Book on hepatitis from page 306 to 313

Book on hepatitis from page 306 to 313

306  Hepatology 2012
One paper also addressed the amount of immune reconstitution achieved on
HAART and the subsequent risk for developing hepatic decompensation in
HIV/HCV-coinfected individuals commencing HAART (Pineda 2007). Those
patients who experienced the highest CD4 cell count gain on HAART were the least
likely to develop further complications of liver disease, again highlighting a
favourable impact of HAART-induced immune reconstitution on the course of liver
disease. As a consequence, the current antiretroviral treatment guidelines of the
European AIDS Clinical Society recommend earlier initiation of antiretroviral
therapy in HIV patients with HCV coinfection (CD4 T cell count between 350-500/µl in asymptomatic patients).
Short-term and long-term virologic success rates of HAART in HIV/HCV
coinfection are, however, limited by an increased risk of hepatotoxicity. Various
studies have shown that the presence of HCV is independently associated with an
increased risk of rises in serum aminotransferases highlighting the need for close
monitoring.
Treatment of hepatitis C in HIV coinfection
The most important reason to treat hepatitis C in HIV-coinfected individuals is the
unfavourable course of hepatitis C in the setting of HIV coinfection particularly
with the increased life expectancy gained by successful HAART. An increased risk
of hepatotoxicity after HAART initiation in HIV/HCV-coinfected patients, possibly
limiting the long-term benefit of HAART in this particular group, further underlines
the need for successful treatment of hepatitis C (Sulkowski 2000). Several studies
have been able to demonstrate that successful treatment of hepatitis C dramatically
reduces subsequent complications of preexisting liver disease. This implies that
once viral clearance is achieved with hepatitis C combination therapy the prognosis
of liver disease dramatically improves (even in the presence of already developed
liver cirrhosis) and once HCV infection is eradicated further liver complications are
very unlikely.
The goal of hepatitis C treatment is to achieve persistently negative HCV RNA
levels. This is generally referred to as a sustained virologic response (SVR). It is
defined as negative HCV RNA six months after completion of HCV therapy.
Negative HCV RNA at the end of the treatment period is described as an end-of-treatment response (EOT). Negative HCV RNA after four weeks of HCV treatment
initiation is referred to as rapid treatment response (RVR). Failure to respond to
treatment is referred to as non-response.
The combination of pegylated interferon and ribavirin is still regarded as standard
therapy in coinfected patients. Table 2 summarizes the main results from
randomized clinical trials investigating the efficacy of pegylated interferon and
ribavirin in HIV/HCV-coinfected individuals. Data from the GESIDA study show
similar efficacy and safety for both pegylated IFN α-2b and pegylated IFN α-2a in
the treatment of chronic HCV infection in HIV-infected patients (Berenguer 2009).
Overall, SVR rates of up to 50% can be achieved (Torriani 2004; Nunez 2007).
The difference in rates of SVR in various studies can be explained mainly by
differences in ribavirin dosages used, fibrosis stage and probably variations in the
IL28B genotype. In the initial HCV treatment trials in HIV-coinfected individuals,
due to the fear of interactions between ribavirin and commonly used NRTIs for HIV
Management of HCV/HIV Coinfection  307
treatment, 800 mg daily dose of ribavirin was chosen for most patients independent
of the prevailing genotype. This led to suboptimal SVR rates. However, in the
PRESCO trial, where weight-adjusted daily ribavirin dosages of 1000-1200 mg
were used independent of genotype, SVR rates almost doubled in comparison to
some of the earlier studies such as APRICOT, most likely due to the higher ribavirin
levels. In spite of this, data from the PARADIGM trial, a double-blind, multicenter
study comparing 800 vs 1000/1200 mg of ribavirin plus PEG-IFN in HCV/HIV-coinfected patients showed no significant differences in the rates of SVR
(Rodriguez-Torres 2009).
In the current guidelines, daily administration of ribavirin 1000 mg (<75 kg body
weight) and 1200 mg (>75 kg body weight) BID is recommended for HCV therapy
in HIV coinfection for all genotypes in combination with pegylated interferon.
