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13. Extrahepatic manifestations of chronic HCV
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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 a result of HCV-triggered cryoglobulinaemia 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 direct
acting antivirals. In cases of mild renal impair ment, sustained viral response
normally leads to amelioration of proteinuria or even full remission of GN.
With high baseline viremia and advanced renal insuiciency, antiviral
therapy is subject to certain limitations (Sabry 2002). Despite amelioration
of proteinuria achieved ater antiviral therapy, signiicant improvement
of renal function is oten lacking (Alric 2004). Ribavirin dosage must be
cautiously adjusted to glomerular iltration rate (GFR), in order to mainly
prevent ribavirin accumulation with consecutive hemolytic anemia
(Fabrizi 2008). RBV-induced hemolytic anemia was eiciently treated by
administration of erythropoietin and erythrocyte concentrates (van Leusen
2008). As determination of RBV blood levels is not an established laboratory
procedure, implementation of such a therapeutic approach in clinical
routine remains arduous. Renal impairment was observed as an adverse
event associated with the use of telaprevir and boceprevir (Mauss 2014). In
patients with severe renal insuiciency (eGF <30 ml/min), data for the use
of simeprevir, ledipasvir, sofosbuvir and other direct acting antivirals are
emerging. Although the use of sofosbuvir is currently not recommend in
patients with eGF <30 ml/min, safety and eicacy of full dose sofosbuvir
regimen was recently shown in this population (Hundemer 2015). The 3 D
regimen, comprising of paritaprevir/ritonavir/ombitasvir + dasabuvir a s well
as the NS5A inhibitor daclatasvir have been safely administered in patients
with severe renal insuiciency (GF <30 ml/min) due to the predominant
biliary elimination of these drugs (Fabrizi 2015). The regimen of grazoprevir
plus elbasvir has been evaluated in a large cohort of 235 HCV patients with
serious renal involvement. These drugs have a renal elimination rate less
than 1%. Therefore, the 3 D regimen as well as grazoprevir plus elbasvir
are currently the only approved combination therapies in end-stage renal
disease (GF <15 ml/min) (Cacoub 2016). However, therapy with glecaprevir/
pibrentasvir is also possible and should be favoured and, if available, replace
the 3 D regimen. Data from a recent cohort of 101 HCV patients with chronic
kidney disease stage 3b, 4 or 5 treated with glecaprevir/pibrentasvir showed
an SV rate of 97% (98/101) with no virologic failure and no safety signals,
which support the use of this regimen in HCV patients with advanced and
end-stage renal disease (Lawitz 2019). Currently, grazoprevir plus elbasvir is
the recommended therapeutic regimen in HCV type 1 patients with severe or
terminal renal insuiciency (AFEF 2016).
Fulminant manifestations with impending acute renal failure can be
treated with corticosteroids, cyclosporine, and other immunosuppressive
drugs such as cyclophosphamide and eventually plasmapheresis (Garini
2007, Margin 1994). In case of simultaneous bone marrow B cell iniltration
and/or resistance to conventional therapy, application of rituximab is
indicated (Roccatello 2004). Rituximab may be used as an alternative irst
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.
Thyroid disease is found to be one of the most common endocrine disorders
in chronic HCV infection (Antonelli 2004). The hypothesis of chronic
immune system stimulation in patients with MC who also presented
autoimmune thyroiditis is underlined by the elevated levels of CXCL9,
CXCL10 and CXCL11 chemokines as well as higher IL-6 levels which can
be found in these patients (Ferri 2017). In vitro experiments showed that
Hepatitis C virus is even capable of infection of human thyroid cells due to
membrane expression of the HCV receptor CD81 (Blackard 2012). There is
also evidence that IFN α may induce thyroid disease or unmask preexisting
silent thyroidopathies (Graves disease, Hashimoto thyroiditis) (Prummel
2003). Furthermore, the presence of thyroid autoantibodies increases the
risk of developing an overt thyroiditis during interferon-based therapy.
The 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). A meta-analysis
of retrospective and prospective studies conirms a higher 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). Similar results were
reported in a recent prospective study from Taiwan with more than 21000
340 341
13. Extrahepatic manifestations of chronic HCV
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participants (hazard ratio 1.53, 95% CI 1.29-1.81) (Lin 2016). Viral induction
of insulin resistance seems to be HCV-speciic, as prevalence of diabetes
mellitus in HBV-infected patients is signiicantly 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. By
altering host lipid metabolism to favour its own replication, HCV infection
leads to hepatic steatosis especially in HCV type 3 infections. Moreover, the
occurrence and severity of steatosis correlates with viral load and response
to interferon-based therapy in HCV type 3 patients (ubbia-Brandt 2001).
Furthermore, HCV-dependent upregulation of cytokine suppressor SOC-3
may be responsible for the induction of cell desensitisation towards insulin.
Peroxisome proliferator-activated receptor-γ coactivator 1α is induced
ater HCV infection, thereby upregulating gluconeogenesis and providing
a potential target for treatment (Shlomai 2012). Insulin resistance in turn
represents an independent risk factor for progression of liver ibrosis and
lower SV in patients with chronic HCV infect ion (Moucari 2008, Kawaguchi
2004). As the development of insulin resistance or type 2 diabetes mellitus
may contribute to the progression of liver disease during HCV infection,
some international guidelines recommend that antiviral treatment should
be promptly initiated in HCV infected patients with insulin resistance or
diabetes (Cacoub 2018).
A causal association is backed up by studies demonstrating that antiviral
therapy resulting in SV correlates with improved diabetic metabolic status
and partial resolution of insulin resistance (Kawaguchi 2007, Zhang 2012).
There is growing evidence that a majority of HCV-infected patients also
sufer from vitamin D deiciency. Recent clinical data show higher vitamin D
levels as an independent predictive factor of SV following antiviral therapy
(Cholongitas 2012). Because of its anti-inlamm atory and anti-ibrotic efects,
vitamin D supplementation might therefore protect against progression of
liver disease (Rahman 2013). HCV-infected patients are at a signiicantly
higher risk of developing osteoporosis and osteoporosis-associated bone
fractures. Chronic HCV infection leads to a reduction in bone density due do
imbalance in calcium and vitamin D homeostasis and a decreased synthesis
of insulin-like growth factor-1 (IGF-1) (Marek 2015). Additionally, it has been
shown that bone density decreases with progression of liver ibrosis due to
HCV (Lin 2012). In another study with relatively young HCV patients (aged
40 – 60 years) without advanced ibrosis, 42% had reduced bone density and
12% osteoporosis (Lai 2015). Furthermore, a large cohort study from Taiwan
with over 10.000 HCV patients and 41.000 controls reported a 1.33-fold
increased incidence of osteoporosis in the HCV group versus controls (Chen
2015). Another study from Denmark compared the overall incidence of bone
fractures from over 12.000 HCV patients and 60.000 matched controls. HCV
patients had a 2.15-fold increased incidence of bone fractures. There was no
signiicant diference in fracture incidence between patients with active
versus successfully treated chronic hepatitis C (Hansen 2014).
Finally, a link between HCV, growth hormone (GH) insuiciency and
low insulin-like growth factor (IGF1) has been hypothesised. Reduced GH
secretion could be the result of a direct inhibitory efect of HCV infection at
the level of the pituitary or hypothalamus (Plöckinger 2007).
Cardiovascular manifestations
There is increasing evidence that chronic HCV infection may also
increase the risk for cardiovasc ular disease. Many direct and indir ect factors
which contribute to the development of atherosclerosis and cardiovascular
disease have been identiied, such as insulin resistance, oxidative stress,
lipopolysaccharides and proinlammatory cytokines (see Figure 4,
Adinoli 2018). A nearly 1.65-fold increase in cardiovascular disease-related
mortality was reported in a large meta-analysis of observational studies.
The risk for cerebrovascular or cardiovascular disease in HCV infection was
even 1.71-fold higher when additional risk factors like diabetes and arterial
hypertension were present (Petta 2016). Moreover, a cohort study from
Taiwan found chronic hepatitis C to be an independent predictor of stroke
(Negro 2014). Another data from a recent American study with a cohort of
1434 HCV-positive participants showed a signiicantly higher incidence of
coronary heart disease events in patients with detectable HCV RNA than in
those who were HCV RNA negative (Pothineni 2014). A 1.43-fold increased
risk of developing peripheral arterial disease (PAD) in chronically HCV
infected Taiwanese patients as compared to uninfected controls might be
suggestive that PAD can be regarded as an extrahepatic manifestation of
chronic HCV infection (Hsu YH 2015). Potential pathomechanisms might
include metabolic factors such as insulin resistance with hyperglycemia,
endothelial dysfunction and inlammation leading to damage of vessels
and instability of plaques but also other systemic processes associated with
the chronic inlammatory state and potentially leading to atherosclerosis
have to be considered (Negro 2015). In addition, chronic HCV infection is
independently associated with peripheral arterial stifness. Compared
to controls, HCV patients had increased arterial stifness with lower
compliance indices in a cohort of 221 participants (Chou 2017).
