Introduction {#s1}
============

Background {#s1-1}
----------

More than 185 million people are chronically infected with hepatitis C virus (HCV) globally.[@b1] In the United States and Canada, an estimated 4.4 million persons have chronic HCV infection. Chronic hepatitis C is associated with substantial morbidity and mortality due to progressive liver fibrosis, liver cirrhosis, liver cancer, liver failure and need for liver transplantation. Recent advances in antiviral therapy based on all-oral, interferon (IFN)-free regimens with direct acting antiviral agents (DAAs) have resulted in significant improvements in safety and viral eradication rates, also known as sustained virologic response (SVR). However, outside of the organ transplant context, very limited data are available that address safety and efficacy in patients undergoing immunosuppressive drug therapy. Although clinical trials have addressed specific populations that are immunocompromised, including those with human immunodeficiency virus (HIV) coinfection and post-liver or -kidney transplantation, patients undergoing other forms of immunosuppressive drug therapy in the context of cancer chemotherapy and the treatment of autoimmune conditions have generally been excluded. As such, the available literature addressing these populations has been limited primarily to case reports or series and to historical IFN-based regimens. Due to the high prevalence of autoimmune conditions and cancer in the general population[@b2] and among those with chronic hepatitis C, more evidence-based guidance is needed to inform clinicians of the implications of immunosuppressive drug therapy on HCV treatment. Herein, we report the results of a systematic review of available literature addressing HCV treatment in patients undergoing pharmacologic immunosuppression, focusing on immunosuppression for purposes other than organ rejection, and identify key gaps in the evidence that form the basis for future research priorities.

Chronic Hepatitis C in Immunosuppressed Patients {#s1-2}
------------------------------------------------

The immunopathogenesis of HCV infection is complex. Immunosuppression might be expected to reduce host-mediated inflammatory pathways that lead to liver damage; it may also reduce immune defenses against direct virally mediated liver injury.[@b3] Steroids used in patients with hepatitis C/autoimmune hepatitis (AIH) overlap syndrome have led to clinical, biochemical and histologic improvements, despite an increase in viral load (VL).[@b4]--[@b9] Inhibitors of tumor necrosis factor-α (TNF-α) appear to be safe for use in patients with HCV.[@b10]--[@b12] Recent studies have argued that rates of hepatocellular carcinoma (HCC) in patients with HCV who were treated for psoriasis with anti-TNF-α agents are no higher than in those not on TNF-α inhibitors, which raises the possibility of a therapeutic role for TNF-α inhibitors for psoriasis in patients with chronic HCV infection.[@b13] Among patients with inflammatory bowel disease (IBD) and HCV infection who are on immunosuppressive therapy, the rate of progression of fibrosis is similar to rates reported in patients not on immunosuppressive therapy.[@b14]

Scientific Rationale for Limiting Treatment {#s1-3}
-------------------------------------------

Treatment of HCV in immunosuppressed patients during the IFN era was complicated by varying effects on HCV and the disease being treated with immunosuppressive agents. Immunosuppression can cause worsening of liver dysfunction in patients infected with HCV.[@b14] For patients on cytotoxic chemotherapy, this may lead to interruption or cessation of chemotherapy, as is reportedly the case for nearly 50% of patients.[@b15] Secondly, IFN can induce flares of autoimmune disorders.[@b16]--[@b18]

There are mechanistic reasons to believe that IFN-based treatment will be less effective in immunosuppressed patients. IFN-based therapy reduces VL through immune-mediated and non-immune-mediated mechanisms. It promotes T-cell survival and proliferation, both of which are strongly associated with successful IFN therapy.[@b19],[@b20] This is in line with primate studies that have shown that viral clearance of initial HCV infection is dependent on cytotoxic T-cells.[@b21]--[@b23] IFN also up-regulates natural killer cell production of the apoptotic particle, TNF-related apoptosis-inducing ligand (TRAIL).[@b24],[@b25] Ribavirin (RBV) possesses T-cell-mediated antiviral effects.[@b20],[@b26] Immunosuppressive therapy, especially cytotoxic chemotherapy, would inhibit innate and adaptive immunity and could be expected to mitigate the immune-mediated effects of IFN and RBV.

However, the success of DAAs in achieving SVR without IFN demonstrates that inhibiting viral replication without inducing an additional immune response may be sufficient to clear HCV. This may be explained partly by the fact that there are no reservoirs of latent virus in infected individuals.[@b25] It is not clear, however, to what extent an intact immune system is necessary for viral eradication with DAAs.

Immunosuppression is a critical component of post-transplant maintenance therapy where concerns of rejection are in opposition to concerns of HCV reactivation.[@b27] Theoretically, immunosuppression reduces the former while increasing the chance of the latter recurring, although the risk is lower than for hepatitis B virus (HBV) reactivation.[@b28],[@b29] In addition, withdrawal of immunosuppressive agents can cause a surge in immune response, leading to flares of hepatitis.[@b28],[@b30] Experience with transplant patients, however, shows that HCV can be treated safely and effectively in the setting of immunosuppression. With IFN-free regimens, rates of SVR in transplant patients without cirrhosis are similar to those in pre-transplant patients.[@b31]--[@b34]

IFN-based treatment is only moderately effective and has frequent and significant side effects and many contraindications.[@b35],[@b36] Significant adverse effects of combination IFN and RBV include depression, cytopenias and flu-like symptoms. Importantly, it is contraindicated in the presence of conditions known to be exacerbated by IFN, such as autoimmune hemolytic anemia,[@b37] thyroid disease[@b38] and AIH.[@b39] Approximately one-quarter of patients who begin the IFN/RBV regimen do not complete the full treatment course.[@b40]

DAAs are more efficacious, safer and more tolerable[@b41]--[@b43] and do not cause potent immune stimulation. Patients who would not qualify for IFN-containing regimens---those with contraindications or severe comorbidities and those for whom the lower cure rate of IFN-containing regimens would be insufficient to justify the risk and cost---might benefit from DAAs. This raises the possibility that patients on immunosuppression may undergo treatment for HCV with IFN-free regimens and expect high rates of viral eradication and few serious adverse effects.

However, understanding of the effects of DAAs in patients on immunosuppression is limited by the fact that randomized controlled trials of DAAs have excluded such patients based on presence of malignancy, cytopenias (e.g. anemia, neutropenia, thrombocytopenia) and contraindications to IFN (e.g. chronic autoimmune diseases).[@b44]--[@b47]

Transplant Experience {#s2}
=====================

Liver Transplant {#s2-1}
----------------

The literature supporting the treatment of hepatitis C in liver transplant recipients is more robust than that for patients on immunosuppressive drug therapy for other indications. In patients with HCV prior to liver transplant, recurrence is nearly universal. Historical IFN-based regimens used in patients with recurrent post-transplant HCV were poorly tolerated and associated with low rates of SVR. A systematic review of IFN-based treatment in liver transplant recipients on immunosuppressive regimens (mostly comprised of tacrolimus, cyclosporine and corticosteroids) revealed pooled SVR rates (24% and 27% with IFN/RBV and polyethylene glycol (peg)IFN/RBV, respectively).[@b48] Acute rejection occurred in 2% to 5% of patients, and a least two-thirds required dose reduction or early discontinuation. More recent reports cite SVR rates that are lower than 50%[@b49]--[@b52] and acute rejection rates that are not significantly higher than those achieved with placebo.[@b49],[@b53]

Updated consensus guidelines of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) now recommend all-oral treatment of hepatitis C in liver transplant recipients.[@b54] Randomized controlled trials have found SVR rates of over 90% in post-transplant patients with F0--F3 fibrosis and compensated cirrhosis, and of 80--85% in post-transplant patients with Child B or C decompensated cirrhosis undergoing antiviral therapy with sofosbuvir/ledipasvir or sofosbuvir/daclatasvir.[@b44],[@b55],[@b56] Serious adverse effects attributed to antiviral therapy were rare, and both regimens were well tolerated. Drug-drug interactions between DAAs and immunosuppressive drugs such as tacrolimus and cyclosporine are common, and require careful attention prior to and throughout the treatment course.