Table 2. Results from randomized clinical trials investigating the efficacy of
pegylated interferon plus ribavirin in HIV/HCV-coinfected individuals.
ACTG5071  APRICOT  RIBAVIC  Laguno  PRESCO
Patients (n)  66  289  194  52  389
PEG-INF α  2a  2a  2b  2b  2a
IV drug use   -  62%  80%  75%  90%
Liver cirrhosis   11%  15%  39% (F3-F4)  19%  28% (F3-F4)
Genotype 1,4  77%  67%  61%  63%  61%
Normal ALT  34%  0%  16%  0%  0%
Mean CD4+  495  520  477  570  546
HAART  85%  83%  83%  94%  74%
Discontinuation
rate due to AE*
12%  25%  17%  17%  9%
Discontinuation
rate due to
other reasons
-  31%  39%  23%  7%
EOT (ITT)**  41%  49%  35%  52%  67%
SVR (ITT)***  27%  40%  27%  44%  50%
*adverse events, **end-of-treatment response, intent-to-treat analysis, ***sustained virological
response, intent-to-treat
The standard dosage for PEG-IFN α-2a is 180 µg s.c. once weekly and for PEG-IFN  α-2b 1.5 µg/kg body weight s.c. once weekly. Duration of therapy is
individualized taking into account factors for HCV treatment response such as
genotype, baseline viral load and virologic response (see Figure 1). Results from the
PRESCO trial indicate that at least some patients may benefit from a longer duration
of HCV combination therapy, of up to 72 weeks (see Figure 1). This mainly refers
to patients infected with HCV genotypes 1 and 4 (Núñez 2007) for whom poorer
response rates have been extensively shown when compared with genotypes 2 and
3.
Based on 4 baseline variables (serum HCV RNA, HCV genotype, liver fibrosis
staging using elastometry, and IL28B genotyping), the Prometheus index has
recently been developed and can optionally be used as a risk calculator for
predicting the likelihood of SVR using PEG-IFN/ribavirin therapy in HIV-HCV-coinfected patients. It is freely available on the web (http://goo.gl/oPBJ9), like the
Framingham score for predicting cardiovascular risk (EACS 2011).
308  Hepatology 2012
With the registration of the first oral direct acting antivirals (DAAs) telaprevir and
boceprevir, treatment recommendations for hepatitis C genotype 1 patients will
change depending on the availability of these new agents. So far, only interim data
is available for both agents (24-week treatment response data) showing significantly
higher rates of undetectable HCV RNA with triple therapy when compared with
standard PEG-IFN plus ribavirin in coinfected patients, similar to the rates seen in
Phase II and III trials in HCV monoinfection (Sherman 2011, Sulkowski 2011). For
patients with HCV genotype 1 infection, telaprevir can be added to PEG-IFN/RBV
standard treatment for 12 weeks at 750 mg every 8 hours. In case of successful
treatment response at week 4 (HCV RNA <1000 IU/mL), telaprevir should be
continued until week 12. If HCV RNA at week 12 is still <1000 IU/mL, dual
therapy with PEG-IFN/ RBV should be continued until week 24. If HCV RNA is
<20 IU/mL at week 24, dual therapy with PEG-IFN/RBV should be continued for
another 24 weeks resulting in a total treatment duration of 48 weeks.
Stop
Figure 1. Algorithm for management of hepatitis C in HIV coinfection. Proposed optimal
duration of hepatitis C virus (HCV) therapy in HIV/HCV-coinfected patients (w: week; G:
genotype) (modified according to Rockstroh 2009).
*In patients with low baseline viral load (<400,000 IU/l) and minimal liver fibrosis.
