The primary reason for death in PLWH has become cancer [17, 18]. A good response to ICIs therapy in some virus-associated lymphomas has been linked to the increased expression of PD-1 and its ligand PD-L1 in virus-associated cancers [19, 20]. Furthermore, virus-driven cancers, such as Kaposi's, NHLs and cervical cancer, may also increase T cell exhaust due to additional chronic viral stimulation increasing the rationale for using ICIs for these cancers [21]. ICIs have significant promise to treat a wide variety of cancers in PLWH. Given the immune-cell sparing nature, ICIs salvage therapy may exert a beneficial effect on patients' ongoing immunosuppressive chemotherapy. A recent retrospective analysis revealed that Pembrolizumab had a 50% response rate in HIV-associated NHL, suggesting that these drugs should be researched further in HIV-associated NHL [22].To show evidence for use in such a patient population, a few previous data have been completed to evaluate the safety and effectiveness of PLWH [23–26].
Our study is the first paper describing the use of PD-1 inhibitors in Chinese patients with HIV-combined malignancies. We reported 15 PLWH with advanced malignancies who were injected with PD-1 inhibitors. Among 15 patients evaluable for response, the DCR was 53.3%, similar to previous studies [25, 26]. The estimated 1-year OS rate was 66.7%, which also resembled that reported by Kathryn Lurain et al [22]. These data were significantly higher than that in cancer patients among PLWH without PD-1 inhibitors [27, 28].
The responses were noticed and TRAEs were favorable among most patients. Some of the patients experienced grade 3–4 adverse reactions, including myelosuppression, infection, and neurological. TRAEs occurred in 8 (53.3%) patients, significantly higher than the 20% reported by Gonzalez-Cao M et al [25]. This study is real-world research, which is closer to clinical reality and more representative. The reason for this disparity may be a result of the fact that patients included in the study were all patients with advanced cancers that had failed after multiple anti-cancer treatments. Ethnicity and the type of pathology are different from that previously reported. The majority of patients (87.5%) who experienced myelosuppression received concomitant chemotherapy or targeted therapy. Thus myelosuppression cannot be excluded in association with oncologic combination therapy. Patients who showed neurological adverse effects were combined with metastatic lesions in the brain. Serious AEs were likely to be generally attributed to complications of progressive cancer in this study. Some patients develop severe infections. However, grade 3 or 4 infections were relatively uncommon in the past PD-1 inhibitors studies (<1% of patients) [29–32].
The role of ICIs in the management of chronic liver viral infections is likewise of immense clinical interest. Twenty participants with chronic HBV infection who were virally suppressed participated in recent open-label research of Nivolumab with and without the HBV vaccine, and the results demonstrated that Nivolumab was both secure and well-tolerated [33]. In the current study, one patient had concomitant hepatitis E and chronic hepatitis B. The cART was TDF, LAM combined with EFV, and none had a reactivation of HEV or HBV during treatment.
During HIV infection, immune checkpoint proteins have been extensively researched, originally in relation to the virus's natural history and T cell function, but more recently in relation to HIV infection sequelae. T cell exhaustion is a characteristic of many chronic viral infections, including HIV. The expression of multiple immune checkpoint proteins on CD4+ and CD8+ T cells is upregulated in untreated HIV infection, including PD-1, CTLA-4, LAG-3 and TIM-3[21, 34, 35]. Many observational studies have shown a strong correlation between clinical outcome and the expression of PD1 on CD4 + or CD8 + T cells. Increased expression of PD-1 was linked to an accelerated decline in the number of CD4 + T cells after acute infection and untreated chronic infection in the absence of ART [34, 36]. ICIs may also be promising candidates for "shock and kill" treatment strategies because they can reactivate the HIV-1 reservoir [37, 38], while simultaneously strengthening antiviral immune responses [34, 39], consequently reducing the HIV-1 reservoir size. Consistent with the study by Uldrick et al [40], our results confirm that PD-1 inhibitor therapy is likewise safe in terms of sustained control of HIV-1 infection. All patients with available data had stable CD4 counts. The present investigation showed that CD4 counts do not seem to be adversely affected by PD-1 inhibitors. In participants for whom data were available, HIV viral levels remained suppressed below the threshold for detection. No patients required a change of cART. We didn't observe any autoimmune disorder activation or episodes. Due to the fact that this trial only included peripheral blood samples from a small number of patients who underwent suppressive cART that completely controlled viral replication, any positive effects of PD-1 inhibitor therapy on plasma HIV viral load may have been obscured. Given interindividual heterogeneity, these restrictions must be properly taken into account, especially for cancer participants. The potential role of ICIs in treatment approaches should be further recognized by ongoing clinical trials of ICIs alone or in combination with latency reversal medicines for cART in HIV-1-infected individuals [25, 41].
All patients in this study received standard oncology treatment before anti-PD-1therapy, which potentially increased the positive effects of PD-1inhibitors. To date, cancer regression or stabilization was noted in 3 patients with lung cancer, 3 patients with NHL, 1 patient with HL, and 1 patient with NPC. Clinical benefits were observed in lung cancer, HL, and NHL. It is consistent with the findings of the most recent Phase 1 study to assess the security of Pembrolizumab in PLWH with advanced cancers [38]. Despite a small number of patients, it is impossible to exclude the fact that cART which reconstituted the immune system of PLWH, may also improve their anticancer activity.
Our study aims to strengthen knowledge regarding the efficacy of ICIs in PLWH with advanced cancers. There is no doubt that HIV and infectious disease professionals should collaborate closely with oncologists in order to promote secure cancer and PLWH treatment options. A multidisciplinary approach is needed in the diagnosis and management of PLWH and cancer, where feasible.
In conclusion, our retrospective study suggests that PD-1 inhibitors treatmentmay be both effective and safe for PLWH with cancer. This study is limited by the small sample size. Meanwhile, all the patients included were male, as PLWH are more commonly male in China, as well as those with cancers [27, 42]. Larger research is required to validate the promising and favorable anticancer activity with PD-1 inhibitors treatmentforPLWH. HIV-infected patients with advanced cancers should be included in future cancer clinical trials.