Download 1 How we treat hepatitis C virus infection in patients

From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Blood First Edition Paper, prepublished online July 21, 2016; DOI 10.1182/blood-2016-05-718643
How we treat hepatitis C virus infection in patients with hematologic malignancies
Harrys A. Torres, M.D.,1 and George B. McDonald, M.D.2
1
Department of Infectious Diseases, Infection Control and Employee Health, The University of
Texas MD Anderson Cancer Center, Houston, Texas. 2Gastroenterology/Hepatology Section,
Clinical Research Division, Fred Hutchinson Cancer Research Center and the University of
Washington School of Medicine, Seattle, Washington.
Short title: Treatment of HCV infection
Key words: hepatitis C virus, direct-acting antiviral therapy, liver disease, oncology,
hematopoietic cell transplant, drug-drug interactions.
Word count (Text): 4,230 (Limit, 4,000)
Word count (Abstract): 150 (Limit, 200)
Number of tables: 4
Number of figures: 1
Number of references: 99
1
Copyright © 2016 American Society of Hematology
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Abbreviations: ALT, alanine aminotransferase; anti-HCV, antibody to hepatitis C virus; DAA,
direct-acting antivirals; GVHD, graft-versus-host disease; HBV, hepatitis B virus; HCT,
hematopoietic cell transplant; HCV, hepatitis C virus; IFN, interferon; NHL, non-Hodgkin
lymphoma; SVR, sustained virologic response.
2
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Abstract
Hepatitis C virus (HCV) infection is not uncommon in cancer patients. Over the past 5 years,
treatment of chronic HCV infection in patients with hematologic malignancies has evolved
rapidly as safe and effective direct-acting antivirals (DAAs) have become the standard-of-care
treatment. Today, chronic HCV infection should not prevent a patient from receiving cancer
therapy or participating in clinical trials of chemotherapy as most infected patients can achieve
virologic cure. Elimination of HCV from infected cancer patients confers virologic, hepatic, and
oncologic advantages. Like the optimal therapy for HCV-infected patients without cancer, the
optimal therapy for HCV-infected patients with cancer is evolving rapidly. The choice of
regimens with DAAs should be individualized after thorough assessment for potential
hematologic toxic effects and drug-drug interactions. This article presents clinical scenarios of
HCV-infected patients with hematologic malignancies, focusing on diagnosis, clinical and
laboratory presentations, complications, and DAA therapy. An up-to-date treatment algorithm is
presented.
3
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Introduction
Hepatitis C virus (HCV) infection is the most common bloodborne infection in the United States,
where the prevalence of HCV infection is estimated to be 1.0% to 1.5%.1 In patients with cancer,
estimates of the prevalence of HCV infection range from 1.5% to 32%.2-6 Chronic HCV infection
is mainly associated with hepatocellular carcinoma and non-Hodgkin lymphoma (NHL).7,8
Management of HCV infection is more challenging in patients with hematologic
malignancies than in patients without cancer because of a higher rate of progression of fibrosis,
more rapid development of cirrhosis, increased viral titers, worse outcome, and exclusion from
some cancer and/or antiviral treatments.9-11 Elimination of HCV from infected patients with
hematologic malignancies has the potential for virologic, hepatic, and oncologic benefits (Table
1).9,12,13 The website http://www.hcvguidelines.org provides continuously updated guidelines for
direct-acting antiviral (DAA) treatment of patients with HCV infection.
Clinical scenarios
Case 1: A 55-year-old man with a 30-year history of chronic HCV infection (genotype 2) was
recently diagnosed with splenic marginal zone lymphoma. His HCV infection had never been
treated because there had been no evidence of progressive hepatic fibrosis or portal hypertension.
DAA therapy was recommended as first-line therapy before chemotherapy.
Discussion, Case 1. This case raises several issues: 1) Can some HCV-associated hematologic
malignancies be cured with DAA therapy without chemotherapy? 2) After DAA therapy has
induced a sustained virologic response (SVR), is there a risk of HCV recurrence following
immunosuppressive chemotherapy? 3) Could antiviral therapy years ago have prevented
4
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
development of this lymphoma, and is chemoprevention a valid indication for DAA therapy in
HCV-infected patients with no evidence of hepatic fibrosis?
Evidence that HCV infection may be causal in the development of lymphoma is based on
several cases in which regression of lymphoma followed elimination of HCV.14 Most patients
with HCV-associated NHL have mild liver disease at the time of lymphoma diagnosis,15
suggesting that DAA therapy should be initiated as early as possible after diagnosis of HCV
infection, regardless of liver disease status, to eradicate HCV infection and thus, prevent
extrahepatic manifestations such as NHL. Evidence for this strategy comes from a Japanese
study in which the annual incidence of lymphoma was compared between 501 HCV-infected
patients who had never received interferon (IFN)-based therapy and 2708 HCV-infected patients
who had received IFN. The subsequent risk of lymphoma was approximately 7 times higher in
patients with persistent HCV infection as in patients with IFN-induced SVR. Among patients
whose therapy eliminated HCV, there were no cases of lymphoma development by 15 years.16
Furthermore, several case series have shown regression of indolent lymphoma in HCV-infected
patients treated with antiviral drugs.14 Current National Comprehensive Cancer Network
guidelines on splenic marginal zone lymphoma recommend treatment of HCV without
chemotherapy as first-line therapy for HCV-infected patients.17 The benefit of giving DAA
therapy without chemotherapy as first-line therapy may extend to patients with other types of
HCV-associated NHL (e.g., diffuse large B-cell lymphoma 18) or patients with HCV-associated
NHL undergoing hematopoietic cell transplant (HCT).19
Some authors have reported detection of HCV RNA in hepatocytes and peripheral blood
mononuclear cells from patients who had achieved SVRs,20 but little is known about the risk of
viral relapse following subsequent chemotherapy. In a study of 30 HCV-infected cancer patients,
5
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
including 15 with hematologic malignancy, who achieved a SVR before cancer therapy, no
patient had viral relapse after cancer therapy.21 The cancer therapies were as follows: rituximab,
cyclophosphamide, cisplatin, 5-fluorouracil, doxorubicin, melphalan, bortezomib, fludarabine,
paclitaxel, sorafenib, lenalidomide, and vincristine, (some patients received combination
therapy).21
These findings indicate that HCV infection is curable in cancer patients and the risk of
HCV recurrence is low once SVR has been achieved, even after chemotherapy-related immune
suppression. These findings also emphasize the importance of identification and treatment of
HCV infection before initiation of chemotherapy.21 Patients with evidence of fibrotic and
necroinflammatory liver disease require monitoring of liver disease progression even when they
have achieved a SVR.
Summary, Case 1. HCV infection appears to contribute to some cases of NHL, and some
patients with HCV infection and NHL can be cured with DAA therapy alone. Once a SVR has
been achieved, the risk that subsequent chemotherapy will lead to recurrent HCV infection is
negligible. Treatment of HCV infection may prevent development of certain types of NHL.
