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.
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300  Hepatology 2012
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302  Hepatology 2012
18. Management of HCV/HIV Coinfection
Christoph Boesecke, Stefan Mauss, Jürgen Kurt Rockstroh
Epidemiology of HIV and HCV coinfection
HIV and HCV share transmission pathways, which explains the high rate of
coinfection with both viruses. Of the 33.3 million HIV-infected persons worldwide
in 2009 it is estimated that at least 5 million of them had concomitant hepatitis C
virus infection. While both viruses are transmitted with high efficacy via blood-to-blood contact, HCV is less easily transmitted sexually. Thus, the prevalence of
hepatitis C coinfection within different countries, regions and populations is closely
related to the prevalence of blood-borne transmission (mainly intravenous drug use)
of HIV. Among HIV-infected patients in Europe, Australia and the US, at least one
out of four is coinfected with hepatitis C (Rockstroh 2004). Hepatitis C coinfection
rates as high as 70% can be found in Eastern European countries like Belarus and
the Ukraine and in Middle Eastern countries such as Iran where intravenous drug
use (IVDU) is the main route of HIV transmission (SeyedAlinaghi 2011). On the
other hand, in Central European countries such as Belgium, Austria or Germany,
where sexual intercourse dominates as mode of HIV transmission, hepatitis C
coinfection rates are rather low, between 10 and 15% (Rockstroh 2005, CDC 2011).
Similar rates can be found in HIV-positive patients in Australia (Jin 2009) and the
UK (Turner 2009). Interestingly, recent data from the US indicate that 25% to 35%
of patients with HIV are coinfected with HCV (Singal 2009, CDC 2011) reflecting
the contribution of at-risk populations such as prison inmates to the overall
numbers. 65-70% of HIV-positive prisoners in the US are coinfected with hepatitis
C, in contrast to 18-25% of the general US HIV-positive population (Weinbaum
2005, CDC 2011). In Asia, coinfection rates of up to 85% have been observed
among Chinese plasma donors whereas in countries with predominantly
heterosexual HIV transmission like Thailand coinfection rates are around 10%
(Qian 2006). In sub-Saharan Africa, where again the primary route of transmission
of HIV is sexual, HCV coinfection rates so far have been reported to be relatively
low.
Although the traditional route of HCV transmission is blood-borne and includes
IVDU, snorting drugs, sharing toothbrushes/razors, and tattooing (Bollepalli 2007),
recent epidemic outbreaks among HIV-positive men who have sex with men
(MSM) from several major European cities such as London, Paris, Amsterdam, and
Berlin as well as more recent reports from the US, Canada Australia and Taiwan
Management of HCV/HIV Coinfection  303
document that HCV may well be sexually transmitted and should therefore also be
taken into account at regular STD screenings (Gotz 2005, Danta 2007, Vogel 2009,
Vogel 2010, Matthews 2011, Schmidt 2011).
HCV is detected in 4-8% of infants born to HCV-infected mothers (Bevilacqua
2009). Dual HCV/HIV infection increases the risk for transmission of both viruses
and high levels of HCV viremia in the mother increases the risk of perinatal HCV
transmission (Zanetti 1995). However, in HIV/HCV-coinfected mothers receiving
HAART and undergoing cesarean section the risk of HCV transmission is strikingly
reduced to less than 1%.
In summary, the prevalence of hepatitis C within the HIV-infected population is
far higher than in the general population where the global burden of hepatitis C is
estimated to be roughly 2%. This highlights the importance of preventing further
spread of hepatitis C infection as one of the major co-morbidities in HIV-infected
individuals. The average estimated risk of transmission for hepatitis C in HIV is
depicted in Table 1. Although they share common routes of infection, the viruses
are transmitted with varying efficacy depending upon the mode of transmission.
Table 1. Average estimated risk of transmission for HIV, HCV and HCV/HIV
coinfection.
Mode of
transmission
HIV  HCV  HCV / HIV coinfection
Perinatal  7-50%  1-7%  1-20%
Sexual contact* 1-3%  <1%  <4%
Needle stick injury  0.3%  <1%  Unknown
* On sexual contact the sexual risk refers to cumulative exposure
Diagnosis of HCV in HIV coinfection
The presence of HCV can be confirmed serologically by the detection of antibodies
to the virus via ELISA testing. Loss of HCV antibodies observed in rare cases in
very advanced immune deficiency in HIV/HCV coinfection does not necessarily
indicate viral clearance (Cribier 1999). Therefore, a single negative HCV antibody
ELISA does not necessarily exclude HCV infection in HIV-positive patients,
especially in severe immune deficiency. Additionally, a rise of liver transaminases
has been proven to be more sensitive in the detection of acute HCV infection in
HIV-positive patients than repeated testing for the presence of antibodies against
HCV (Thomson 2009). However, in more than 80% of HIV-positive individuals
with positive HCV antibodies, HCV RNA is detected in the blood. Higher
concentrations of HCV RNA are found in HIV-positive individuals than in HIV-negative patients with hepatitis C (Perez-Olmeda 2002). Interestingly, recent data
from a cross-trial comparison showed that HIV-positive patients were less likely to
present with elevated serum ALT and clinical signs or symptoms of hepatitis than
HIV-negative patients (Vogel 2009). In observations from hemophiliac patients,
mean HCV RNA concentrations increased by 1 log10 over the first two years after
HIV seroconversion (Eyster 1994). Levels of HCV viremia increase eight times
faster in HIV-positive individuals than in HIV-negative patients with hepatitis C.