Due to drug-drug interactions and limited drug-interaction studies, telaprevir can
currently only be safely combined with raltegravir, boosted atazanavir or efavirenz
(with efavirenz, telaprevir doses need to be increased to 1125 mg every 8 hours) in
combination with tenofovir and emtricitabine or abacavir and lamivudine. Recently
published pharmacokinetic (PK) data on the combination of telaprevir with
raltegravir shows no influence on telaprevir PK, but telaprevir increased raltegravir
levels by about 30%. This interaction is not considered clinically significant and
suggests that these drugs can be used together without dose adjustment or concerns
regarding effect on safety or efficacy  (van Heeswijk 2011). Treatment with
boceprevir  for patients with HCV genotype 1 infection is different, with a
mandatory 4-week lead-in Phase with PEG-IFN/RBV to reduce hepatitis C viral
load and subsequently lower the risk of rapidly developing resistance against
boceprevir. If a >2 log drop in HCV RNA is achieved at week 4 boceprevir is added
Management of HCV/HIV Coinfection  309
to PEG-IFN/RBV. Therapy duration then depends on response rates at subsequent
time-points. So far, no official recommendations exist as clinical trials are ongoing.
While boceprevir seemed to have a lower potential for drug-drug interactions with
ART vs. telaprevir due to its simultaneous metabolisation by the aldo-keto reductase
and the cytochrome P450 pathway (Dore 2011), recent study results have changed
that view. Coadministration of boceprevir reduced mean trough concentrations of
ritonavir-boosted atazanavir, lopinavir and darunavir by 49, 43 and 59 percent,
respectively. Mean reductions of 34 to 44 percent and 25 to 36 percent were
observed in AUC and Cmax of atatzanavir, lopinavir and darunavir.
Coadministration of ritonavir-boosted atazanavir with boceprevir did not alter the
exposure of boceprevir, but coadministration of boceprevir with lopinavir/ritonavir
or ritonavir-boosted darunavir decreased the exposure of boceprevir by 45 and 32
percent, respectively. Due to these interactions the concomitant use of boceprevir
with HIV protease inhibitors is not recommended (Merck 2012).
Unlike HAART, HCV treatment offers the possibility of eradicating HCV within
defined treatment periods and this clearly appears potentially advantageous for the
subsequent management of the patient’s HIV infection. Every patient should be
considered for HCV treatment when the benefits of therapy outweigh the risks.
Benefits of therapy also need to be measured in the context of rapid liver fibrosis
progression in HIV/HCV coinfection and improved HCV treatment outcome under
optimized management in these patients. Information on liver fibrosis staging is
important for making treatment decisions in coinfected patients. However, a liver
biopsy is not mandatory for decisions on treatment of chronic HCV infection.
Recently introduced noninvasive markers such  as blood tests or transient
elastography constitute new and exciting means of assessing liver disease in HIV
and hepatitis-coinfected individuals (Rockstroh 2009, Resino 2011). When liver
biopsy or non-invasive tests for assessing hepatic fibrosis (e.g., elastometry by
Fibroscan
®
, Echosense, France) demonstrate lower grades of liver fibrosis (F0-F1)
regardless of HCV genotype, treatment can be deferred. Assessment of fibrosis
should be repeated frequently to monitor progression. It is especially important to
perform a liver disease stage assessment in patients with a low likelihood of
achieving SVR. In addition, insulin resistance (which can be determined using the
homeostasis model assessment of insulin resistance [HOMA-IR] score) has been
reported as a negative predictor of achieving SVR and therefore may also be
considered during evaluation.
Current therapy is particularly recommended in all patients with a high likelihood
of achieving an SVR, i.e., patients infected with genotype 2 or 3 and those infected
with genotype 1 if the viral load is below 600,000 IU/ml and/or if the IL28B-CC
genotype is present (EACS 2011). If chronic hepatitis C is detected early in the
course of HIV infection (before the initiation of HAART) treatment for chronic
HCV is advised. However, if a coinfected patient has severe immune deficiency
(CD4 count <200 cells/ml), the CD4 count should be improved using HAART
before beginning HCV treatment. Patients with a CD4 relative percentage of >25%
are more likely to achieve SVR than those with lower CD4 percentages (Opravil
2008). If an early virologic response of at least 2 log10 reduction in HCV RNA
compared with baseline is not achieved by week 12, treatment should be
discontinued as an SVR is unlikely. The current European recommendations for
treatment initiation of PEG-INF and ribavirin for HIV/HCV-coinfected patients are
310  Hepatology 2012
shown in Figure 1. The procedures for diagnosis of hepatitis C, assessment of liver
disease stage and control examinations before and during HCV therapy are
summarized in Table 3.