Case 2. A 60-year-old woman was diagnosed with acute myeloid leukemia and was found to be
HCV antibody (anti-HCV) positive with detectable HCV-RNA and evidence of genotype 1a
infection. She had a history of unexplained abnormally high serum aminotransferase levels for
over 20 years. There were no signs of cirrhosis or portal hypertension. Approximately 6 months
after leukemia remission was achieved with chemotherapy, the patient was started on sofosbuvir
and ledipasvir. Within 4 weeks of treatment with DAAs, serum alanine aminotransferase (ALT)
6
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
levels normalized, and HCV-RNA became undetectable. The patient achieved a SVR12
(undetectable HCV-RNA at 12 weeks after completion of therapy). She is undergoing periodic
follow-up examinations to check for evidence of relapse as a donor search is underway.
Discussion, Case 2. This case raises several important issues: 1) the importance of early
diagnosis of HCV infection, 2) the importance of monitoring for virologic complications of HCV
infection during chemotherapy, and 3) the optimal sequencing of DAA therapy and
chemotherapy.
Among patients infected with HCV, those with hematologic malignancies, and especially
patients who have undergone HCT, have a more rapid rate of fibrosis progression and a higher
risk of developing cirrhosis than patients without cancer.22 Among patients with cancer, HCV
screening and early diagnosis, assessment of liver fibrosis, and elimination of HCV will likely
improve long-term outcomes.9 Groups for whom HCV screening is recommended include
candidates for HCT,23 patients with hematologic malignancies24 and other cancer patients as
recommended in patients without cancer.1,23,25 HCV screening is recommended before starting
selected chemotherapy agents (e.g., rituximab, alemtuzumab) and before enrolment on clinical
trials with investigational antineoplastic agents. Discovery of HCV infection in a patient newly
diagnosed with a hematologic malignancy should prompt virologic tests and fibrosis assessments
(Table 2).
In HCV-infected cancer patients, ALT levels should be monitored during chemotherapy
because immunocompromised cancer patients can experience acute exacerbation of chronic
HCV infection (also known as hepatitis flare), which is indicated by a significant elevation of
serum ALT levels over the baseline level.26 In a retrospective study of 308 HCV-infected
7
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
patients treated for cancer, 11% developed an acute exacerbation of chronic HCV infection,
defined as a 3-fold or greater increase in serum ALT level from baseline in the absence of
infiltration of the liver by cancer, use of hepatotoxic medications, blood transfusion within 1
month of elevation of ALT level, or other hepatic viral infection.26 Acute exacerbation of HCV
infection during chemotherapy prompted clinicians to discontinue chemotherapy in nearly half of
infected patients.26 The diagnostic work-up to confirm acute exacerbation of HCV infection must
consider a range of possibilities and take into account that multiple causes of liver inflammation
can be present at the same time. In a patient who has undergone HCT, additional diagnoses to
consider include the hepatitic presentation of graft-versus-host disease (GVHD), infection with
other viruses, drug-induced liver injury, and hypoxic hepatitis.27
HCV-infected cancer patients undergoing immunosuppressive therapy may also
experience increased HCV replication (also known as HCV reactivation), which has been
defined as an increase in HCV-RNA viral load of at least 1 log10 IU/mL over baseline after
chemotherapy or immunosuppressive therapy26 (chronically infected patients have stable HCVRNA levels that may vary by approximately 0.5 log10 IU/mL).28 The increased replication of
HCV and the resulting high blood titers of virus appear to be associated with a more indolent
course than hepatitis B virus (HBV) reactivation;11 there are only a few reports of deaths
associated with increased HCV replication, some of them related to development of fibrosing
cholestatic hepatitis C (see Case 5, below).29,30
Little is known about acute exacerbation and reactivation of HCV infection in patients
with hematologic malignancies and HCT recipients, although some data were published
recently.19,31-33 In general, in patients with hematologic malignancies and HCV infection, ALT
level should be evaluated at baseline and periodically during chemotherapy or
8
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
immunosuppressive therapy to identify unusual cases of more severe hepatocellular injury or
fibrosing cholestatic hepatitis C. Routine monitoring of HCV RNA is not recommended;
however, HCV RNA should be measured in all patients at entry into care, and viral load should
be monitored in patients receiving HCV treatment according to standard-of-care management for
patients without cancer.12
Eradication of HCV may normalize liver function, allowing access to drugs that would
otherwise be contraindicated, including agents with hepatic metabolism.34 SVR would prevent
HCV reactivation and hepatic flare after chemotherapy, thus avoiding discontinuation or dose
reduction of chemotherapy and possibly the risk of hepatic decompensation during cancer care.26
Longer-term benefits would include prevention of progression to cirrhosis, reduction in the risk
of second primary cancers (hepatocellular carcinoma and NHL),18,35 and improved survival of
patients with these secondary cancers.19,36,37
The advent of DAAs has rendered IFN-containing regimens obsolete for treatment of
HCV infection, and the benefits of DAA therapy outweigh the risks in HCV-infected patients
with hematologic malignancies (Table 1). Contraindications to treatment with DAAs in HCVinfected patients with hematologic malignancies are shown in Table 3.
To improve the response to HCV therapy and avoid development of viral resistance,
DAA therapy should not be interrupted or given intermittently. DAA-based regimens can be
completed in 8 to 12 weeks in most patients with selected cases requiring up to 24 weeks of
treatment,12,38 enabling eradication of HCV during chemotherapy-free periods. Severe adverse
effects and hematologic toxic effects are uncommon (occurring in fewer than 5% of patients) in
cancer patients receiving IFN-free or ribavirin-free DAA-containing regimens.19,39
9
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
As of 2016, we do not recommend simultaneous administration of chemotherapy and
DAAs. However, preliminary data in a small group of cancer patients, including some with
hematologic malignancies, showed that concomitant chemotherapy and DAA therapy is
feasible.40 Because we have only limited clinical understanding of drug-drug interactions and
chemotherapy tolerability in HCV-infected patients, simultaneous therapies should be used with
caution.
Summary, Case 2: Elimination of HCV with DAAs, either before or after cancer therapy, has
not been studied in randomized trials, but SVR could confer several benefits to patients with
hematologic malignancies, particularly if the malignant disorder is driven by an HCV-related
chronic inflammatory state. Short-term benefits of HCV eradication include normalization of
liver function, prevention of HCV reactivation and hepatic flare after chemotherapy, and
possibly better outcomes if an allogeneic transplant was carried out. Longer-term benefits of
SVR would include prevention of progression to cirrhosis, reduction in the risk of second
primary cancers, and improved survival.
Case 3. A 38-year-old man has acute myeloid leukemia in first remission. He is being considered
for allogeneic HCT. His 44-year-old brother is HLA-matched and has chronic HCV infection but
no signs of portal hypertension. An unrelated donor search has identified an HLA-matched 32year-old woman who is anti-HCV negative.
Discussion, Case 3. This case raises 2 questions: 1) Can HCV be cleared from the matched
sibling donor in a timely way so that the sibling can donate hematopoietic cells without risk of
10
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
passing HCV to the patient? 2) If treatment of the infected donor did not clear HCV, who would
be the optimal donor, the HCV-infected HLA-matched sibling or an uninfected HLA-matched
unrelated donor?
