CATIE News

19 December 2019 

Changes in CD4+ cell count after cancer treatment linked to survival among HIV-positive people

  • A U.S. study reviewed the medical records of 196 HIV-positive people treated for cancer
  • Chemotherapy and radiation treatment were linked to declines in CD4+ immune cells
  • Researchers suggest earlier immunotherapy may help HIV-positive people with cancer

Thanks to potent combination HIV treatment (ART), scientists expect many HIV-positive people to live long, healthy lives. However, longer lifespans can be accompanied by health conditions associated with aging, including increased risks for cardiovascular disease, thinning bones and problems maintaining a normal level of blood sugar.

Regardless of people’s HIV status, as they age, their immune systems weaken somewhat and their overall risk for cancer increases. As a result, cancers unrelated to HIV have become an important cause of illness and death in HIV-positive people in the current era.

A team of scientists at Johns Hopkins University, Baltimore, Maryland, have analysed health-related information collected from several thousand HIV-positive people since the late 1990s. The scientists focused on nearly 200 people who were treated for cancer. Participants received chemotherapy and/or radiation or they received surgery.

The team found that “after initial cancer treatment, every 100 cell decrease in CD4+ count resulted in a 27% increase [in the risk of death].” This decline occurred in participants who received chemotherapy and/or radiation rather than surgery alone. The risk also remained regardless of participants’ viral load.

We caution readers that although the results of this study are interesting, they are not definitive. As is explained later in our bulletin, the scientists were not able to collect some important data. Furthermore, 37% of participants had a detectable viral load when they were diagnosed with cancer. This lack of viral suppression may have played a role in the subsequent decline in CD4+ cell counts and their risk of dying.

Other scientists who reviewed the results from the Johns Hopkins team called for more research to explore the effects of immune-based cancer therapies in HIV-positive people. Such therapies enhance the immune system’s ability to detect and fight tumours.

Study details

Johns Hopkins University has been monitoring the health of several thousand HIV-positive people for decades. The scientists involved in the cancer study analysed these data and focused on cancers diagnosed among HIV-positive people between January 1, 1997, and September 30, 2014. After their diagnosis of cancer, participants were monitored for up to five years or to March 1, 2016.

Data from 196 HIV-positive people with cancer were analysed. Their average profile at the time they entered the study was as follows:

  • age – 50 years
  • 69% men, 31% women
  • CD4+ cell count – 300 cells/mm3
  • HIV viral load – although most participants (63%) had a suppressed viral load, 37% (72 people) did not; of those 72 people, 23 had never initiated ART

Scientists subdivided participants into two groups as follows:

  • those who received chemotherapy and/or radiation treatment, also known as radiotherapy (61% of participants)
  • those who received surgery (39% of participants)

Results

The most common cancers diagnosed were as follows:

  • lymphoma – 17%
  • lung cancer – 12%
  • anal cancer – 7%
  • breast cancer – 6%

Survival

Among the 196 participants, scientists found that after chemotherapy and/or radiation treatment was initiated, for every 100 CD4+ cell decrease, participants’ risk of death rose by 27%. This increased risk occurred regardless of a person’s viral load, the type of cancer or the severity of cancer.

Among participants who entered the study with relatively high CD4+ cell counts and who survived, CD4+ counts returned to their pre-cancer treatment levels about 18 months after initiation of cancer treatment.

Changes in viral load

In general, among people who entered the study with a suppressed viral load, chemotherapy and/or radiation did not have a significant impact on viral load. However, among participants who entered the study with a detectable viral load, their viral load decreased significantly after the initiation of treatment. The scientists advanced this explanation for the decline in viral load:

“the monitoring and engagement in health care associated with ongoing chemotherapy and/or radiotherapy may improve ART uptake or ART adherence and rejects the concern that more intensive cancer treatment regimens may negatively affect ART adherence.”

Bear in mind

The scientists stated, “We believe the association between lower CD4+ cell counts after cancer treatment and higher mortality supports the hypothesis that immune status in persons with HIV can influence mortality after cancer diagnosis.”

They further stated, “The results of this cohort study suggest that maintaining a high CD4+ cell count after cancer diagnosis has clinically meaningful implications for survival.”

Notes on the present study

There are a number of imperfections in this study, including the following:

  • The scientists reported on a variety of cancers and their treatment. It would have been better if the study had been larger and the precise regimens (i.e., dosage, schedule) of anti-cancer agents and the effects of the cancer treatments had been compared among participants with cancer.
  • A large proportion of participants – 37% – had a detectable viral load when they entered the study; a subset of this group of people had not initiated ART when they entered the study. It is plausible that the lack of viral suppression and very late initiation of ART could have affected the decline in participants’ CD4+ cell counts and survival during the study.
  • The precise ART regimens used by participants were not reported. It would have been interesting to find out if there were differences in the changes in CD4+ cell counts and survival depending on the ART regimen used.
  • The reasons people died were not reported; this is unfortunate. If the causes of death were known, this information could help other HIV-positive people who develop cancer in the future. For instance, if many participants had died from causes related to infections, then it could be possible to reduce the risk of future deaths by prescribing antibiotics, antifungals and so on, during the period when CD4+ counts were low.
  • The study was observational in design. Such studies are good at finding associations between one issue and another; in this case between declines in CD4+ cell counts after the initiation of cancer treatment and an increased risk of death. However, observational studies cannot prove “cause and effect”.