Kidney Transplant {#s2-2}
-----------------

No drugs are currently approved for the treatment of hepatitis C in kidney transplant recipients. IFN-containing regimens are generally avoided in renal transplant recipients because of an increased risk of graft rejection. A 2014 meta-analysis showed that IFN-containing regimens achieved SVR in 34%, but approximately one-third of patients failed to complete the treatment course, of whom approximately half discontinued due to graft dysfunction.[@b57] Accordingly, renal society guidelines from the IFN era suggest treating hepatitis C in renal transplant recipients only when the benefits outweigh the significant risk of rejection from IFN (e.g. fibrosing cholestatic hepatitis, cirrhosis or life-threatening vasculitis).[@b58] These guidelines suggested that although conventional immunosuppression can be used in this context, the evidence base to support specific therapies post-renal transplant is largely of very low quality, including case reports and case series.

Recent reports do suggest that all-oral DAA regimens appear to be well tolerated and efficacious in patients following renal transplantation.[@b59]--[@b62] One randomized controlled trial by Colombo et al[@b63] reported at the International Liver Congress in April 2016 revealed that sofosbuvir/ledipasvir for 12 or 24 weeks was associated with an SVR of 98% (112/114) in GT1 or 4 treatment-naïve or experienced patients post-renal transplant, and was associated with favorable safety, with no events of acute rejection.

Other Transplant {#s2-3}
----------------

We are aware of no studies examining the treatment of hepatitis C in recipients of other types of solid organ transplants. We were also unable to find studies in patients who had received stem cell transplants. One series of hepatitis C treatment in patients who had received bone marrow transplants excluded patients on immunosuppressive drug therapy.[@b64] A letter to the editor reports outcomes of five patients treated for hepatitis C after autologous stem cell transplantation but does not report immunosuppressive regimens that were used.[@b65]

Methods {#s3}
=======

We conducted a systematic search of Medline (OVID), Cochrane Library, Embase and CINAHL in February 2016 for publications with the following terms: antineoplastic protocols, chemotherapy, antineoplastic agents, neoplasms/drug therapy, immunosuppressive agents, glucocorticoids, TNF-α, calcineurin inhibitors, and hepatitis c/drug therapy. We excluded citations with the keyword "organ transplantation" and limited our search to English language articles. Conference abstracts from the AASLD, the European Association for the Study of Liver (EASL), and the Asian Pacific Association for the Study of Liver (APASL) from 2015 and 2016 were reviewed in a targeted fashion, and one abstract from an international conference in February 2016 was included.[@b66]

Long-term steroid regimens with more than 20 mg of prednisone equivalent per day were considered to be immunosuppressive. Patients who received rituximab administrations as early as 1 month before initiation of antiviral therapy were included. Otherwise, administration of any immunosuppressive agent while the patient was being treated for HCV was considered to be concomitant with antiviral therapy. Trials without clear description of the timing of drug therapy were excluded. Pharmacologic dosing trials were excluded as well.

Studies were characterized by their study design (e.g. randomized controlled trial), sample size, treatment regimens and outcomes. Outcomes for the disease for which immunosuppressive therapy was administered was judged to be positive if partial response or complete response was achieved or if otherwise described as being generally positive. If the treatment was repeated due to relapse, we chose to report the results of the first course only.

SVR was defined as undetectable HCV RNA at 12 weeks after the end of treatment for all-oral, IFN-free regimens, and 24 weeks after the end of treatment for historical IFN-based regimens. If RNA levels were not reported at 24 weeks but were reported at a later time point (e.g. at 36 weeks after the end of treatment) SVR at that point was used. Reports on cryoglobulinemic vasculitis are reported separately (i.e. not grouped by agent), as multiple classes of immunosuppressive therapies were often used and the primary intent of IFN-based treatment was as much treatment of vasculitis as treatment of HCV infection per se.

Results {#s4}
=======

Literature Search Results {#s4-1}
-------------------------

A total of 2916 citations were retrieved through our search of the databases ([Fig. 1](#f01){ref-type="fig"}). Of these, 143 were duplicates, leaving 2273 unique works. Abstracts from four international society meetings (AASLD, EASL, APASL, and Digestive Disease Week) were also reviewed to identify relevant studies, contributing one abstract from February 2016.[@b66] The studies were screened by KO and 96 studies were identified as possibly meeting criteria. After further review, 56 were included in this systematic review ([Fig. 1](#f01){ref-type="fig"}). The studies selected for this review included 8 prospective interventional studies (n = 185 patients), including 3 randomized controlled, trials (n = 76 patients), one non-randomized controlled trial (n = 76 patients), and four other prospective interventional trials (n = 33 patients). The studies also included 4 prospective cohort studies (n = 84 patients), 15 retrospective cohort studies, case-control studies, and case series (n = 80 patients), and 29 case reports (n = 33 patients). Approximately 40% of studies addressed cryoglobulinemia ([Table 2](#t02){ref-type="table"}). Ten studies comprising only 19 patients reported the results of cancer patients. Five studies with an average of 31 patients each reported the results of immunosuppressive agents used for the treatment of hepatitis C. IBD and other autoimmune disorders (e.g. rheumatoid arthritis) made up the remainder (19 studies and 93 patients).

###### Study designs

  Study Design                      Studies   Patients
  --------------------------------- --------- ----------
  Case report                       29        33
  Case series                       10        44
  Case-control                      2         11
  Retrospective cohort              3         25
  Prospective cohort                4         84
  Prospective interventional        4         33
  Non-randomized controlled trial   1         76
  Randomized controlled trial       3         76
  **Total**                         **56**    **382**

###### Reasons for immunosuppression

  Reason for Immunosuppression   Studies   Patients
  ------------------------------ --------- ----------
  Cryoglobulinemia/vasculitis    22        116
  Cancer                         10        19
  HCV -- trial                   5         154
  IBD                            8         60
  Autoimmune -- Other            11        33
  **Total**                      **56**    **382**

![PRISMA chart.](JCTH-4-206-g001){#f01}

Cryoglobulinemia and Vasculitis {#s4-2}
-------------------------------

In HCV-associated cryoglobulinemic vasculitis, B-cell expansion causes elevated levels of immunoglobulins that in turn can lead to skin ulcers, renal disease, neuropathy and other symptoms.[@b67] Both IFN-based antiviral therapy and immunosuppressive agents (e.g. rituximab) are components of regimens used to treat HCV-associated vasculitis.[@b68]--[@b70] A number of studies have investigated the use of combination antiviral therapy and anti-CD20 antibodies to treat HCV-associated cryoglobulinemia, vasculitis or a combination of the two. As the primary intent is resolution of symptoms and organ dysfunction, rather than treatment of HCV, clinical response of renal function, skin ulcers and other manifestations of vasculitis are often described in detail but viral response rates, including SVR, are often not reported. Nonetheless, we can assess the efficacy and safety of anti-HCV agents used concomitantly with immunosuppressants in these settings.

In total, 22 studies reported outcomes of 116 patients ([Table 3](#t03){ref-type="table"}). In the nine studies that reported VL at 24 weeks after treatment or later, on aggregate, 56% of patients achieved SVR; this finding was roughly similar to the usual efficacy of the various IFN-based regimens used in these studies. Nine patients required cessation or interruption of therapy secondary to adverse effects related to the medications. In the three studies with more than 10 patients, 46 of 80 patients (58%; range, 55--59%) reached SVR; all three used rituximab with pegIFN and RBV.[@b71]--[@b73] Similarly, clinical response of the cryoglobulinemia was seen in 84 of the 110 patients (76%). Adverse effects of IFN, RBV and rituximab did not appear to be more common than in patients not on immunosuppressive therapy. In a prospective cohort study of 38 patients on rituximab and various corticosteroids, other immunosuppressive agents or plasma exchange, three patients died (cirrhosis, liver carcinoma, unknown) but mortality was not significantly different from the control group (2/55 died from liver carcinoma).[@b71]