However SV in HCV infection results in an increase in total and LDL
cholesterol, which seems contradictory to the data reported above (Mauss
2017). The interaction of terminating a possibly proatherogenic chronic
infection which results in an increase of proatherogenic lipids requires
further research to draw a clinical relevant concusion.
342 343
First data on DAA therapy efects in patients with advanced liver
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ibrosis and compensated cirrhosis revealed a signiicant improvement in
carotid atherosclerosis measured by intima media thickness and carotid
thickening, although data about major cardiovascular outcomes under DAA
therapy are still absent (Petta 2018).A recent nationwide cohort study from
Taiwan demonstrated a signiicant reduction in the incidence of end-stage
renal disease, acute coronary syndrome and ischemic stroke in HCV treated
patients compared to untreated controls. Treated patients also showed a
signiicant improvement in non-liver death-related survival (see Figure 5,
Hsu YC 2015). The current available data show that the eradication of HCV
by DAA therapy is associated with an improvement of atherosclerosis and
metabolic conditions which may lead to the development of cardiovascular
disease at least in the short term and at early disease stages, yet further
studies are needed to clarify these results (Adinoli 2018).
Occasionally, chronic HCV infection has been seen in association
with other cardiac pathologies such as chronic myocarditis and dilated/
hypertrophic cardiomyopathy. Pathogenesis seems to rely on genetic
predisposition and is assumed to be immunologically triggered (Matsumori
2000).
13. Extrahepatic manifestations of chronic HCV
Figure 4. Direct and indirect factors associated with the development of atherosclerosis and
cardiovascular disease in HCV patients and the possible effec t of viral clearance by DAA
therapy. (IR: insulin resistance, OXS: oxidative stress, LPS: lipopolysaccharide, according to
Adinolfi LE et al. 2018).
Figure 5. A) Overall mortalit y sur vival curves for non-liver related causes in treated and
untreated patients with chronic HCV infection B) and C) Cumulative incidence of extrahepatic
outcomes between treated and untreated HCV cohorts for end-stage renal disease and acute
coronar y syndrome (according to Hsu YC et al. 2015).
Central nervous manifestations
Numerous central nervous manifestations have been described in
association with HCV infection. Cr yoglobulinemic 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 deiciency have been observed (Aktipi 2007).
Furthermore, chronic HCV infection is associated with signiicant
impairment of quality of life. 35-68% of HCV patients sufer 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 well as
functional magnetic resonance spectroscopy studies suggest altered
neurotransmission in HCV-infected patients (Weissenborn 2006, Forton
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13. Extrahepatic manifestations of chronic HCV
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2001). In addition, signiicant tr yptophan deicienc y is detectable in patients
with chronic HCV infection. Deiciency of tryptophan-derived serotonin is
likely to favour 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).
While the aetiology of cognitive dysfunction in HCV patients is not
completely understood, it is hypothesised that the virus has a direct
neurotoxic efect by entering the CNS via the PBMCs. This may be
accompanied by an indirect neurotoxic efect via cerebral and/or systemic
inlammation, for example increased pro-inlammatory cytokines over
many years of infection. These cytokines may cross the blood-brain barrier
and contribute to cognitive disorders (Senzolo 2011). More recent studies
indicate that brain microvascular endothelial cells serve as a preferential
site of HCV tropism and replication and that alteration of the blood-brain
barrier could lead to activation of microglia and entry of inlammatory
cytokines (Fletcher 2012). Supporting new data shows evidence for the
afection of mostly memory tasks in HCV-infected children with signiicant
correlations between endogenous cytokines like IL-6 and IFN α and
cognitive dysfunction (Abu Faddan 2014).
Signiicant improvements of mental health and central nervous
manifestations (i.e. fatigue and health related quality of life) have been
consistently demonstrated during interferon-free DAA-based regimens
(Younossi 2014a, Younossi 2014b). A recent study evaluated a signiicant
improvement in health related quality of life due to DAA therapy in patients
with cryoglobulinemic vasculitis (Saadoun 2015b). According to recent
guidelines (EASL 2018), the presence of such EHM (i.e. debilitating fatigue)
should be regarded as a priority treatment indication with DAA, even in the
absence of signiicant liver damage (Negro 2015).
Dermatologic manifestations
A multitude of cutaneous disorders has been sporadically associated
with chronic HCV infection (Hadziyannis 1998). Epidemiologic studies have
conirmed the existence of a strong correlation between the sporadic form
of porphyria cutanea tarda (PCT) and HCV, though the presence of HCV in
PCT patients seems to be subject to strong regional factors. Indeed, HCV
prevalence in PCT patients is above 50% in Italy, while only 8% in Germany
(Fargion 1992, Stölzel 1995). Because therapy with PEG-IFN and ribavirin
may exacerbate the cutaneous manifestations in PCT patients, these
individuals might strongly beneit from therapy with DAAs (Negro 2015).
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-D6 has been recognised as a major predisposing factor
for development of lichen planus in HCV positive patients. One hypothesis
suggests that geographical luctuation of HLA-D6 is responsible for the
diverse prevalence among HCV patients (Gandolfo 2002). A recent study
from Japan showed seven HCV patients with oral lichen planus who were
treated with daclatasvir and asunaprevir for 24 weeks. In addition to the
SVR24 rate of 100%, the cutaneous manifestations disappeared in four and
improved in the remaining three subjects, underlining the close association
between replicative HCV infection and oral lichen planus (Nagao 2016).
Recent data from a large cohort of HCV-infected patients showed a
higher incidence and mortality for several types of non-liver cancers in
individuals with HCV compared to the general population such as pancreas,
lung, kidney and rectum malignancies. However it remains elusive if higher
smoking rates in the observed HCV cohort could have been a possible
confounding factor (Allison 2015). New data from a french population
showed only hematological malignancies and oral cancer to be at higher
risk in HCV patients compared to the general population. Especially HCV
cirrhosis was associated with a higher age-adjusted incidence of non-liver
cancers, even ater achieving SV (Allaire 2018).
Idiopathic pulmonary ibrosis (IPF) may potentially be 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 indings consistent with a chronic alveolitis. Alveolar lavage in the
same patients ater completion of antiviral therapy showed a remission of
inlammatory activity (Yamaguchi 1997). Involvement of CGs in the genesis
of IPF is also probable (Ferri 1997).
Several ocular abnormalities such as sicca syndrome due to reduced
lacrimation as well as a peripheral corneal ulceration which is called
Mooren’s ulcer have been reported in association with HCV infection,
although the pathogenesis of such abnormalities is not completely
understood (Wilson 1993, Tang 2016).
Miscellaneous manifestations
Recent data from a large cohort of HCV-infected patients showed a
higher incidence and mortality for several types of non-liver cancers in
individuals with HCV compared to the general population such as pancreas,
lung, kidney and rectum malignancies. However it remains elusive if higher
smoking rates in the observed HCV cohort could have been a possible
confounding factor (Allison 2015). New data from a french population
346 347
13. Extrahepatic manifestations of chronic HCV
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showed only hematological malignancies and oral cancer to be at higher
risk in HCV patients compared to the general population. Especially HCV
cirrhosis was associated with a higher age-adjusted incidence of non-liver
cancers, even ater achieving SV (Allaire 2018). A higher prevalence of
extrahepatic malignancies than expected was also found in a cohort of
431 HCV patients who were treated with DAAs in Israel. The incidence of
lymphoma was about 100 times higher than in the general population. Also,
the incidence of pancreatic, endocervix, breast and squamous cell lung
carcinoma increased 29-, 1.6-, 136- and 2,5-fold, respectively. One possible
cause might be down-regulating of immune response ater successful DAA
therapy with higher vulnerability to the development of neoplasia, yet
larger multicentered studies are required to conirm these results (Khoury
2019).
