Human immunodeficiency virus (HIV) and cancer have been intimately linked since the first cases of HIV were identified after investigation of unusually high rates of Kaposi's sarcoma in patients without other risk factors. HIV not only impairs the immune system but also drives a chronic inflammatory response. The significance of the chronic inflammatory response has become more evident, as patients with HIV survive longer on antiretroviral therapy, developing cancers more typical of the aging population. Cancer treatment offered to patients with HIV includes traditional cytotoxic chemotherapy, surgery, and radiation. Some oncologists abbreviate courses or reduce doses of treatment in patients with HIV. The promising field of immunotherapy, exemplified by immune checkpoint inhibitors (ICIs), has revolutionized cancer care. Some of the first studies of ICIs conceived of these agents as an approach to overcome “immune exhaustion” in patients with HIV and other chronic viral infections. In fact, clinical trials are underway to assess the impact of ICIs on patients with HIV with low CD4 counts, despite virologic suppression. Experience with ICI in patients with HIV and cancer is limited, but available studies suggest that HIV remains well-controlled, with CD4 count stable to increasing and viral load stable to decreasing. Immune-related adverse effects have varied, with one case series reporting higher than expected rates, but immune reconstitution inflammatory syndrome has not been reported. In addition to these other therapies, stem cell transplant (SCT) has been demonstrated to be safe and effective. In selected patients with HIV, SCT has even led to the cure of HIV, as noted in two confirmed cases. The treatment of patients with HIV and cancer will benefit from clinical trials designed for this population, as well as new guidelines to aid oncologists in providing care for these patients. Collaboration between oncologists and HIV providers is essential in managing the treatment of HIV during cancer therapy, as well as addressing infectious and other complications that arise. This collaboration will lead to continued improvement in the management of this growing patient population.
Modern cancer treatment encompasses modalities from surgery to traditional chemotherapy, radiation, stem cell transplant (SCT), chimeric antigen receptor (CAR) T-cell therapy, and immunotherapy. The challenge of treating patients with HIV with cancer in the early days before antiretroviral therapy (ART), when Kaposi's sarcoma (KS), cervical cancer, and B-cell lymphomas were hallmarks of the severe immunocompromised state associated with end-stage acquired immune deficiency syndrome (AIDS), was daunting. With treatment for Human immunodeficiency virus (HIV) lacking at that time, opportunistic infections, as direct complications of severe compromise of the immune response, led to significant and early mortality in these patients. Since that time, the diagnosis and treatment of HIV and cancer have both changed dramatically. HIV is now a chronic disease, with control of the virus feasible, if patients adhere to ART, and life expectancy comparable to non-HIV-infected patients. Patients with HIV now develop other chronic diseases associated with aging, such as cardiovascular disease, diabetes mellitus, and cancer. Patients with HIV, in the ART era, have a lower incidence of AIDS-defining cancers, now with a rise in non-AIDS-defining cancers, such as lung and anal cancer [Figure 1]. This points to the importance of HIV screening and treatment in cancer prevention and the continuum of care for patients with cancer[4–6] [Table 1]. Unfortunately, however, 15% of patients with HIV are not aware of the diagnosis. These undiagnosed, untreated patients are estimated to serve as a source of transmission of HIV in approximately 50% of patients.
The diagnosis and treatment of HIV is particularly important for patients with cancer,, given the impact on outcomes of cancer treatment, reduction in transmission of an oncogenic virus, and adherence to quality of care, with the US preventive services task force (USPSTE) giving routine HIV testing of patients 15–65 years of age (regardless of risk factors) an A-level recommendation. In fact, the recent NCCN Guidelines for the treatment of cancer in patients living with HIV states, “all patients with a cancer diagnosis should be screened for HIV.” Despite these recommendations and the impact of HIV diagnosis and treatment on cancer outcomes, HIV screening rates in patients with cancer and survivors are low. A retrospective study of HIV testing among cancer survivors showed that only 41% of those under the age of 65 years had ever been tested for HIV.
The relationship between HIV infection and cancer is attributed to many consequences of HIV infection, particularly impairment of the immune system. The incidence of cancer in patients with HIV is comparable to solid organ transplant patients, although with differences in cancer types. HIV infection also results in chronic inflammation, with elevated interleukin-6 associated with increased risk of various cancers. Of interest are statins, which not only reduce cholesterol, but also have anti- inflammatory activity. The pleiotropic effects of statins result in decreased all-cause mortality in patients with HIV, with decrease in non-AIDS-defining cancers. The use of ART has reduced the overall incidence of cancer among patients with HIV although with continued rates higher than the general population.
