related mortality
was significantly lower in cART patients with
compensated cirrhosis compared to untreated patients
(unadjusted HR 0.5; 95 % CI 0.3 to 0.9). Adding the results
of this study to the meta-analysis had a limited effect on
the overall findings (RR 0.46, 95 % CI 0.28 to 0.75).
Liver disease outcomes
Liver disease outcomes were reported too diversely, or
in too few studies for meta-analysis and we synthesised
the findings narratively [
24, 25, 27–30, 32, 33, 35, 36
summary of the findings from these studies is presented
in Table 3.
End-stage liver disease and decompensation events
Three studies reported data on end-stage liver disease or
liver decompensation events [
27, 29, 32
]. Two of these
studies found at least one statistically significant effect in
favour of cART [
ART: 0.279 (0 · 122–0 · 414); untreated: 0.255 (0 · 079–0 · 473); untreated: 145 (SD 43, range 2–610) (time of measurement UC)
aI = Intervention, C = Control
bMedian follow-up 5 years (IQR 2.9-7.5)
cAt HCV infection
One study  found no difference between patients with
haemophilia receiving cART and/or ARV monotherapy and
untreated patients in the risk of developing end-stage liver
disease over 35 years (RR 1.00; 95 % CI 0.37 to 2.71).
However, patients receiving cART survived longer before
progressing to end-stage liver disease compared with untreated
patients (30.3 vs. 20.0 years; HR 3.14; 95 % CI 1.27 to 7.08).
Two studies reported on the risk of liver
decompensation in patients with liver cirrhosis [
]. One 
found a significantly lower risk of a new event of
decompensation in cART patients with stable cirrhosis who
had experienced decompensation in the past (HR 0.376;
95 % CI 0.161 to 0.883). However, no statistically
significant difference was found in the subgroup of patients
with no previous decompensation at baseline. Similarly,
the other [
] found no significant difference between
cART and untreated patients in the risk of
decompensation in individuals with cirrhosis.
Seven studies reported on liver damage in patients with
no cirrhosis at baseline, expressed in terms of odds/
hazard of fibrosis progression, [
24, 25, 28, 30, 33
and/or progression rate [
25, 35, 36
]. Of the five studies
that reported the odds/hazard of fibrosis progression, only
one reported a statistically significant difference between
intervention and control. This study [
significantly lower odds of liver fibrosis progression in patients
on cART with protease inhibitors (PI) (OR 0.4; 95 % CI
0.2 to 0.7) and in patients who switched from a PI
based regimen to efavirenz during the course of their
treatment (OR 0.3; 95 % CI 0.1 to 0.7), but not with
Of the three studies that reported fibrosis progression
rates, two found a difference in favour of cART [
and one found no difference between cART and no
treatment . One [
] found slower median rates of
fibrosis progression in patients treated with cART
compared with untreated patients, regardless of regimens
used. However, the difference was only statistically
significant for some regimens (zidovudine/lamivudine and
stavudine/lamivudine). Another [
] found a slower mean
rate of fibrosis progression over approximately 15 years in
patients undertaking cART at follow-up, although the
difference did not reach statistical significance.
We included 14 studies evaluating the association
between cART and/or ARV monotherapy and liver disease
progression and liver-related mortality in patients
coinfected with HIV and hepatitis C. In most studies the
majority of patients had a history of IDU, except for two
studies that included only or mostly participants with
haemophilia. cART was found to be associated with a
substantial reduction in liver-related mortality, with a
chance/hazard around one-third of that in untreated
patients. Pooled estimates from unadjusted analyses also
showed a clear association in favour of cART for
preventing liver-related mortality. A subgroup analysis
including nearly all patients with haemophilia also found a
reduced incidence of liver related mortality in
individuals receiving cART, but there were too little data to
provide an accurate estimate or to determine if the effect
differed from other populations. Findings for other
liverrelated outcomes were less consistent, although no
studies reported that lack of cART or ARV
monotherapy was associated with significantly better liver-disease
Strengths and limitations
This systematic review was conducted following the
general principles recommended in CRD Guidance for
Undertaking Reviews in Health Care, and the reporting
guidance of the PRISMA and MOOSE statements [
Study quality was assessed systematically and considered
when interpreting the findings. Whenever possible, data
on treatment effect for individual studies were extracted
or calculated, even when quantitative synthesis was not
undertaken. The review was completed within a ten-week
timeframe to meet the needs of the Department of Health
in England and due to time constraints we did not search
for conference abstracts, included only English language
studies and one reviewer screened titles and abstracts.