Idiopathic pulmonary ibrosis (IPF) may potentially be 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 indings consistent with a chronic alveolitis. Alveolar lavage in the
same patients ater completion of antiviral therapy showed a remission of
inlammatory activity (Yamaguchi 1997). Involvement of CGs in the genesis
of IPF is also probable (Ferri 1997).
Several ocular abnormalities such as sicca syndrome due to reduced
lacrimation as well as a peripheral corneal ulceration which is called
Mooren’s ulcer have been reported in association with HCV infection,
although the pathogenesis of such abnormalities is not completely
understood (Wilson 1993, Tang 2016).
References
Abu Faddan NH, S hehata GA, Abd Elhafeez HA , Mohamed AO, Hassan HS, Abd E l Sameea F. Cognitive func tion and endogenous cytokin e
levels in children w ith chronic hepatitis C . J Viral Hepat 2014 Dec 15. doi: 10. 1111/jvh.12373. [Epub ahead of print]
Adinoli LE, Rinaldi L, Nevola R. Chronic hepatitis C, atherosclerosis and cardiovascular disease: What impact of direct-acting antiviral
treatments? World J Gastroente rol 2018;24:4617-21.
Afdhal N, McHutchis on J, Brown R, Jacob son I, Manns M, Poo rdad F, et al. Thrombocytop enia associated wi th chronic liver disease . J Hepatol
2008;48:1000-7.
Afdhal NH, Dusheiko G, Giannini EG, et al. Final Results of ENABLE 1, a Phase 3, Multicenter Study of Eltrombopag as an Adjunct
for Antiviral Treatment of Hepatitis C Virus-Related Chronic Liver Disease Associated With Thrombocytopenia . Hepatology
2011;54:1427-8.
Agnello V, G. Ábel. Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia. Arthritis
Rheumatism 1997;40: 2007-2015.
Agnello V, De Rosa, FG . Extrahepatic dise ase manifestations of HCV infecti on: some current issues . J Hepatol 2004;40:341-352.
Aktipi KM, Ravagl ia S, Ceroni M. S evere recurrent myelitis in patie nts with hepatitis C virus infectio n. Neurology2007;68 :468-9.
Allaire M, Nahon P, Layese et al. Extra h epatic cancers are the leading cause of death in cirrhoti c patients achieving HBV control or HCV
eradication . Hepatology 2018 Apr 16. doi: 10 .1002/hep.30034.
Allison RD, Tong X, Moo rman AC, et al. Increased inci dence of cancer and cancer-re lated mortality among persons with c hronic hepatitis C
infection, 20 06-2010. J Hepatol 2015; 63:822-28.
Alric L, Plaisier E, Thébault S, Péron JM, Rostaing L, Pourrat J, et al. Inluence of antiviral therapy in hepatitis C virus-associated
cryoglobul inemic MPGN. Am J Kidney Di s 2004;43:617-23.
Antonelli A, Ferri C , Pampana A, et al . Thyroid disorders in chronic hep atitis C. Am J Med 2004;117:10- 3.
Arase Y, Ikeda K, Mura shima N, Chayama K, Tsubota A , Koida I, et al. Glomerul onephritis in autopsy cases with h epatitis C virus infection.
Intern Med 1998;37:836 -40.
Arcaini L, Me rli M, Passamonti F, Bruno R , Brusamolino E, S acchi P, et al. Impact of trea tment-related liver toxicity on the o utcome of HCV-
positive non-Hod gkin’s lymphomas. 2010 ;85:45-50.
Aref S, Sleem T, El M enshawy N, Ebrahiem L, Ab della D, Fouda M, et al. Antip latelet antibodies contribute to th rombocytopen ia associated
with chronic hepati tis C virus infection. Hemato logy 2009;14:277-81.
Besson C , Canioni D, Lepage E, Po l S, Morel P, Lederlin P, et al. Charac teristics and outcome of difuse l arge B-cell lymphoma in hep atitis C
virus-positive pat ients in LNH 93 and LNH 98 Groupe d’Etude des Lymphom es de l’Adulte programs. J C lin Oncol 2006;24: 953-60.
Blackard JT, Kong L, Huber AK, Tomer Y. Hepatitis C virus infection of a thyroid cell line: implications for pathogenesis of HCV and
thyroiditis. Thyroid 2012;23:863-70 .
Bonacci M , Lens S, Londono MC, et a l. Virologic, Clinical , and Immune Response Outcomes of Pat ients With Hepatitis C Virus-Associated
Cryoglobul inemia Treated With Direct-acting Antivirals . Clin Gastroenterol Hep atol 2016. doi:10.1016/j. cgh.2016.0 9.158.
Boonyapisit K , Katirji B. Severe e xacerbation of hepati tis C-associated vas culitic neuropathy followin g treatment with interferon alpha: a c ase
report and literature revi ew. Muscle Nerve 2002; 25:909-13.
Bordin G, Ballare M, Zigrossi P, Bertoncelli MC, Paccagnino L, et al. A laboratory and thrombokinetic study of HCV-associated
thrombocytopen ia: a direct role of HCV in bone marrow exha ustion? Clin Exp Rheumatol 1995;Sup pl 13:S39-43.
Bruchfeld A, Lindahl K, Stahle L, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and
renal insuic iency. Nephrol Dial Transplant 2 003;18:1573-80.
Bussel JB , Cheng G, Saleh MN, Psa ila B, Kovaleva L, Meddeb B , et al. Eltrombopag for th e treatment of chronic idiopathi c thrombocytopenic
purpura. New E ngl J M 2007;357:2237-47.
Cacoub P, Sbai A, Hausfater P, et al. Central nervous system involvement in hepatitis C virus infection. Gastroenterol Clin Biol
1998;2 2:631-33.
Cacoub P, Desbois AC, Isnard-Bagnis C, et al. Hepatitis C virus infection and chronic kidney disease: Time for reappraisal. J Hepatol
2016;65:82- 94.
Cacoub P, Desbois AC, Comarmond C, Saadoun D. Impact of sustained virological response on the extrahepatic manifestations of chronic
hepatitis C: a m eta-analysis. Gut 2018;67: 2025-34.
Cacoub P, Si Ahmed SN , Ferfar Y, Pol S, Thabut D, Hezo de C, Alric L, Comarmon d C, Ragab G, Quartucc io L, Hegazy M, Poynard T, Rig on
MR, Saado un D, Longterm Eicacy of Inte rferon-Free
Antiviral Treatment Regimens in Patients With Hepatitis C Virus-Associated Cryoglobulinemia Vasculitis, Clin Gastroenterol Hepatol
2019;17:518-26.
Calleja JL , Albillos A, Moreno -Otero R, et al. S ustained response to inte rferon-alpha or to interferon-alp ha plus ribavirin in hepatitis C v irus-
associated s ymptomatic mixed cryogl obulinaemia. Alime nt Pharmacol Ther 1999;13:1179- 86.
Carrozzo M, Ga ndolfo S, Carbone M, C olombatto P, Broccoletti R , Garzino-Demo P, et al . Hepatitis C virus infection in Itali an patients with
oral lichen pla nus: a prospective case- control study. J Oral Pathol Med 1996; 25:527-33.
Carta MG, Hardoy MC , Garofalo A, Pisano E , Nonnoi V, Intilla G, et al. Associ ation of chronic hepatitis C with majo r depressive disorders:
irrespective of inte rferon-alpha therapy. Clin Pract Ep idemol Ment Health 2007;3: 22.
Chao TC, Chen CY, Yang YH, et al . Chronic hepatitis C virus infec tion associated with primar y warm-type autoimmune hemolytic anem ia. J
Clin Gastroe nterol 2001;33:232-33.
Chen CH, Lin CL , Kao CH. Relation Betwe en Hepatitis C Virus Exposure and Ris k of Osteoporosis: A Nationwid e Population-Based Study.
Medicine 2015;94(47):e2086.
Chen YC, Lin HY, Li CY, Lee MS , Su YC. A nationwide co hort study suggests that hep atitis C virus infection is ass ociated with increase d risk of
chronic kidney disease. Kidney Int 2014;85:1200-7.
Chiao EY, Engels EA, Kramer JR, Pietz K, Henderson L, Giordano TP, Landgren O. Risk of immune thrombocytopenic purpura and
autoimmune hemolyti c anemia among 120 908 US vet erans with hepatitis C virus infecti on. Arch Intern Med 2009;169 :357-63.