Despite these drawbacks, the study’s findings are important and point to the need for larger and more detailed studies with HIV-positive people who have cancer.

An external view – immune-based therapies

Commenting on the present study’s findings in the journal JAMA Oncology, a team of specialists in HIV and cancer treatment who were not part of the study stated that the association between the decline in CD4+ cell count and the subsequently increased risk of death “suggests that introduction of immune-based therapies earlier in the course of cancer management may limit additional immunosuppression and be particularly beneficial for HIV-associated cancers.” They expanded on this point as follows:

“Clinical research is increasingly focused on appropriate use of checkpoint inhibitors and other immunotherapeutic agents in people with HIV and cancer, including several recent and ongoing studies of monoclonal antibodies [that target certain proteins called checkpoints on the surface of cells of the immune system].”

Examples of checkpoints on the immune system are as follows:

  • PD-1 (programmed cell death 1)
  • PD-L1 (programmed cell death ligand 1)
  • CTLA-4 (cytotoxic T-lymphocyte-associated protein 4)

A simple explanation of how these proteins exert their effects is that they dampen the immune system’s ability to respond to microbes and/or cancers. In the past several years, therapies that disable these checkpoints have been approved for the treatment of certain cancers in Canada and other high-income countries.

Some small studies have investigated the effects of these therapies specifically in HIV-positive people who have cancer, and the preliminary results are promising. In the spring, more detailed results from experiments with the use of checkpoint inhibitors in HIV-positive people will appear on the CATIE website.

Immune checkpoints and HIV

If left untreated, HIV infection causes considerable immunological dysfunction and eventually people develop AIDS. A closely related virus, SIV (simian immunodeficiency virus), causes an AIDS-like condition in susceptible monkeys. Both viruses can cause cells of the immune system to become what scientists call “exhausted.” That is, these cells are unable to fight infections and tumours in their hosts. In particular, scientists have found that immunologically exhausted CD4+ and CD8+ cells from people with HIV tend to have relatively high levels of checkpoints on their surface. This suggests that HIV may cause immunological dysfunction in part by increasing the expression of checkpoints by the immune system.

There are many checkpoints in the immune system, and drugs have been approved to interfere with at least three immune checkpoints in some cancers. Much research on the immune system and checkpoint inhibitors lies ahead.

Reducing cancer risk

Until 1996, HIV infection was considered to be ultimately fatal. The advent of ART has meant that HIV-positive people can expect to have a near-normal life expectancy, but this means that more emphasis may be needed to help HIV-positive people reduce their cancer risk. Some of the steps that will reduce this risk are as follows:

  • speaking to a doctor about getting vaccinations against hepatitis B virus and HPV (human papillomavirus)
  • getting help from a doctor, nurse or pharmacist to support the process of quitting smoking
  • reducing alcohol intake
  • if engaged in injecting or inhaling street drugs: seeking help from harm reduction organizations to minimize the risk of infection from cancer-causing viruses
  • getting screening for, and if necessary, treatment for hepatitis B and C infections
  • getting advice about good dietary habits
  • learning stress management techniques
  • getting advice on ways to help to manage anxiety, depression and other mental health issues
  • engaging in regular doctor-approved physical activity

Resources

Large study finds advanced stage cancer more common in HIV-positive peopleCATIE News

Delays in cervical cancer screening among some HIV-positive Canadian womenCATIE News

Quitting smoking – impact on cancer riskTreatmentUpdate 230

Probiotics and the response to immunotherapy for cancerTreatmentUpdate 226

—Sean R. Hosein

REFERENCES:

  1. Calkins KL, Chander G, Joshu CE, et al. Immune status and associated mortality after cancer treatment among individuals with HIV in the antiretroviral therapy era. JAMA Oncology. 2020; in press.
  2. Bender Ignacio R, Ddungu H, Uldrick TS. Untangling the effects of chemotherapy and HIV on CD4 counts—implications for immunotherapy in HIV and cancer. JAMA Oncology. 2020; in press.
  3. Puronen CE, Ford ES, Uldrick TS. Immunotherapy in people with HIV and cancer. Frontiers in Immunology. 2019 Aug 28;10:2060.
  4. Althoff KN, Gebo KA, Moore RD, et al. Contributions of traditional and HIV-related risk factors on non-AIDS-defining cancer, myocardial infarction, and end-stage liver and renal diseases in adults with HIV in the USA and Canada: a collaboration of cohort studies. Lancet HIV. 2019 Feb;6(2):e93-e104.
  5. Bally APR, Neeld DK, Lu P, et al. PD-1 expression during acute Infection Is repressed through an LSD1-blimp-1 axis. Journal of Immunology. 2020; in press.