###### Cryoglobulinemia and vasculitis

  Study                       Type                   n    Age   Male, %   Immunosuppression                                                                                                                                  AT                                                                      Outcomes                                                                                                                                                                                                            Adverse Effects                                                                                                                                             SVR, %   Clinical Response, %
  --------------------------- ---------------------- ---- ----- --------- -------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------- -------- ----------------------
  Sise, 2016[@b76]            Case series            5    N/A   N/A       Rituximab × 4 pts Ustekinumab × 1 pt                                                                                                               Sofosbuvir + ribavirin or sofosbuvir + simeprevir × 12 wks              SVR12 in 3/4 pts on rituximab and 0/1 pts on ustekinumab (relapsed)                                                                                                                                                 Not reported separately                                                                                                                                     60%      
  Saadoun, 2014[@b75]         Prospective cohort     4    N/A   N/A       Rituximab given 1 mo before AT                                                                                                                     pegIFNα + RBV × 48 wks + telaprevir × 12 wks or boceprevir × 44 wks     PR in 2/4 and CR in 2/4                                                                                                                                                                                             Not reported separately                                                                                                                                              100%
  Humphries, 2014[@b74]       Case report            1    59    100%      Methylprednisolone 500 mg × 2d and plasmapheresis × 5                                                                                              Telaprevir, IFN, RBV × 24 wks                                           PR. Progressed to ESRD on HD 7 wks after end of tx. SVR achieved                                                                                                                                                    Anemia requiring transfusions, EPO, and interruption of IFN and RBV                                                                                         100%     0%
  Wu, 2013[@b81]              Case report            1    57    0%        Methylprednisolone 40 mg/d started with AT                                                                                                         PegIFN α-2b + RBV                                                       Thrombocytopenia resolved. Renal function improved. Cryoglobulins persistently high                                                                                                                                 None reported                                                                                                                                                        100%
  Zaidan, 2012[@b126]         Case report            2    44    50%       Case 3: Cyclophosphamide and "IV steroid pulses." Later prednisone 50 mg/d Case 4: Prednisone PO 1 mg/kg/day × 5d, plasma exchange, rituximab IV   PegIFN-α-2a + RBV                                                       Case 3: HCV: SVR at unknown time point. Purpura resolved. Renal function PR. Case 4: Skin lesions resolved. Renal function recovered                                                                                None reported                                                                                                                                                        100%
  Rodrigo, 2012[@b127]        Case report            1    34    100%      Prednisolone 10 mg BID + cyclophosphamide                                                                                                          PegIFN-2α + RBV                                                         Skin lesions healed. Weakness improved. No relapse in 6 mo                                                                                                                                                          None reported                                                                                                                                                        100%
  Kiremitci, 2012[@b82]       Case report            1    34    0%        Methylprednisolone 0.5 mg/kg/d started with AT                                                                                                     PegIFN α2                                                               Nodules resolved. Renal function normalized but the relapsed                                                                                                                                                        None reported                                                                                                                                                        0%
  Colucci, 2011[@b128]        Case report            1    53    0%        Rituximab before and cyclosporin A concurrent with AT                                                                                              PegIFN α × 12 mo                                                        SVR not achieved                                                                                                                                                                                                    No fever, pain or allergic reactions                                                                                                                        0%       
  Butterly, 2010[@b129]       Case series            1    44    100%      Rituximab                                                                                                                                          PegIFN                                                                  No improvement in vasculitis                                                                                                                                                                                        0%                                                                                                                                                                   0%
  Saadoun, 2010[@b71]         Prospective cohort     38   58    32%       Rituximab +/− concurrent steroids, other immunosuppressive agents or plasma exchange                                                               PegIFN-α2a or 2b + RBV × 48 wks                                         Similar SVR (22/38 vs 33/55 in control). Shorter time to clinical remission Higher rates of CR (28/38 vs 40/55) and PR (9/38 vs 13/55). 3 Deaths (cirrhosis, liver carcinoma, unknown) (no diff compared to cntl)   AE from AT in 21 and from rituximab in 10. Treatment interrupted in 5/38 (cytopenia × 2, depression, psoriasis flare, neuropathy flare) (5/55 in control)   58%      79%
  Dammacco, 2010[@b72]        RCT                    22   63    32%       Rituximab + methylprednisolone prior to and during AT                                                                                              PegIFN-α2a or 2b + RBV × 48 wks                                         SVR (13/22 vs 4/15 in control). Higher CR (12/22 vs 5/15). Lower PR (5/22 vs 5/15). Relapses (2/22 vs 3/15)                                                                                                         Cytopenias, fevers, other mild AEs                                                                                                                          68%      77%
  Terrier, 2009[@b73]         Retrospective cohort   20   61    30%       Rituximab. Some also received CS or plasmapheresis                                                                                                 PegIFN-α2b + RBV starting 1 mo after last rituximab. × 12 mo (median)   Higher SVR (11/20 vs 0/12 in control).Higher clinical response of vasculitis: CR 16, PR 3, NR1, relapse 3 (7/12, 1/12, 4/12, 4/12 in Cntl)                                                                          Generally well tolerated                                                                                                                                    55%      80%
  Ahmed, 2008[@b83]           Case report            1    35    100%      Methylprednisolone before AT. Prednisone PO 40 mg/d started with AT                                                                                PegIFN α (≥3 mo) Added RBV after 3 mo                                   Renal function improved. Albumin still elevated (38 g/L)                                                                                                                                                            None major                                                                                                                                                           100%
  Koziolek, 2007[@b130]       Case report            1    38    0%        Prednisolone 1 mg/kg started ∼3 mo before AT. Cryoprecipitate after starting AT                                                                    PegIFN + RBV                                                            Arthralgias and proteinuria improved                                                                                                                                                                                Symptomatic anemia. RBV stopped                                                                                                                                      100%
  Saadoun, 2006[@b131]        Prospective cohort     4    N/A   N/A       Rituximab                                                                                                                                          pegIFN α-2b/IFN-α2b + RBV × ≥6 mo                                       Clinical response in 1/4                                                                                                                                                                                            Unclear                                                                                                                                                              25%
  Saadoun, Aids 2006[@b132]   Retrospective cohort   2    47    50%       Case 7: IVIG (2 g/kg/mo) + corticosteroids Case 8: Corticosteroids only                                                                            INF-α + RBV × ≥6 mo                                                     Case 7: relapse to IFN-RBV, no SVR, no response to IS Case 8: CR to IFN-RBV, SVR, no response to IS                                                                                                                 None following immunosuppression                                                                                                                            50%      50%
  Neri, 2005[@b133]           Case report            1    63    0%        Cyclophosphamide + prednisone                                                                                                                      pegIFN-α2b                                                              Symptomatic improvement. Died 4 mo later of nephritic syndrome and sepsis. SVR not achieved                                                                                                                         None                                                                                                                                                        0%       0%
  Mendez, 2001[@b134]         Case report            2    46    100%      Case 4: plasmapheresis + IVIG Case 6: plasmapheresis + corticosteroids                                                                             IFN                                                                     Case 4: "Improved clinically and ... doing well." Case 6: Necrotizing vasculitis responded. Hepatitis and viremia persisted. Died of MI 7y later                                                                    None reported                                                                                                                                                        100%
  Cacoub, 2001[@b135]         Case control           5    N/A   N/A       Prednisone (1 mg/kg/d) reduced to 10 mg/d. Plasma exchange × 12                                                                                    IFN-α × 18--36 mo                                                       Complete recovery in 5/5 (except ESRD in 1). No deaths                                                                                                                                                              None reported                                                                                                                                                        100%
  Mercie, 2000[@b84]          case report            1    40    0%        Corticosteroid bolus monthly and "oral corticosteroids" (1 mg/kg/d) slowly tapered                                                                 IFN × 18 mo                                                             HCV relapsed. Favorable course of vasculitis without reactivation                                                                                                                                                   None reported                                                                                                                                               0%       100%
  Kiyomoto, 1999[@b136]       Case report            1    69    0%        Cryofiltration + prednisolone 30 mg/d                                                                                                              IFN-α                                                                   Renal function deteriorated. Nephrotic syndrome recurred                                                                                                                                                            Flu-like symptoms, pancytopenia. Fever caused a 1 wk interruption                                                                                                    0%
  David, 1996[@b137]          Case report            1    39    100%      Prednisone 100 mg/d + azathioprine × ∼10 d. Plasmapheresis + cyclophosphamide later added                                                          IFN-α × 8 mo                                                            No new symptoms while on IFN. Strength started improving after 5--6 mo                                                                                                                                              Hemorrhagic cystitis. Cyclophosphamide DCed                                                                                                                          100%

Few studies report the use of DAAs in cryoglobulinemia or vasculitis. Humphries et al[@b74] reported a case of cryoglobulinemic vasculitis manifesting as membranoproliferative glomerulonephritis (MPGN) and skin ulcers that was treated with telaprevir, pegIFN and RBV concurrent with methylprednisolone and plasmapheresis. SVR was achieved, but the MPGN progressed to end-stage renal disease by 7 weeks after treatment. The case was also complicated by anemia requiring interruption of treatment and transfusions of packed red blood cells. In a prospective cohort study of telaprevir or boceprevir and pegIFN and RBV in four patients who had been treated for mixed cryoglobulinemic vasculitis with rituximab 1 month prior, two patients achieved partial response and two achieved complete response;[@b75] SVR was not reported.