The highest concentrations for HCV viremia have been reported in patients who
subsequently developed liver failure.
304  Hepatology 2012
Interestingly, spontaneous clearance of HCV RNA has been observed in some
HIV/HCV-coinfected patients experiencing significant immune reconstitution
following HAART initiation (Fialaire 1999, Thomson 2009). In contrast, there are
also patients with positive HCV antibodies and negative HCV RNA in which HCV
RNA was noted to re-emerge frequently in combination with a flare of liver
transaminases after initiation of HAART. Therefore, regular monitoring of HCV
RNA levels is warranted in HIV/HCV-coinfected patients.
The distribution of HCV genotypes in HIV-positive patients reflects the route of
transmission. Genotype 1b accounts for 2/3 of post-transfusion HCV infections and
is the predominant genotype in hemophiliacs. In contrast, genotypes 1a and 3a are
more common in intravenous drug users (Pol 1994, Soriano 2008).
Natural course of hepatitis C in HIV coinfection
Various studies have demonstrated that underlying HIV infection weakens the
immune response to hepatitis C, thereby diminishing the chance of spontaneous
viral clearance of HCV infection. Interestingly, data from the European epidemic of
sexually transmitted acute hepatitis C infection in HIV-positive individuals suggest
that despite underlying HIV infection spontaneous resolution of HCV may occur in
up to 20-30% of newly infected patients (Vogel 2010, Thomson 2010). Recently,
genome-wide association studies identified single nucleotide polymorphisms (SNP)
near the IL28B gene encoding for interferon lambda that comprise a crucial part of
the host’s innate immune defence against HCV in HCV monoinfection (Thomas
2009). Individuals with the CC genotype were more than three times likely to clear
HCV RNA and to better respond to standard HCV therapy compared with
individuals with CT and TT genotypes (Rauch 2010, Grebely 2010, Nattermann
2011, Rallón 2011). Similar observations have been made in HIV/HCV coinfected
individuals (Clausen 2010). Interestingly, these SNPs could explain differences in
spontaneous clearance rates between different ethnicities as the frequency of the
protective allele varies across ethnic groups with a much lower frequency in those
of African origin compared to Asian patients with Europeans being in-between
(Thomas 2009).
Numerous large cohort studies have demonstrated that once chronic hepatitis C is
established the presence of HIV leads to a faster HCV clinical progression due to
the lack of critical CD4+ T cell responses against HCV (Danta 2008). In the
American multicenter Hemophiliac Cohort Study liver failure occurred in 9% of
multitransfused HCV/HIV-coinfected adult hemophiliacs without an AIDS-defining
opportunistic infection or malignancy (Eyster 1993). In the same time period, no
case of liver failure was observed in HCV-positive HIV-negative hemophiliacs.
Subsequently, several studies have confirmed the unfavorable course of hepatitis C
in HIV-coinfected hemophiliacs, particularly in the setting of progressive
immunodeficiency and lower CD4 counts (Rockstroh 1996, Puoti 2000).
In addition, the time interval between HCV exposition and development of
cirrhosis was found to be shortened in coinfected subjects. Indeed, within 10-15
years of initial HCV infection, 15-25% of HIV-coinfected patients develop cirrhosis
compared with 2-6% of HIV-negative patients (Soto 1997). Importantly, mortality
due to advanced liver disease occurs ten years earlier in coinfected hemophiliacs
than in HIV-negative hemophiliacs with hepatitis C (Darby 1997). The incidence of
Management of HCV/HIV Coinfection  305
hepatocellular carcinoma seems also to be higher in coinfected patients (Giordano
2004).
Effect of hepatitis C on HIV infection
As clear as HIV’s influence on the accelerated disease progression for HCV-associated liver disease is, HCV’s influence on the course of HIV disease is
conflicting. The Swiss Cohort first revealed a blunted CD4 cell response associated
with a faster progression to AIDS after initiation of HAART in HIV/HCV-coinfected patients (Greub 2000). Interestingly, four-year follow-up data from the
same cohort study did not detect significant differences with regard to CD4 cell
count recovery between HCV-positive and HCV-negative HIV-positive patients
(Kaufmann 2003). Subsequent studies have indeed found that after adjusting for use
of HAART, no difference in CD4 cell count recovery can be observed (Sulkowski
2002). Updated information from an analysis of the EuroSIDA cohort, after taking
into account ongoing chronic (persistent HCV replication) and resolved (positive
HCV antibodies but negative HCV RNA) hepatitis C infection, confirm that no
difference in CD4 cell count recovery is observed in patients with chronic hepatitis
C infection and detectable HCV RNA in comparison to HIV-monoinfected patients
(Rockstroh 2005). In addition, data from the same cohort revealed that CD4-positive
T cell recovery in HIV-positive patients with maximal suppression of HIV
replication is not influenced by HCV serostatus in general or HCV genotype or level
of HCV in particular (Peters 2009).