This means that relevant studies may have been missed,
and the risk of publication bias cannot be ruled out.
Quantitative assessment of publication bias was
considered inappropriate due to the limited number of included
studies. Despite the limitations of our searches, we believe
it is unlikely that any potential missed studies would
cART combination antiretroviral therapy, PI protease inhibitors, NVP nevirapine
ap < 0.05
bARV monotherapy patients formed 62 % of the comparator group in this analysis
cIshak score ≥ F3 measured with liver biopsy
dOdds of slower fibrosis proression (fibrosis progression rate ≥0.2 vs <0.2), fibrosis measured with liver biopsy
e≥1 Knodell-Ishak stage increase between two liver biopsies
fMETAVIR Fibrosis stage (0 to 3) measured by liver biopsy/length of HCV infection
gIn years, measured with liver biopsy
h≥1 Scheuer stage increase between two liver biopsies spaced by ≥1 year
iLiver stiffness value ≥9.5 kPa or died of liver disease
jSubgroup without previous decompensation at baseline
kAge, undetectable HIV viraemia, genotype 3, ALT and necroinflammatory activity at baseline, time between liver biopsies, HCV treatment response
significantly modify the findings of the main analyses on
liver-related mortality and our main conclusions. This is
because the observed effect associated with cART is
Findings from most studies on liver-related mortality
were synthesised quantitatively. Adjusted and unadjusted
results were pooled separately as an attempt to address
potential confounding. Adjusted mortality values could
only be combined based on the (inaccurate) assumption
that odds and hazard ratios are equivalent, and this
approach could create heterogeneity across studies because
of different analysis methods used to obtain the adjusted
results; therefore these results need to be interpreted
with caution. However, the pooled estimates from
adjusted and unadjusted values did not differ significantly,
and both suggested substantial benefits of cART.
Liver disease outcomes were reported too diversely, or
in too few studies for statistical pooling. This limits the
strength of the findings on liver disease progression.
There were too few studies to conduct meta-regression
or further subgroup analyses to explore the moderating
effect of several relevant factors, including age, liver
disease severity, baseline CD4 count, HBV co-infection,
cointervention with HCV therapy, time since HCV/HIV
infection, HIV treatment duration treatment history of
HCV infection or alcohol abuse.
Unsurprisingly, no RCTs were identified and all
included studies were observational. Given the known
overall survival benefits associated with cART, it would
be unethical to randomise patients to no cART. Half of
the studies adjusted for potential confounders such as
age or sex, although the variables accounted for varied
across the studies. For instance, only two studies
controlled for alcohol misuse in their analyses. Although
attempts were made to address the risk of confounding in
the analyses, risk of confounding cannot be ruled out.
The pooled analyses showed heterogeneity, particularly
for the meta-analysis of adjusted results, which limits
the strength of the review findings.
Studies might have been affected by a survivorship
bias if patients in the intervention group who survived
long enough to receive treatment had slower HCV
progression, and therefore may have had better
HCVrelated outcomes [
]. The use of a time-dependent
variable or Cox proportional hazards modelling taking HCV
duration or progression into account might have
remedied this bias. However, no studies reported using this
technique. On the other hand, it is possible that
comparison groups had levels of immunosuppression that
were considered sufficiently high for their treatment
to be delayed [
]. In this case, patients in the
ART group may have had poorer health at treatment
initiation, and may therefore have been at higher risk
of liver disease progression. Unfortunately, reporting
of participant characteristics in the studies was
insufficient to support or reject these assumptions.
Reasons for not receiving cART or ARV monotherapy
were generally not reported. However, given that cART,
and previously ARV monotherapy, would likely be
recommended to most HIV/HCV co-infected individuals,
particularly those with high HIV viral load, reasons for
not receiving treatment were likely influenced by
individual patient choice. Those receiving cART may be less
likely to be active IDUs (for example, ex-IDUs on
methadone programmes) and may have different
lifestyles (for example, less alcohol and substance abuse)
compared to those who do not receive cART. Reporting
of baseline differences between cART/ARV monotherapy
and untreated groups was often limited. Although no
studies reported significant differences between groups
such as current alcohol, IDU or other substance abuse,
and although some studies adjusted for these variables in
their analyses, it is still possible that those who received
treatment for HIV were different to those who did not for
reasons that may have influenced liver-related outcomes.