In the only study addressing the use of an all-oral regimen, three out of four patients on rituximab treated with sofosbuvir with RBV or simeprevir achieved SVR12.[@b76] One patient on ustekinumab (a monoclonal antibody that targets IL-12 and IL-23) experienced a relapse of HCV.

Overall, IFN-based antiviral therapy appears to perform reasonably well in patients on immunosuppressive therapy for cryoglobulinemia/vasculitis. The major caveats to these conclusions are that the quality of evidence is low, represented mostly by case reports and retrospective observational studies. DAAs were shown to be able to achieve SVR in this population, but with only three studies addressing this subject---of which two used regimens containing both DAAs and IFN---it is impossible to know if similar results can be expected in clinical practice.

Glucocorticoids {#s4-3}
---------------

Glucocorticoids have potent anti-inflammatory and immunosuppressive effects at higher doses. They inhibit leukocyte infiltration into sites of tissue damage and repress transcription of inflammatory cytokines.[@b77] Withdrawal of steroids can cause these inflammatory processes to rebound. Some have investigated the use of this phenomenon for the treatment of HCV infection with mixed effects.[@b78]--[@b80]

The effect of steroids can be clouded by other immunosuppressive agents that are frequently administered concomitantly. Five case reports discuss high-dose steroids used in the absence of other immunosuppressive therapies and concomitantly with antiviral therapy ([Table 4](#t04){ref-type="table"}).[@b81]--[@b85] Four studies reported on patients with MPGN and/or vasculitis; three of four patients achieved a favorable clinical response and one of two achieved SVR.[@b81]--[@b84] Overall, SVR was achieved in three of four patients for which it was reported. No major adverse effects were reported.

###### Steroids

  Study                   Type          n    Age   Male, %   Reason for IS                                          Immunosuppression                                                                    AT                               Outcomes                                                                              Adverse Effects     SVR, %   Clinical Response, %
  ----------------------- ------------- ---- ----- --------- ------------------------------------------------------ ------------------------------------------------------------------------------------ -------------------------------- ------------------------------------------------------------------------------------- ------------------- -------- ----------------------
  Wu, 2013[@b81]          Case report   1    57    0%        Cryoglobulinemia - MPGN                                Methylprednisolone 40 mg/d                                                           PegIFN-α2b + RBV                 Thrombocytopenia resolved. Renal function improved. Cryoglobulins persistently high   None reported                100%
  Kiremitci, 2012[@b82]   Case report   1    34    0%        Cryoglobulinemia - MPGN, skin eruptions, pneumonitis   Methylprednisolone 0.5 mg/kg/d                                                       PegIFN-α2                        Nodules resolved. Renal function normalized but the relapsed                          None reported                0%
  Ahmed, 2008[@b83]       Case report   1    35    100%      MPGN type 1. Cryoglobulin negative                     Methylprednisolone before AT. Prednisone 40 mg/d started with AT                     PegIFN-α. RBV added after 3 mo   Renal function improved. SVR. Albumin still elevated (38 g/L)                         None major          100%     100%
  Mercie, 2000[@b84]      Case report   1    40    0%        Churg Strauss                                          Corticosteroid bolus monthly and "oral corticosteroids" (1 mg/kg/d) slowly tapered   IFN × 18 mo                      HCV relapsed. Favorable course of vasculitis without reactivation                     None reported       0%       100%
  Oeda, 2012[@b85]        Case report   2    50    0%        AIH + HCV                                              Prednisolone 30--40 mg/d prior to AT reduced to 20 mg/d when AT started              PegIFN-α2b + RBV × 24--48 wks    SVR in 2/2. ALT and IgG normalized in 2/2.                                            None reported       100%     100%
  Efe, 2013[@b86]         Case series   13   N/A   NA        AIH + HCV                                              Prednisone 20--40 mg/d +/− azathioprine                                              INF +/− RBV                      HCV: SVR in 7/13, NR in 6/13                                                          No relapse of AIH   54%      100%

Efe et al[@b86] reports the results of a retrospective study of patients with HCV infection and AIH. Thirteen patients received immunosuppression with prednisone at a dose of 20--40 mg/day. An unknown number of these patients received azathioprine as well. After 3--6 months of immunosuppression, levels of alanine transaminase and aspartate transaminase fell below twice the upper limit of normal, and antiviral therapy with IFN with or without RBV was initiated. SVR was achieved in 7/13 and no relapse of AIH was observed. A report of two patients with AIH and HCV treated with pegIFN-α2b and RBV while taking 20 mg/day of prednisolone reported achievement of SVR and good clinical response for both.[@b85] Overall, the use of glucocorticoids with IFN-based regimens achieved SVR in 10 of 17 patients (59%).

Based on these reports, treatment of chronic HCV infection with IFN-based regimens in patients on immunosuppressive doses of corticosteroids appears as safe and as effective as in patients not on immunosuppression. This conclusion should be considered in light of the caveat that the data is sparse and of low quality. A single case series accounts for 13 of 19 total patients in these studies. Furthermore, these conclusions have become less relevant with the advent of DAAs. Unfortunately, there are no reports of all-oral DAA regimens used in patients on glucocorticoids in the absence of other immunosuppressive agents.

Cytotoxic Chemotherapy for Cancer {#s4-4}
---------------------------------

Treatment of chronic HCV infection in patients on chemotherapy for cancer presents a unique challenge and opportunity. Cirrhosis and chronic hepatitis are reportedly three-fold more common in those with cancer than in the general population.[@b87] Studies in patients with hematological malignancies suggest the prevalence of chronic HCV infection may range between 1.5% and 32%, depending on the type of malignancy and the population studied.[@b88] Chronic infection with HCV is associated with 1.6-fold \[lung cancer, non-Hodgkin's lymphoma (NHL)\] to 48.6-fold (liver cancer) increased risk of cancer.[@b89] AASLD guidelines do not address treatment of HCV in patients with cancer other than to recommend against monitoring for HCV recurrence in patients who achieved SVR.[@b54] Large trials of antiviral therapy for HCV have excluded patients on chemotherapy, making the literature on this topic sparse.

Seven studies with a total of 11 patients describe IFN-based regimens administered concomitantly with cytotoxic chemotherapy for patients with cancer ([Table 5](#t05){ref-type="table"}). All but one is a case report. Six patients had solid tumors (colon, breast, HCC) and five suffered from hematologic malignancies \[acute lymphoblastic leukemia (ALL), NHL, multiple myeloma (MM)\]. In the largest study, 5-fluorouracil (5FU) was infused into the hepatic artery in four patients with HCC.[@b90] Partial response of the HCC was seen in all patients. SVR was not reported. Overall, three of five (60%) patients in whom SVR was reported achieved this end-point. In two studies, HCV VL was undetectable at an unknown time point and SVR was not explicitly reported.[@b90],[@b91] One study reported achieving early virologic response but antiviral therapy was ongoing.[@b92]