Effect of HAART on hepatitis C
In HIV/HCV-coinfected patients starting antiretroviral therapy a transient increase
in HCV RNA levels may occur at week 4 but thereafter no significant changes in
concentrations of HCV RNA happen over the first six months of treatment
(Rockstroh 1998). However, a 1 log10 decrease of HCV RNA has been reported in
HIV/HCV-coinfected individuals receiving more than 12 months of HAART and
having significant immune reconstitution. Other investigators, however, have not
observed this decrease in HCV RNA. Moreover, eradication of HCV has been
reported in individual patients receiving HAART following CD4 count recovery.
There is increasing evidence that HAART-induced immune reconstitution might
reverse the unfavorable accelerated course for hepatitis C in patients with severe
HIV-associated immune deficiency (Verma 2006, Vogel 2009). Taking into account
that liver disease progresses especially in those whose CD4 count drops below
200/µl it is appealing to think that CD4 increases on HAART may impact the
further course of liver disease. In an early study of 162 individuals with HIV/HCV
coinfection who underwent liver biopsy, the use of protease inhibitors as part of
their HAART regimen was associated with significantly lower rates of progression
of liver fibrosis that could not be explained by other cofactors (Benhamou 2000).
These findings were then confirmed by several cohort analyses which showed that
HIV/HCV-coinfected individuals on HAART had significantly lower liver-related
mortality than patients receiving either suboptimal (one or two nucleoside reverse
transcriptase inhibitors) or no antiretroviral therapy (Qurishi 2003).

Book on hepatitis from page 282 to 299

Book on hepatitis from page 282 to 299

282  Hepatology 2012
HCV-related glomerulonephritis
Glomerulonephritis (GN) constitutes a rare extrahepatic complication of chronic
HCV. Predominant manifestations are cryoglobulinemic or non-cryoglobulinemic
membranous proliferative GN and mesangioproliferative GN. Far less common is
membranous nephropathy (Arase 1998). Other forms of GN do not correlate
significantly with HCV infection (Daghestani 1999). Microhematuria and
proteinuria are among the most frequent medical findings in patients with
membranous proliferative GN. Approximately 50% of patients exhibit a mild renal
insufficiency. 20-25% may present an acute nephritic syndrome (hematuria,
hypertension and proteinuria), as in 25% of patients nephrotic syndrome represents
the initial manifestation. In contrast, >80% of patients with HCV-related
membranous nephropathy suffer primarily a nephrotic syndrome (Doutrelepont
1993,  Rollino 1991). The mesangioproliferative form proceeds mostly
asymptomatically, with typical findings such as hematuria and proteinuria often
missing (McGuire 2006).
The pathomechanism of renal impairment is yet not fully understood. It can be
hypothesized that glomerular injury is primarily caused by a deposition of
circulating immunocomplexes containing anti-HCV antibodies, HCV antigens and
complement factors. Formation and deposition of such immunocomplexes occurs
also in the absence of CGs. HCV-proteins in glomerular and tubulointerstitial
structures are immunohistologically detectable in approximately 70% of patients
with chronic HCV (Sansonno 1997). Further possible pathomechanisms of
glomerular injury encompass formation of glomerular autoantibodies, glomerular
impairment due to chronic hepatic injury, or IgM overproduction with consecutive
glomerular IgM deposition as result of HCV-triggered cryoglobulinemia type II. GN
prevalence in HCV patients is estimated at 1.4% and is comparably high due to its
prevalence among blood donors (Paydas 1996).
HCV-induced GN has mostly a benign prognosis (Daghestani 1999). 10-15% of
patients with nephritic syndrome experience spontaneous complete or partial
remission. Frequently persisting mild proteinuria exhibits no tendency to
progression. It is estimated that only approximately 15% of the patients with HCV-related GN develop terminal renal failure requiring dialysis (Tarantino 1995).
Nevertheless, presence of kidney impairment is considered to be a negative
prognostic factor for long-term survival (Ferri 2004).
Patients with HCV-related GN should be primarily treated with antivirals. In
cases of mild renal impairment, sustained viral response normally leads to
amelioration of proteinuria or even full remission of GN. With high baseline
viremia and advanced renal insufficiency, antiviral therapy is subject to certain
limitations (Sabry 2002). Despite amelioration of proteinuria achieved after antiviral
therapy, significant improvement of renal function is often lacking (Alric 2004).
