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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