Cancer Treatment in Patients Living with HIV
The treatment of cancer has evolved, from surgery to radiation and cytotoxic chemotherapy to immunotherapy and stem cell transplantation. The treatment of HIV has also evolved from multiple daily doses, poorly tolerated, ineffective regimens, to single daily pill with minimal toxicity able to completely suppress circulating virus. These significantly improved HIV treatment regimens have led to a greater willingness by oncologists to treat cancer in patients living with HIV. A survey of oncologists showed that 79% are willing to provide the standard of care treatments for patients with HIV, even though 69% felt that guidelines were insufficient for the care of these patients. Of interest, 20% of radiation oncologists would use lower radiation doses, with 27% treating smaller fields and 31% discontinuing altogether in the setting of adverse events. In addition, 18% of medical oncologists would not use standard chemotherapeutic agents, with 48% of those reducing doses and/or fewer cycles and 51% discontinuing chemotherapy if adverse events arise. Recent studies, however, show that HIV-infected patients with non-AIDS-defining cancers are diagnosed at a younger age with cancer and have similar outcomes to HIV-negative patients. Despite these comparable outcomes, patients with HIV are less likely to receive cancer treatment than age-matched patients without HIV, particularly among the increasing elderly population with HIV. Elderly patients with HIV were 20% less likely to receive cancer treatment, with 75% of this difference due to HIV itself and 24% attributable to cancer stage and other comorbidities at diagnosis. In the next sections, we will address the current approach to cancer treatment in patients with HIV, with the new National Comprehensive Cancer Network (NCCN) Guidelines available to guide the treatment of common HIV-related cancers [Table 2].
One common theme in the upcoming sections is the uncertainty in managing patients with cancer and HIV, given a lack of data regarding HIV patients in clinical trials, due to the exclusion of these patients from the clinical trials. This hesitance to include patients with HIV in oncology clinical trials has been attributable to concerns regarding immunodeficiency, particularly in the time prior to effective ART. Later, concerns arose regarding the role of drug–drug interactions and impact of adherence to ART on cancer treatment. Given the increasing complexity of the separate fields of oncology and HIV, the potential for collaborative treatment options has been slow to materialize. In an attempt to explore this opportunity, the Friends of Cancer Research HIV Working Group showed that 74% of studies leading to the Food and Drug Administration (FDA) approval for cancer treatments excluded patients with HIV specifically or those with infection generally. This has led to the design of multiple clinical trials targeting HIV-associated malignancies and other cancers in patients with HIV. These studies emphasize immunotherapy and targeted therapy, as opposed to traditional cytotoxic chemotherapy approaches. These clinical trials will provide important information regarding the safety and effectiveness of immunotherapy in patients with HIV and cancer.
Positron emission tomography–computed tomography (PET-CT) is a tool used for monitoring response to cancer treatment, but a recent study has potential implications in the interpretation of PET-CT in patients with HIV and cancer. The study examined the association between metabolic activity on fludeoxyglucose PET prior to ART initiation and subsequent incidence of immune reconstitution inflammatory syndrome (IRIS). The study conducted at the US National Institutes of Health examined the incidence of IRIS in thirty patients newly diagnosed with HIV with low CD4 counts (<100 cells/μL), as they initiated ART. IRIS occurs within the 1st month after starting ART, occurring in up to 40% of patients with HIV, typically with severe immunodeficiency, as demonstrated by low CD4 counts. IRIS may unmask autoimmune disease, such as sarcoidosis, or infections, such as tuberculosis or cryptococcosis, in patients with HIV. In addition to unmasking autoimmune disease and infection, up to 29% of patients may develop “paradoxical KS-IRIS” within the 1st year after starting ART. In the study of thirty high-risk patients for IRIS, 33% developed IRIS, with 60% of those cases associated with mycobacterial infection (84% Mycobacterium tuberculosis). Of note, the thirty patients in this study were all noted to have opportunistic and other infections at HIV diagnosis, ranging from toxoplasmosis to cryptococcosis to Pneumocystis jirovecii pneumonia to syphilis. Therefore, this is a severely immunocompromised group, but the findings point out the importance of HIV screening, understanding of baseline infection risk, and the utility of a tool such as PET-CT for monitoring outcomes of cancer therapy in patients with HIV but taking into IRIS as an important consideration in the interpretation of PET-CT in patients with cancer and HIV.. Overall, it should be noted that IRIS is not reported in solid tumors, although is commonly seen with KS and lymphoma.