PEG-IFN and ribavirin dosage must be cautiously adjusted to glomerular filtration
rate (GFR), in order to mainly prevent ribavirin accumulation with consecutive
hemolytic anemia (Fabrizi 2008). Even in advanced renal failure, use of ribavirin is
recommended due to the superior efficacy of combination therapy vs. IFN
monotherapy (Bruchfeld 2003, Baid-Agrawal 2008). In patients with GFR <30
ml/min ribavirin dosage should not exceed 600 mg/week. Careful dosage
augmentation may be undertaken in the absence of side effects. Ribavirin dosages
Extrahepatic Manifestations of Chronic HCV  283
up to 100-400 mg/day was done under vigilant blood level monitoring in dialysis
patients. Ribavirin-induced hemolytic anemia was efficiently treated by
administration of erythropoietin and erythrocyte concentrates (van Leusen 2008).
As determination of ribavirin blood levels is not an established laboratory
procedure, implementation of such a therapeutic approach in clinical routine
remains arduous. No dose reduction is required with respect to renal impairment for
the two licensed protease inhibitors boceprevir and telaprevir (see also Chapters 14
and 15).
Fulminant manifestations with impending acute renal failure make administration
of corticosteroids, immunosuppressive drugs such as cyclophosphamide and
eventually plasmapheresis necessary (Garini 2007,  Margin 1994). In cases of
simultaneous bone marrow B cell infiltration and/or resistance to conventional
therapy, application of rituximab is indicated (Roccatello 2004). Rituximab may be
used as an alternative first line therapy in severe renal manifestations (Roccatello
2008). Antiviral and immunosuppressive therapy should always be supplemented
with ACE inhibitors or AT1 receptor antagonists (Kamar 2006).
Endocrine manifestations
Thyroid disease is found more commonly in patients with chronic HCV infection
than in the general population. About 13% of HCV-infected patients have
hypothyroidism and up to 25% have thyroid antibodies (Antonelli 2004). There is
also evidence that IFN α may induce thyroid disease or unmask preexisting silent
thyroidopathies (Graves disease, Hashimoto thyroiditis) (Prummel 2003). In
addition, some studies suggest that thyroid autoimmune disorders were significantly
present in patients with chronic hepatitis C during but not before IFN α therapy
(Marazuela 1996, Vezali 2009). Therefore, the role of chronic hepatitis C infection
per se in the development of thyroid disorders remains to be determined. The
presence of autoantibodies against thyroid with/or without clinical manifestations
increases the risk of developing an overt thyroiditis significantly during antiviral
therapy. Therefore, monitoring of the thyroid function should be performed during
treatment.
Association between chronic HCV infection and development of insulin
resistance and diabetes mellitus has been discussed in the past (Knobler 2000;
Mason 1999, Hui 2003, Mehta 2003). In the meantime, a causal association is
backed up by studies demonstrating that antiviral therapy with consecutive
sustained viral response correlates with improved diabetic metabolic status and
resolution of insulin resistance (Kawaguchi 2007). A recently published meta-analysis of retrospective and prospective studies confirms a high risk for the
development of diabetes mellitus type II in patients with chronic HCV infection
(OR=1.68, 95%, CI 1.15-2.20) (White 2008). Viral induction of insulin resistance
seems to be HCV-specific, as prevalence of diabetes mellitus in HBV-infected
patients is significantly lower (White 2008, Imazeki 2008). The pathomechanism of
HCV-induced insulin resistance is yet not fully understood. It has been suggested
that the appearance of insulin resistance could correlate with certain genotypes of
HCV. Furthermore, HCV-dependent upregulation of cytokine suppressor SOC-3
may be responsible for the induction of cell desensitisation towards insulin. Insulin
284  Hepatology 2012
resistance in turn represents an independent risk factor for progression of liver
fibrosis in patients with chronic HCV infection (Moucari 2008, Kawaguchi 2004).
Finally, a link between HCV, growth hormone (GH) insufficiency and low
insulin-like growth factor (IGF-1) has been hypothesized. Reduced GH secretion
could be the result of a direct inhibitory effect of HCV infection at the level of the
pituitary or hypothalamus (Plöckinger 2007).
Dermatologic and miscellaneous manifestations
A multitude of cutaneous disorders has been sporadically associated with chronic
HCV infection (Hadziyannis 1998). Epidemiologic studies have confirmed the
existence of a strong correlation between the sporadic form of porphyria cutanea
tarda (PTC) and HCV, though the presence of HCV in PTC patients seems to be
subject to strong regional factors. Indeed, HCV prevalence in PTC patients is higher
than 50% in Italy, while only 8% in Germany (Fargion 1992, Stölzel 1995).
Strong evidence of a close association between HCV and lichen planus was
provided by studies performed in Japan and southern Europe (Nagao 1995,
Carrozzo 1996), yet these observations do not apply to all geographic regions
(Ingafou 1998). HLA-DR6 has been recognized as a major predisposing factor for
development of lichen planus in HCV-positive patients. One hypothesis suggests
that geographical fluctuation of HLA-DR6 is responsible for the diverse prevalence
among HCV patients (Gandolfo 2002).