Cholongitas E , Theocharidou E , Goulis J, Tsochatzis E, Akrivi adis E, Burroughs AK. Revi ew article: the extra-skeletal efec ts of vitamin D in
chronic hepatit is C infection. Aliment Pha rmacol Ther 2012;35:634-46.
Chou CH, Ho CS , Tsai WC et al. Efects of chroni c hepatitis C infection on arte rial stifness. J Am Soc Hype rtens 2017;11:716-23.
Colantoni A, D e Maria N, Idilman R, Van Th iel DH. Polymerase chain re action for the detection of HCV-RNA: cryog lobulinaemia as a caus e
for false negative res ults. Ital J Gastroenterol Hep atol 1997;29:273-77.
Cormier EG, Tsamis F, Kajumo F, Durso RJ, Gardn er JP, Dragic T. CD81 is an e ntry coreceptor for hepatitis C virus . Proc Natl Acad Sci US
2004;101 :7270-4.
Craxì A, Lai G , Zignego AL. Hep atitis C virus (HCV) infection: a systemic dis ease. Mol Aspects Med 2 008;29:85-95 .
Daghestani L , Pomeroy C. Renal m anifestations of hepatitis C i nfection. Am J Med 1999;106 :347-54.
De Almeida AJ, Campos-de-Magalhaes M, Okawa MY, Vieira de Oliveira R, et al. Hepatitis C virus-associated thrombocytopenia: a
controlled prosp ective, virological stu dy. Ann Hematol 2004;83:434-40.
De la Serna-Hig uera C, Bárcena-Marug án R, Sanz-de Villalobos E . Hemolytic anemia secon dary to alpha-interferon treatment in a pati ent
with chronic C hepati tis. J Clin Gastroentero l 1999;28:358-9 .
De Sanjose S, Benavente Y, Vajdic CM et al. Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the
international lymph oma epidemiology con sortium. Clin Gastro enterol Hepatol 2008; 6:451-8.
Drugs at FDA. Eltrombopag olamine, NDA 022291. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.
Label_ApprovalHistory#labelinfo
Doutrelepont J -M, Adler M, Willem s M, Durez P, Yap SH. Hepatitis C virus i nfection and membranopro liferative glomerulonephriti s. Lancet
1993;341 :317.
Duberg AS, N ordström M, Törner A, Reich ard O, Strauss R, Janzon R , et al. Non-Hodgki n’s lymp homa and other nonhepati c malignancies in
Swedish patie nts with hepatitis C virus infection . Hepatology 2005;41:652- 59.
El-Serag HB , Christie IC, Puenpatom A , Castillo D, Kanwal F, Kramer JR. The e fects of sustained virologic al response to direct-acting anti-
viral therapy on the risk of e xtrahepatic manifestation s of hepatitis C infection . Aliment Pharmacol Ther 2 019;49:1442-7.
European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018;https://doi.
org/10.1016/j.j hep.2018.03 .026
348 349
13. Extrahepatic manifestations of chronic HCV
https://t.me/medicina_free
Fabrizi F, Lunghi G, Messa P, Martin P. Therapy of hepatitis C virus-associated glomerulonephritis: current approaches. J Nephrol
2008;21: 813-25.
Fabrizi F, Messa P. Therapy of hepatitis C by direct-acting anti-virals: the end of HCV in dialysis population? Expert Rev Clin Pharmacol
2015;8:785-93 .
Fallahi P, Ferrari SM , Giugglioli D et al . Chemokines in the Path ogenesis and as The rapeutical Markers and Targets of HCV Chron ic Infection
and HCV Extrahepati c Manifestations. Curr Dru g Targets 2017;18:786-93.
Fargion S, Piperno A, Cappellini MD, et al. Hepatitis C virus and porphyria cutanea tarda: evidence of a strong association. Hepatology
1992;16:1322- 6.
Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa
interferon. J Hepato l 1996;24:38-47.
Fernandéz A . An unusual case of autoimmune he molytic anemia in treatment na ïve hepatitis C virus infection . Hematology 2006;11:385-87.
Ferri C, La Civita L , Fazzi P, Solfanelli S, Lomb ardini F, Begliomini E, et al . Intestinal lung ibrosis and rhe umatic disorders in patients with
hepatitis C virus infe ction. Br J Rheumatol 1997;36: 360-65.
Ferri C, Sebastiani M, Guiggiolo D, Cazzato M, Longombardo G, Antonelli A, et al. Mixed cryoglobulinaemia: demographic, clinical, and
serologic feat ures and survival in 231 patients. S emin Arthritis Rheum 2004;33:355-74.
Ferri C, Antonelli A , Mascia M.T, et al . B cells and mixed cryogl obulinemia. Autoimmun R ev 2007;7:114-20.
Ferri C, Ramos- Casals M, Zigneg o AL, et al. International diag nostic guidelines for pati ents with HCV-related extrahepatic manife stations.
A multidiscip linary expert statement. Auto immun Rev 2016;15:1145-60.
Ferri C, Cola ci M, Fallahi P et al. Thyroid involvem ent in Hepatitis C Virus-Infected Patients with /without Mixed Cryo globulinemia. Front
Endocrinol (Laus anne) 2017; 8:159. doi: 10.3389/fendo.2017.00159.
Flemming JA, Lowe CE . Successful tre atment of hepatitis C, g enotype 3, with sofos buvir/ledipasvir in decom pensated cirrhosis comp licated by
mixed cryogl obulinaemia. BM J Case Rep 2016;pii: bcr2016215293 . doi: 10.1136/bcr-2016- 215293.
Fletcher NF, Wilson GK , Murray J, Hu K, Lewis A, Reynolds GM, et al. Hepatitis C Virus Infects the Endothelial Cells of the Blood-Brain
Barrier. Ga stroenterol 2012; 142:634-43.
Forton DM, Alls op JM, Main J, et al. Evi dence for a cerebral efect of th e hepatitis C virus. Lancet 2 001;358:38-9.
Forton DM, Taylor-Robi nson SD, Thomas HC . Cerebral dysfunction in chro nic hepatitis C infection . J Viral Hepat 2003;10:81- 6.
French Associ ation for the Liver Study (AFEF). AFEF recommendations o n the management of viral hepat itis C. 2016.
Gandolfo S , Carrozzo M. Lichen pla nus and hepatitis C virus infecti on. Minerva Gastroe nterol Dietol 2002;48 :89.
García-Suárez J, Burgaleta C, Hernanz N, Albarran F, Tobaruela P, Alvarez-Mon M . HCV-associated thrombocytopenia: clinical
characteristic s and platelet response at er recombinant alpha2b -interferon therapy. Br J Haematol 20 00;110:98-103
Garini G, Allegri L, Lannuzzella F, Vaglio A, Buzio C. HCV-related cryoglobulinemic glomerulonephritis: implications of antiviral and
immunosuppres sive therapies. Acta Biom ed 2007;78:51-9.
Giannelli F, Moscarella S, Giannini C, Caini P, Monti M, et al. Efect of antiviral treatment in patients with chronic HCV infection and
t(14;18) translocation. Blood 2003;102 :1196-201.
Giordano TP, Henderson L, Landgren O, Chiao EY, Kramer JR, El-Serag H, Engels EA. Risk of non-Hodgkin lymphoma and
lymphoproliferative pre cursor diseases in US v eterans with hepatitis C virus. JAMA 20 07;297:2010-7.
Gragnani L, Fabbrizzi A, Triboli E, et al. Triple antiviral therapy in hepatitis C virus infection with or withput mixed cryoglobulinaemia: A
prospective, c ontrolled pilot study. Dig Liver D is 2014;46:833-7.
Gragnani L, Fognani E, Piluso A, et al. Long-Term Efect of HCV Eradication in Patients With Mixed Cryoglobulinemia: A Prospective,
Controlled, O pen-Label, Cohort S tudy. Hepatology 2015;61:1145-53.
Gragnani L , Visentini M, Fognani E, et al. Prospective study of guidelin e-tailored therapy with direct-acting antivirals for hepatitis c virus-
associated m ixed cryoglobulin emia. Hepatology 2016; 64:1473 -82.
Hadziyannis SJ . Skin diseases ass ociated with hepatitis C virus i nfection. J Eur Acad Derm atol Venereol 1998;10:12-21 .
Hansen AB, Omland LH, Krarup H, Obel N; DANVI cohort study. Fracture risk in hepatitis C virus infected persons: results from the
DANVI cohort study. J Hepatol 2014;61(1):15-21.