###### Cancer Chemotherapy

  Study                        Type                               n   Age   Male, %   Reason for IS             Immunosuppression                                                         AT                             Outcomes                                                                        Adverse Effects                                                                                                  SVR, %   Clinical Response, %
  ---------------------------- ---------------------------------- --- ----- --------- ------------------------- ------------------------------------------------------------------------- ------------------------------ ------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------------- -------- ----------------------
  Matovina-Brko, 2014[@b92]    Case report                        1   60    0%        Breast cancer             Docetaxel + trastuzumab × 1y and radiotherapy                             IFN-α2a + RBV × 6 mo           EVR. No active disease, complications, or HCV                                   Grade 4 neutropenia and grade 3 hepatotoxicity × 1 wk (AT and chemo delayed)                                              100%
  Gentile, 2013[@b138]         Case report                        1   60    100%      Colon cancer (adjuvant)   XELOX (capecitabine + oxaliplatin)                                        IFN-α2a                        SVR                                                                             Diarrhea and neuropathy (both grade 1). Cytopenias with nadirs WBC 2.38, Hb 10.5, PLT 81,000. No transaminitis   100%     100%
  Ayyub, 2011[@b139]           Case report                        1   22    100%      ALL                       Vincristine + 6-MP (Patient had been on MTX and dexamethasone)            PegIFN-α2a + RBV × 72 wks      SVR Remission of ALL                                                            Neutropenia requiring IFN reduction and filgrastim                                                               100%     100%
  Papaevangelou, 2010[@b140]   Case report                        2   9     100%      Pt 1: ALL Pt 3: B-NHL     Pt 1: ALL BFM 95 Pt 3: NHL BFM 95                                         IFN-a + RBV. 18--24 mo         SVR 1/2. Both patients in remission.                                            Pt 1: Fever after IFN. Pt 3 transient subclinical hypothyroid                                                    50%      100%
  Kasai, 2009[@b90]            Prospective interventional study   4   68    75%       HCC                       5FU - intraarterial to hepatic artery (250 mg/d) days 1--5 of each week   PegIFN-α2b + RBV × 8--20 wks   HCV VL undetectable in 4/4 at unclear time point. PR of HCC in 4/4. No deaths   Thrombocytopenia × 1. Leukopenia /anorexia × 1                                                                            100%
  Lakatos, 2006[@b91]          Case report                        1   50    0%        Multiple myeloma          Thalinomide begun 2 mo before IS                                          PegIFN-α2b + RBV × 12 mo       EVR, ETR. New compression fractures                                             None reported                                                                                                             0%
  Waldron, 1999[@b141]         Case report                        1   11    100%      ALL (b-cell precursor)    Etoposide, Ara-C, cyclophosphamide, vincristine, prednisone × 24 wks      IFN-α                          No SVR. ALL in remission 72 mo after                                            Neutropenia and thrombocytopenia requiring dose adjustments                                                      0%       100%

Taken in aggregate, the studies reported positive clinical responses in 10 of 11 patients. In six patients with hematological malignancies, four (ALL in three, B-cell NHL in one) experienced remission. In a case report of MM, disease progressed to involve new compression fractures at 4 months after thalidomide was initiated.

Adverse events were generally mild and limited to those known to be associated with the agents used. Cytopenias were common in patients with hematological malignancies. In three studies (three patients total), therapy was interrupted or modified as a result. In one study of docetaxel and trastuzumab for breast cancer, grade 4 neutropenia and grade 3 hepatotoxicity caused a delay in antiviral therapy and chemotherapy.[@b92]

While these reports give us some sense of possible outcomes, it is undoubtedly too little to give clinicians much confidence when contemplating the treatment of HCV in their patients on cytotoxic chemotherapy. The paucity of data on this topic is especially unfortunate given that cancer is a relatively prevalent disease and that cytotoxic chemotherapy has long been a mainstay of therapy. Significantly, no studies report the use of modern all-oral DAA regimens in patients on cytotoxic chemotherapy for cancer.

Other Immunosuppressive Agents in Cancer {#s4-5}
----------------------------------------

In a study examining IFN-based antiviral therapy in the setting of various hormonal agents (trastuzumab, tamoxifen, letrozole), SVR was achieved in 3 of 6 patients ([Table 6](#t06){ref-type="table"}).[@b88] Kyvernitakis et al[@b93] describe the use of IFN in a patient on treatment with photopheresis and denileukin diftitox for mycosis fungoides; skin lesions improved in this study, but SVR was not achieved. One case report describes all-oral antiviral regimens in patients undergoing immunotherapy for cancer.[@b94] Pembrolizumab combined with ledipasvir and sofosbuvir in a patient with advanced melanoma led to "excellent" response, normal transaminases and undetectable VL at an unknown time point. It should be noted that although antiviral therapy was started, at 9 cycles into a 15-cycle course of pembrolizumab it was not completely clear if pembrolizumab was continued while the patient was treated for HCV infection. However, given the novelty of the case---immunotherapy given concomitantly with DAAs---we felt somewhat compelled to include it.

###### Other treatments for cancer

  Study                      Type           n   Age   Male, %   Reason for IS       Immunosuppression                                               AT                                                                Outcomes                                                                                                                          Adverse Effects                                                     SVR, %   Clinical Response, %
  -------------------------- -------------- --- ----- --------- ------------------- --------------------------------------------------------------- ----------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------- -------- ----------------------
  Torres, 2015[@b88]         Case-control   6   N/A   N/A       Various cancers     Trastuzumab, tamoxifen, letrozole                               IFN +/− RBV +/− nitazoxanide                                      SVR in 3/6 (2/3 traztuzumab, 1/2 tamoxifen, 0/1 letrozole). Not sig different from pts in study not on IS                         Not reported separately                                             50%      
  Kyvernitakis, 2014[@b93]   Case series    1   34    0%        Mycosis fungoides   Photopheresis and denileukin diftitox (diptheria toxin + IL2)   IFN-a × 18 mo                                                     Skin lesions and pruritis improved. Circulating peripheral CD4+/CD26− clonal T cells fell from 96.1% to 50.9%. SVR not achieved   Headaches and non-compliance led to multiple interruptions of IFN   0%       100%
  Davar, 2015[@b94]          Case report    1   59    0%        Advanced melanoma   Pembrolizumab × 15 cycles                                       Ledipasivir + Sofosbuvir started after cycle 9 of pembrolizumab   Melanoma: "excellent PR." Undetectable HCV VL and normal ALT and AST after 6 additional cycles of pembrolizumab                   None reported                                                                100%

Trials of Immunosuppressive Agents for the Treatment of HCV Infection {#s4-6}
---------------------------------------------------------------------

Three interventional studies comprising 97 patients examined the use of thalidomide and cyclosporin A for the treatment of HCV infection ([Table 7](#t07){ref-type="table"}). SVR was achieved in 42/76 (55%) patients in the largest study, a non-randomized controlled trial of cyclosporin A and IFN-α2b compared to IFN-α2b alone.[@b95] There was no significant difference in discontinuation of therapy or adverse events. Two single-armed prospective interventional trials of chemotherapeutic agents and IFN for the treatment of HCV infection were unable to achieve SVR. In a trial of cyclosporin and IFN-αcon-1, hypertension and neutropenia required dose reductions of cyclosporin and IFN respectively.[@b96] In a trial of thalidomide and pegIFN-α2b with RBV, thalidomide was discontinued in 2 of 11 patients due to vasovagal syncope and delirium.[@b97] Overall, it appears that the addition of cytotoxic chemotherapy reduces the efficacy of IFN-based antiviral therapy.

###### Trials of chemotherapeutic agents for HCV infection

  Study                      Type                               n    Age                                        Male, %   Immunosuppression   AT                              Outcomes                                 Adverse Effects                                                                                                                                               SVR, %
  -------------------------- ---------------------------------- ---- ------------------------------------------ --------- ------------------- ------------------------------- ---------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------- --------
  Pardo-Yules, 2012[@b142]   Prospective interventional study   11   49                                         55%       Thalidomide         PegIFN-α2b + RBV × 24--48 wks   Relapse - 2/11; NR - 9/11; SVR - 0/11    Thalidomide stopped in 2/11 2/2 vasovagal syncope and delirium. Mild neuropathy after stopping AT for no response                                             0%
  Cotler, 2003[@b96]         Prospective interventional study   10   46[^1^](#table7fn1){ref-type="table-fn"}   70%       Cyclosporin A       IFN-αcon-1 × 24--48 wks         SVR in 0/10                              No new renal dysfunction. Triglyceridemia was common. HTN requiring CSA dose reduction in 2/10. Neutropenia requiring reduction of IFN in 5/10. FLS in 9/10   0%
  Inoue, 2003[@b95]          Non-randomized controlled trial    76   52                                         68%       Cyclosporin A       IFN-α2b                         SVR in 42/76 (14/44 in INF only group)   AEs were not significantly greater than in the control group. No new renal dysfunction                                                                        55%

Median

TNF-α Inhibitors {#s4-7}
----------------

TNF-α is an inflammatory cytokine involved in the expression of other pro-inflammatory cytokines. Inhibitors of TNF-α are routinely used for the treatment of autoimmune disorders, such as IBD, rheumatoid arthritis and psoriasis. These agents, however, have been associated with an increased risk of serious infectious diseases, but data regarding worsening of HCV infection are conflicting.[@b98]--[@b101] In a review of 216 patients (260 patient-years of follow-up) with HCV infection treated with TNF-α inhibitors, these agents were withdrawn due to suspected worsening HCV infection only three times.[@b98]