Table 3. Diagnostic procedures for hepatitis C in HIV coinfection (adapted from
Rockstroh 2008).
Diagnosis of hepatitis C
HCV Ab (positive 1-5 months after infection, may rarely be lost with immunosuppression)
HCV RNA levels (while not prognostic for progression, it is for response to treatment)
Status of liver damage
Grading of fibrosis (e.g., Fibroscan, liver biopsy, serum fibromarkers)
Hepatic synthetic function (e.g., coagulation, protein, albumin, CHE)
Ultrasound and AFP every 6 months in cirrhotics (gastroscopy upon diagnosis of cirrhosis
and every 1-2 years thereafter)
Before HCV treatment
HCV genotype and serum HCV RNA
The choice of antiretrovirals while on HCV therapy
The choice of the best-tolerated HIV drugs is crucial for completing the planned
treatment duration of hepatitis C therapy of 24-72 weeks (Vogel 2010). ddI use has
been independently associated with increased adverse event rates including lactic
acidosis and hepatic decompensation in patients who have liver cirrhosis prior to
commencement of PEG-IFN/RBV therapy (Mauss 2006). Apparently, ribavirin
enhances the phosphorylation of ddI and thereby leads to an increased risk of
pancreatitis and mitochondrial toxicity in subjects receiving concomitant ribavirin
and ddI therapy (Moreno 2004). ddI use is therefore contraindicated in combination
with ribavirin, especially in patients who have already developed liver cirrhosis. The
use of HIV antiretrovirals such as AZT and d4T are also discouraged whenever
possible, as increased toxicity can be expected. RBV + AZT is associated with
enhanced anemia (Alvarez 2006) while RBV + d4T is associated with increased
mitochondrial toxicity and weight loss and a high potential to worsen pre-existing
lipoatrophy. Patients on atazanavir-containing HAART may develop jaundice due
to an increase in total serum bilirubin levels following initiation of ribavirin
(Rodriguez-Novoa 2008). As abacavir and ribavirin are both guanosine analogs it is
speculated that there may be interference or competition in the phosphorylation
pathway. Data from cohorts using lower dosages of ribavirin suggest lower SVR
results in patients on abacavir-containing HAART (Bani-Sadr 2007). However, in
the presence of therapeutic ribavirin levels no difference was observed between
abacavir and other nucleosides in achieving SVR in HIV/HCV-coinfected patients
receiving PEG-IFN/ribavirin therapy and concomitant HAART in other cohorts
(Laufer 2008, Amorosa 2010, Berenguer 2011).
Treatment of HCV for relapsers or non-responders
Patients with a history of previous HCV therapy who were either non-responders or
who relapsed while on previous HCV therapy need to be reassessed with regard to
new HVC treatment optimizing the dose and duration (see Table 4) as well as
potentially adding a new HCV protease inhibitor in HCV GT 1 patients. As soon as
Management of HCV/HIV Coinfection  311
sustained virologic response results from currently ongoing pilot trials of the new
HCV protease inhibitors in HIV/HCV coinfection become available, treatment
recommendations for hepatitis C genotype 1 in HIV-positive patients will change.
Recent results from the SLAM-C trial (ACTG 5178) have attenuated hopes that
maintenance therapy with PEG-INF might be beneficial for non-responders.
Table 4. Classification of and interventions for HCV/HIV-coinfected patients who are
non-responders/relapsers to prior IFN-based therapies.