Where reported, most participants had a history of
IDU. This should be taken into account when
interpreting the results of the review. Most participants included
in the studies were under 50 years of age and the burden
of other co-morbidities is likely to be higher in older
populations. This, in addition to the toxicity of other
treatments, may impact differently upon liver disease.
This limits the applicability of the findings to older
populations, especially given the increasing life expectancy
of people with HIV and HCV, and the growing
proportion of people with HIV aged 50 years and over.
We identified only studies from high-income countries
and note that the applicability of the review findings to
low- and middle-income countries is uncertain.
Implications for policy, practice and further research
This systematic review provides an up-to-date synthesis
of the available evidence on the effect of cART and ARV
monotherapy on liver disease progression and
liverrelated mortality in individuals co-infected with HIV and
hepatitis C. This review, together with another review
on quality of life and extrahepatic conditions in
individuals with chronic hepatitis C, [
] was commissioned as
part of ongoing policy consideration about the shape of
support for those affected by hepatitis C or HIV from
historic NHS blood treatments before donor screening
tests or virus inactivation methods were available in the
UK. A public consultation on reform of the existing
financial and other support available was announced in
The findings of this review support the use of cART in
patients co-infected with HIV and HCV as recommended
by current guidelines [
]. Given the increased risk of
liver-related morbidity and mortality in patients
coinfected with HIV and HCV and the limited evidence on
the impact of cART on liver disease progression, the need
for monitoring liver-disease progression in this population
clearly remains. Future management of patients
coinfected with HIV and HCV is likely to evolve with the
advent of new directly acting antivirals (DAAs) for the
treatment of HCV, [
] and recent trials have found high
sustained virologic response (SVR) rates in non-cirrhotic
patients co-infected with HIV and HCV with certain DAA
Few included studies reported data separately for
different antiretroviral classes and combinations. Several
studies comparing different ARV regimens did not
compare cART and/or ARV monotherapy with no HIV
treatment and were therefore excluded from our review.
Given the ubiquitous use of cART in HIV management,
a systematic review on the acute and chronic effect of
different cART regimens would be relevant. The
mechanisms by which liver disease mortality is reduced with
cART are still largely unknown [
]. Further research
would clarify whether the effect of cART on liver-disease
progression and mortality may occur through immune
reconstitution, viral suppression or a combination of
The use of cART was found to be associated with a
significantly reduced risk of liver-related mortality in patients
co-infected with HIV and HCV. Evidence of a positive
association with liver disease progression is less clear,
although there is no evidence to suggest that the absence of
cART and/or ARV monotherapy is preferable.
Additional file 1: Search strategy. (DOCX 14 kb)
Additional file 2: Quality assessment and risk of bias. (DOCX 17 kb)
We thank members of our advisory group, including Joseph Peaty and Mark
Ward from Tainted Blood for providing testimonies on living with HIV,
Hepatitis C and haemophilia and undergoing antiretroviral therapy, for
suggesting references for inclusion, and for commenting on the draft report.
We also thank Professor James Thomas, UCL Institute of Education, University
College London, for his advice and support, and Dave Fox, Information
Specialist at CRD, University of York, for conducting the bibliographic searches.
Guarantor of the article: Amanda Sowden
We confirm that the manuscript has not been published previously, in any
language, in whole or in part, and is not currently under consideration
elsewhere. Please note that a linked report was published on the EPPI Centre
This is an independent report commissioned and funded by the Policy
Research Programme in the UK Department of Health. The Department of
Health approved the design of the study, and played no part in the
collection, analysis and interpretation of data, or writing of the manuscript.
The views expressed are not necessarily those of the funder.
AL, MS, GB and AJS contributed to the protocol development. AL and MS
performed the study selection, data extraction, quality assessment, narrative
synthesis and contributed to the analyses; MS performed the statistical
analyses. WI provided clinical advice throughout the review. AS took overall
responsibility for the project and contributed to all aspects. AL wrote the
paper, MS, WI, GB and AS revised the manuscript. All authors have contributed
to and agreed on the content of the manuscript.
Will Irving has served as a speaker, a consultant and an advisory board
member for Janssen Cilag, Bristol-Myers Squibb, and has received research
funding from Gilead Sciences, Janssen Cilag and educational grants from
Boehringer Ingelheim, Gilead Sciences and MSD. The authors declare they
have no other competing interests.
Consent for publication
Ethics approval and consent to participate
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