Five reports on TNF-α inhibitors describe etanercept being used with IFN-based treatments in a total of 25 patients ([Table 8](#t08){ref-type="table"}).[@b13],[@b102]--[@b105] Flares of underlying autoimmune disorders were rare---one patient had a flare of rheumatoid arthritis and one patient experienced a recurrence of neuralgia. A trial of etanercept in combination with IFN and RBV for the treatment of HCV achieved SVR in 8 of 19 patients (42%), which was somewhat higher than in the control group (8/25, 32%) who were treated with IFN and RBV only.[@b105] Two of 19 patients withdrew because of adverse effects, although nausea was less common than in a control group. Otherwise, SVR was reported only in two case reports. In a report of rheumatoid arthritis treated with etanercept concomitantly with pegIFN-α and RBV, SVR was achieved but initiation of antiviral therapy was followed by a flare of rheumatoid arthritis that required steroids.[@b104] A patient with psoriasis treated with etanercept concomitantly with pegIFN-α2a and RBV achieved SVR and improvement in the symptoms of psoriasis, but glossopharyngeal neuralgia recurred and required surgical nerve excision.[@b103] Taken together, the results of these studies show that IFN-based treatments can be given to patients on TNF-α inhibitors, but flares of underlying autoimmune diseases can occur. Moreover, one study has an outsized influence on the results due to the absence of other studies with large numbers of patients.

###### TNF-α inhibitors

  Study                    Type                                    n    Age   Male, %   Immunosuppression                                     AT                                              Outcomes                                                                                                         Adverse Effects                                                                                                                                  SVR, %
  ------------------------ --------------------------------------- ---- ----- --------- ----------------------------------------------------- ----------------------------------------------- ---------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------ --------
  Basu, 2016[@b66]         Controlled trial                        35   50    74%       Various TNF-α inhibitors                              LDV + SOF + RBV × 8 wks or LDV + SOF × 12 wks   SVR12 in 34/35 (100% study retention)                                                                            Anemia to Hb \< 8.5 in 2/35. Severities of other AE are unclear.                                                                                 97%
  Bartalesi, 2013[@b103]   Case report                             1    53    100%      Etancercept 50 mg 2 × /wk then 1 × /wk                PegIFN-α2a + RBV                                SVR. Psoriasis much improved (PASI 18.9 \--\> 3.0)                                                               Recurrence of glossopharyngeal neuralgia requiring surgical nerve excision. Anemia for which the pt received EPO. Neutropenia (850/mm^3^)        100%
  Navarro, 2013[@b13]      Cohort study                            3    47    100%      Etanercept                                            IFN + RBV                                       Psoriasis improved in 2/3. HCV VL became undetectable in 2/2 with VL measurements. AST and ALT improved in 3/3   No significant AEs. No sx of hepatitis while on IS                                                                                               
  Behnam, 2010[@b102]      Case report                             1    56    100%      Etancercept 50 mg/wk                                  IFN-α + RBV × 24 wks                            Psoriasis was stable. Liver enzymes and HCV VL decreased markedly                                                None reported                                                                                                                                    
  Jazwinski, 2011[@b104]   Case report                             1    53    100%      Etancercept 50 mg/wk. Prednisone × 6 d for RA flare   PegIFN-α + RBV × 24 wks                         SVR. RA flared after starting AT                                                                                 RA flare                                                                                                                                         100%
  Zein, 2005[@b105]        Randomized controlled trial (phase 2)   19   44    90%       Etancercept 25 mg 2 × /wk                             IFN-α2b × 24--48 wks                            SVR in 8/19 (8/25 in control patients on IFN + RBV only). Greater decline in fibrosis compared to control        2/19 withdrew 2/2 anemia and IFN allergic reaction. (1 withdrew from control). Other AEs similar except nausea was less common with etanercept   42%

In an abstract addressing all-oral DAA regimens, Basu et al[@b66] report the results of a controlled trial in which a predominantly male (26/35, 74%) and ethnically diverse group of patients on various TNF-inhibitors for IBD who were treated with ledipasvir and sofosbuvir for 12 weeks (n = 18) or in combination with RBV for 8 weeks (n = 17). All patients completed antiviral therapy and SVR12 was achieved in 34 of 35 total patients. Adverse effects were common and similar between the two groups, except for anemia, which was more common in the RBV group (8/17 vs 2/18). Overall, gastrointestinal discomfort and diarrhea were experienced by 15 and 4 patients respectively. This is an important trial both for its study design and because of the use of modern treatment regimens. Its findings should give clinicians greater confidence in administering these antiviral treatments to patients on TNF-α inhibitors.

Antimetabolites {#s4-8}
---------------

Azathioprine is a purine analog and prodrug of mercaptopurine. These compounds inhibit DNA synthesis, particularly in leukocytes, and thus inhibit inflammation.[@b106] Three studies examined the use of azathioprine in patients treated with IFN-based regimens ([Table 9](#t09){ref-type="table"}). Results were mixed. In a case series of patients with IBD, one of three patients achieved SVR and two patients required steroids for flares of Crohn's disease.[@b107] In a case report of a 54-year-old man treated with azathioprine, prednisone, pegIFN and RBV for AIH-HCV overlap syndrome, AIH went into remission but HCV VL never reached undetectable levels.[@b108] The patient developed respiratory failure secondary to Pseudomonal pneumonia and both immunosuppression and antiviral therapies were discontinued.

###### Antimetabolites

  Study                          Type          n   Age   Male, %   Reason for IS   Immunosuppression                 AT                                     Outcomes                                                   Adverse Effects                                                                                     SVR, %
  ------------------------------ ------------- --- ----- --------- --------------- --------------------------------- -------------------------------------- ---------------------------------------------------------- --------------------------------------------------------------------------------------------------- --------
  Noguchi, 2011[@b111]           Case report   1   39    0%        RA              Methotrexate + bucillamine        PegIFN-α2a + RBV                       SVR achieved                                               MTX decreased 2/2 leukopenia (1.8) and thrombocytopenia (68,000). MTX then increased 2/2 RA flare   100%
  Wan, 2009[@b108]               Case report   1   54    100%      AIH + HCV       Azathioprine + prednisone taper   IFN-α2b switched to PEG-IFN on day 7   No SVR. HCV always detectable. AIH in clinical remission   Pseudomonal PNA @ wk 20. AT and IS discontinued                                                     0%
  Peyrin-Biroulet, 2008[@b109]   Case series   8   47    63%       IBD             Azathioprine                      PegIFN-α2b + RBV                       AT or azathioprine was restarted in 8/8                    Pancytoenia (all pts; selected for this) EPO in 7/8, G-CSF in 5/8, pRBCs in 2/8                     
  Scherzer, 2008[@b107]          Case series   3   47    67%       Crohn's         Azathioprine                      PegIFN-α2a + RBV × 24 wks              SVR, NR, relapse                                           Increased CD activity in 2/3 (required steroids)                                                    33%

Adverse effects from concomitant use of RBV and azathioprine can be severe. In a retrospective study of eight patients on IFN, RBV and azathioprine who developed severe pancytopenia, erythropoietin (EPO), packed red blood cells and granulocyte-colony stimulating factor (G-CSF) were required in seven, two, and five patients respectively.[@b109] Time to recovery ranged from 4 to 7 weeks.

Methotrexate inhibits the metabolism of folate, which is required for nucleoside synthesis. In addition to this canonical function, methotrexate may also exert a direct immunosuppressive effect by inhibiting cell adhesion molecules.[@b110] One case report describes a patient treated with pegIFN-α2a and RBV while on methotrexate for rheumatoid arthritis.[@b111] SVR was achieved but cytopenias (nadir white blood cell (WBC) count of 1.8, platelet (PLT) count of 68,000) and a rheumatoid arthritis flare required the methotrexate dose to be decreased and then increased. After completion of the patient's antiviral therapy, she was started on a prednisolone taper and adalimumab for worsening rheumatological symptoms.

Few conclusions can be drawn from this limited evidence base, but these cases demonstrate that SVR is feasible with IFN-based regimens, although their use may be limited by adverse effects. Data supporting the use of all-oral regimens in patients undergoing antimetabolite therapy are needed to support recommendations in this population.