A 2015 report from the American Society for Blood and Marrow Transplantation Task
Force extensively covers diagnosis and management of HCV infection in hematopoietic cell
donors and HCT candidates and recipients.23 Virtually all HCV-infected donors will transmit
virus to recipients.41 Case reports of HCV-infected marrow donors treated with IFN or ribavirin
demonstrate that clearance of HCV from the bloodstream prevents passage of virus, an effect
that does not require a SVR, just temporary cessation of viremia, during which marrow or
peripheral blood is harvested.42,43 DAAs are very effective in clearing HCV and work rapidly;
thus, when the best HLA-matched donor is HCV-infected, treatment with DAAs should be
instituted as early as possible.23,24 Most infected donors will attain undetectable HCV-RNA
within 4 weeks of initiation of DAA therapy.44
If no uninfected HLA-matched donor is available and if time does not permit treatment of
the infected donor to eliminate HCV from the infusion product, the use of an HCV-infected
hematopoietic inoculum into an HCV-uninfected recipient is not contraindicated. The risk of
dying from the underlying hematologic malignancy without HCT far outweighs the risk of
acquiring potentially curable HCV.23 However, the donor should be assessed for advanced liver
disease, extrahepatic manifestations of HCV (e.g., NHL), and coinfections (e.g., HIV) that might
contraindicate donation.23 Using an HCV-infected sibling donor is preferable to an HLAmatched unrelated donor, as the natural history of HCV infection in allografted patients is
usually benign in the early years following HCT.45 After transplant, DAA therapy can be given
to the recipient. For most patients with early hematologic malignancy, survival after HCT with
11
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
hematopoietic cells donated by an HLA-matched sibling is superior to survival after an unrelated
donor transplant.46
Summary, Case 3. An HCV-infected donor should not be an absolute contraindication for
HCT.23 The risk of passage of virus from an infected donor can be greatly reduced by DAA
therapy that results in undetectable HCV-RNA. When time does not permit sufficient antiviral
treatment of an HLA-matched sibling donor to achieve undetectable HCV-RNA, using an HCVinfected, HLA-matched sibling donor will usually yield better oncologic outcomes than using an
HLA-matched uninfected and unrelated donor.
Case 4. A 62-year-old man presented with an abdominal mass. At operation, biopsy revealed a
T-cell lymphoma; also noted were ascites and a nodular-appearing liver with chronic hepatitis,
fibrosis, and regenerative nodules on histopathologic examination. Laboratory studies revealed
the following values: total serum bilirubin, 1.3 mg/dL; serum ALT, 122 U/L; alkaline
phosphatase, 87 U/L; albumin, 2.4 mg/L; international normalized ratio, 1.6; platelets,
92,000/mm3; hepatitis B surface antigen, negative; and anti-HCV, positive. The patient’s
cirrhosis was classified as Child-Turcotte-Pugh class B.
Discussion, Case 4. This case raises 2 issues: 1) the impact of cirrhosis on the disposition of
chemotherapy drugs, and 2) the risk of liver failure due to cancer therapy or drugs used in
supportive care.
Dosing of drugs (including chemotherapy) in patients with cirrhosis is an inexact science,
in part because of the complexity of drug disposition in the liver, which depends on hepatic
12
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
perfusion, extraction, metabolism, excretion, and differences in protein binding of individual
drugs.47,48 No single method allows estimation of the pharmacokinetics and pharmacodynamics
of a drug in an individual patient with liver dysfunction. Dose adjustments are often necessary in
patients with cholestatic liver injury,49,50 but adjustments are usually not necessary in patients
with chronic HCV infection, except in the case of certain high-dose myeloablative conditioning
regimens for HCT, for which the risk of fatal sinusoidal obstruction syndrome is almost 10 times
as high in patients with chronic HCV infection as in patients without HCV infection.51-53 The
most accurate method of dose adjustment is therapeutic drug monitoring, in which the dose is
personalized in real time according to an individual patient’s clearance of a drug to achieve the
target plasma exposure.54-56 In patients for whom HCT is planned, therapeutic monitoring of
busulfan is widely used to avoid graft rejection and relapse of some malignant disorders (low
exposure) and toxic effects (high exposure).57,58 For drugs with unpredictable pharmacokinetics
(e.g., cyclophosphamide59 and melphalan60), therapeutic drug monitoring is the only logical
approach to dosing, not only in patients with cirrhosis but also in patients with normal liver
function. However, clinical use of therapeutic drug monitoring is for the most part limited to
specialized centers. Therefore, most patients with cirrhosis or cholestasis must rely on other
dose-adjustment methods.
Another method for dose adjustment involves triaging cirrhotic patients into ChildTurcotte-Pugh classes A, B, or C (http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp).
For many chemotherapy drugs, pharmacokinetic information for patients with Child-TurcottePugh class A or B cirrhosis is available from the drug manufacturer; such information is based
on US Food and Drug Administration and European Medicines Agency guidance on determining
the pharmacokinetics of study drugs in patients with impaired hepatic function.61,62 For patients
13
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
with class A or B cirrhosis, dose reductions of 50% to 75% are often recommended, depending
on whether the drug in question is a high-liver-extraction drug (extraction dependent on hepatic
perfusion) or a low-liver-extraction drug (extraction dependent on hepatocyte metabolism and
elimination).47 For high-extraction drugs, dose reductions are needed. For low-extraction drugs,
the degree of protein binding affects dose adjustment, with highly bound drugs not needing dose
reduction. Drugs with low protein binding are dose-reduced in parallel with the estimated
reduction in hepatic functional reserve (based on the Child-Turcotte-Pugh class). Chemotherapy
dose-adjustment recommendations have been published that are based on findings of serum liver
tests, mostly serum bilirubin levels.49,50,62 The main goals of dose adjustment are to avoid
systemic side effects from toxic plasma concentrations and to provide adequate drug
concentrations when low exposure is anticipated.
If the patient in this case were scheduled for HCT, the questions would be as follows:
What conditioning regimen could this patient with cirrhosis tolerate? Should DAA therapy be
attempted before transplant? Is mycophenolate mofetil contraindicated as GVHD prophylaxis?
High-dose myeloablative regimens containing sinusoidal endothelial cell toxins
(cyclophosphamide, etoposide, thiotepa, melphalan, gemtuzumab ozogamicin, and total body
irradiation >12 Gy) have been largely abandoned in patients with chronic hepatitis (HCV
infection, nonalcoholic steatohepatitis, or alcoholic hepatitis) in favor of less liver-toxic
regimens.51,52 If there is an imperative to use a CY-based regimen in a cirrhotic patient, the dose
should be 90 mg/kg to 100 mg/kg (instead of 120 mg/kg), dose-adjusted if possible, and either
separated in time from BU or given first in order (e.g., CY/ targeted BU).59,63,64 Reducedintensity regimens may avoid sinusoidal injury, but cirrhotic patients remain at risk for liver
failure from GVHD, infection-related cholestasis, hypoxic hepatitis, tumor infiltration, and drug-
14
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
induced liver injury resulting from drugs used in supportive care, including herbal therapies.52,6568
Ascitic fluid should be drained prior to administration of hydrophilic drugs such as fludarabine
and methotrexate,52 and if mycophenolate mofetil is used, it should be dose-adjusted if the serum
albumin level is low.69 Supportive care should include ursodiol for prevention of cholestatic liver
injury, antibiotics to prevent bacterial translocation during neutropenia, and attention to portal
pressures and hepatorenal syndrome.