Traditional cancer therapy
The provision of surgery, radiation, and chemotherapy has been shown to be safe in patients with HIV with a variety of cancers, with monitoring of coexisting liver or kidney disease, risk of esophageal or other gastrointestinal toxicity from chemotherapy or radiation that could prevent the absorption or tolerance of ART, and also bone marrow suppression.[29,30] The current HIV treatment has been dramatically simplified, with several single-pill daily regimens available and fewer drug–drug interactions than the past.[30,31] The newly published guidelines from the NCCN for the management of patients with cancer and HIV point out the importance of proceeding with cancer treatment, if needed, without delay, while working with HIV providers to assess drug–drug interactions and risk of opportunistic infections.
The next section of this review will focus on immunotherapy, which will include a discussion of checkpoint inhibitors as well as a brief discussion of the use of CAR T-cells in patients with HIV.
Immune checkpoints serve to reduce “collateral” damage from an unrestrained immune response that culminates in autoimmune destruction of tissues and organs. Given the critical role of the immune response and the finding that cancers and chronic viral infections can result in overexpression of these molecules, approaches to inhibit these constraints on the immune system were developed. These immune checkpoint inhibitors (ICIs) consist predominantly of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1) inhibitors. The first FDA approved for the treatment of cancer with ICIs was the anti-CTLA-4 agent ipilimumab, approved for the treatment of melanoma in 2011. The field of ICIs is continuously evolving, expanding from melanoma and non-small lung cancer to hematologic malignancies, now including studies of new ICIs T-cell immunoglobulin mucin-3 and lymphocyte-activation gene-3. This review will focus on the most studied ICIs: CTLA-4, PD-1, and PD-L1. Although oncology clinical trials with ICIs historically excluded patients with HIV, we will bring attention to the safety of ICIs in patients with cancer and HIV, pointing to their potential to address coexisting opportunistic and other infections.
As mentioned above, studies of patients with HIV noted “immune exhaustion,” exemplified by patients in whom the CD4 count does not recover, despite suppression of virus to low or undetectable levels. Immune exhaustion is characterized by T-cells from these patients expressing higher levels of PD-1 than patients who recovered CD4 counts. The immune exhaustion with chronic viral infection and immunity to tumors was initially described in 2006 in a mouse model of lymphocytic choriomeningitis virus (LCMV), in which the PD-1 was upregulated in exhausted T-cells, with attenuation of this effect by administering antibodies to PD-L1. This approach decreased the viral load of LCMV, but, interestingly, the administration of antibody to CTLA-4 did not achieve the same result.
Early studies of the ICIs pointed toward a role for increased PD-1 expression in patients with HIV in the poor recovery of CD4 count, despite well-controlled or undetectable viral load. As might be expected, these patients with low CD4 count exhibited higher rates of HIV-related and unrelated complications. Higher expression of PD-1 on HIV-specific CD8+ cells correlated with higher HIV viral loads and inversely with CD4 counts. These findings led to a clinical trial of an inhibitor of PD-L1, BMS-936559, in patients with controlled HIV (undetectable viral load and CD4 >350 cells/μL). Patients who received the single infusion of BMS-936559 exhibited no Grade 3 or higher adverse effects, but the percentage of HIV-1 Gag-specific CD8+ T-cells increased, though not significantly from baseline (0.09%–0.20%, P = 0.14). Based on the potential impact of PD-1 inhibition on “immune exhaustion” for patients with controlled HIV viral load but failure to recover CD4 count, a randomized, double-blinded, placebo-controlled study of a single dose of pembrolizumab is enrolling patients (NCT03367754). The study will enroll patients with controlled HIV (HIV viral load <40 copies/mL) but failure to have significant recovery of CD4 cells despite virologic control (CD4: 100–350 cells/mL) with 60 patients monitored over 96 weeks for adverse effects, with the secondary outcome measure of decreased expression of PD-1 on lymphocytes. This study will provide information on the safety of this approach in patients with HIV in the absence of cancer but should also reassure oncologists examining treatment options for patients with patients with HIV infection and cancer.