Idiopathic pulmonary fibrosis (IPF) represents potentially an EHM, as prevalence
of anti-HCV in patients with this disease is notably high (Ueda 1992). Interestingly,
alveolar lavage in therapy-naïve HCV patients yielded frequent findings consistent
with a chronic alveolitis. Alveolar lavage in the same patients after completion of
antiviral therapy showed a remission of inflammatory activity (Yamaguchi 1997).
Involvement of CGs in the genesis of IPF is also probable (Ferri 1997).
Numerous central nervous manifestations have been described in association with
HCV infection. Cryoglobulinemic or non-cryoglobulinemic vasculitis of cerebral
blood vessels may be responsible for the relatively high prevalence of both ischemic
and hemorrhagic strokes in young HCV-positive patients (Cacoub 1998).
Transverse myelopathies leading to symmetrical paraparesis and sensory deficiency
have been recently observed (Aktipi 2007).
Furthermore, chronic HCV infection is associated with significant impairment of
quality of life. 35-68% of HCV patients suffer from chronic fatigue, subclinical
cognitive impairment and psychomotor deceleration. Symptoms of depression are
evident in 2-30% of HCV patients examined (Perry 2008, Forton 2003, Carta 2007).
Psychometric as functional magnetic resonance spectroscopy studies suggest altered
neurotransmission in HCV-positive groups (Weissenborn 2006, Forton 2001). In
addition, significant tryptophan deficiency is detectable in patients with chronic
HCV infection. Resulting deficiency of the tryptophan-derived serotonin is likely to
favor an occurrence of depressive disorders. There is evidence to suggest that
antiviral therapy can lead to elevation of tryptophan blood levels and thus contribute
to amelioration of depressive symptoms in HCV patients (Zignego 2007c).
Occasionally, chronic HCV infection has been seen in association with cardiac
pathologies such as chronic myocarditis and dilatative/hypertrophic
Extrahepatic Manifestations of Chronic HCV  285
cardiomyopathy. Pathogenesis seems to rely on genetic predisposition and is
assumed to be immunologically triggered (Matsumori 2000).
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Management of HBV/HIV coinfection  291
17. Management of HBV/HIV coinfection
Stefan Mauss and Jürgen Kurt Rockstroh
Introduction
The prevalence and transmission routes of HBV coinfection in the HIV+ population
vary substantially by geographic region (Alter 2006, Konopnicki 2005). In the
United States and Europe the majority of HIV+ homosexual men have evidence of
past HBV infection, and 5-10% show persistence of HBs antigen with or without
replicative hepatitis B as defined by the presence of HBV DNA (Konopnicki 2005).
Overall, rates of HBV/HIV coinfection are slightly lower among intravenous drug
users compared to homosexual men and much lower among people infected through
heterosexual contact (Núñez 2005).
In endemic regions of Africa and Asia, the majority of HBV infections are
transmitted vertically at birth or before the age of 5 through close contact within
households, medical procedures and traditional scarification (Modi 2007). The
prevalence among youth in some Asian countries has substantially decreased since
the introduction of vaccination on nationwide scales (Shepard 2006). In Europe
vaccination of children and members of risk groups is reimbursed by health care
systems in most countries.
The natural history of hepatitis B is altered by simultaneous infection with HIV.
Immune control of HBV is negatively affected leading to a reduction of HBs
antigen seroconversion. If HBV persists, the HBV DNA levels are generally higher
in untreated patients (Bodsworth 1989, Bodsworth 1991, Hadler 1991). In addition,
with progression of cellular immune deficiency, reactivation of HBV replication
despite previous HBs antigen seroconversion may occur (Soriano 2005). In the
untreated HIV-positive population, faster progression to liver cirrhosis is reported
for HBV/HIV-coinfected patients (Puoti 2006). Moreover, hepatocellular carcinoma
may develop at an earlier age and is more aggressive in this population (Puoti 2004,
Brau 2007).
Being HBV-coinfected results in increased mortality for HIV-positive individuals,
even after the introduction of highly active antiretroviral combination therapy
(HAART), as demonstrated by an analysis of the EuroSIDA Study, which shows a
3.6-fold higher risk of liver-related deaths among HBsAg-positive patients
compared to HBsAg-negative individuals (Konopnicki 2005, Nikolopoulos 2009)
(Figure 1). In the Multicentre AIDS Cohort Study (MACS), an 8-fold increased risk
of liver-related mortality was seen among HBV/HIV-coinfected compared to HIV-
292  Hepatology 2012
monoinfected individuals, particularly among subjects with low nadir CD4-postive
cell counts (Thio 2002). An independent observation from a large cohort confirming
this association is the reduction in mortality for HBV/HIV-coinfected patients
treated with lamivudine compared to untreated patients (Puoti 2007). This result is
even more remarkable because lamivudine is one of the least effective HBV
polymerase inhibitors due to a rather rapid development of resistance. In general,
due to its limited long-term efficacy, lamivudine monotherapy for HBV cannot be
considered as appropriate therapy (Matthews 2011).