Drug-induced liver injury resulting from anticancer drugs has been reviewed
elsewhere.62,66,70 HCV is a risk factor for drug-induced liver injury from some drugs, and there
are case reports of increased viral titers and more severe HCV infection after recovery of
immunity following immunosuppressive chemotherapy.30,71,72 A cirrhotic patient would be at
greater risk than someone without cirrhosis for worsening HCV-related liver inflammation.
Treatment of HCV-infected cirrhotic patients with DAAs can be successful in achieving a SVR,
but should probably be deferred until the course of hematologic malignancy is clear.
Summary, Case 4. HCV-infected patients with cirrhosis are challenging to treat because of the
difficulty of determining proper doses of cytotoxic and immunosuppressive drugs and the
increased risk of liver failure as a result of any number of hepatic insults. Questions about dosing
of chemotherapy drugs in cirrhotic patients are best addressed by experienced pharmacologists.
Case 5. A 56-year-old man with acute myeloid leukemia in first complete remission was treated
with a reduced-intensity conditioning regimen and unrelated cord blood transplant with
tacrolimus and mycophenolate mofetil for GVHD prophylaxis. Before transplant, he was found
to be infected with HCV genotype 1b, and rs12979860 genotype (previously known as
15
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
interleukin-28B) TT. Before transplant, findings on liver tests and imaging were normal. At day
80 after transplant, the patient developed nausea, vomiting, and diarrhea, elevated values on liver
function tests (ALT, 139 U/L; total serum bilirubin, 3.9 mg/dL), confusion, and coagulopathy.
Endoscopic biopsy confirmed gut GVHD, and the patient was started on prednisone 1
mg/kg/day. By day 96 after transplant, the patient was more deeply jaundiced; a liver biopsy
showed fibrosing cholestatic hepatitis. Treatment with the combination of ombitasvir,
paritaprevir, ritonavir, dasabuvir, and weight-based ribavirin was considered, but the risk of
drug-drug interactions was thought to be high (e.g., increased level of tacrolimus with resulting
central nervous system toxic effects and peripheral neuropathy).
Discussion, Case 5. This case raises several important questions: 1) Is it safe for an HCVinfected patient to undergo HCT? 2) What serious complications of HCV infection can be
expected after HCT? 3) How important is monitoring for drug-drug interactions in HCV-infected
patients receiving DAA therapy?
This patient developed fibrosing cholestatic hepatitis, a rare and potentially fatal
complication characterized by periportal fibrosis, ballooning degeneration of hepatocytes,
prominent cholestasis, and paucity of inflammation related to a high intracellular load of either
HBV or HCV and viral protein.29,73,74 Fibrosing cholestatic hepatitis has been described after
HCT, organ transplant, and some chemotherapy regimens.29,75-78 In an HCT recipient, fibrosing
cholestatic hepatitis C must be differentiated from other manifestations of cholestatic liver injury
(e.g., GVHD, drug-induced liver injury, and cholestasis of infection).52
In both the liver transplant and HCT settings, use of mycophenolate mofetil has been
linked to development of fibrosing cholestatic hepatitis C; thus, this drug should probably not be
16
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
used in HCV-infected patients.29,79 In the HCT setting, DAAs against HCV would likely reduce
the burden of intracellular virus29 and reduce the mortality rate of fibrosing cholestatic hepatitis
C, as has been observed with successful DAA therapy of fibrosing cholestatic hepatitis C in the
liver transplant setting.80-82 In a parallel situation, the frequency of fibrosing cholestatic hepatitis
B in HCT recipients has plummeted since the introduction of pre-emptive use of lamivudine or
entecavir.83
When possible, DAA therapy for HCV-infected HCT candidates should be completed
before HCT. If DAA therapy cannot be completed until after HCT, DAA therapy can be deferred
until after immune reconstitution except in patients who develop fibrosing cholestatic hepatitis C
and probably on cases of severe HCV reactivation post HCT.33
The drawback of deferring DAA therapy for HCV infection until after HCT is the
propensity of DAAs for drug interactions, including altered disposition of several drugs
commonly used in HCT patients.23 The drugs most impacted by DAAs are components of
conditioning regimens, calcineurin inhibitors, and sirolimus, but review of the isoenzymes
responsible for drug metabolism suggests that many of the drugs used in supportive care are
similarly affected by DAAs.23 Current databases (http://www.hep-druginteractions.org and
Lexicomp online) should be consulted along with the product prescribing information to ensure
the safety of delivering DAAs together with medications such as acid reducers, antidepressants,
antihypertensives, phosphodiesterase inhibitors, novel oral anticoagulants, macrolide antibiotics,
and HMG Co-A inhibitors. Some experts advocate waiting for 6 months after HCT to start DAA
therapy, to allow tapering of immunosuppressive agents and GVHD prophylaxis; this practice
might result in higher SVR rates and avoid drug-drug interactions with calcineurin inhibitors.23
The majority of HCV-infected HCT recipients do not have an adverse course in the years
17
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
following HCT despite greatly increased titers of circulating virus following conditioning
therapy.45
It is not currently known whether the high rates of HCV clearance with DAAs in the
general population and in organ transplant patients can be replicated in HCT patients in the early
post-HCT period, as full immune reconstitution does not occur until more than 1 year after
allogeneic HCT and both immunosuppressive therapy and GVHD will delay return of
immunity.84,85 Preliminary data show that DAAs are safe and effective (SVR rate, 85%) in HCVinfected HCT recipients.19
The choice of DAA regimen should be guided by several factors (e.g., the patient’s prior
antiviral treatment, HCV genotype, and degree of liver disease) and should be individualized
after thorough assessment for potential hematologic toxic effects and drug-drug interactions.
Several articles have been recently published on drug interactions with DAAs.86-89
Recommended dosage adjustments for patients with renal impairment are now available.12 For
currently approved DAAs in 2016, no dose adjustments are necessary for patients with liver
dysfunction, including those with decompensated cirrhosis.12,82 This issue have to be re-visited
with each new DAA that is approved; and HCV guidelines and the manufacturer's package insert
should be consulted.
Summary, Case 5. Transplant physicians must be aware of the risk of fibrosing cholestatic
hepatitis C, especially in patients whose GVHD prophylaxis includes mycophenolate mofetil or
enteric-coated mycophenolic acid. The role of DAAs in patients undergoing HCT has yet to be
defined, but on the basis of preliminary data, we envision eliminating HCV before transplant or
administering DAAs after transplant to prevent development of fibrosing cholestatic hepatitis C
18
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
and other adverse effects of HCV infection. Patients with a diagnosis of fibrosing cholestatic
hepatitis C after HCT should receive DAA therapy. Close attention to drug-drug interactions will
be necessary when DAAs are prescribed to allograft recipients.
Conclusions
HCV is now curable by DAAs in most patients, including those with hematologic malignancies.
Elimination of HCV from infected patients offers potential virologic, hepatic, and oncologic
benefits.