5-Aminosalicylic Acid (ASA) Derivatives {#s4-9}
---------------------------------------

Like azathioprine, the 5-ASA derivatives sulfasalazine and mesalamine are used to reduce inflammation in IBD and various autoimmune diseases, often in combination with other immunosuppressive agents. In the four studies that examined their use in patients with IBD who were undergoing IFN-based antiviral regiments, SVR was achieved in 7 of 12 patients ([Table 10](#t10){ref-type="table"}).[@b107],[@b112]--[@b114] Two of the 12 patients were also on azathioprine; both achieved SVR. One case report describes a new diagnosis of ulcerative colitis due to a flare that closely followed initiation of IFN-based antiviral therapy.[@b112] SVR was not reported. Increased IBD activity during concomitant antiviral and immunosuppressive therapy was observed in 5 of 13 total patients. Severity of the IBD flares was variable; one patient required steroids, mesalamine and antibiotics, while another patient required budesonide.

###### 5-ASA derivatives

  Study                   Type          n   Age   Male, %   Reason for IS   Immunosuppression                                                           AT                                                                Outcomes                                                          Adverse Effects                                                                                                                                              SVR, %
  ----------------------- ------------- --- ----- --------- --------------- --------------------------------------------------------------------------- ----------------------------------------------------------------- ----------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------ --------
  Hahn, 2015[@b115]       Case series   1   50    100%      RA              Hydroxychloroquine, methylprednisolone 8 mg QD, sulfasalazine               Sofosbuvir/ledipasvir/GS-9451 × 6 wks                             SVR24                                                             RA flare after completion of AT                                                                                                                              100%
  Mitoro, 1993[@b112]     Case report   1   34    100%      UC              Sulfasalazine for treatment of UC flare that followed initiation of IFN-α   IFN-α × ∼2.5 mo. Restarted 1 wk after sulfasalazine was started   ALT decreased but not normalized                                  Initial administration of IFN-α caused a flare of UC. There was no recurrence after IS was started                                                           
  Allen, 2013[@b113]      Case series   7   53    56%       IBD             Mesalamine (+ azathioprine in 2/7 pts)                                      IFN + RBV × 3--12 mo                                              SVR in 4/7 (2/2 on mesalamine and AZA; 2/5 on mesalamine alone)   IBD flare in 1/7 patients. No treatment stopped because of cytopenia                                                                                         67%
  Alok, 2010[@b114]       Case report   1   58    100%      Crohn's         Mesalamine                                                                  PegIFN-α2a + RBV                                                  SVR. Bowel symptoms exacerbated                                   Budesonide given for IBD flare 13 wks into AT. Loperamide given for worsening IBD symptoms (CRP wnl) 8 mo into AT. Anemia requiring reduction of ribavirin   100%
  Scherzer, 2008[@b107]   Case series   4   54    50%       Crohn's         Mesalamine                                                                  PegIFN-α2a + RBV × 48 wks                                         SVR in 2/4. Relapse in 2/4                                        Increased CD activity in 3/4 (required steroids + ABX + mesalamine; steroids; and mesalamine)                                                                50%

In the setting of IBD, IFN-based antiviral therapy appears equally effective at achieving SVR. The frequency of IBD flares does seem high given that 5-ASA derivatives are typically administered for more mild disease. It would be helpful to compare the frequency of exacerbations against the frequency in patients on other agents for IBD. Unfortunately, this is limited by the sparseness of data for patients on other therapies for IBD.

One case report describes a man treated for rheumatoid arthritis with hydroxychloroquine, low-dose corticosteroids and sulfasalazine. Twenty-four weeks after a 6-week course of sofosbuvir, ledipasvir and GS-9451 (an HCV NS1 protease inhibitor), HCV VL was undetectable.[@b115] The patient did, however, experience a flare of the rheumatoid arthritis at 1 week after completing the antiviral therapy.

Overall, the literature suggests that SVR can be achieved with all-oral DAA regimens; however, more data are needed to clarify the impact of concomitant 5-ASA treatment on treatment outcomes, and conversely the potential role of HCV therapy on autoimmune disease activity.

Other Immunosuppressive Agents {#s4-10}
------------------------------

A number of studies report antiviral therapy used in the setting of immunosuppressant regimens that do not fit adequately within the groups above ([Table 11](#t11){ref-type="table"}). One single-armed interventional study of pegIFN-α2a and RBV in patients with sickle cell disease on hydroxyurea achieved SVR in 6 of 8 total patients, while transfusions and pain crises decreased.[@b116] Adverse effects were not described in detail.

###### Other immunosuppressive agents

  Study                   Type                               n    Age                                         Male, %   Reason for IS   Immunosuppression   AT                          Outcomes                                                                                    Adverse Effects                                                                           SVR, %
  ----------------------- ---------------------------------- ---- ------------------------------------------- --------- --------------- ------------------- --------------------------- ------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------- --------
  Agha, 2013[@b116]       Prospective interventional study   8    30[^1^](#table11fn1){ref-type="table-fn"}   63%       SSD             Hydroxyurea         PegIFN α2a + RBV            SVR: 6/8 SSD: overall decrease in median transfusion and pain crises                        "Well-tolerated" and "without relevant side effects." All completed the study             75%
  Azhar, 2010[@b118]      Case report                        1    40                                          0%        AIH + HCV       MMF                 Consensus IFN + RBV         SVR Achieved. No hepatitis flares                                                           Cytopenias requiring filgrastim and EPO                                                   100%
  Scherzer, 2008[@b107]   Case series                        1    56                                          100%      Crohn's         MMF                 PegIFN-α2a + RBV × 48 wks   SVR                                                                                         Increased CD activity requiring dilation of stenosis                                      100%
  Cornberg, 2002[@b117]   Prospective cohort                 38   45                                          79%       HCV (trial)     MMF × 24 wks        IFN-α2a × 24 wks            Study discontinued due to inefficacy. After 12 wks of therapy, only 1/29 had negative HCV   No serious AEs. No signs of diminished liver function. Not worse than IFN-α monotherapy   

Median

Three studies described mycophenolic acid administered concomitantly with IFN. The largest of these was a single-armed prospective interventional trial of a 24-week course of mycophenolic acid and IFN-α2a for the treatment of chronic HCV infection in 38 previous non-responders.[@b117] The study was discontinued after an interim analysis at 12 weeks found that only 1 of 29 patients assessed at that point had undetectable VL. No patients experienced serious adverse effects or diminished hepatic function. In a case report of mycophenolic acid administered concomitantly with consensus IFN and RBV to a patient with AIH and HCV infection, SVR was achieved.[@b118] No hepatitis flares were observed but the patient did require filgrastim and EPO. In another study, a patient on mycophenolic acid for Crohn's disease was treated with pegIFN-α2a and RBV.[@b107] SVR was achieved but the patient experienced increased IBD activity and required dilation of a stenotic region of bowel. Taken together, these studies show that IFN-based antiviral therapy can cause a range of side effects in patients on mycophenolate mofetil. Furthermore, as in the studies of cytotoxic chemotherapy applied as an adjunct to IFN for the treatment of HCV, adding mycophenolate mofetil does not increase effectiveness.

DAAs {#s4-11}
----

The majority of the studies in this review examine the use of historical IFN-containing regimens. However, DAAs have supplanted these regimens for the treatment of chronic HCV infection.

Two studies investigate the use of historical regimens of telaprevir or boceprevir in combination with IFN ([Table 12](#t12){ref-type="table"}). In four patients who had received rituximab 1 month prior for the treatment of mixed cryoglobulinemia, SVR was not reported and adverse effects were not reported separately for these patients from the larger study population in either study.[@b75] In a patient undergoing plasmapheresis and 2 days of high-dose methylprednisolone for MPGN and skin ulcers secondary to cryoglobulinemia, SVR was achieved but renal dysfunction progressed to end-stage renal disease and severe anemia required transfusions, erythropoietin and interruption of IFN and RBV.[@b74]

###### Direct-acting agents with interferon

  Study                   Type                 n   Age   Male, %   Reason for IS                                                    Immunosuppression                                       AT                                                                     Outcomes                                                           Adverse Effects                                                       SVR, %
  ----------------------- -------------------- --- ----- --------- ---------------------------------------------------------------- ------------------------------------------------------- ---------------------------------------------------------------------- ------------------------------------------------------------------ --------------------------------------------------------------------- --------
  Saadoun, 2014[@b75]     Prospective cohort   4   N/A   N/A       Mixed cryoglobulinemia vasculitis                                Rituximab given 1 mo before AT                          PegIFN-α + RBV × 48 wks + telaprevir × 12 wks or boceprevir × 44 wks   PR in 2/4 and CR in 2/4                                            Not reported separately                                               
  Humphries, 2014[@b74]   Case report          1   59    100%      Type II cryoglobulinemia (manifesting as MPGN and skin ulcers)   Methylprednisolone 500 mg × 2d and plasmapheresis × 5   IFN, RBV, telaprevir × 24 wks                                          PR. Progressed to ESRD on HD 7 wks after end of tx. SVR achieved   Anemia requiring transfusions, EPO, and interruption of IFN and RBV   100%