Figure 1. Association of HBV/HIV coinfection and mortality (Konopnicki 2005). More than
one cause of death allowed per patient; p-values from chi-squared tests.
These two large cohort studies (EuroSIDA and MACS) plus data from HBV
monoinfection studies showing a reduction in morbidity and mortality justify
treatment of hepatitis B in HBV/HIV-coinfected patients. HBV is often treated
simultaneously with HIV, as some nucleoside and nucleotide reverse transcriptase
inhibitors are active as HBV polymerase inhibitors as well. Therefore, antiretroviral
therapy should be adjusted according to HBV status wherever possible to avoid
higher pill burden and additional toxicities. A less frequent but more challenging
situation is the initiation of HBV therapy in HIV-coinfected individuals who are not
on antiretroviral therapy. Treatment with interferon is one possible therapeutic
option in this situation. The main limitation of some HBV polymerase inhibitors
may be induction of HIV resistance by the anti-HBV agents as they act
simultaneously as HIV reverse transcriptase inhibitors.
Management of HBV/HIV coinfection  293
Figure 2. Treatment algorithm for therapy of HBV in HIV-coinfected patients (EACS 2011).
a) Cirrhotic patients should be referred for variceal assessment, have regular HCC monitoring
and be referred early for transplant assessment.
b) See Figure 5 for assessment of HBV Rx indication. Some experts strongly think that any
HBV-infected patient requiring HAART should receive TDF + 3TC or FTC unless history of TDF
intolerance, particularly in HIV/HBV coinfected patients with advanced liver fibrosis (F3/F4).
c) If patient is unwilling to go on early HAART, adefovir and telbivudine may be used as an
alternative to control HBV alone. Recently a case report suggested anti-HIV activity of
telbivudine. In vitro data using an assay able to demonstrate anti-HIV activity of entecavir failed
to detect an influence of telbivudine on the replicative capacity of HIV-1. Treatment duration: in
patients not requiring HAART and on treatment with telbivudine +/– adefovir, or those on
HAART where nucleoside backbone needs changing, anti-HBV therapy may be stopped
cautiously in HBeAg+ patients who have achieved HBe seroconversion or HBs seroconversion
for at least six months or, after HBs seroconversion; for at least six months in those who are
HBeAg-.
d) Treatment length: 48 weeks for PEG-INF; on-treatment quantification of HBsAg in patients
with HBeAg-negative chronic hepatitis B treated with PEG-INF may help identify those likely to
reach HBs-antigen seroconversion with this therapy and optimize treatment strategies.
e) In some cases of tenofovir intolerance (i.e., renal disease), entecavir or tenofovir in doses
adjusted to renal clearance in combination with effective HAART may be advisable. NRTI
substitution should only be performed if feasible and appropriate from the perspective of
maintaining HIV suppression. Caution is warranted in switching from a tenofovir-based regimen
to drugs with a lower genetic barrier, e.g., FTC/3TC, in particular in lamivudine-pretreated
cirrhotic patients, as viral breakthrough due to archived YMDD mutations has been observed.
This has also been described in individuals with previous 3TC HBV resistance who have been
switched from tenofovir to entecavir.
HBV therapy in HBV/HIV-coinfected patients
without HIV therapy
The recommendations of the updated European AIDS Clinical Society (EACS) for
the treatment of chronic hepatitis B in HIV-coinfected patients without antiretroviral
therapy are shown in Figure 2 (EACS 2011). Starting hepatitis B therapy depends
on the degree of liver fibrosis and the HBV DNA level. Using the level of HBV
294  Hepatology 2012
replication as the basis for treatment decisions is an important change of paradigm
in HBV therapy. This decision is based on the results of the REVEAL study (Iloeje
2006). REVEAL followed the natural course of chronic hepatitis B without liver
cirrhosis in about 3700 Taiwanese patients for more than 10 years. In these HBV-monoinfected patients an HBV DNA of >10,000 copies/ml (i.e., 2000 IU/ml) had a
markedly increased risk of developing liver cirrhosis and hepatocellular carcinoma
(Figure 3). This association was even observed in patients with normal ALT levels
(Chen 2006) (Figure 4).
Figure 3. REVEAL Study: Association of HBV DNA levels and liver cirrhosis (Iloeje 2006).
Figure 4. REVEAL Study: Association of HBV DNA with the development of
hepatocellular carcinoma (Chen 2006).
Management of HBV/HIV coinfection  295
It should be mentioned that this cohort consisted of Asian patients without HIV
coinfection predominantly infected at birth or in early childhood. However, the
results were considered too important not to form part of the management of HIV-coinfected patients.
Usually patients with an HBV DNA of less than 2000 IU/ml have no substantial
necroinflammatory activity in the liver and therefore a benign course of fibrosis
progression and a low risk for the development of hepatocellular carcinoma.