The potential benefits of ICIs in the treatment of HIV have led to clinical trials, mentioned previously, to determine their utility in overcoming “immune exhaustion” of chronic HIV infection, manifested by persistently low CD4 count, despite viral suppression. Although clinical trials with ICIs for the treatment of cancer excluded patients with HIV, recent retrospective studies have examined the benefit of ICIs in cancer patients with HIV. Given that HIV itself and smoking exposure lead to increased PD-L1 expression, PD-1 shows a particular promise. A study of patients with NSCLC also showed that tumors from patients with HIV had higher CD8, CD20, and macrophage infiltration, compared to patients without HIV. A recent systematic review of ICI in patients with HIV and various advanced cancers showed comparable cancer treatment outcomes to patients without HIV. An objective response rate, in patients on whom outcome data were available, showed 30% of non-small cell lung cancer, 27% of melanoma, and 63% of KS patients responded to ICI. In addition, only 9% of all the patients included in the study experienced Grade 3 or higher immune-related adverse effect (irAE), with no reports of IRIS. Of the patients receiving the ipilimumab-containing therapy, 67% of six patients developed an irAE. Notably, none of the patients developed an immune reconstitution inflammatory syndrome, and of three patients with chronic hepatitis B or C, none showed an increase in liver function tests after treatment. Patients with undetectable HIV rarely (7%) developed detectable virus after treatment, but 83% of patients with previously detectable virus showed a decrease in viral load. An ongoing study of pembrolizumab in patients with HIV, partially reported in the review, shows that patients maintain viral suppression while on ICI.
A more recent retrospective study conducted in the VA system, too recent to be included in the above review, studied the outcomes in 15 patients with HIV who received nivolumab for various indications, including two off label. The study showed 14% complete response (2/15), exclusively among Hodgkin's lymphoma patients (2/2). Among the patients with non-small-cell lung cancer, 14% showed partial response, 14% showed stable disease, and 71% immediately progressed. In this case series, however, the rate of irAE was 40%, with 27% (4/15) exhibiting pneumonitis. The pneumonitis cases accounted for all Grade 3 or above irAEs (27%), with one of those four cases in a patient currently smoking at the diagnosis of pneumonitis. The HIV viral load remained stable or decreased in all cases, and CD4 count increased in 70% of cases.
The examination of ICIs shows that they may have benefits in the treatment of HIV and based on limited data show potential for cancer treatment in patients with HIV and cancer. A common concern with the treatment of patients living with cancer and HIV regards drug–drug interactions. This is one of the major benefits of ICIs, which exhibit no known interactions with ART. Multiple studies and guidelines suggest that it is not necessary to delay cancer treatment for that of HIV.[6,40] In fact, HIV guidelines identify AIDS-associated malignancies as one of the indications for urgent initiation of ART. If there is a concern regarding the gastrointestinal tolerability or renal insufficiency attributable to various etiologies, ART regimens have been changed to enfuvirtide, an HIV fusion inhibitor, alone, administered by daily injection. In addition, a recent study of an anti-CD4 monoclonal antibody infusion showed that virologic suppression could be maintained for up to 8–16 weeks of ART interruption. Of note, however, CD4+ regulatory T-cells decreased (31%–56%), although overall CD4+ count remained stable. Of interest, the authors also noted a transient decrease in CTLA-4 and PD-1 after administration of this anti-CD4 monoclonal antibody. Adverse effects of Grade 2 or higher that occurred in >10% of individuals included rash (14%), eosinophilia (14%), and AST elevation (14%).
In summary, the limited available data regarding the use of ICIs in patients with HIV and cancer, given exclusion of patients with HIV from previous clinical trials, suggest that the patients who receive ICI have comparable outcomes to non-HIV-infected patients. In addition, ICIs rarely increase HIV viral load but more commonly maintain or even improve the control of HIV.[19,39] Drug–drug interactions have not been identified between ICIs and ART. Reassuringly, opportunistic infections were not described as complications of ICI. Continued vigilance for irAE will be necessary, however, given the most recent series showing a 40% rate, with four patients (27%) showing pneumonitis, all Grade 3 or higher.
Chimeric antigen receptor T-cell therapy
Genetically engineered allogeneic or autologous CAR T-cells with specific activity against tumor cells exemplify a highly toxic, but effective, approach to cancer therapy. Most common toxicities include cytokine release syndrome and CAR T-cell-related encephalopathy syndrome, which can occur concurrently and may be difficult to differentiate from infection.[44,45] Clinical trials are ongoing to develop CAR T-cell therapies to cure HIV, specifically to address the reservoir of HIV infection. As of this writing, however, HIV remains an exclusion criterion for eligibility for CAR T-cell therapy for cancer treatment. As the understanding and management of complications of CAR T-cell therapy for cancer evolves, future studies may include patients with HIV. A cautionary note is that precancer treatment protocols, such as those in our institution for SCT, that include infection screening with HIV viral load may inaccurately suggest HIV infection. This finding is based on cross-reactivity with a CAR T-cell lentiviral vector, as noted in a recent case report.