HCV infection should not contraindicate cancer therapy, and patients with chronic HCV
infection and hematologic malignancies should not be excluded from clinical trials of
chemotherapy or antiviral therapies. However, hepatologists and infectious diseases specialists
with experience in treating HCV should participate in the diagnostic work-up, monitoring, and
treatment of infected patients.
Using a standardized approach since 2009, we demonstrated that HCV therapy is feasible
in many cancer patients.90 In general, the DAA combinations recommended for cancer patients
mimic those used for patients without cancer.12 DAAs used to treat HCV in 2016 and their most
common side effects are shown in table 4.93-99 Our management algorithm for HCV-infected
patients with hematologic malignancies is depicted in Figure 1. The optimal therapy for HCVinfected patients with cancer is evolving rapidly and will continue to evolve as new DAAs are
approved and as more studies are reported.
19
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Acknowledgements
The authors thank Stephanie Deming, The University of Texas MD Anderson Cancer Center, for
editorial assistance.
Authorship
Contributions: H.A.T. and G.B.M. wrote the manuscript, and both authors read and approved
the final version of the manuscript.
Conflict-of-interest disclosure:
H.A.T. is or has been the principal investigator for research grants from Gilead Sciences, Merck
& Co., Inc., and Vertex Pharmaceuticals, with all funds paid to MD Anderson Cancer Center.
H.A.T. is or has been a paid scientific advisor for the Gilead Sciences, Janssen Pharmaceuticals,
Inc., Merck & Co., Inc., Vertex Pharmaceuticals, Genentech, Novartis, Astellas Pharma, Pfizer
Inc., and Theravance Biopharma, Inc.; the terms of these arrangements are being managed by
MD Anderson Cancer Center in accordance with its conflict of interest policies. G.B.M. has no
conflicts of interest to report with regard to the content of this manuscript.
Correspondence: Harrys A. Torres, MD, FACP, FIDSA. Department of Infectious Diseases,
Infection Control and Employee Health, Unit 1460, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; e-mail: [email protected]
20
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Table 1. Benefits of HCV treatment in patients with hematologic malignancies9,12,13
Infectious and hepatic
1. Prevention of long-term complications such as liver cirrhosis and end-stage liver disease
2. Prevention of hepatocellular carcinoma as a primary or secondary cancer in patients with
chronic HCV infection
3. Improvement of long-term survival
4. Treatment of extrahepatic manifestations (cryoglobulinemia, fatigue)
Oncologic
1. Allowing patients access to multiple clinical trials of cancer chemotherapies, including trials of
agents with hepatic metabolism
2. Prevention of some HCV-associated hematologic malignancies (e.g. non-Hodgkin lymphoma)
or decrease of the relapse rate of those malignancies
3. Cure of selected HCV-associated hematologic malignancies without chemotherapy
21
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Table 2. Initial evaluation of HCV-infected patients with hematologic malignancies
History and clinical
Laboratory tests
Virologic tests
Imaging/staging studies
findings
History
• Alcohol abuse
Routine
• Complete blood count,
• Metabolic risk factors
AST, ALT, total
• Vaccination status
bilirubin,
against HAV and HBV
HCV
Imaging
• HCV-RNA
Abdominal sonography
quantitation
or computed tomography
• HCV genotype
alkaline phosphatase,
albumin, PT/PTT/INR,
BUN, creatinine
Physical examination
Others
Co-infections
Noninvasive markers of
• Symptoms/signs of
• Alpha-fetoprotein
• Anti-HAV
fibrosis
• GGT
• HBsAg
• Vibration-controlled
• Cryoglobulins
• Anti-HBs
cirrhosis
• Anti-HBc
• Anti-HIV
transient elastography a
• Serum fibrosis
panela
Selected cases
Selected cases
Pathology
• Interleukin 28B
• HCV resistance
• Liver biopsy
polymorphism
testing
Abbreviations: HAV, hepatitis A virus; HBV hepatitis B virus; AST, aspartate aminotransferase;
ALT, alanine aminotransferase; PT, prothrombin time; PTT, partial thromboplastin time; INR,
international normalized ratio; BUN, blood urea nitrogen; GGT, gamma-glutamyl transpeptidase;
anti-HAV, antibody to hepatitis A virus; HBsAg, hepatitis B surface antigen; anti-HBs, antibody to
22
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
hepatitis B surface antigen; anti-HBc, antibody to hepatitis B core antigen; anti-HCV, anti-HIV,
antibody to HIV.
a
Sonography-based vibration-controlled transient elastography (FibroScan VCTE; Echosens, Paris,
France) and serologic marker panels for detection of fibrosis have not been studied in HCV-infected
patients with hematologic malignancies; thus, results should be interpreted with caution.
23
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Table 3. Subgroups of HCV-infected patients with hematologic malignancies for whom
DAA therapy is contraindicated
Patients with uncontrolled hematologic malignancy or other comorbidities associated with a life
expectancy of less than 12 months owing to non–liver-related conditions a
Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) b
Pregnant women and men whose female partners are pregnant if ribavirin is considered
Patients with major drug-drug interactions with chemotherapy or immunosuppressive agents that
cannot be temporarily discontinued
Patients with known hypersensitivity or intolerance to drugs used to treat HCV
a
Extrapolated from recommendations in HCV-infected patients without cancer.12
b
While waiting for efficacy and safety data in infected patients with hematologic malignancies.
As liver transplantation is the only available treatment for decompensated cirrhosis,12,91 these
patients should be managed by providers with expertise in that condition, ideally in a liver
transplant center. Of note, incurable extrahepatic malignancies are considered a contraindication
to listing for liver transplantation,92 therefore, some patients with hematologic malignancies may
not be eligible for this intervention.
24
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Table 4. DAAs used to treat HCV in 2016 and their most common side effects93-99
Sofosbuvir
•
Fatigue, headaches
Simeprevir
•
Fatigue,a headaches,a nausea,a,b rash (including photosensitivity),b pruritusb
Daclatasvira
•
Fatigue, headaches, anemia, nausea
Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir
•
Fatigue, nausea,c pruritus,c other skin reactions (e.g. rash, erythema, eczema),
insomniac and asthenia
Ledipasvir-Sofosbuvir
•
Fatigue, headache and asthenia
Elbasvir-Grazoprevir
•
Fatigue, headache, nausea, anemiac
Sofosbuvir-Velpatasvir
•
Headache, fatigue, anemia,c nausea,c headache, insomnia,c and diarrheac
Abbreviations: DAA, direct-acting antivirals; HCV, hepatitis C virus.
a
Most common adverse reactions reported in combination with sofosbuvir and ribavirin.
b
Most common adverse reactions reported with in combination with pegylated interferon-
alfa and ribavirin.
c
Most common adverse reactions reported in combination with ribavirin.
25
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Figure 1. Treatment algorithm for patients with hematologic malignancies and chronic
HCV infection in 2016.
26
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
References
1.
Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of
chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep.
2012;61(RR-4):1-32.
2.
Fujii Y, Kaku K, Tanaka M, et al. Hepatitis C virus infection in patients with leukemia.
Am J Hematol. 1994;46(4):278-82.
3.