However, especially in patients harbouring HBV precore mutants, fluctuations in
HBV DNA and ALT are not rare. Monitoring of the activity of the HBV DNA and
ALT accompanied by an abdominal ultrasound every 6-12 months is recommended.
In the case of HBV DNA <2000 IU/ml and elevated transaminases and/or signs of
advanced liver fibrosis, alternative causes of hepatitis and liver toxicity should be
excluded.
For patients with HBV DNA >2000 IU/ml the ALT level is the next decision
criterion. Patients with normal ALT should be assessed for liver fibrosis by liver
biopsy or elastometry. In case of lack of substantial liver fibrosis (METAVIR stage
F0/1) monitoring of the activity of the HBV DNA and ALT accompanied by an
ultrasound every 3-6 months is recommended. In the presence of liver fibrosis of
METAVIR F2 or higher, hepatitis B treatment should be initiated.
For patients with HBV DNA >2000 IU/ml and increased ALT, treatment for HBV
is an option particularly in the presence of relevant liver fibrosis.
In patients not taking antiretroviral therapy, pegylated interferon α-2a or -2b
seems a suitable option. However, data in the literature for HIV-coinfected patients
on interferon therapy for HBV infection are limited and not very encouraging
(Núñez 2003). For pegylated interferons no data from larger cohorts exist and one
study combining pegylated interferon with adefovir  did not show encouraging
results (Ingiliz 2008). Favourable factors for treatment success with interferon are
low HBV DNA, increased ALT, HBV genotype A or infection with HBV wild type.
Alternatively patients can be treated with polymerase inhibitors. However, due to
their antiretroviral activity tenofovir, emtricitabine and lamivudine are
contraindicated in the absence of effective HIV therapy. In contrast to in vitro data
reported by the manufacturer, antiretroviral activity and induction of the HIV
reverse transcriptase mutation M184V was reported for entecavir (MacMahon
2007). Currently only telbivudine and adefovir are considered reasonably safe
treatment options. There is limited  in vivo data for adefovir to support this
recommendation (Delaugerre 2002; Sheldon 2005). For telbivudine in vitro data are
available showing a specific inhibitory activity on the HBV polymerase and no
effect on HIV (Avilla 2009). However, in contrast with this, two case reports have
suggested antiretroviral activity of telbivudine (Low 2009, Milazzo 2009).
Because of its greater antiviral efficacy, telbivudine is preferred by most experts
to adefovir (Chan 2007). Alternatively an add-on strategy of telbivudine to adefovir
in the case of not fully suppressive antiviral therapy or primary combination therapy
of both drugs can be considered although clinical data are not yet available for this
strategy.
As both drugs have limitations in the setting of HBV-monoinfected patients due
to considerable development of resistance to telbivudine and the limited antiviral
efficacy of adefovir, the initiation of antiretroviral therapy using tenofovir plus
296  Hepatology 2012
lamivudine or emtricitabine should be considered, particularly in HIV-coinfected
patients with advanced liver fibrosis.
The treatment duration is determined by HBe antigen or HBs antigen
seroconversion, like with HBV-monoinfected patients. In case of infection with a
precore mutant HBs antigen seroconversion is the biological endpoint.
Treatment of chronic hepatitis B in HBV/HIV-coinfected patients
For patients on antiretroviral therapy a wider choice of polymerase inhibitors is
available. In principle, the treatment algorithm of Figure 5 is based on the same
principles as outlined above (EACS 2011).
Initiating antiretroviral therapy with tenofovir resulted in higher rates of HBe
antigen loss and seroconversion as expected from HBV-monoinfected patients
(Schmutz 2006, Piroth 2010). This may be due to the additional effect of immune
reconstitution in HIV-coinfected patients adding another aspect to the
immunological control of HBV replication.
For patients with HBV DNA <2000 IU/ml and no relevant liver fibrosis no
specific antiretroviral regimen is recommended. However when choosing an HBV
polymerase inhibitor, the complete suppression of HBV DNA is important to avoid
the development of HBV resistance mutations. The activity of the HBV infection in
these patients should be assessed at least every six months as part of routine
monitoring of the HIV infection including an ultrasound due to the slightly
increased risk of hepatocellular carcinoma.
Figure 5. Treatment algorithm for HBV therapy in patients with antiretroviral therapy
(EACS 2011).
When HBV DNA is above 2000 IU/ml in naïve  patients a combination of
tenofovir plus lamivudine/emtricitabine to treat both infections is recommended.
Even for patients who harbour lamivudine-resistant HBV due to previous therapies
Management of HBV/HIV coinfection  297
this strategy stands. The recommendation to continue lamivudine/emtricitabine is
based on the delay of resistance to adefovir seen when doing so (Lampertico 2007).
For patients with liver cirrhosis a maximally active continuous HBV polymerase
inhibitor therapy is important to avoid hepatic decompensation and reduce the risk
of developing hepatocellular carcinoma. Tenofovir plus lamivudine/emtricitabine is
the treatment of choice. If the results are not fully suppressive, adding entecavir
should be considered (Ratcliffe 2011). At least every six months, assessement of the
liver by ultrasound for early detection of hepatocellular carcinoma is necessary. In
patients with advanced cirrhosis gastroscopy should be performed as screening for
esophageal varices.
