Cancer immunotherapy is transforming the way we treat patients with cancer. Immune checkpoint inhibitor (ICI) therapy is a type of cancer immunotherapy that works through suppression of immune inhibitory pathways such as the programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) axis and the cytotoxic lymphocytes antigen proteins (CTLA-4) pathway [1]. The impressive outcomes with ICI therapy in clinical trials led to approval of several ICIs by the U.S. Food and Drug Administration (FDA) in multiple advanced malignancies. For example, for the first-line treatment of patients with non-small-cell lung cancer (NSCLC) without actionable alterations, ICI therapy, either alone or in combination with chemotherapy improves survival compared to chemotherapy alone and is now considered standard of care [2–5]. Similarly, ICI therapy has improved outcomes in patients with melanoma [6, 7], renal cell carcinoma (RCC) [8–10] and many other cancers [11]. The majority of early clinical trials of ICIs excluded patients with chronic viral infections such as human immune-deficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) due to concerns about viral reactivation, toxicity, and efficacy in these populations.

Limited data from the literature exist on the safety and efficacy of ICI therapy in patients with chronic viral infection and advanced-stage cancer. A clinical trial of the anti-PD-1 antibody pembrolizumab in patients with HIV on anti-retroviral therapy and advanced-stage cancer, reported that pembrolizumab did not impair CD4+ cell counts or viral suppression [12, 13]. Likewise, a systematic review showed that ICI therapy was not associated with new safety signals in patients with HIV infection and advanced-stage cancer [14]. Although a few case studies reported HBV reactivation upon ICI therapy [15, 16], clinical trials of ICI therapy in patients with hepatocellular carcinoma (HCC) did not show evidence of reactivation of HBV/HCV [17, 18]. While reassuring, these analyses involve small patient numbers and the treatment was mainly limited to ICI monotherapy. In order to shed further light on the safety and efficacy of ICI therapy in patients with concomitant cancer and chronic viral infections, we performed a retrospective analysis of cancer patients with chronic viral infection (HIV, HBV, or HCV) who were treated with ICI containing regimens including chemotherapy plus ICI therapy.

We have developed a comprehensive REDCap based immuno-oncology database (IO database) at MedStar Health Hospitals to capture real world data of patients treated with ICI therapy. Pharmacy records were used to identify patients treated with either anti-PD (L)-1 (nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab), anti-CTLA-4 (ipilimumab) as a single agent or in combination with other ICIs (ipilimumab plus nivolumab) or chemotherapy/targeted therapy [carboplatin plus pemetrexed plus pembrolizumab (carbo/pem/pembro), carboplatin plus paclitaxel plus pembrolizumab (carbo/taxol/pembro) and brentuximab plus nivolumab]. In this database, we have collected a total of 769 patients treated at 5 MedStar Health hospitals (MedStar Georgetown University Hospital, MedStar Washington Hospital Center, MedStar Franklin Square Hospital, MedStar Good Samaritan Hospital, and MedStar Union Memorial Hospital) during the time frame of January 2011 to April 2018. A total of 50 patients with chronic viral infections (HIV, HBV and/or HCV) were identified from the database. Patient’s HIV/HBV/HCV status was attained based on ICD-9/10 codes and manual review of medical chats which was performed for each patient. HCV patients in virologic remission after therapy were included. Objective response rate (ORR) was measured using RECIST version 1.1 criteria [19]. The patients without any follow-up scans either due to clinical deterioration or lost to follow up were assumed to progressive disease (PD) as best ORR. Two patients with Hodgkin’s lymphoma (HD) and 1 patient with Burkitt’s lymphoma were not included in response evaluation since RECIST is not the standard response criteria used for lymphoma. CTCAE version 4.03 was used to grade immune-related adverse events (irAEs). Bio-informatics support was used to abstract patients’ demographics, co-morbidities, treatment history, and toxicity from electronic medical records. Data was extracted using SQL queries. R and Python programming was used for data cleansing, calculations, code mapping, and aggregation. Patients’ RECIST confirmed response and toxicity were verified for each patient by the investigators. Additional data collected manually included HIV viral load, CD4+ T-cell counts, HIV medication history, HCV viral load, HCV treatment history, HBsAg, HBsAb, HBcAb, HBeAb, HBV viral load and HBV treatment if available. Pre-treatment values were defined as any values obtained before the first dose of ICI therapy and post-treatment values as any values obtained after the first dose of ICI therapy. A low CD4+ T-cell count was defined as < 100 cells/ul. Descriptive statistics were applied to summarize the data. Tumors samples were classified as PD-L1+ if PD-L1 expression was noted in ≥1% of tumor cells using the Dako PD-L1 IHC 22C3 PharmDx clone (n = 9) or the VENTANA PD-L1 (SP-142) (n = 1) assay.