Category  Subgroup  Recommended intervention
Suboptimal treatment  Suboptimal schedule
• Interferon monotherapy
• Low doses of ribavirin
• Short length of therapy
Re-treatment using
combination therapy of
PEG-IFN α plus weight-based
dose of ribavirin
Limiting toxicities &
poor adherence
Optimal support (SSRI,
paracetamol/NSAID*,
adherence
support, use of
hematopoietic
growth factors**)
Optimal treatment with
virologic failure
Relapse (HCV RNA
negative at the end
of treatment)
Re-treatment using
combination
therapy of PEG-IFN
plus weight-based
ribavirin dosing
(consider longer
treatment duration)
Non-response
(no HCV RNA
negativization
during treatment)
Wait until new antivirals
become available either
through clinical trials or
upon licensure
*NSAID, non-steroidal anti-inflammatory drugs; PEG, polyethylene glycol; SSRI, selective
serotonin reuptake inhibitors.
**Data on the use of hematopoietic growth factors in HIV/HCV co-infection so far is limited to an
improvement in quality of life but not antiviral efficacy; treatment with growth factors is currently
mostly off-label in Europe.
Treatment of acute HCV in HIV
As SVR rates following treatment of acute HCV infection are higher than for
treatment of chronic HCV, HCV RNA should be measured at initial presentation
and 4 weeks later in patients with acute HCV infection. Treatment should be offered
in patients without a decrease of 2 log10 of HCV RNA at 4 weeks compared with
initial HCV RNA and to patients with persistent serum HCV RNA 12 weeks after
diagnosis of acute HCV. Duration of treatment should be based on rapid virologic
response (RVR) regardless of genotype. Patients who do not achieve a ≥2 log10
decrease in HCV RNA level at week 12 should discontinue therapy (NEAT 2010).
Uncontrolled pilot studies of treatment of acute HCV infection in HIV-coinfected
312  Hepatology 2012
patients demonstrate SVR rates above 60% mostly with combination therapy of
PEG-IFN/RBV for 24-48 weeks (Boesecke 2011). Furthermore, recently presented
data from a large European cohort for the first time revealed the beneficial influence
of GT 2/3 infection on treatment outcomes in the setting of acute hepatitis C
suggesting different cure rates depending on HCV genotype similar to the genotype
effects seen in chronic HCV therapy. In this cohort, patients with GT 2/3 infection
were almost three times more likely to reach SVR than patients with GT 1/4
infection (Boesecke 2011). Unfortunately, clear guidance on treatment duration or
the role of ribavirin is difficult at this point due to the lack of controlled data.
Liver transplantation in HIV/HCV-coinfected
patients
In general, HIV/HCV-coinfected individuals develop more rapid HCV-related
hepatic injuries such as liver fibrosis and cirrhosis. Additionally, HIV/HCV
coinfection is associated with an increased rate of hepatocellular carcinoma (HCC).
Typically HCC occurs in HIV/HCV-coinfected patients at an earlier age and the
course is more aggressive with a shorter survival compared to HCV-monoinfected
individuals. Therefore, the presence of esophageal varices using upper-gastrointestinal endoscopy should be monitored in patients with liver cirrhosis every
1-2 years, and an ultrasound of the liver and a serum α-fetoprotein determination
should be performed at least every 6 months in patients with F3/F4 fibrosis
according to the recommendations of the European Consensus Guidelines (Alberti
2005).
Liver transplantation should be considered in patients with decompensated liver
cirrhosis, as this is a contraindication for HCV treatment. To fulfill the selection
criteria for a liver transplant in HIV/HCV-coinfected individuals the CD4+ count
has to be at least 100 cells/ml. Additionally, the patient has to have either
undetectable HIV viremia (<400 copies/ml) or at least rational treatment options to
control HIV infection successfully after liver transplantation. Further
contraindications for transplantation are opportunistic diseases, ongoing alcohol or
drug abuse, HCC metastasis in other organs, a second malignant disease,
cardiopulmonary disease or older age with an elevated risk of mortality related to
the operation. Recent data from a large US cohort sheds light on survival rates after
liver transplantation (Mindikoglu 2008). The estimated 2-year survival rate was
found to be somewhat lower in HIV-positive patients (70%) compared with HIV-negative patients (81%). This was mostly attributable to HBV or HCV coinfection.