Stem Cell Transplantation
With ART regimens offering well-tolerated daily treatment options with fewer drug–drug interactions and increasing alternatives for patients who develop renal or hepatic toxicity on cancer treatment, autologous and allogeneic SCTs have been successfully utilized to treat patients with HIV.[21,40] Multiple studies of autologous SCT have been conducted, for various lymphomas, with clinical trials conducted by the AIDS Malignancy Consortium (BMT CTN 0803/AMC 071) showing no statistically significant difference in overall survival, progression-free survival, or treatment-related mortality between HIV-positive and HIV-negative patients.[21,49] Of note, however, the CD4 count, as with initial overall white blood cell count, may be low and take up to a year to recover. In addition, the viral load may transiently increase but typically without associated complications. Allogeneic SCT for patients with HIV has not been as well-studied, but small studies have suggested that it is feasible and safe in select patients, with well-controlled HIV and appropriate baseline screening for opportunistic infections at baseline.[21,50] Given the lower pill burden, fewer drug–drug interactions, and better-tolerated ART regimens, there is no longer a need to disrupt ART in the peritransplant period.[40,50] In addition to baseline screening for opportunistic infections, patients should receive appropriate prophylaxis, based on CD4 counts. Otherwise, monitoring and prophylaxis of infection should be according to guidelines for HIV-negative patients.[21,50]
A unique role for allogeneic SCT is the potential to cure HIV, with two cases published in peer-reviewed journals.[21,22] Patients who undergo stem cell transplantation from donor with a CCR5Δ32 mutation, which inactivates the CCR5 receptor gene, have cells that are not infected by HIV variants that interact with the CCR5 coreceptor. The “Berlin” patient underwent allogeneic stem cell transplantation after a 2nd relapse, from a donor homozygous for the CCR5Δ32 mutation, subsequently exhibiting control of HIV, off ART, for over a decade.[23,24] One other case of HIV cure has been reported to date, in a Hodgkin's lymphoma patient who underwent a single allogeneic transplant from a donor with homozygous CCR5Δ32 mutation. Efforts continue to replicate these successes, particularly with a recent suggestion of a graft-versus-HIV effect, but it is challenging to find otherwise suitably matched donors and overcome treatment complications or relapse of underlying malignancy.
Treatments for both cancer and HIV have dramatically advanced, improving outcomes for both diseases. The outcomes of patients with HIV (on ART) are comparable to those without HIV. ART controls virus replication, resulting in decreased inflammation and improved function of the immune system, leading to decreased risk of classically AIDS-defining cancers, in particular, but all cancers in patients with HIV, in general. The treatment of patients with cancer and HIV has been challenging, with guidelines for care not previously available and oncology clinical trials typically excluding patients with HIV.
The initial critical step is the identification of HIV, with a recommended screening of all patients undergoing cancer treatment.[6,9] Once patients are identified, collaboration between a provider familiar with HIV and the oncologist is important. This linkage to HIV care will facilitate prompt initiation of an HIV regimen, with understanding of oncologic treatment facilitating ART that will minimize adverse effects and drug–drug interactions.[6,40] This approach will assure that patients with HIV are treated similarly to those with other chronic diseases, such as hypertension, diabetes, or rheumatologic diseases.
Guidelines are now available for the management of patients with cancer and HIV. In addition, retrospective studies have shown that traditional therapy with cytotoxic chemotherapy, surgery, and radiation are safe. Stem cell transplantation has been demonstrated not only to be safe but also when feasible to undergo transplant from a patient with the CCR5Δ32 mutation, which inactivates the CCR5 receptor gene, leading to the potential cure of HIV.[22,23] The development of ICIs for treatment of cancer stemmed from the treatment of chronic viral infection with ICIs. Initial studies of ICIs for cancer excluded patients with HIV, but retrospective studies have shown that ICIs are an effective approach for cancer in patients with HIV.[19,39] Caution, however, is needed in closely monitoring irAEs, with rates as high as 40% in a small recent case series of patients with HIV receiving nivolumab. In the case series, Grade 3 or higher irAEs were exclusively cases of pneumonitis, emphasizing the need for baseline HIV testing and collaboration with HIV providers to assess the risk for baseline presence of infectious etiologies of pneumonitis. The use of CAR T-cells for cancer is not currently allowed for patients with HIV, although CAR T-cells are being studied for the treatment of HIV reservoirs.
Recent efforts have used allogeneic SCT, ICIs, and CAR T-cells for the potential cure of HIV, with allogeneic and ICIs also used for cancer treatment. The data for the treatment of cancer in patients with HIV are lacking, given the exclusion from clinical trials. The design of clinical trials using ICIs and other approaches to cancer treatment for patients with HIV will enhance the options for treatment in this growing population.
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