People living with HIV can safely use immune checkpoint inhibitors to treat cancer, and they appear to benefit as much as HIV-negative people, according to a study published in the Journal of Clinical Oncology.
In this retrospective analysis, which included 390 people with HIV, about 20% experienced immune-related adverse events, similar to the rate for people without HIV. In a matched cohort of people with non-small-cell lung cancer – the most common malignancy – overall survival was similar for HIV-positive and HIV-negative people.
“This study should give some level of confidence to clinicians who are treating patients living with HIV and cancer,” lead study author Dr Abdul Rafeh Naqash of the University of Oklahoma’s Stephenson Cancer Center said in a press release. “This study is also important because it represents the real-world population that we would see in the clinic. It provides a level of assurance that immune checkpoint inhibitors are broadly safe for people with HIV and have the potential to effectively treat several types of solid tumour cancers.”
As people with HIV live longer thanks to effective antiretroviral therapy (ART), non-AIDS cancers have become a leading cause of death. Studies have shown that HIV-positive people are at increased risk for certain cancers compared with the general population, even if their HIV is well controlled. They also tend to have more advanced cancer at diagnosis and higher cancer-related mortality.
The oncology field is undergoing a paradigm shift from traditional chemotherapy that indiscriminately kills fast-growing cells to targeted therapies and immune-based therapies that help the immune system fight cancer. But people living with HIV have been excluded from pivotal clinical trials of these new treatments, leaving clinicians uncertain about whether they are safe and effective for this population. Because people with HIV may have impaired immune function, experts have been concerned that they might not respond as well or might experience harmful side effects.
The most widely used type of immunotherapy, immune checkpoint inhibitors, act on receptors that regulate immune activity. Some cancers can interfere with PD-1 receptors on T-cells and turn off immune responses. Drugs that block the interaction between PD-1 and PD-L1, its binding partner on cancer cells, release the brakes and restore T-cell activity. Cemiplimab (Libtayo), nivolumab (Opdivo) and pembrolizumab (Keytruda) are PD-1 inhibitors, while atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi) block PD-L1.
Naqash and fellow investigators with the Cancer Therapy using Checkpoint inhibitors in PWH-International (CATCH-IT) consortium analysed objective response rates (tumour shrinkage) and safety outcomes among people with HIV who received PD-1 or PD-L1 checkpoint inhibitors to treat various advanced cancers. The researchers also compared progression-free survival (time until cancer worsens) and overall survival in matched groups of HIV-positive and HIV-negative patients with non-small-cell lung cancer.
The main analysis included 390 people with HIV treated at 33 academic medical centres in North America, Europe and Australia between January 2015 and October 2021. Most (85%) were men and the median age was 58 years. They were on antiretroviral treatment (usually an integrase inhibitor regimen), 94% had an HIV viral load below 400 and 70% had a CD4 count of 200 of higher.
The participants had more than 10 types of solid tumours or blood cancers, the most common being non-small-cell lung cancer (29%), liver cancer (11%), head and neck cancer (10%), anal cancer (7%), melanoma (7%), small-cell lung cancer (6%) and Kaposi sarcoma (5%). A majority (70%) received PD-1 or PD-L1 inhibitors as monotherapy, while the rest combined them with chemotherapy, targeted therapy or a different type of checkpoint inhibitor.
"In general, people with HIV should receive the same standard, full-dose cancer therapy used in the general population."
In this analysis, objective response rates were 69% for non-melanoma skin cancer, 67% for Hodgkin lymphoma, 60% for Kaposi sarcoma, 47% for melanoma, 31% for non-small-cell lung cancer, 29% for non-Hodgkin lymphoma, 19% for small-cell lung cancer, 16% for liver cancer, 16% for anal cancer and 11% for head and neck cancer. These rates are comparable to those seen in studies of people without HIV.
One concern with checkpoint inhibitors is while they restore immune responses against cancer, they can also unleash the immune system more broadly, leading to inflammation of organs throughout the body.
In this analysis, one in five HIV-positive patients experienced immune-related adverse events of any grade, including 8% with severe events (grade 3 or higher). The most common severe events were colitis (gut inflammation) and pneumonitis (lung inflammation). People who received checkpoint inhibitors with chemotherapy had similar rates of adverse events, while those who combined them with targeted therapies had fewer side effects. Patients who combined two different types of checkpoint inhibitors had the most immune-related adverse events. There was one treatment-related death.
In the matched non-small-cell lung cancer cohorts, which included 61 HIV-positive and 110 HIV-negative people, the two-year progression-free survival rate was 18% for people with and without HIV, and the overall survival rate was 42% in both groups. Progression-free survival was 0.06 months shorter and overall survival was 2.23 months longer for people with HIV. The objective response rate was a bit lower in the HIV-positive group (28% versus 36%), but the difference was not statistically significant. Immune-related adverse events occurred with similar frequency, 20% and 22%, respectively, as did severe events, 12% and 9%, respectively.
The study was large enough to look at outcomes among people with greater immune suppression. Those with a CD4 count under 200 had comparable overall survival and a slightly lower adverse event rate compared to those with higher CD4 cell levels, perhaps because those with a weaker immune system were less likely to experience side effects due to an overactive immune response. This led the researchers to conclude that arbitrary CD4 cut-offs for use of immune checkpoint inhibitors are not warranted.
No significant changes in CD4 counts or HIV viral load were observed during treatment, although three people who combined different checkpoint inhibitors experienced transient low-level viral load elevations. The six people with active opportunistic infections when they started checkpoint inhibitors did not experience worsening disease.
Immune checkpoint inhibitors are also being studied as a potential HIV cure strategy. PD-1 is involved in suppressing CD8 killer T cells that target HIV as well as cancer, and PD-1 is heavily expressed on exhausted T cells that have lost their ability to function. Some studies suggest that blocking the interaction between PD-1 and PD-L1 can restore HIV-specific CD8 cell activity, leading to a reduction in viral load. PD-1 is heavily expressed on CD4 helper T cells that harbour hidden HIV, and it may play a role in maintaining viral latency. However, the current study was unable to assess the impact of checkpoint inhibitors on the viral reservoir.
The study underscores the importance of multidisciplinary teams to care for HIV-positive people with cancer, including oncologists, infectious disease specialists and pharmacists, to monitor viral load and adherence and manage potential drug interactions and opportunistic infections.
“All people with HIV should be on ART throughout the course of cancer management, and there is almost no clinical scenario in which I discontinue ART. However, I sometimes do change the ART regimen depending on the cancer treatment plan, presence of opportunistic infections and need for supportive medications,” Dr Kathryn Lurain of the US National Institutes of Health wrote in an accompanying commentary. She added that she generally avoids regimens containing boosters (ritonavir or cobicistat), which can interact with many other medications.
The study also shows that there is no reason to exclude people with well-controlled HIV from clinical trials of new cancer therapies. In recent years, the US National Cancer Institute has expanded its eligibility criteria to enable more cancer patients with coexisting conditions, including HIV, to enrol in trials.
“In general, people with HIV should receive the same standard, full-dose cancer therapy used in the general population unless there are data for specific cancer regimens in people with HIV,” Lurain wrote. “Learning from the experience in [PD-1 and PD-L1] agents, future cancer clinical trials should include and seek to actively enrol people with HIV, so that they have equal and timely access to emerging cancer therapies.”
El Zarif T et al. Safety and activity of immune checkpoint inhibitors in people living with HIV and cancer: a real-world report from the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium. Journal of Clinical Oncology, online ahead of print, 16 May 2023.
Luain K. Treating cancer with people with HIV. Journal of Clinical Oncology, online ahead of print, 2 June 2023.