We identified 50 patients with HIV, HBV and HCV co-morbidities. Table 1 outlines patient infections and co-infections. Clinical characteristics and tumor types are presented in Table 2. The median age of patients in both the HIV and HBV/HCV cohorts was 62 years. The majority of patients were treated with anti-PD-(L)1 monotherapy (n = 43). One patient received combination ipilimumab and nivolumab and 6 patients were treated with anti-PD-(L)1/chemotherapy/targeted therapy combination (4 with carbo/pem/pembro). The most common type of cancer in the HIV cohort was NSCLC (57%, n = 12). HCC (47%, n = 16) was the most common type of cancer in the HBV/HCV cohort, followed by NSCLC (29%, n = 10).Tab1

Classification of HIV, HBV, and HCV infections

ICI therapy has reshaped the landscape of treatments in a broad array of cancers. Patients with chronic viral infection such as HIV, HBV, and HCV have been historically excluded from clinical trials of ICIs. Therefore, the efficacy and safety profile of ICI therapy has been largely unexplored, limiting physician’s ability to make informed treatment decisions for these patients. Here we report the results from our retrospective study of cancer patients with chronic viral infection treated with ICI therapy, which is one of the largest case series to date.

In the HIV cohort, in line with previous studies [12, 14], ICI therapy did not appear to adversely affect CD4+ T-cell counts or HIV viral load, although the number of patients with paired pre- and post-treatment values was small. Early evidence suggests that CD4+ T-cell counts may increase with PD-1 monotherapy [12, 14, 20]. Ongoing trials of ICI therapy in HIV-infected patients (NCT03304093, NCT03094286, NCT02595866, NCT02408861) are expected to shed light on the anti-viral efficacy of ICI therapy. The incidence of grade 3 or higher irAEs was 14%, which is comparable to the results from a recently published systematic review and a phase I trial of pembrolizumab [12, 14]. Chemotherapy plus ICI therapy – a treatment regimen that is being increasingly utilized in certain types of cancer such as NSCLC – did not seem to increase the risk of irAEs in patients with HIV infection, though this should be verified in future studies. ICI therapy showed anti-tumor activity with an ORR of 25%. In patients with NSCLC which is one of the most common non-AIDS defining cancers in HIV-infected patients [21]; 3 of 4 patients (75%) responded to anti-PD-1 and chemotherapy treatment in the first-line setting and 1 of 7 (13%) had a partial response to anti-PD-1 monotherapy in the second-line setting and beyond. Of note, responders included those with low a CD4 T-cell count. These efficacy results are largely consistent with those from landmark trials that excluded patients with HIV infection [2, 3, 22, 23].

In the HBV/HCV cohort, among the 6 patients with known pre- and post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation. This is in line with the results from clinical trials of anti-PD-1 therapy in patients with HCC [17, 18]. Grade 3 or higher irAEs and ORR were similar to those observed in the clinical trials of anti-PD-1 therapy. As with the HIV cohort, combined chemotherapy and ICI therapy did not seem to increase the risk of irAEs, though definitive conclusion could not be drawn due to the small number of patients treated with the combination.

Several studies have shown that upregulation of PD-1 is associated with virus-specific CD8+ T-cell functional exhaustion in patients with HIV, HBV, or HCV infection [24–26] and PD-1/PD-L1 blockade restored the function of exhausted virus-specific CD8+ T cells in a preclinical model [27], providing a rationale for assessing antiviral effects of immunotherapy targeting the PD-1/PD-L1 pathway. However, it is unclear if anti-PD-(L)1 monotherapy alone would constitute a treatment strategy for chronic viral illness. For example, conflicting data exist on the anti-viral efficacy of anti-PD-1 therapy in patients with cancer [28–30]. Studies have shown that other immune checkpoints such as TIGIT, LAG-3, and TIM-3 may play a role in promoting tumor immune evasion and exhaustion of virus-specific T cells [31–34], suggesting that combination ICI therapy may need to be explored to effectively treat both cancer and chronic viral infection. Improving our understanding of pathways establishing viral latency and tumor resistance to ICI therapy will be critical to the rational development of immunotherapy in patients suffering from cancer and chronic viral illness.

Our study has several limitations. First, important viral parameters (e.g. CD4+ T-cell count, viral titer, antibody titer) were not collected in the majority of patients, restricting our ability to fully elucidate the anti-viral efficacy of ICI therapy in the patients included in the study. Monitoring of HIV, HBV and HCV viral load as well as CD4 count for PLWH during cancer treatment is necessary for patient safety and should be part of standard care for these patients. Second, while tumor response was able to be assessed in most patients, tumor assessment was not performed consistently, and some patients did not have imaging after initiation of ICI therapy, mainly due to clinical deterioration or loss to follow up. Despite these limitations, we believe that this case series provides evidence to help oncologists and their patients to inform decisions regarding the application of ICI therapy.

In summary, in this case series, we find that toxicity and efficacy rates were similar to those observed in patients without chronic viral infections, supporting the use of ICI therapy in this patient population and the inclusion of such patients’ in future ICI-based trials. Viral reactivation was not observed among HIV or HBV/HCV patients and anti-tumor activity was seen with anti-PD-(L)1 therapy alone or in combination with chemotherapy. Prospective studies are needed to validate these findings.

In this case series of cancer patients with HIV, HBV, or HCV infection treated with ICI therapy including chemotherapy plus immunotherapy, we found that the safety and efficacy profile of ICI therapy is similar to that observed in those without chronic viral illness. These results suggest that ICI therapy is a safe and effective treatment option for patients with HIV, HBV, or HCV infection suffering from advanced-stage cancer.