Hegazy MT, Hussein MA , Quartuccio L, Fawzy M , Zoheir N, Ellawindi MI, et al . Treatment of Cryogl obulinemic Vasculitis with So fosbuvir
in Four Combinat ion Protocols [abstract]. Arthritis Rheumatol 2 016;68(suppl 10).
Hui JM, Sud A , Farrell GC, Bandara P, et al . Insulin resistance is asso ciated with chronic hepatitis C vi rus infection and ibrosis pro gression.
Gastroenterology 2003;125:1695-704.
Hundemer GL , Sise ME, Wisocky J , et al. Use of sofosbuvir-b ased direct-acting antiviral th erapy for hepatitis C viral infecti on in patients with
severe renal insu iciency. Infect Dis (Lond) 2015;47:924-9.
Hsu YC, Ho HJ, Huang YT, et al. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus
infection. G ut 2015;64:495-503.
Hsu YH, Muo CH, Liu CY, et al . Hepatitis C virus infection increa ses the risk of developing perip heral arterial disease: A 9-yea r population-
based cohort s tudy. J Hepatol 2015;62:519-25 .
Iga D, Tomimatsu M, Endo H, Ohkawa S-I, Yamada O. Improvement of thrombocytopenia with disappearance of HCV RNA in patients
treated by interferon-a th erapy: possible etiolo gy of HCV-associated immune throm bocytopenia. Eur J Ha ematol 2005;75:417-23.
Imazeki F, Yokosuka O, Fu kai K, Kanda T, Kojima H, Sai sho H. Prevalence of diab etes mellitus and insuli n resistance in patients with chro nic
hepatitis C: c omparison with hepatitis B viru s-infected and hepatitis C viru s-cleared patients. Live r international 2008; 28:355-62.
Ingafou M, Porter SR, Scully C , Te o CG. No evidence of HCV infection or liver disease in B ritish patients with oral lichen planus. Int J Oral
Maxillofac Su rg 1998;27:65-6.
Kamar N, Rostaing L , Alric L. Treatment of hep atitis C-virus-related glomerul onephritis. Kidney Int 2006 ;69:436-9.
Kawaguchi T, Yoshida T, Harada M , Hisamoto T, Nagao Y, et al. Hep atitis C virus down-regulates insul in receptor substrates 1 and 2 throu gh
up-regulatio n of suppressor of cytokine si gnaling 3. Am J Pathol 20 04;165:1499-508.
Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, ß-cell function, and hepatic expression of insulin
receptor subst rates 1 and 2. Am J Gastroentero l 2007;102:1-7.
Khiani V, Kelly T, Adeel S, Jen sen D, Mohanty SR. Acute i nlammatory demyelinating p olyneuropathy associated with p egylated interferon a
2a therapy for chronic h epatitis C virus infection . World J Gastroenterol 2008 ;14:318-21.
Khoury J, Nassar G, Kramsky R, Saadi T. Extrahepatic Malignancies Ater Treatment with Direct Antiviral Agents for Chronic HCV
Infection. J G astrointest Cancer 2019 Aug 13. do i: 10.1007/s12029-019- 00293-y.
Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. 2018. KDIGO 2018 clinical practice guideline for the
prevention, di agnosis, evaluation , and treatment of hepatitis C in c hronic kidney disease . Kidney Int Suppl 2018;8: 91-165.
Knobler H, Sch ihmanter R, Zifroni A , Fenakel G, Schat tner A. Increased ris k of diabetes in noncirrhoti c patients with chronic hep atitis C virus
infection. M ayo Clin Proc 2000;75:355-9 .
Koskinas J, Kilidireas C, Karandreas N, Kountouras D, Savvas S, et al. Severe hepatitis C virus-related cryoglobulinaemic sensory-motor
polyneuropathy treated with pegylated interferon-a2b and ribavirin: clinical, laboratory and neurophysiological study. Liver Int
2007;27:414-20.
Lai JC, Sho back DM, Zipperstein J , et al. Bone Mineral Dens ity, Bone Turnover, and Systemic Inlammation in Non- cirrhotics with Chronic
Hepatitis C . Dig Dis Sci 2015;60 (6):1813-19.
LawitzE, Flisia k R, Abunimeh M et al. E icacy and safety of g lecaprevir/pibrentasvir in renal ly impaired patients with chroni c HCV infection.
Liver Int 2019 Dec 10. doi : 10.1111/liv.14320.
Levine JW, Gota C, Fessler BJ, et al . Persistent cryoglobulinemic vasculitis following successful treatment of hepatitis C virus. J Rheumatol
2005;32:1164-7.
Lidove O, Cacoub P, Ma isonobe T, Servan J, Thib ault V, Pi ette JC, et al. Hepatitis C virus i nfection with peripheral neuropathy is n ot always
associated w ith cryoglobulinaemi a. Ann Rheum Dis 2001;60 :290-2.
Lin JC, Hsieh TY, Wu CC, et al. Association between chronic hepatitis C virus infection and bone mineral density. Calcif Tissue Int
2012;91(6):423-9.
Lin YJ, Shaw TG, Yang HI, et a l. Chronic hepatitis C virus infe ction and the risk for diabetes: a co mmunity-based prospec tive study. Liver Int
2016 Jul 1. doi: 10 .1111/liv.13194.
Lunel F, Musset L , Cacoub P, Franguel L, C resta P, Perri M, et al. Cryoglo bulinemia in chronic liver d iseases: role of hepatit is C virus and liver
damage. Gastroenterology 1994;106:1291-300.
Machida K, Cheng KT, Sung VM, Shimodaira S , Lindsay KL, et al. Hepatitis C virus induces a mutator phenotype: enhanced mutations of
immunoglobu lin and protooncogene s. Proc Natl Acad Sci USA 2 004;101:4262-7.
Mahale P, Engels EA, Li et al. The efect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus
infection. G ut 2018;67:553-61.
Mason AL, Lau JY, Hoan g N, et al. Associati on of diabetes mellitus a nd chronic hepatitis C virus infe ction. Hepatology 1999 ;29:328-33.
Marek B, Kajdaniuk D, Niedziołka D, et al. Growth hormone/insulin-like growth factor-1 axis, calciotropic hormones and bone mineral
density in youn g patients with chronic viral hep atitis. Endokrynol Pol 2 015;66(1):22-9
Margin S, Cra xi A, Fabiano C, et al . Hepatitis C viraemia in chron ic liver disease: relation ship to interferon alpha or cortic osteroid treatment.
Hepatology 1994;19: 273-9.
Matsumori A, Yutani C , Ikeda Y, Kawai S, Sasayama S . Hepatitis C virus from the hearts of pati ents with myocarditis and cardiomyopathy.
Lab Invest 2000; 80:1137-42.
Matsuo K, Kusano A , Sugumar A , Nakamura S , Tajima K, Mueller NE. Efect of hepatitis C virus infection on the risk of non-Hodgkin’s
lymphoma: a meta-ana lysis of epidemiologi cal studies. Cancer S ci 2004;95:745-52.
Mauss S, Hue ppe D, Alshuth U.Renal imp airment is frequent in chroni c hepatitis C patients unde r triple therapy with telaprevir or bo ceprevir.
Hepatology 2014;59:46 -8.
Mauss S, B erger F, Wehmeyer MH et al. Efec t of antiviral therapy for HCV on lipid levels . Antivir Ther. 2017;21(1):81-88.
McGuire BM , Julian BA, Bynon JS Jr, Cook WJ , King SJ, Curtis JJ, et al . Brief communication: G lomerulonephritis in p atients with hepatitis C
cirrhosis underg oing liver transplantation . Ann Intern Med 2006;144:735-41.
McHutchison JG , Dusheiko G, Shif man ML, Rodriguez-Torres M, Sigal S , Bourliere M, et al . Eltrombopag for thrombocytop enia in patients
with cirrhosis ass ociated with hepatitis C . N Engl J Med 2007;357:2227-36 .
Mele A, Pulsoni A, Bianco E, Musto P, Szklo A, Sanpaolo MG, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian
multicenter cas e-control study. Blood 20 03;102:996-9 .
Mehta SH, Branc ati FL, Strathdee SA , Pankow JS, et al. Hep atitis C virus infection and inc ident type 2 diabetes . Hepatology 2003;38:50 -6.
Molnar MZ, Alhourani HM, Wall B M, et al. Association of Hep atitis C Viral Infection With Incidence and Progression of Chronic Kidney
Disease in a L arge Cohort of US Veterans. Hep atology 2015;61:1495-502.
