Parag Mahale

Acute exacerbation and reactivation of chronic hepatitis C virus infection in cancer patients

BACKGROUND & AIMS Data on acute exacerbation and reactivation of chronic hepatitis C virus (HCV) infection following chemotherapy are very limited. We sought to characterize the episodes of acute exacerbation and viral reactivation of HCV infection in cancer patients. METHODS The medical records of HCV-infected patients seen at our institution (2008-2009) were analyzed retrospectively. Acute exacerbation was defined as greater than 3-fold increase in serum level of alanine aminotransferase, and viral reactivation as ≥ 1 log(10) IU/ml increase of HCV viral load following chemotherapy. RESULTS Acute exacerbation occurred in 33 (11%) of 308 patients with proven HCV infection. Patients with acute exacerbation more often had underlying hematological malignancies (73% vs. 29%; p<0.001) and lymphopenia (6% vs. 0%; p=0.01) than patients without it. In multivariate analysis, underlying hematological malignancies (p=0.02; odds ratio, 3.2; 95% confidence interval, 1.2-8.7) and use of rituximab (p=0.004; odds ratio, 4.2; 95% confidence interval, 1.6-10.9) were associated with acute exacerbation. Patients with acute exacerbation received higher median cumulative dose of rituximab than those without exacerbation. Discontinuation of chemotherapy due to liver dysfunction was more common in patients with acute exacerbation than in patients without it (45% vs. 11%; p<0.001). Eight (36%) of 22 patients with known pre- and post-chemotherapy viral load had viral reactivation. CONCLUSIONS Acute exacerbation and reactivation of chronic HCV infection occur often after chemotherapy. Liver dysfunction can lead to discontinuation of potentially life-saving chemotherapy in nearly one-half of the patients with exacerbation of HCV infection.

Concomitant use of direct-acting antivirals and chemotherapy in hepatitis C virus-infected patients with cancer.

Antiviral therapy improves hepatic outcomes in hepatitis C virus (HCV)‐infected cancer patients. However, such patients are not treated simultaneously with antivirals and chemotherapy, owing to overlapping toxicities with previous standard of care treatment of pegylated interferon and ribavirin.

Association Between Hepatitis C Virus and Head and Neck Cancers.

BACKGROUND Hepatitis C virus (HCV) infection is associated with hepatocellular carcinoma and non-Hodgkins lymphoma. In 2009, MD Anderson established the first US clinic for treating HCV-infected cancer patients, where we observed an unexpectedly large number of patients with head and neck cancers (HNCs). We sought to determine whether HCV is associated with HNCs. METHODS In this case-control study, medical records of cancer patients tested for HCV antibodies at our center from 2004 through 2014 were identified. Case subjects had new-onset primary oropharyngeal or nonoropharyngeal (oral cavity, nasopharynx, hypopharynx, or larynx) HNCs. Control subjects had smoking-associated (lung, esophagus, or urinary bladder) cancers. Biopsy reports of oropharyngeal cancers tested for human papillomavirus (HPV) were reviewed. Patients with lymphoma were excluded. Multivariable logistic regression models were constructed. All statistical tests were two-sided. RESULTS Of 34 545 cancer patients tested for HCV antibodies, 409 case subjects (164 oropharyngeal and 245 nonoropharyngeal) and 694 control subjects (378 lung, 168 esophagus, and 148 urinary bladder) were studied. The prevalence of HCV seropositivity was higher in oropharyngeal cancer patients (14.0%, 95% confidence interval [CI] = 8.7% to 19.4%, vs 6.5%, 95% CI = 4.6% to 8.3%), particularly HPV-positive oropharyngeal cancer patients (16.9%, 95% CI = 8.7% to 24.9%, vs 6.5%, 95% CI = 4.6% to 8.3%), and nonoropharyngeal HNC patients (20.0%, 95% CI = 14.9% to 25.0%, vs 6.5%, 95% CI = 4.6% to 8.3%) than in control subjects. Adjusted models showed a statistically significant association of HCV seropositivity with nonoropharyngeal (except nasopharyngeal) HNCs (odds ratio [OR] = 2.85, 95% CI = 1.38 to 5.88) and HPV-positive oropharyngeal cancers (OR = 2.97, 95% CI = 1.31 to 6.76). CONCLUSIONS HCV is associated with nonoropharyngeal (except nasopharyngeal) and HPV-positive oropharyngeal HNCs. Further studies are required to explore the possible interaction between HCV and HPV, and the association between HCV and other HPV-related malignancies.