Other studies have shown good outcome results in the setting of HBV/HIV
coinfection when compared to HBV mono-infection (Vogel 2005, Baccarani 2011).
This highlights the major problem in HCV/HIV-coinfected transplant recipients:
HCV re-infection of the transplanted organ. Recurrence of chronic hepatitis C in the
liver graft is frequently observed in HIV-positive patients and a more rapid
progression to graft cirrhosis and liver disease-related mortality compared to HCV-monoinfected patients has been reported. Therefore, combination therapy with
pegylated interferon plus ribavirin seems to be the best management option 1-3
months after liver transplantation and after re-infection with hepatitis C virus is
detected.
Management of HCV/HIV Coinfection  313
In the context of post-transplant immunosuppression, it is important to point out
that there are crucial pharmacokinetic drug-drug interactions at the level of the
cytochrome P450 metabolism and P-glycoprotein induction between the key
immunosuppressive drugs tacrolimus or cyclosporin A and the antiretroviral agents
used for HIV therapy. In addition the HCV protease inhibitors telaprevir and
boceprevir increase the drug levels of tacrolimus and cyclosporin A substantially.
Determinations of the plasma levels of the antiretroviral drugs and tacrolimus or
ciclosporine are necessary. Furthermore, the doses of cyclosporin A or tacrolimus
usually need to be reduced when the patient is treated concomitantly with an HIV
protease inhibitor, especially if boosted with ritonavir (Vogel 2004). By contrast,
NNRTIs can lower the concentrations of immunosuppressive drugs. The increase of
drug levels of tacrolimus and to a lesser extent ciclosporin A by telaprevir may
prevent the concomitant use of these drugs with telaprevir.
Conclusion
HIV has been shown to accelerate the progression of hepatitis C and to result in
higher liver disease-related mortality and morbidity in HIV/HCV-coinfected
patients compared to HCV-  or HIV-monoinfected individuals. Enhanced
hepatotoxicity of HAART as well as drug-drug interactions between HAART and
ribavirin clearly underline the need for specific treatment strategies. A number of
important clinical studies have established PEG-IFN plus ribavirin combination
therapy as the current gold standard allowing sustained virologic response rates of
almost 50% in HIV/HCV-coinfected individuals under optimized management
conditions (weight-based ribavirin and individualized treatment duration).
Nevertheless, the proportion of patients not treatable or those who relapse,
especially in patients with genotype 1 infection, remains high. However as soon as
sustained viral response results from currently ongoing pilot trials of the new HCV
protease inhibitors in HIV/HCV coinfection become available treatment
recommendations for hepatitis C genotype 1 in HIV patients will change.
References
Alberti A, Clumeck N, Collins S, et al. ECC Jury. Short statement of the first European
Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol. 2005;42:615-24. (Abstract)
Alvarez D, Dieterich DT, Brau N, Moorehead L, Ball L, Sulkowski MS. Zidovudine use but not
weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected
persons. J Viral Hepat. 2006;13:683-9. (Abstract)
Amorosa VK, Slim J, Mounzer K, et al. The influence of abacavir and other antiretroviral agents
on virological response to HCV therapy among antiretroviral-treated HIV-infected
patients. Antivir Ther. 2010;15:91-9. (Abstract)
Baccarani U, Adani GL, Bragantini F, et al. Long-term outcomes of orthotopic liver
transplantation in human immunodeficiency virus-infected patients and comparison
with human immunodeficiency virus-negative cases. Transplant Proc. 2011;43:1119-22. (Abstract)
Bani-Sadr F, Denoeud L, Morand P, et al. Agence Nationale pour la Recherche contre le SIDA
et les Hépatites Virales HC02-Ribavic Study Team. Early virologic failure in HIV-coinfected hepatitis C patients treated with the peginterferon-ribavirin combination:
does abacavir play a role? J Acquir Immune Defic Syndr. 2007;45:123-5. (Abstract)