Moucari R, Ass elah T, Cazals-Hatem D, Voitot H, et al. In sulin resistance in chronic hep atitis C: Association with gen otypes 1 and 4, serum
HCV RNA level, and liver ibros is. Gastroenterolo gy 2008;134:416-23.
Nagao Y, Sata M , Ta nikawa K, Itoh K, Kameyama T. Lic hen planus and hepatitis C virus in the n orthern Kyushu region of Japan. Eur J Cli n
Invest 1995;25:910-4 .
Nagao Y, Kimura K, Kawahigashi Y, Sata M. Successful Treatment of Hepatitis C Virus-associated Oral Lichen Planus by Interferon-free
Therapy with Direc t-acting Antivirals. Clin Transl Gastro enterol 2016;7:e179.
Negro F. Facts and i ctions of HCV and comorbiditie s: Steatosis, diabete s mellitus, and cardiovasc ular diseases. J Hep atol 2014;61:69-78.
Negro F, Forton D, Craxi A , et al. Extrahepati c Morbidity and Mortalit y of Chronic Hepatitis C . Gastroenterology 2015;149:1345-60.
Nomura H, Tanimoto H, Kajiwara E, Shimono J, Maruyama T, Yamashita N, et al. Factors contributing to ribavirin-induced anemia. J
Gastroenterol Hepatol 2004;19:1312-7.
Paydas S, N. Seyrek, G. Gonlusen, Y. Sagliker. The frequencies of hepatitis B virus markers and hepatitis C virus antibody in patients with
glomerulonep hritis. Nephron 1996;74:617-9 .
Perry W, Hilsabec k C, Hassanein TI. C ognitive dysfunction in chroni c hepatitis C: a review. Dig D is Sci 2008;53:307-21 .
Persico M, Ag litti A, Caruso et al. E icacy and safety of new direct ant iviral agents in hepatitis C virus-infec ted patients with difuse large
B-cell no n-Hodgkin’s lymphoma. Hepatology 2018 ;67:48-55.
Petrarca A, Rigacci L, Caini P, et al. Safety and eicacy of rituximab in patients with hepatitis C virus-related mixed cryoglobulinemia and
severe liver disea se. Blood 2010;116:335-42.
Petta S, Maid a M, Macaluso FS , et al. Hepatitis C Virus Infection Is Ass ociated With Increased Cardiovas cular Mortality: A Meta-Analysis
of Observati onal Studies. Gast roenterology 2016:doi:10 .1053/j.gastro.2 015.09.007.
350 351
13. Extrahepatic manifestations of chronic HCV
https://t.me/medicina_free
Petta S, Adinol i LE, Fracanzani AL , et al. Hepatitis C virus eradic ation by direct-acting antiviral agents i mproves carotid atherosclerosis in
patients with severe l iver ibrosis. J Hepatol 2018 ;https://doi.org/10.1016/j.jhep. 2018.02.015
Plöckinger U, Krüger D, Bergk A, Weich V, Wiedenmann B, Berg T. Hepatitis-C patients have a reduced growth hormone (GH) secretion
which improves durin g long-term therapy with pegylated int erferon-a. Am J Gastroenterol 2 007;102:2724-31.
Pothineni NVKC, De longchamp R, Vallurupall i S, et al. Impact of hepati tis C seropositivity on the risk of c oronary heart disease events . Am J
Cardiol 2014;114:1841-5 .
Prummel MF, Laurberg P. Interferon- alpha and autoimmune thyroid dise ase. Thyroid 2003;13:547-51.
Rahman AH, Branch AD. Vitami n D for your patients with chronic hep atitis C? J Hepatol 2013;58:184-9 .
Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with
chronic immune throm bocytopenic purpura . Br J Haematol 2005;129: 818-24.
Ramos-Cas als M, Stone JH, Cid MC , Bosch X. Th e cryoglobulinaemi as. Lancet 2012;379:348-6 0.
Ray RB, Meyer K, Ray R . Suppression of ap optotic cell death by hepat itis C virus core protein. Virolo gy 1996;226:176-82 .
Roccatello D, Baldovino S, Rossi D, Mansouri M , Naretto C, et al. Long-term efects of anti-CD20 monoclonal antibody treatment of
cryoglobul inaemic glomerulonep hritis. Nephrol Dial Transpl ant 2004;19:3054-61.
Roccatello D, B aldovino S, Rossi D, Gi achino O, Mansouri M , et al. Rituximab as a Therap eutic Tool in Severe Mixed Cry oglobulinemia. C lin
Rev Allergy Immunol 200 8;34:111-7.
Rollino C., D. Roccatello, O Giachino, B . Basolo, G. Piccoli. Hepatitis C virus Infection and membranous glomerulonephritis. Nephron
1991;59:3 19-20.
Roque Afonso AM, Ji ang J, Penin F, Tareau C, Samuel D , Petit MA, et al. Nonrando m distribution of hepatitis C viru s quasispecies in pla sma
and peripheral b lood mononuclear ce ll subsets.J Virol 1999;73: 9213-21.
Rubbia-Brandt L , Giostra E, Menth a G, Quadri G, Negro F Exp ression of liver steatosis in hep atitis C virus infection and pattern o f response
to α-interferon. J H epatol 2001;35:307.
Saadoun D, Asselah T, Resche-Rigon M, Bedossa P, Valla D, et al. Cryoglobulinemia is associated with steatosis and ibrosis in chronic
hepatitis C . Hepatology 2006;43:1337-45.
Saadoun D, Res che-Rigon M, Sene D, P erard L, Piette JC, Cac oub P. Rituximab combined with P eg-Interferon-Ribavirin in refractory HCV-
associated c ryoglobulinemia va sculitis. Ann Rheum Dis 20 08;67:1431-36.
Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med
2011;3 65:2067- 77.
Saadoun D, Resche Rigon M, Pol S, et al. PegIFNα/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed
cryoglobulinemia vasculitis. J Hepatol 2015a;62:24-30.
Saadoun D, Thibault V, Si Ahmed SN, et al. Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis:
VASCUVALDIC study. Ann Rheum Dis 2015b:1-6.
Saadoun D, Pol, S, Ferfar Y et al. Eicacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia
Vasculitis. Gastroenterol 2017;153:49-52.
Sabry AA , Sobh MA, Sheaa shaa HA, Kudesia G, Wild G , Fox S, et al. Efec t of combination therapy (ribavirin and i nterferon) in HCV-related
glomerulopathy. Nep hrol Dial Transplant 2002;17:1924-30 .
Sakamuro D, Furuk awa T, Takegami T. Hepati tis C virus nonstructural protein N S3 transforms NIH 3T3 cells. J Virol 1995;69:3893-6 .
Sansonno D, Gesualdo L, Manno C, Schena FP, Dammacco F. Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-
infected patient s with cryoglobulinemi c membranoproliferative glome rulonephritis. Hepatol ogy 1997;25,1237-44.
Sansonno D, D e Re V, Lauletta G, Tucci FA, B oiocchi M, Damm acco F. Monoclonal antib ody treatment of mixed cryoglo bulinemia resistant
to interferon alpha with an ant i-CD20. Bloo d 2003;101:3818-26.
Senzolo M , Schif S, D’Aloiso CM , Crivellin C, Cholon gitas E, Burra P, et al. Ne uropsychologica l alterations in hepatitis C in fection: The role of
inlammation . World J Gastroenterol 2011;17:3369-74.
Shahin AA , Zayed HS, Said M , Amer SA. Eicacy an d safety of sofosbuvir-base d, interferon-free therapy: The Ma nagement of rheumatologi c
extrahepatic m anifestations associa ted with chronic hepatitis C virus i nfection. Z Rheumatol 2018 ;77:621-8.
Shlomai A, Rechtman MM, Burdelova EO, Zilberberg A, Hofman S, Solar I, et al. The metabolic regulator PGC-1α links hepatitis C virus
infection to hepat ic insulin resistance . J Hepatol 2012;57:867-73.
Silvestri F, Barillari G, Fanin R, Pipan C, Falasca E, Salmaso F, et al. Hepatitis C virus infection among cryoglobulinemic and non-
cryoglobulinemic B-cell non-Hodgkin’s lymphomas. Haematologica 1997;82:314-7.
Sise ME, Bloom AK, Wisocky J et al. Treatment of Hepatitis C Virus-Associated Mixed Cryoglobulinemia with Direct-Acting Antiviral
Agents. Hepatolo gy 2015;doi: 10.1002/ hep.28297.