The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection

Background and aim Chronic HCV infection is associated with several extrahepatic manifestations (EHMs). Data on the effect of sustained virological response (SVR) on the risk of EHMs are limited. Methods We conducted a retrospective cohort study using data of patients from the US Veterans Affairs HCV Clinical Case Registry who had a positive HCV RNA test (10/1999-08/2009). Patients receiving interferon-based antiviral therapy (AVT) were identified. SVR was defined as negative HCV RNA at least 12 weeks after end of AVT. Risks of eight incident EHMs were evaluated in Cox regression models. Results Of the 160 875 HCV-infected veterans, 31 143 (19.4%) received AVT, of whom 10 575 (33.9%) experienced SVR. EHM risk was reduced in the SVR group compared with untreated patients for mixed cryoglobulinaemia (adjusted HR (aHR)=0.61; 95% CI 0.39 to 0.94), glomerulonephritis (aHR=0.62; 95% CI 0.48 to 0.79), porphyria cutanea tarda (PCT) (aHR=0.41; 95% CI 0.20 to 0.83), non-Hodgkin’s lymphoma (NHL) (aHR=0.64; 95% CI 0.43 to 0.95), diabetes (aHR=0.82; 95% CI 0.76 to 0.88) and stroke (aHR=0.84; 95% CI 0.74 to 0.94), but not for lichen planus (aHR=1.11; 95% CI 0.78 to 1.56) or coronary heart disease (aHR=1.12; 95% CI 0.81 to 1.56). Risk reductions were also observed when patients with SVR were compared with treated patients without SVR for mixed cryoglobulinaemia, glomerulonephritis, PCT and diabetes. Significant reductions in the magnitude of aHRs towards the null with increasing time to initiation of AVT after HCV diagnosis were observed for glomerulonephritis, NHL and stroke. Conclusions Risks of several EHMs of HCV infection are reduced after AVT with SVR. However, early initiation of AVT may be required to reduce the risk of glomerulonephritis, NHL and stroke.

Hepatitis C virus infection and the risk of cancer among elderly US adults: A registry-based case-control study

Hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC) and subtypes of non‐Hodgkin lymphoma (NHL). Associations with other cancers are not established. The authors systematically assessed associations between HCV infection and cancers in the US elderly population.

Antiviral therapy improves overall survival in hepatitis C virus-infected patients who develop diffuse large B-cell lymphoma

Chronic Hepatitis C virus (HCV) infection is associated with increased incidence of non‐Hodgkin lymphoma. Several studies have demonstrated regression of indolent lymphoma with antiviral therapy (AVT) alone. However, the role of AVT in HCV‐infected patients with diffuse large B‐cell lymphoma (DLBCL) is unclear. We therefore analyzed AVTs impact on oncologic outcomes of HCV‐infected patients (cases) who developed DLBCL. Cases seen at our institution (June 2004–May 2014) were matched with uninfected counterparts (controls) and then divided according to prior AVT consisting of interferon‐based regimens. We studied 304 patients (76 cases and 228 controls). More cases than controls had extranodal (79% vs. 72%; p = 0.07) and upper gastrointestinal (GI; 42% vs. 24%; p = 0.004) involvement. Cases never given AVT had DLBCL more refractory to first‐line chemotherapy than that in the controls (33% vs. 17%; p = 0.05) and exhibited a trend toward more progressive lymphoma at last examination compared to controls (50% vs. 32%; p = 0.09) or cases given AVT (50% vs. 27%; p = 0.06). Cases never given AVT had worse 5‐year overall survival (OS) rates than did the controls (HR, 2.3 [95% CI, 1.01–5.3]; p = 0.04). Furthermore, AVT improved 5‐year OS rates among cases in both univariate (median [Interquartile range]: 39 [26–56] vs. 16 [6–41] months, p = 0.02) and multivariate analyses (HR = 0.21 [95% CI, 0.06–0.69]; p = 0.01). This study highlights the negative impact of chronic HCV on survival of DLBCL patients and shows that treatment of HCV infection is associated with a better cancer response to chemotherapy and improves 5‐year OS.