Markovic S, Drozina G, Vovk M, Fidler-Jenko M. Reactivation of hepatitis B but not
hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective
study in 305 patients. Hepatogastroenterology. 1999;46(29):2925-30.
4.
Faggioli P, De Paschale M, Tocci A, et al. Acute hepatic toxicity during cyclic
chemotherapy in non Hodgkin's lymphoma. Haematologica. 1997;82(1):38-42.
5.
Vento S, Cainelli F, Longhi MS. Reactivation of replication of hepatitis B and C viruses
after immunosuppressive therapy: an unresolved issue. Lancet Oncol. 2002;3(6):333-40.
6.
Iqbal T, Mahale P, Turturro F, Kyvernitakis A, Torres HA. Prevalence and association of
hepatitis C virus infection with different types of lymphoma. Int J Cancer. 2016;138(4):1035-7.
7.
Allison RD, Tong X, Moorman AC, et al. Increased incidence of cancer and cancer-
related mortality among persons with chronic hepatitis C infection, 2006-2010. J Hepatol.
2015;63(4):822-8.
8.
Nieters A, Kallinowski B, Brennan P, et al. Hepatitis C and risk of lymphoma: results of
the European multicenter case-control study EPILYMPH. Gastroenterology. 2006;131(6):187986.
9.
Torres HA, Mahale P, Blechacz B, et al. Effect of hepatitis C virus infection in patients
with cancer: addressing a neglected population. J Natl Compr Canc Netw. 2015;13(1):41-50.
27
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
10.
Borchardt RA, Torres HA. Challenges in managing hepatitis C virus infection in cancer
patients. World J Gastroenterol. 2014;20(11):2771-6.
11.
Torres HA, Davila M. Reactivation of hepatitis B virus and hepatitis C virus in patients
with cancer. Nat Rev Clin Oncol. 2012;9(3):156-66.
12.
American Association for the Study of Liver Diseases (AASLD) and the Infectious
Diseases Society of America (IDSA). HCV Guidance: Recommendations for testing m, and
treating hepatitis C. http://www.hcvguidelines.org. Accessed July 11, 2016.
13.
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment
of hepatitis C: an update. Hepatology. 2009;49(4):1335-74.
14.
Hartridge-Lambert SK, Stein EM, Markowitz AJ, Portlock CS. Hepatitis C and non-
Hodgkin lymphoma: the clinical perspective. Hepatology. 2012;55(2):634-41.
15.
Torres HA, Mahale P. Most patients with HCV-associated lymphoma present with mild
liver disease: a call to revise antiviral treatment prioritization. Liver Int. 2015;35(6):1661-4.
16.
Kawamura Y, Ikeda K, Arase Y, et al. Viral elimination reduces incidence of malignant
lymphoma in patients with hepatitis C. Am J Med. 2007;120(12):1034-41.
17.
National Comprehensive Cancer Network (NCCN). Splenic Marginal Zone Lymphoma.
Version 1, 2016.
18.
Economides MP, Mahale P, Turturro F, et al. Development of Non-Hodgkin Lymphoma
as a Second Primary Cancer in Hepatitis C Virus-Infected Patients with a Different Primary
Malignancy. Leukemia and lymphoma 2016; In press.
19.
Kyvernitakis A, Mahale P, Popat UR, et al. Hepatitis C Virus Infection in Patients
Undergoing Hematopoietic Cell Transplantation in the Era of Direct-Acting Antiviral Agents.
Biol Blood Marrow Transplant. 2016;22(4):717-22.
28
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
20.
Radkowski M, Gallegos-Orozco JF, Jablonska J, et al. Persistence of hepatitis C virus in
patients successfully treated for chronic hepatitis C. Hepatology. 2005;41(1):106-14.
21.
Mahale P, Okhuysen PC, Torres HA. Does chemotherapy cause viral relapse in cancer
patients with hepatitis C infection successfully treated with antivirals? Clin Gastroenterol
Hepatol. 2014;12(6):1051-4 e1.
22.
Peffault de Latour R, Levy V, Asselah T, et al. Long-term outcome of hepatitis C
infection after bone marrow transplantation. Blood. 2004;103(5):1618-24.
23.
Torres HA, Chong PP, De Lima M, et al. Hepatitis C Virus Infection among
Hematopoietic Cell Transplant Donors and Recipients: American Society for Blood and Marrow
Transplantation Task Force Recommendations. Biol Blood Marrow Transplant.
2015;21(11):1870-82.
24.
Mallet V, van Bömmel F, Doerig C, et al. Management of viral hepatitis in patients with
haematological malignancy and in patients undergoing haemopoietic stem cell transplantation:
recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5). Lancet
Infect Dis 2016;16:606-17.
25.
Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and
public health management of persons with chronic hepatitis B virus infection. MMWR Recomm
Rep. 2008;57(RR-8):1-20.
26.
Mahale P, Kontoyiannis DP, Chemaly RF, et al. Acute exacerbation and reactivation of
chronic hepatitis C virus infection in cancer patients. J Hepatol. 2012;57(6):1177-85.
27.
Sakai M, Strasser SI, Shulman HM, et al. Severe hepatocellular injury after
hematopoietic cell transplant: incidence, etiology and outcome. Bone Marrow Transplant.
2009;44(7):441-7.
29
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
28.
McGovern BH, Birch CE, Bowen MJ, et al. Improving the diagnosis of acute hepatitis C
virus infection with expanded viral load criteria. Clin Infect Dis. 2009;49(7):1051-60.
29.
Evans AT, Loeb KR, Shulman HM, et al. Fibrosing cholestatic hepatitis C after
hematopoietic cell transplantation: report of 3 fatal cases. Am J Surg Pathol. 2015;39(2):212-20.
30.
Vento S, Cainelli F, Mirandola F, et al. Fulminant hepatitis on withdrawal of
chemotherapy in carriers of hepatitis C virus. Lancet. 1996;347(8994):92-3.
31.
Mahale P, Thomas SK, Kyvernitakis A, Torres HA. Management of Multiple Myeloma
Complicated by Hepatitis C Virus Reactivation: The Role of New Antiviral Therapy. Open
Forum Infect Dis. 2016;3(1):ofv211.
32.
Varma A, Saliba RM, Torres HA, et al. Outcomes in hepatitis C virus seropositive
lymphoma and myeloma patients after autologous stem cell transplantation. Bone Marrow
Transplant. 2016;51(7):999-1001.
33.
Oliver NT, Nieto YL, Blechacz B, et al. Severe hepatitis C reactivation as an early
complication of hematopoietic cell transplantation Bone Marrow Transplantation 2016;In press.
34.
van Schaik RH. CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist
Updat. 2008;11(3):77-98.
35.
Mahale P, Kaseb AO, Hassan MM, Torres HA. Hepatocellular carcinoma as a second
primary cancer in patients with chronic hepatitis C virus infection. Dig Liver Dis.
2015;47(4):348-9.
36.
Miyatake H, Kobayashi Y, Iwasaki Y, et al. Effect of previous interferon treatment on
outcome after curative treatment for hepatitis C virus-related hepatocellular carcinoma. Dig Dis
Sci. 2012;57(4):1092-101.
30
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
37.
