Effect of Hepatitis B and C Infection on Recruitment for Cancer Clinical Trials

TO THE EDITOR:

We read in a recent Journal of Clinical Oncology the position paper by ASCO and Friends of Cancer Research.¹ The comprehensive and important review effectively advocates that fit patients with HIV and cancer should be included in cancer clinical trials and that they should not be excluded a priori by their HIV-seropositive status. Factors that should be considered include CD4⁺ cell count, HIV viral load, and the presence or absence of opportunistic infections. The intent of the authors was not to review every single eligibility criteria that might occur in the course of a clinical trial consideration; however, additional issues exist, which impede clinical trial participation among this group of patients and to which we would also like to call attention.

In a retrospective analysis, we sought to review several factors that prevented enrollment of patients with HIV and non-Hodgkin lymphoma (NHL) into clinical trials of the National Institutes of Health–sponsored AIDS Malignancy Consortium (AMC). We used an electronic database of patients with AIDS-associated diffuse large B-cell lymphoma and primary effusion lymphoma who sought care at Montefiore Medical Center between the years 2005 and 2017. Each patient was matched to an AMC clinical trial that was open at the time of primary or relapsed NHL diagnosis. We reviewed inclusion and exclusion criteria for each of the available clinical trials, patient demographics, data about whether a clinical trial was offered, reasons for nonenrollment, and survival. Seventy-three patients were assessable for this analysis; the population consisted of African Americans (50%) and Hispanics (14%) with stages III and IV (87%) disease. Fourteen patients (19%) met inclusion and exclusion criteria and were offered participation in an AMC clinical trial; 15 patients (20%) who were eligible for lymphoma protocol participation were not offered AMC trial participation. The overall enrollment rate was 10%. The majority of patients (ie, 45[62%] of 73 patients) did not meet the inclusion or exclusion criteria of available AMC trials. The most common factors for patient ineligibility were hepatitis B virus (HBV) or hepatitis C virus (HCV) seropositivity criteria (31%), poor compliance with medical directives (29%), and poor performance status secondary to advanced illness (25%).

The US Food and Drug Administration released a black box warning to call attention to the potentially fatal risk of HBV reactivation with anti-CD20 therapy. Before this warning, infection with HBV or HCV typically was not used to exclude patients from lymphoma clinical trials. Why is this important? There are 400 million chronic carriers of HBV worldwide and 800,000 to 1.4 million in the United States; the prevalence ranges from 0.3% to 0.5% in the general population and 4% to 17% in HIV-positive people.² The rate of reactivation after anti-CD20 therapy or immunosuppressive therapy for patients who are Hepatitis B surface antigen positive or anti–Hepatitis B core antibody positive is 32%,³ whereas the reactivation rate is between 8.9% and 41.5% in HBsAg-negative/anti-HBc–positive patients.⁴ Studies have also shown that HBV antiviral therapy in the form of lamivudine and entecavir has been effective to control reactivation in HBV-seropositive patients who receive rituximab with and without combination chemotherapy.^5,6 In patients with cancer, the prevalence of HCV infection ranges from 1.5% to 32%.⁷ Prospective studies of HCV reactivation have shown that 10% of patients have hepatitis flares and that reactivation is not associated with liver failure or liver-related deaths.⁸

Most current cancer clinical trials in the HIV and non-HIV populations mandate assessment for HBV and HCV serology status and exclusion of study volunteers who are seropositive or have detectable HBV or HCV viral loads. Among important considerations for these patients is whether the degree of liver dysfunction is sufficiently poor to preclude clinical trial participation and whether treatment will include immunomodulating agents. We suggest the following be applied for patients who meet liver function test criteria—either transaminase measures or Child-Pugh criteria in the absence of cirrhosis: Patients with a positive HBV polymerase chain reaction or with HBV surface antigen positivity should be allowed to start treatment if they are receiving prophylactic anti–HBV therapy. In patients with HCV polymerase chain reaction positivity, monitoring of liver function tests should be recommended, and the patients should not be excluded from studies. Increasingly, cancer trials are including novel checkpoint inhibitors and immunotherapies including adoptive cell therapy to treat patients with cancer. Those patients with viral coinfection (HIV, HBV, and HCV) are also excluded from these trials because of concerns about enhanced risk of reactivation. These trials should have a subsection to study the effect of these therapies in HIV-, HBV-, and HCV-positive patients. Overall, HIV, HBV, and HCV infections represent global problems. Additional research is needed to study the effect of these infections, and clinical trials should adapt to include patients with these infections. In the meantime, the friends of ASCO HIV Working Group are to be commended for providing a clarion call for including patients with HIV infection and cancer more broadly into cancer clinical trials.