Hepatitis C virus genotype distribution varies by underlying disease status among patients in the same geographic region: A retrospective multicenter study

BACKGROUND Hepatitis C virus (HCV) is a known carcinogen with considerable genetic heterogeneity: six different genotypes have been identified. HCV genotype distribution varies from country to country. In the United States, the most prevalent genotypes are 1a, and 1b followed by genotypes 2, and 3. OBJECTIVES To examine whether the distribution of HCV genotypes differed by cancer status among patients in the same area. STUDY DESIGN We reviewed epidemiologic and virological data of 636 patients with HCV infection evaluated at 3 institutions in Houston, Texas, in 2008 and 2009. RESULTS We included 129 cancer patients (53 with hematologic malignancies and 76 with solid tumors), 333 immunocompetent patients, and 102 HIV-co-infected patients. The prevalence of genotype 1 (G-1) was 66% among cancer patients, 84% among immunocompetents (P=0.00004), and 99% among HIV-co-infected patients (P<0.00001). G-2 and G-3 were more common in cancer patients than other patients. Demographics, risk factors, and duration of HCV infection were similar between cancer and immunocompetent patients. G-1 was more prevalent in immunocompetents (84%) than in patients with hepatocellular carcinoma (74%, P=0.08) or lymphoma (59%, P=0.001). G-2 was more prevalent in lymphoma patients (24%) than in immunocompetents (8%, P=0.003); cancer risk was 3 times as great with G-2 as with other genotypes (OR 3.72, 95% CI 1.38-9.76). CONCLUSIONS This multicenter retrospective study provides evidence of differences in HCV genotype distribution by underlying disease among geographically related patients and suggests a possible greater carcinogenic potential of some variants. Large-scale prospective studies are warranted to investigate HCV genotype distribution in other regions.

Hepatitis C virus reactivation in patients receiving cancer treatment: A prospective observational study

Hepatitis C virus (HCV) reactivation in patients receiving cancer treatment has been reported in retrospective studies. We sought to determine prospectively the incidence, predictors, and clinical significance of HCV reactivation during cancer treatment. HCV‐infected patients receiving cancer treatment at our institution between November 2012 and July 2016 were studied. Reactivation was defined as an increase in HCV‐RNA ≥1 log10 IU/mL over baseline and hepatitis flare as an increase in alanine aminotransferase to ≥3 times the upper limit of normal. One hundred patients were studied, 50 with hematologic malignancies and 50 with solid tumors. Reactivation occurred in 23 (23%) patients, including 18 (36%) patients with hematologic malignancies and 5 (10%) patients with solid tumors. In univariate analysis, patients with reactivation were more likely than those without reactivation to have prolonged lymphopenia (median, 95 versus 22 days; P = 0.01) and to have received rituximab (44% versus 9%; P < 0.0001), bendamustine (22% versus 0%; P < 0.001), high‐dose steroids (57% versus 21%; P = 0.001), or purine analogs (22% versus 5%; P = 0.02). Rituximab (odds ratio = 9.52; P = 0.001), and high‐dose steroids (odds ratio = 5.05; P = 0.01) retained significance in multivariable analysis. Of the 23 patients with reactivation, 10 (43%) had hepatitis flare. No patient with reactivation experienced liver failure or liver‐related death within 36 weeks after initiation of cancer treatment. Fourteen patients with hepatitis flare, six of whom had reactivation, required discontinuation or dose reduction of cancer treatment. Conclusion: HCV reactivation occurred in 23% of HCV‐infected patients receiving cancer treatment, and most had an unremarkable clinical course. However, reactivation can affect the cancer treatment plan. Our findings suggest that HCV infection should not contraindicate cancer therapy and infected patients should have access to multiple cancer treatments with close monitoring while receiving regimens associated with HCV reactivation. (Hepatology 2018;67:36‐47).

Most patients with HCV‐associated lymphoma present with mild liver disease: a call to revise antiviral treatment prioritization

Hepatitis C virus (HCV) is associated with development of B‐cell non‐Hodgkin lymphoma (HCV‐NHL). Antiviral therapy (AVT) is prioritized in HCV‐infected patients with significant fibrosis/cirrhosis. It is unknown whether current recommendations based on liver parameters cover the risk of HCV‐NHL development. We aimed to evaluate the liver disease stages of patients with HCV‐NHL.