Four studies examined the use of all-oral regimens in 42 patients who were on an array of immunosuppressive agents ([Table 13](#t13){ref-type="table"}).[@b66],[@b76],[@b94],[@b115] SVR was achieved in 38 of 41 patients (92.6%) reportedly. Adverse effects included one patient with a flare of rheumatoid arthritis and two patients with anemia (hemoglobin, 8.5). One study describes a patient treated with ledipasvir and sofosbuvir while receiving immunotherapy for advanced melanoma;[@b94] SVR was not reported. In general, it appears that all-oral regimens can be very effective even when patients are on immunosuppressive medications. More data in larger cohorts are needed to strengthen the evidence base for the use of all-oral DAAs in patients undergoing immunosuppressive drug therapy; although this will likely represent a preferred strategy for treatment over IFN-based regimens, which have been associated with autoimmune disease flares requiring increased immunosuppression[@b104],[@b107],[@b111],[@b114],[@b115] and serious adverse events, including death.[@b71],[@b105],[@b108]

###### All-oral DAA regimens

  Study               Type                          n    Age   Male, %   Reason for IS            Immunosuppression                                               AT                                                                Outcomes                                                                                                          Adverse Effects                                       SVR, %
  ------------------- ----------------------------- ---- ----- --------- ------------------------ --------------------------------------------------------------- ----------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------- ----------------------------------------------------- --------
  Basu, 2016[@b66]    Randomized controlled trial   35   50    74%       IBD                      TNF-α antagonists maintained for the entire duration of AT      LDV + SOF + RBV 1000 mg × 8 wks or LDV + SOF × 12 wks             SVR12 in 34/35 (100% study retention)                                                                             Hb \< 8.5 in 2. Severities of other AEs are unclear   97%
  Sise, 2016[@b76]    Case series                   5    N/A   N/A       Mixed cryoglobulinemia   Rituximab × 4 pts Ustekinumab × 1 pt                            Sofosbuvir + ribavirin or sofosbuvir + simeprevir × 12 wks        SVR12 in 3/4 pts on rituximab and 0/1 pts on ustekinumab (relapsed)                                               Not reported separately                               60%
  Hahn, 2015[@b115]   Case series                   1    50    100%      Rheumatoid arthritis     Hydroxychloroquine, methylprednisolone 8 mg QD, sulfasalazine   sofosbuvir/ledipasvir/GS-9451 ×6 wks                              SVR24                                                                                                             RA flare 1 wk after completion of AT                  100%
  Davar, 2015[@b94]   Case report                   1    59    0%        Advanced melanoma        Pembrolizumab ×15 cycles                                        Ledipasivir + Sofosbuvir started after cycle 9 of pembrolizumab   Melanoma: "excellent PR." Undetectable HCV VL and normal ALT and AST after 6 additional cycles of pembrolizumab   None reported                                         

Discussion {#s5}
==========

Hepatitis C is the most common chronic bloodborne infection in the United States.[@b119] In those with acute HCV infection, approximately 80% will develop chronic hepatitis C.[@b120] Untreated chronic infection can lead to liver fibrosis, cirrhosis, HCC, liver failure and need for liver transplant. Extra-hepatic complications include type-1 MPGN, cryoglobulinemia and vasculitis. The development of all-oral DAA regimens, which are more effective and more tolerable than IFN-based regimens, provide clinicians with the opportunity to prevent these negative outcomes in patients who are unsuitable for IFN-based therapy. Concomitant administration of immunosuppressive therapy may at first seem antithetical to the rationale behind IFN-based regimens; however, a growing body of evidence has been reported that supports their efficacy and safety. Trials of antiviral therapy in patients coinfected with HIV and HCV or on immunosuppressive therapy for solid organ transplant have demonstrated that treating HCV in immunocompromised patients can be effective at achieving SVR, albeit at lower rates than in patients with intact immune systems.[@b31]--[@b34],[@b121],[@b122]

While virologic relapse after SVR was seldom reported in the studies we examined, experience from coinfected patients also shows that recurrence of HCV after achieving SVR is rare. A recent systematic review of non-transplant patients who were treated and achieved SVR in the IFN era revealed a 5-year risk of recurrence of 15%, as compared to the 0.95% reported among monoinfected patients without a recognized risk factor (injection drug use, men who have sex with men or imprisonment) and the 10.67% reported among monoinfected patients with a recognized risk factor.[@b123] However, two of the four studies of coinfected patients drew their subjects exclusively from populations with recognized risk factors (men who have sex with men and incarcerated patients). Indeed, all cases of recurrence were confirmed to be reinfection rather than late relapse. A separate study of six patients with lupus treated with pegIFN and RBV reported late relapse in two patients.[@b124]

The key limitation to the development of guideline statements addressing HCV treatment in patients undergoing immunosuppressive drug therapy is the poor quality of evidence, with a predominance of retrospective cohorts and case series; only eight prospective interventional trials evaluating 185 patients were identified in this systematic review. Available data strongly suggest that all-oral DAA regimens are well tolerated and associated with similar rates of SVR as those reported in patients without immunosuppression, and are unlikely to precipitate autoimmune disease activity.[@b19],[@b125]

Conclusion {#s6}
==========

Patients on immunosuppressive therapy represent a neglected population that may stand to benefit from advances in antiviral therapy for HCV infection. While IFN-based regimens can be safe and effective in some settings, side effects are significant and efficacy is far from perfect. Furthermore, evidence is lacking in key areas, such as patients with cancer. DAAs have potential to greatly increase the number of patients treated for HCV, but there is scant data on the use of these agents in immunosuppressed patients outside of the transplant setting. Adequately powered studies, ideally prospective observational cohort or multicenter randomized controlled trials, are needed to further strengthen the evidence base to inform guidelines on optimal all-oral treatment regimens for patients with HCV who are undergoing immunosuppressive drug therapy.

5FU

:   5-fluorouracil

AASLD

:   American Association for the Study of Liver Diseases

ABX

:   antibiotics

AE

:   adverse effect

AIH

:   autoimmune hepatitis

ALL

:   acute lymphoblastic leukemia

APASL

:   Asian Pacific Association for the Study of Liver

ASA

:   aminosalicylic acid

AT

:   antiviral therapy

BFM

:   Berlin-Frankfurt-Münster

CD

:   Crohn's disease

CR

:   complete response

CRP

:   C-reactive protein

DAA

:   direct acting antiviral

EASL

:   European Association for the Study of Liver

EPO

:   erythropoietin

ESRD

:   end-stage renal disease

EVR

:   early viral response

G-CSF

:   granulocyte-colony stimulating factor

Hb

:   hemoglobin

HBV

:   hepatitis B virus

HCC

:   hepatocellular carcinoma

HCV

:   hepatitis C virus

HIV

:   human immunodeficiency virus

IBD

:   inflammatory bowel disease

IDSA

:   Infectious Diseases Society of America

IFN

:   interferon

IS

:   immunosuppression

MM

:   multiple myeloma

MPGN

:   membranoproliferative glomerulonephritis

MTX

:   methotrexate

NHL

:   non-Hodgkin's lymphoma

NK cell

:   natural killer cell

NR

:   no response

PASI

:   psoriasis area severity index

peg

:   polyethylene glycol

PLT

:   platelets

PR

:   partial response

QD

:   daily

RA

:   rheumatoid arthritis

RBV

:   ribavirin

RNA

:   ribonucleic acid

SSD

:   sickle cell disease

SVR

:   sustained virologic response

TNF-α

:   tumor necrosis factor-α

TRAIL

:   TNF-related apoptosis-inducing ligand

UC

:   ulcerative colitis

VL

:   viral load

WBC

:   white blood cells

wnl

:   within normal limits

XELOX

:   Xeloda-oxaliplatin

[^1]: **Conflict of interest:** None

[^2]: Drafting of the manuscript (KO), contributing to the conception and design (KO, JKL), contributing to critical revisions of the manuscript (JKL).