Breitenstein S, Dimitroulis D, Petrowsky H, et al. Systematic review and meta-analysis of
interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br
J Surg. 2009;96(9):975-81.
38.
Asselah T, Boyer N, Saadoun D, Martinot-Peignoux M, Marcellin P. Direct-acting
antivirals for the treatment of hepatitis C virus infection: optimizing current IFN-free treatment
and future perspectives. Liver Int. 2016;36(Suppl 1):47-57.
39.
Kyvernitakis A, Mahale P, Torres HA. Safety and tolerability of different antiviral
regimens for chronic hepatitis c virus infection in cancer patients. . Hepatol Int 2015;9 (Suppl ,
abstract 1235):S272.
40.
Mahale P, Kyvernitakis A, Kantarjian H, et al. Concomitant use of chemotherapy and
antivirals in hepatitis C virus infected cancer patients. The Liver Meeting 2015® 66th Annual
Meeting of the American Association for the Study of Liver Diseases; 2015 November 13-17;
San Francisco, CA. . p. Hepatology. 2015: 60(1)suppl; abstr 1160.
41.
Shuhart MC, Myerson D, Childs BH, et al. Marrow transplantation from hepatitis C virus
seropositive donors: transmission rate and clinical course. Blood. 1994;84(9):3229-35.
42.
Hsiao HH, Liu YC, Wang HC, et al. Hepatitis C transmission from viremic donors in
hematopoietic stem cell transplant. Transpl Infect Dis. 2014;16(6):1003-6.
43.
Vance EA, Soiffer RJ, McDonald GB, et al. Prevention of transmission of hepatitis C
virus in bone marrow transplantation by treating the donor with alpha-interferon.
Transplantation. 1996;62(9):1358-60.
44.
Beckerich F, Hezode C, Robin C, et al. New nucleotide polymerase inhibitors to rapidly
permit hematopoietic stem cell donation from a positive HCV-RNA donor. Blood.
2014;124(16):2613-4.
31
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
45.
Strasser SI, Myerson D, Spurgeon CL, et al. Hepatitis C virus infection and bone marrow
transplantation: a cohort study with 10-year follow-up. Hepatology. 1999;29(6):1893-9.
46.
Pasquini M, Zhu X. Current use and outcome of hematopoietic stem cell transplantation
CIBMTR summary slides, 2014.
47.
Stirnimann G, Reichen J. Drug prescription in liver disease. 2 ed. ed: Oxford UK: Blackwell
Publishing Ltd.; 2012.
48.
Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis - a
practical guide. Aliment Pharmacol Ther. 2013;37(12):1132-56.
49.
Field KM, Dow C, Michael M. Part I: Liver function in oncology: biochemistry and
beyond. Lancet Oncol. 2008;9(11):1092-101.
50.
Field KM, Michael M. Part II: Liver function in oncology: towards safer chemotherapy
use. Lancet Oncol. 2008;9(12):1181-90.
51.
Bodge MN, Culos KA, Haider SN, Thompson MS, Savani BN. Preparative regimen
dosing for hematopoietic stem cell transplantation in patients with chronic hepatic impairment:
analysis of the literature and recommendations. Biol Blood Marrow Transplant. 2014;20(5):6229.
52.
McDonald GB. Hepatobiliary complications of hematopoietic cell transplantation, 40
years on. Hepatology. 2010;51(4):1450-60.
53.
McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver
toxicity, and mortality following hematopoietic stem cell transplantation. Blood.
2003;101(5):2043-8.
32
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
54.
de Jonge ME, Huitema AD, Tukker AC, et al. Accuracy, feasibility, and clinical impact
of prospective Bayesian pharmacokinetically guided dosing of cyclophosphamide, thiotepa, and
carboplatin in high-dose chemotherapy. Clin Cancer Res. 2005;11(1):273-83.
55.
de Jonge ME, van den Bongard HJ, Huitema AD, et al. Bayesian pharmacokinetically
guided dosing of paclitaxel in patients with non-small cell lung cancer. Clin Cancer Res.
2004;10(7):2237-44.
56.
Furman WL, Baker SD, Pratt CB, et al. Escalating systemic exposure of continuous
infusion topotecan in children with recurrent acute leukemia. J Clin Oncol. 1996;14(5):1504-11.
57.
Radich JP, Gooley T, Bensinger W, et al. HLA-matched related hematopoietic cell
transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide
preparative regimen. Blood. 2003;102(1):31-5.
58.
Slattery JT, Sanders JE, Buckner CD, et al. Graft-rejection and toxicity following bone
marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant.
1995;16(1):31-42.
59.
McCune JS, Batchelder A, Guthrie KA, et al. Personalized dosing of cyclophosphamide
in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients
with hematologic malignancy. Clin Pharmacol Ther. 2009;85(6):615-22.
60.
Nath CE, Trotman J, Tiley C, et al. High melphalan exposure is associated with improved
overall survival in myeloma patients receiving high dose melphalan and autologous
transplantation. Br J Clin Pharmacol. 2016.
61.
U.S. Department of Health and Human Services (FDA C, CBER). Guidance for Industry.
Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and
impact on dosing and labeling.
33
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
072123.pdf. 2003.
62.
Floyd J, Kerr TA. Chemotherapy hepatotoxicity and dose modification in patients with
liver disease. In: Drews RE, Lindor KD, eds UpToDate Waltham MA: http://www.uptodate.com.
2016.
63.
McDonald GB, McCune JS, Batchelder A, et al. Metabolism-based cyclophosphamide
dosing for hematopoietic cell transplant. Clin Pharmacol Ther. 2005;78(3):298-308.
64.
Rezvani AR, McCune JS, Storer BE, et al. Cyclophosphamide followed by intravenous
targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical
outcomes. Biol Blood Marrow Transplant. 2013;19(7):1033-9.
65.
Hogan WJ, Maris M, Storer B, et al. Hepatic injury after nonmyeloablative conditioning
followed by allogeneic hematopoietic cell transplantation: a study of 193 patients. Blood.
2004;103(1):78-84.
66.
McDonald GB, Frieze D. A problem-oriented approach to liver disease in oncology
patients. Gut. 2008;57(7):987-1003.
67.
Stine JG, Lewis JH. Hepatotoxicity of antibiotics: a review and update for the clinician.
Clin Liver Dis. 2013;17(4):609-42, ix.
68.
Kaplowitz N, DeLeve LD. Drug Induced Liver Disease. . 3 ed. ed. London UK Elsevier
Inc. 2013.
69.
Li H, Mager DE, Sandmaier BM, et al. Population pharmacokinetics and dose
optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil. J
Clin Pharmacol. 2013;53(4):393-402.
70.
DeLeve LD. Cancer chemotherapy. 3 ed. ed. London UK: Elsevier Inc. 2013.
34
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
71.
de Pree C, Giostra E, Galetto A, Perrin L, Zulian GB. Hepatitis C virus acute
exacerbation during chemotherapy and radiotherapy for oesophageal carcinoma. Ann Oncol.
1994;5(9):861-2.
72.
Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with
antiretroviral therapy in adults infected with human immunodeficiency virus and the role of
hepatitis C or B virus infection. JAMA. 2000;283(1):74-80.