For patients with hepatic decompensation and full treatment options for HBV and
stable HIV infection, liver transplantation should be considered, as life expectancy
seems to be the same as for HBV-monoinfected patients (Coffin 2007, Tateo 2009).
Patients with hepatocellular carcinoma may be considered liver transplant
candidates as well, although according to preliminary observations from small
cohorts, the outcome may be worse than for HBV-monoinfected patients with
hepatocellular carcinoma (Vibert 2008).
In general, tenofovir can be considererd the standard of care for HBV in HIV-coinfected patients, because of its efficacy and its strong HBV polymerase activity.
Tenofovir has been a long-acting and effective therapy in the vast majority of
treated HBV/HIV-coinfected patients (van Bömmel 2004, Mathews 2009, Martin-Carbonero 2011, Thibaut 2011). No conclusive pattern of resistance mutations has
been identified in studies or cohorts (Snow-Lampart 2011). But resistance is likely
to occur in patients  with long-term therapy as with any other antiviral. In
prospective controlled studies tenofovir was clearly superior to adefovir for
treatment of HBe antigen-positive and HBe antigen-negative patients (Marcellin
2008).
The acquisition of adefovir resistance mutations and multiple lamivudine
resistance mutations may impair the activity of tenofovir (Fung 2005, Lada 2008,
van Bömmel 2010), although even in these situations tenofovir retains activity
against HBV (Berg 2008, Petersen 2009).
In lamivudine-resistant HBV the antiviral efficacy of entecavir in HIV-coinfected
patients is reduced, as it is in HBV monoinfection (Shermann 2008). Because of this
and the property of tenofovir as an approved antiretroviral, tenofovir is the preferred
choice in treatment-naïve HIV-coinfected patients who have an antiretroviral
treatment indication. The use of entecavir, telbivudine
or adefovir as an add-on to tenofovir or other drugs in the case of not fully
suppressive antiviral therapy has not been studied in HIV-coinfected patients so far.
The decision to do so is made on a case-by-case basis.
It was a general belief originating from the history of antiretroviral therapy that
combination therapy of tenofovir plus lamivudine/emtricitabine would be superior
to tenofovir monotherapy, in particular in patients with highly replicative HBV
infection. However, to date no conclusive studies supporting this are available
(Schmutz 2006, Mathews 2008, Mathews 2009).
In the case of development of HIV resistance to tenofovir it is important to
remember its HBV activity before switching to another regimen without antiviral
activity against HBV. Discontinuation of the HBV polymerase inhibitor without
298  Hepatology 2012
maintaining the antiviral pressure on HBV can lead to necroinflammatory flares that
can result in acute liver decompensation in serious cases.
A matter of concern is the potentially nephrotoxic effect of tenofovir. In patients
treated with tenofovir monotherapy nephrotoxicity is rarely observed (Heathcote
2011, Mauss 2011). However in HIV-infected patients treated with tenofovir as part
of an antiretroviral combination therapy renal impairment has been frequently
reported and may be associated in particular with the combined use of tenofovir and
HIV protease inhibitors (Mauss 2005,  Fux 2007,  Goicoecha 2008). Regular
monitoring of renal function in HBV/HIV-coinfected patients including estimated
glomerular filtration rate and assessment of proteinuria is necessary.
Management of resistance to HBV polymerase
inhibitors
Issues concerning the avoidance and management of resistance to HBV polymerase
inhibitors are discussed in detail in Chapter 10.
Conclusion
The number of available HBV polymerase inhibitors for chronic hepatitis B has
increased substantially over the last few years. In general though, the choice is
confined to two mostly non-cross-resistant classes, the nucleotide and nucleoside
compounds. In HIV-coinfected patients where antiretroviral therapy is not indicated
the choice is more limited with only adefovir and telbivudine as treatment options.
Alternative options in these patients may be interferon therapy or the initiation of
full antiretroviral therapy, which is currently preferred by most experts, although
both toxicities and costs may increase.
For HBV/HIV-coinfected patients on antiretroviral therapy the treatment of
choice is tenofovir in the majority of treatment-naïve or lamivudine-pretreated
cases. Due to rapid development of resistance in not fully suppressive HBV therapy
lamivudine or emtricitabine monotherapy should not be considered in the vast
majority of cases. A combination of tenofovir plus lamivudine or emtricitabine as a
primary combination therapy has theoretical advantages, but studies supporting this
concept have not been published to date.
In general, treatment of HBV as a viral disease follows the same rules as HIV
therapy, aiming at a full suppression of the replication of the virus to avoid the
development of resistance. Successful viral suppression of hepatitis B results in
inhibition of necroinflammatory activity, reversion of fibrosis and the ultimate goal
of immune control of the infection.
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