Srinivasan R . Autoimmune hemolytic anemia in t reatment naïve chronic hepatit is C infection. J Clin G astroenterol 2001;32:245-7.
Stölzel U, Köstler E , Koszka C, Stöler-Meilicke M, Schuppan D, Somasundaram R , et al. Low prevalence of hepatitis C virus infection in
porphyria cutanea tard a in Germany. Hepatology 1995;21:1500 -3.
Tang L, Marcell L , Kottilil S. Systemic manifestations of hepatitis C infection. Infect Agent Cancer 2016;11:29. doi: 10.1186/
s13027-016-0 076-7.
Takehara K, Otsuka T, Arai T, Matsuzaki Y, et al. Detection of hepatitis C virus (HCV) in platelets of type C chronic liver diseases by
polymerase chai n reaction (PC). Gastroenterolo gy 1994;106:A995.
Tarantino A, Campise M, Bani G, Confalonieri R , Bucci A, Montoli A, et al. Long-term predictors of survival in essential mixed
cryoglobul inemic glomeruloneph ritis. Kidney Int 1995;47:618-23.
Tembl JI, Ferrer JM, Sevilla MT, Lago A, Mayordomo F, Vilchez JJ. Neurologic complications associated with hepatitis C virus infection.
Neurology 1999;19 :889-95 .
Ueda T, Ohta K, S uzuki N, Yamaguchi M, Hirai K , et al. Idiopathic pu lmonary ibrosis and high p revalence of serum antibodi es to hepatitis C
virus. Am Rev respire D is 1992;146:266-8.
Vallisa D, Bernuzzi P, Arcaini L, Sacchi S, Callea V, Marasca R, et al . Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-
grade, B-c ell, non-Hodgkin’s lymphoma: a multic enter Italian experience . J Clin Oncol 2005;23 :468-73.
van Leusen R, Adang RP, de Vries RA, Cnossen TT, Konings CJ, Schalm SW, Tan AC. Pegylated interferon a lfa-2a (40 kD) and ribavirin in
haemodialysis p atients with chronic hepatit is C. Nephrol Dia l Transplant 2008;23:721-5 .
Vigano M, Lampertico P, Rumi MG, Folli C, Maggioni L, et al . Natural history and clinical impact of cryoglobulins in chronic Hepatitis C:
10-year prosp ective study of 343 patients. Gastroe nterology 2007;133:835-42.
Visentini M, D el Padre M, Colantuono S et a l. Long-lasting pe rsistence of large B-c ell clones in hepatitis C viru s-cured patients with comp lete
response of mi xed cryoglobulinae mia vasculitis. Liver Int 2019;39 :628-32.
Wang CS, Yao WJ, Wan g ST, Chang TT, Chou P. Strong associ ation of Hepatitis C virus (HCV) infection an d thrombocytopenia: impli cations
from a survey of a commun ity with hyperendemic HCV infectio n. Clin Infect Dis 2004;39 :790-6.
Weiner SM, B erg T, Berthold C, Weber S , Peters T, Blum H, et al. A cli nical and virological s tudy of hepatitis C virus-related c ryoglobulinemia
in Germany. J Hepatol 1998 ;29:375-84
Weissenborn K , Ennen JC, Bokemeyer M, Ahl B, Wurster U, Tillmann H, et al. Monoaminergic neurotransmission is altered in hepatitis C
virus infected pati ents with chronic fatigue and co gnitive impairment. Gut . 2006;55:1624-30.
Weitz IC. Treatment of immune thrombocytopenia associated with interferon therapy of hepatitis C with the anti- CD20 monoclonal
antibody, rituxima b. Am J Hematol 2005;78:138-41.
White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: A systematic review and meta-analysis. J Hepatol
2008;49 :831-44.
Wilson SE, Le e WM, Murakami C, et al . Mooren’s corneal ulcers and hepatit is C virus infection. N Engl J M ed 1993;329:62.
Wintrobe M, Bu ell M. Hyperproteinemia ass ociated with multiple myeloma. With re port of a case in which extraordinar y hyperproteinemia
was associated with thrombosis of the retinal veins and symptoms suggesting Raynoud’s disease. Bull Johns Hopkins Hosp
1933;52:15 6-65.
Wang Y, Bare P, De Giorgi V, et al. Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system.
Hepatology 2016; 64:1900-10.
Wong VS, Egne r W, Elsey T, Brown D, Alexander GJ. Inci dence, character and clini cal relevance of mixed cryo globulinaemia in pati ents with
chronic hepatit is C virus infection. Clin E xp Immunol 1996;104:25-31.
Yamaguchi S, Kubo K , Fujimoto K, Hanao ka M, Hayasaka M, et a l. Bronchoalveolar l avage luid indings in p atients with chronic hepatiti s C
before and ater treatm ent with interferon alpha. Tho rax 1997;52:33-7.
Younossi ZM, Stepanova M, Gerber L, et al . Improvement of central fatigue is associated with sustained virologic response (SV) following
sofosbuvir (SOF) conta ining regimens. J Hepa tol 2014a;60(suppl):S308.
Younossi ZM, St epanova M, Henry L. et a l. Minimal impact of sofos buvir and ribavirin on health related qual ity of life in chronic hepatitis C
(CH-C). J Hepatol 2 014b;60:741-7.
Younossi ZM, Park H , Henry L, Adeyemi A, S tepanova M. Extrahepat ic manifestations of hepatiti s C: a meta-analysis of prevalence , quality
of life, and econom ic burden. Gastroe nterology 2016;150:1599-1608 .
Zhang W, Rao HY, Feng B, Liu F, Wei L . Efects of Interferon-Alpha Treatment on the Incidence of Hyperglycemia in Chronic Hepatitis C
Patients: A Systemati c Review and Meta-Analysis. Plo S One 2012;7:e39272.
Zignego AL , Macchia D, Monti M, Th iers V, Mazzetti M, Foschi M, et a l. Infection of peripheral mo nonuclear blood cells b y hepatitis C virus.
J Hepatol 1992;382 -6.
Zignego AL , Giannelli F, Marrocchi ME , Mazzocca A, Ferri C, G iannini C, et al. T(14;18) translocati on in chronic hepatitis C virus infect ion.
Hepatology 200 0;31:474-9.
Zignego AL, Ferri C, Pileri SA , Caini P, Bianchi FB. Extrahepatic manifestations of the Hepatitis C Virus infection: a general overview and
guidelines fo r clinical approach . Dig Liver Dis 2007a;39: 2-17.
Zignego AL, Giannini C, Ferri C. Hepatitis C virus-related lymphoproliferative disorders: an overview. World J Gastroenterol
2007b;13:2467-78.
Zignego AL, Cozzi A, Carpenedo R, Giannini C, Rosselli M, Biagioli T, et al. HCV patients, psychopathology and tryptophan metabolism:
analysis of the efects of p egylated interferon plus ribavirin t reatment. Dig Liver Dis 2 007c;39:107-11.
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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 positive gay men
have evidence of past HBV infection, and 5–10% show persistence of HBsantigen, with or without replicative hepatitis B as deined by the presence
of HBV DNA (Konopnicki 2005). Overall, rates of HBV/HIV coinfection are
slightly lower among intravenous drug users compared to gay 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 scariication
(Modi 2007). The prevalence among youth in most 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 promoted and 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 afected leading to a
reduction of HBs-antigen seroconversion. If HBV persists, the HBV DNA
levels are generally higher in HIV positive patients not on antiretroviral
therapy (Bodsworth 1989, Bodsworth 1991, Hadler 1991). In addition, with
progression of cellular immune deiciency, reactivation of HBV replication
despite previous HBs-antigen seroconversion may occur (Soriano 2005).
However, ater immune recovery due to antiretroviral therapy, HBe-antigen
and HBs-antigen seroconversion occur in a higher proportion of patients
compared to HBV monoinfected patients treated for chronic hepatitis B
(Schmutz 2006, Piroth 2010, Kosi 2012).
In untreated HIV infection, 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
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individuals, even ater the introduction of efective antiretroviral therapy
(AT), 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/HIVcoinfected compared to HIV-monoinfected individuals, particularly among
subjects with low nadir CD4+ cell counts (Thio 2002). Even at present,
despite the widespread use of tenofovir, HBV/HIV coinfection is still
associated with an increased morbidity (Crowell 2014), and liver-related
deaths in HBV/HIV-infected patients still do occur (Rosenthal 2014).
