Book on hepatitis from page 300 to 305

Book on hepatitis from page 300 to 305

300  Hepatology 2012
Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil
for chronic hepatitis B. N Engl J, et al. Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues. AIDS
2011;25:73-9.
Matthews GV, Avihingsanon A, Lewin SR, et al. A randomized trial of combination hepatitis B
therapy in HIV/HBV coinfected antiretroviral naïve individuals in Thailand. Hepatology
2008;48:1062-9. (Abstract)
Matthews GV, Seaberg E, Dore GJ, Bowden S, Lewin SR, Sasadeusz J, et al. Combination
HBV therapy is linked to greater HBV DNA suppression in a cohort of lamivudine-experienced HIV/HBV coinfected individuals. AIDS 2009;23:1707-15. (Abstract)
Matthews GV, Manzini P, Hu Z, et al. Impact of lamivudine on HIV and hepatitis B virus-related
outcomes in HIV/hepatitis B virus individuals in a randomized clinical trial of
antiretroviral therapy in southern Africa. AIDS 2011;25:1727-35. (Abstract)
Mauss S, Berger F, Schmutz G. Antiretroviral therapy with tenofovir is associated with mild
renal dysfunction. AIDS 2005;19:93-5. (Abstract)
Mauss S, Berger F, Filmann N, et al. Effect of HBV polymerase inhibitors on renal function in
patients with chronic hepatitis B. J Hepatol 2011;55:1235-40. (Abstract)
McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir - effects on HIV-1
replication and resistance. N Engl J Med 2007;356:2614-21. (Abstract)
Milazzo L, Caramma I, Lai A, et al. Telbivudine in the treatment of chronic hepatitis B:
experience in HIV type-1-infected patients naive for antiretroviral therapy. Antivir Ther
2009;14:869-72. (Abstract)
Modi A, Feld J. Viral hepatitis and HIV in Africa. AIDS Rev 2007;9:25-39. (Abstract)
Núñez M, Puoti M, Camino N, Soriano V. Treatment of chronic hepatitis B in the human
immunodeficiency virus-infected patient: present and future. Clin Infect Dis
2003;37:1678-85. (Abstract)
Nikolopoulos GK, Paraskevis D, Hatzitheodorou E, et al. Impact of hepatitis B virus infection on
the progression of AIDS and mortality in HIV-infected individuals: a cohort study and
meta-analysis. Clin Infect Dis 2009;48:1763-71. (Abstract)
Núñez M, Soriano V. Management of patients co-infected with hepatitis B virus and HIV. Lancet
Infect Dis 2005;5:374-82. (Abstract)
Petersen J, Ratziu V, Buti M, et al. Entecavir plus tenofovir combination as rescue therapy in
pre-treated chronic hepatitis B patients: An international multicenter cohort study. J
Hepatol 2011. [Epub ahead of print] (Abstract)
Piroth L, Pol S, Lacombe K, Miailhes P, et al. Management and treatment of chronic hepatitis B
virus infection in HIV positive and negative patients: the EPIB 2008 study. J Hepatol
2010;53:1006-12. (Abstract)
Puoti M, Bruno R, Soriano V, et al. Hepatocellular carcinoma in HIV-infected patients:
epidemiological features, clinical presentation and outcome. AIDS 2004;18:2285-93.
(Abstract)
Puoti M, Cozzi-Lepri A, Arici C, et al. Impact of lamivudine on the risk of liver-related death in
2,041 HBsAg- and HIV-positive individuals: results from an inter-cohort analysis.
Antivir Ther 2006;11:567-74. (Abstract)
Puoti M, Torti C, Bruno R. Natural history of chronic hepatitis B in co-infected patients. J
Hepatol 2006;44:65-70. (Abstract)
Ratcliffe L, Beadsworth MB, Pennell A, Phillips M, Vilar FJ. Managing hepatitis B/HIV co-infected: adding entecavir to truvada (tenofovir disoproxil/emtricitabine) experienced
patients. AIDS 2011;25:1051-6. (Abstract)
Schmutz G, Nelson M, Lutz T, et al. Combination of tenofovir and lamivudine versus tenofovir
after lamivudine failure for therapy of hepatitis B in HIV-coinfection. AIDS
2006;20:1951-4.
Sheldon JA, Corral A, Rodés B, et al. Risk of selecting K65R in antiretroviral-naive HIV-infected
individuals with chronic hepatitis B treated with adefovir. AIDS 2005;19:2036-8.
(Abstract)
Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology
and vaccination. Epidemiol, et al. Entecavir therapy for lamivudine-refractory chronic
hepatitis B: improved virologic, biochemical, and serology outcomes through 96
weeks. Hepatology 2008;48:99-108. (Abstract)
Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to tenofovir disoproxil fumarate
detected after up to 144 weeks of therapy in patients monoinfected with chronic
hepatitis B virus. Hepatology 2011;53:763-73.
Management of HBV/HIV coinfection  301
Soriano V, Puoti M, Bonacini M. Care of patients with chronic hepatitis B and HIV co-infection:
recommendations from an HIV-HBV international panel. AIDS 2005;19:221-240.
Soriano V, Mocroft A, Peters L, et al. Predictors of hepatitis B virus genotype and viraemia in
HIV-infected patients with chronic hepatitis B in Europe. J Antimicrob Chemother
2010;65:548-55. (Abstract)
Tateo M, Roque-Afonso AM, Antonini TM, et al. Long-term follow-up of liver transplanted
HIV/hepatitis B virus coinfected patients: perfect control of hepatitis B virus replication
and absence of mitochondrial toxicity. AIDS 2009;23:1069-76. (Abstract)
Thibault V, Stitou H, Desire N, Valantin MA, Tubiana R, Katlama C. Six-year follow-up of
hepatitis B surface antigen concentrations in tenofovir disoproxil fumarate treated
HIV-HBV-coinfected patients. Antivir Ther 2011;16:199-205. (Abstract)
Thio C, Seaberg E, Skolasky R. HIV-1, hepatitis B virus, and risk of liver-related mortality in the
Multicenter AIDS Cohort Study (MACS). Lancet 2002;360:1921-6. (Abstract)
Van Bömmel F, Wünsche T, Mauss S, et al. Comparison of adefovir and tenofovir in the
treatment of lamivudine-resistant hepatitis B virus infection. Hepatology
2004;40:1421-5. (Abstract)
Van Bömmel F, de Man RA, Wedemeyer H, et al. Long-term efficacy of tenofovir monotherapy
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analogues. Hepatology 2010;51:73-80. (Abstract)
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).