73.
Davies SE, Portmann BC, O'Grady JG, et al. Hepatic histological findings after
transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing
cholestatic hepatitis. Hepatology. 1991;13(1):150-7.
74.
Dixon LR, Crawford JM. Early histologic changes in fibrosing cholestatic hepatitis C.
Liver Transpl. 2007;13(2):219-26.
75.
Ceballos-Viro J, Lopez-Picazo JM, Perez-Gracia JL, et al. Fibrosing cholestatic hepatitis
following cytotoxic chemotherapy for small-cell lung cancer. World J Gastroenterol.
2009;15(18):2290-2.
76.
Cooksley WG, McIvor CA. Fibrosing cholestatic hepatitis and HBV after bone marrow
transplantation. Biomed Pharmacother. 1995;49(3):117-24.
77.
Delladetsima JK, Boletis JN, Makris F, et al. Fibrosing cholestatic hepatitis in renal
transplant recipients with hepatitis C virus infection. Liver Transpl Surg. 1999;5(4):294-300.
78.
Lau JY, Bain VG, Davies SE, et al. High-level expression of hepatitis B viral antigens in
fibrosing cholestatic hepatitis. Gastroenterology. 1992;102(3):956-62.
79.
Kornberg A, Kupper B, Tannapfel A, Hommann M, Scheele J. Impact of mycophenolate
mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation. Int
Immunopharmacol. 2005;5(1):107-15.
35
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
80.
Giard JM, Terrault NA. Severe Cholestatic Hepatitis C in Transplant Recipients: No
Longer a Threat to Graft Survival. Clin Gastroenterol Hepatol. 2015;13(11):2002-4.
81.
Leroy V, Dumortier J, Coilly A, et al. Efficacy of Sofosbuvir and Daclatasvir in Patients
With Fibrosing Cholestatic Hepatitis C After Liver Transplantation. Clin Gastroenterol Hepatol.
2015;13(11):1993-2001 e1-2.
82.
Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and Sofosbuvir Plus Ribavirin for
Treatment of HCV Infection in Patients With Advanced Liver Disease. Gastroenterology.
2015;149(3):649-59.
83.
Lau GK, He ML, Fong DY, et al. Preemptive use of lamivudine reduces hepatitis B
exacerbation after allogeneic hematopoietic cell transplantation. Hepatology. 2002;36(3):702-9.
84.
Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic cell
transplantation. Curr Opin Hematol. 2012;19(4):324-35.
85.
Clave E, Busson M, Douay C, et al. Acute graft-versus-host disease transiently impairs
thymic output in young patients after allogeneic hematopoietic stem cell transplantation. Blood.
2009;113(25):6477-84.
86.
Dick TB, Lindberg LS, Ramirez DD, Charlton MR. A clinician's guide to drug-drug
interactions with direct-acting antiviral agents for the treatment of hepatitis C viral infection.
Hepatology. 2016;63(2):634-43.
87.
Sebhatu P, Martin MT. Genotype 1 hepatitis C virus and the pharmacist's role in
treatment. Am J Health Syst Pharm. 2016;73(11):764-74.
88.
Honer Zu Siederdissen C, Maasoumy B, Marra F, et al. Drug-Drug Interactions With
Novel All Oral Interferon-Free Antiviral Agents in a Large Real-World Cohort. Clin Infect Dis.
2016;62(5):561-7.
36
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
89.
MacBrayne CE, Kiser JJ. Pharmacologic Considerations in the Treatment of Hepatitis C
Virus in Persons With HIV. Clin Infect Dis. 2016;63 Suppl 1(S12-23).
90.
Torres HA, Adachi JA, Roach LR, et al. Hepatitis C clinic operated by infectious disease
specialists at a comprehensive cancer center: help is on the way. Clin Infect Dis. 2012;54(5):7402.
91.
Curry MP. Direct acting antivirals for decompensated cirrhosis. Efficacy and safety are
now established. J Hepatol. 2016;64(6):1206-7.
92.
Martin P, DiMartini A, Feng S, Brown R, Jr., Fallon M. Evaluation for liver
transplantation in adults: 2013 practice guideline by the American Association for the Study of
Liver Diseases and the American Society of Transplantation. Hepatology. 2014;59(3):1144-65.
93.
Daklinza™ (daclatasvir). Prescribing Information Revised: 4/2016. Bristol-Myers
Squibb Company. Princeton N, USA.
94.
Epclusa® (sofosbuvir and velpatasvir). Prescribing Information Revised: 6/2016. Gilead
Sciences IFC, CA, USA.
95.
Harvoni® (ledipasvir and sofosbuvir). Prescribing Information Revised: 6/2016. Gilead
Sciences IFC, CA, USA.
96.
Olysio (simeprevir). Prescribing Information Revised: 5/2016. Janssen Therapeutics
DoJP, LP Titusville NJ, USA.
97.
Sovaldi® (sofosbuvir) . Prescribing Information Revised: 8/2015. Gilead Sciences IFC,
CA, USA.
98.
Viekira pak (ombitasvir p, and ritonavir tablets; dasabuvir tablets). Prescribing
Information Revised: 6/2016. AbbVie Inc., North Chicago, IL, USA
37
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
99.
Zepatier™ (elbasvir and grazoprevir). Prescribing Information Revised: 1/2016. Merck
Sharp & Dohme Corp. NJ, USA.
38
Patient with positive anti-HCV positive
HCHCV RNA before initiation of chemotherapy or immunosuppressive therapy
Undetectable
Detectable
No further work upa
Need for urgent cancer
treatment or HCT
Yes
HCT
• Assess severity of liver disease
• Conditioning regimen
considerations
• Avoid mycophenolate mofetil
• Consider antiviral treatment with
combination of DAAs +/ribavirin before or after HCT b
No
Chemotherapy or Immunotherapy
Does the patient have a
evidence of indolent
lymphoma that is potentially
curable with DAA treatment?
Uncontrolled or progressive
cancer
Monitoring for viral reactivation
and hepatitis flare b
Yes
No
No
At least 3-6 months of cancer in
remission
• Focus on management
of chronic liver disease
without antiviral
treatment
Genotypes 1-6
• Consider antiviral treatment with
combination of DAAs +/- Ribavirind
• Consult HCV specialistc
• Consider antiviral
treatment with
combination of DAAs +/Ribavirind
a) Patient had either spontaneous resolution of acute HCV, false positive anti-HCV or sustained virological response post treatment.
b) See text.
c) Specialist on Infectious Diseases, Hepatology or Gastroenterology.
d) As recommended in selected cases for patients without cancer as of July 2016.
Yes
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Prepublished online July 21, 2016;
doi:10.1182/blood-2016-05-718643
How we treat hepatitis C virus infection in patients with hematologic
malignancies
Harrys A. Torres and George B. McDonald
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Advance online articles have been peer reviewed and accepted for publication but have not yet
appeared in the paper journal (edited, typeset versions may be posted when available prior to
final publication). Advance online articles are citable and establish publication priority; they are
indexed by PubMed from initial publication. Citations to Advance online articles must include
digital object identifier (DOIs) and date of initial publication.
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of
Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.