The beneicial impact of treatment of HBV in HBV/HIV coinfection was
irst demonstrated by data from a large cohort showing a reduction in
mortality with lamivudine treatment compared to untreated patients (Puoti
2007). This result is even more remarkable because lamivudine is the least
efective HBV polymerase inhibitor due to the rapid development of drug
resistance. In general, because of its limited long-term eicacy, lamivudine
monotherapy cannot be considered as appropriate therapy for either mono
HBV infection or HBV/HIV coinfection (Matthews 2011).
Figure 1. Association of HBV/HIV coinfection and mortalit y (Konopnicki 20 05). More than
one cause of death allowed per patient; p-values from chi-squared tests.
In addition, two large cohort studies (EuroSIDA and MACS) plus data
from HBV monoinfection studies showing a reduction in morbidity and
mortality established the need to treat chronic hepatitis B in HBV/HIVcoinfected patients.
Treatment of chronic hepatitis B in HBV/HIVcoinfected patients on antiretroviral therapy
In general, starting hepatitis B therapy depends on the degree of liver
ibrosis and the HBV DNA level. But as AT is now recommended for all HIV
patients independent of CD4-count to reduce HIV-associated morbidity
and mortality and to prevent HIV transmission, all HBV/HIV-coinfected
patients are considered eligible for AT by current guidelines (e. g. EACS
2016). The previous complicated recommendations for how to treat chronic
hepatitis B in patients without AT are now obsolete. As antiretroviral
drugs that are also active against HBV can usually be used, interferonbased treatment of HBV is now rarely indicated. Data in the literature for
HIV-coinfected patients on interferon therapy for HBV infection are limited
and not very encouraging (Núñez 2003). In addition, intensiied treatment
studies combining pegylated interferon with adefovir or intensifying TDF
therapy with pegylated interferon for one year showed no increase in HBV
seroconversion rates (Ingiliz 2008, Boyd 2016).
In general, tenofovir is the standard of care for HBV in HIV-coinfected
patients, because of its strong HBV polymerase activity and antiretroviral
eicacy. Tenofovir has been a long-acting and efective therapy in the
vast majority of treated HBV/HIV-coinfected patients (van Bömmel 2004,
Mathews 2009, Martin-Carbonero 2011, Thibaut 2011). Its antiviral eicacy
is not impaired in HBV/HIV-coinfected compared to HBV-monoinfected
patients (Plaza 2013). No conclusive pattern of resistance mutations has
been identiied in studies or cohorts (Snow-Lampart 2011). These data are
still valid at the end of 2016. In theory, resistance may occur in patients on
long-term therapy, as with any other antivirals.
For patients with HBV DNA <2000 IU/mL and no relevant liver ibrosis,
no speciic AT regimen is recommended. However due to the favourable
resistance proile a regimen including tenofovir is the irst choice. When
choosing an HBV polymerase inhibitor, complete suppression of HBV DNA
is important to avoid the development of HBV drug resistance.
When HBV DNA is above 2000 IU/mL in HBV treatment naïve patients
a combination of tenofovir plus lamivudine/emtricitabine to treat
both infections is usually recommended. Even for patients who harbor
lamivudine-, telbivudine- or adefovir-resistant HBV due to previous
therapies this strategy stands. The recommendation to continue lamivudine/
emtricitabine is based on delayed resistance to adefovir seen when doing so
(Lampertico 2007), but the same efect has not been in combination with
tenofovir (Berg 2010, Patterson 2011).
Initiating AT including tenofovir resulted in higher rates of HBe
antigen loss and seroconversion as expected from HBV-monoinfected
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patients (Schmutz 2006, Piroth 2010, Kosi 2012). This may be due to the
additional efect of immune reconstitution in HBV/HIV coinfected patients
complicating the immunological control of HBV replication.
For patients with advanced liver ibrosis or liver cirrhosis a maximally
active continuous HBV polymerase inhibitor therapy is important to
avoid further ibrosis progression and hepatic decompensation and to
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 (Ratclife 2011).
A reduction in the incidence of hepatocellular carcinoma has been shown
for patients on HBV polymerase inhibitors compared to untreated patients,
strengthening the antiproliferative efects of suppressive antiviral therapy
(Hosaka 2012).
Liver ultrasound is needed at least every six months, for early detection
of hepatocellular carcinoma. In patients with advanced cirrhosis,
esophagogastroscopy should be performed as screening for oesophageal
varices. For patients with hepatic decompensation and full treatment
options for HBV and who have stable HIV infection, liver transplantation
should be considered as posttransplant life expectancy seems to be the
same as for HBV-monoinfected patients (Coin 2007, Tateo 2009). Patients
with hepatocellular carcinoma may also be considered liver transplant
candidates, although according to preliminary observations from small
cohorts, the outcome may be worse than for HBV-monoinfected patients
(Vibert 2008).
In prospective controlled studies, tenofovir was clearly superior to
adefovir for the 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
2012, van Bömmel 2010), although even in these situations tenofovir retains
suicient activity against HBV (Berg 2010, Patterson 2011, Petersen 2012).
In lamivudine-resistant HBV the antiviral eicacy of entecavir in HIVcoinfected patients is reduced, as it is in HBV monoinfection (Shermann
2008). Because of this and the property of tenofovir as a fully active
antiretroviral, tenofovir-DF is the preferred choice in treatment-naïve HBV/
HIV coinfected patients who will use AT. The use of entecavir, telbivudine
or adefovir as an add-on to tenofovir or other drugs in the case of not fully
suppressive antiviral HBV therapy has not yet been studied in HBV/HIV
coinfection. This decision should be made on a case-by-case basis.
Based on the history of AT, combination HBV therapy of tenofovir
plus lamivudine/emtricitabine was expected to be superior to tenofovir
monotherapy, in particular in patients with highly replicative HBV
infection. However, this hypothesis has not as yet been supported by
studies (Schmutz 2006, Mathews 2008, Mathews 2009, Price 2013). There
are data showing better viral suppression for entecavir and tenofovir-DF
compared to entecavir monotherapy in highly replicative patients with
HBV-monoinfection, but no such a study is available for a comparison with
tenofovir monotherapy (Lok 2012).
In the case of HIV resistance to tenofovir, it is usually important to
continue using tenofovir for HBV activity when switching to other AT.
Discontinuation of the HBV polymerase inhibitor without maintaining
the antiviral pressure on HBV can lead to necroinlammatory lares that
can result in acute liver decompensation, particularly in patients with liver
cirrhosis.
In 2015, tenofovir alafenamide (TAF) was approved as antiretroviral
therapy in Europe and the US. TAF is a new formulation of tenofovir with
lower plasma exposure of the active drug tenofovir compared to tenofovir
diproxovil fumarate (TDF). TAF has not shown superior antiviral activity
against HIV or HBV compared to TDF, but may ofer advantages concerning
long term toxicities involving bone and kidney over TDF (Agarwal 2015,
Sax 2015). TAF can substitute TDF as HBV therapy in HBV/HIV-coinfected
patients (Gallant 2016). In November 2016, TAF was approved for HBV
treatment in the US, followed by the approval in Europe in January 2017.
The potentially nephrotoxic efect of TDF is a concern. Although
nephrotoxicity is rarely observed in HIV negative patients treated with
TDF monotherapy (Heathcote 2011, Mauss 2011), renal impairment has
been more frequently reported in HIV positive patients using TDF as a
component in AT and may be associated in particular with the combined
use of TDF and ritonavir-boosted HIV protease inhibitors (Mauss 2005, Fux
2007, Goicoecha 2008, Mocrot 2010). In addition, the recently approved
cytochrome P450 3A inhibitor cobicistat can also increase creatinine levels.
Regular monitoring of renal function in HBV/HIV-coinfected patients
including estimated glomerular iltration rate (eGFR) and assessment
of proteinuria is necessary. In the case of a reduced eGFR, TDF should be
substituted by TAF or should be dosed at a reduced frequency according to
the label. In the case of signiicant proteinuria, TDF should also be replaced
by TAF. Alternatively in speciic situations in the cas e of tenofovir asso ciated
nephrotoxicity tenofovir can also be replaced by entecavir.
Conclusion
The number of available HBV polymerase i nhibitors for chronic hepatitis
B has increased substantially over the last few years. In general, the choice
is conined to two mostly non-cross-resistant classes, the nucleotide and
nucleoside compounds.
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