Prevalence and association of hepatitis C virus infection with different types of lymphoma

To the Editor, Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, affecting about 4.1 million people (1.6%) of the US population. Chronic HCV infection has been associated with extrahepatic hematological manifestations such as mixed cryoglobulinemia and lymphoma. Several reports support an association of HCV infection with the development of non-Hodgkin lymphomas (NHLs). Furthermore, eradication of the chronic HCV infection has been correlated with regression of certain NHLs. However, studies of patients with HCV infection and specific histological types of NHL and Hodgkin lymphoma (HL) are limited. We thus sought to determine the prevalence of HCV seropositivity in patients with different subtypes of NHL and HL and its association with these subtypes. We conducted a case–control study, abstracting data from the electronic medical records of cancer patients screened for HCV antibodies (anti-HCV) at The University of Texas MD Anderson Cancer Center from June 2004 to May 2014. HCV cases were defined as patients who tested positive for antiHCV. Among this group, patients with available information on detectable HCV-RNA or history of HCV infection treatment were considered to be chronically infected with HCV. NHL and HL cases were classified for subtype-specific analysis using the International Classification of Diseases, Ninth Revision, Clinical Modification codes and nested classification by the International Lymphoma Epidemiology Consortium Pathology Working Group. Controls were cancer patients without lymphoma and hepatocellular carcinoma who were screened for anti-HCV during the same period. The v test was used to calculate prevalence of HCV-seropositivity and the odds ratio (OR) as a measure of association with lymphoma. Bonferroni correction was performed to adjust p values, reducing false-positive rates owing to multiple testing. Hence, the p value for statistical significance was 0.0036. All hypothesis testing was two-sided. Statistical analyses were conducted using the Stata/IC software program (version 11.0; StataCorp, College Station, TX). The study was approved by the MD Anderson Institutional Review Board. Of 34,545 patients tested for anti-HCV during the study period, 8,310 (24.1%) had lymphoma (NHL, 7,030 [84.6%]; HL, 1,280 [15.4%]). Of these patients, 198 (2.4%) were positive for anti-HCV and considered cases, consisting of 173 with NHLs and 25 with HLs. We confirmed chronic HCV infection in 114 of the 173 (65.9%) NHL cases and 11 of the 25 (44.0%) HL cases. The overall prevalence of HCV-seropositivity was higher in the NHL patients (2.5%) than in the HL patients (1.9%) or controls (1.7%). HCV-seropositivity was significantly associated with NHL (OR, 1.5 [95% confidence interval (CI), 1.2–1.8]; p5 0.0030) but not HL (Table 1). Of the 173 patients with NHL, 153 (88.4%) had B-cell NHL, 16 (9.2%) had T-cell NHL and 4 (2.3%) had other lymphomas. When compared with that in the controls, HCV prevalence was higher in patients with B-cell NHLs (2.6%), with a significant association between HCV-seropositivity and B-cell NHL (OR, 1.6 [95% CI, 1.3–1.9]; p< 0.0001). The HCV prevalence in the T-cell NHL cases was similar to that in the controls (1.7%). In a subtype-specific analysis, the most common B-cell NHLs in the patients were diffuse large B-cell lymphoma (DLBCL; 43.9%), marginal zone (MZ) lymphoma (11.6%) and follicular lymphoma (10.6%). The prevalence of HCV-seropositivity was greater in the cases than in the controls for all B-cell NHL subtypes except follicular lymphoma, with the highest prevalence noted for MZ lymphoma (3.9%), Burkitt lymphoma (3.8%) and DLBCL (3.7%) (Table 1). Compared with controls, DLBCL had a 2.2-fold greater association with HCV-seropositivity (95% CI, 1.7–2.8; p< 0.0001), and MZ lymphoma had a 2.3-fold greater association with it (95% CI, 1.4–3.5; p5 0.0006). The most prevalent T-cell NHL was mycosis fungoides/S ezary syndrome, and patients with it had a slightly higher HCV infection prevalence (1.9%) than did the controls (1.7%). The predominant HL subtype was nodular sclerosis, and patients with it had an HCV infection prevalence of 2.2%. The association between HCV-seropositivity and either T-cell NHL or HL subtypes was not statistically significant. This is one of the largest studies to systematically evaluate the association of anti-HCV with different subtypes of NHL and HL. We found that HCV-seropositivity was associated with some but not all B-cell NHL subtypes. This finding enabled us to better define the subset of non-liver cancers linked with chronic HCV infection. The association of HCV-seropositivity with B-cell NHL but not T-cell NHL or HL can be supported by a proposed mechanism of chronic antigenic stimulation by HCV in specific B-cell clones, which induces malignant lymphoproliferation. In addition to generalized binding of HCV E2 protein to CD81, the HCV NS3/IgG antigen binds with a B-cell receptor, explaining selective proliferation of B-cell subtypes analogous to B-cell receptor segments, such as DLBCL and MZ lymphoma. Le tt er to th e E di to r