Puzzle over whether HIV accelerates cancer progression

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Although people living with HIV may be diagnosed with cancer at an earlier stage because they get more consistent care than the general population, it is also possible that a higher likelihood of late cancer diagnosis among people with HIV is an indication that HIV may accelerate cancer progression, according to research presented at the 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018) last month in Boston.

Prior research has shown that people with HIV are more likely to develop several types of cancer, though for other types there appears to be no difference between HIV-positive and HIV-negative people. The increase in risk among people with HIV is especially notable for virus-linked cancers such as cervical and anal cancer (caused by human papillomavirus), liver cancer (caused by hepatitis B and C) and certain types of lymphoma (associated with Epstein-Barr virus).

Keri Calkins and colleagues from Johns Hopkins University in Baltimore compared outcomes among HIV-positive people with cancer enrolled in the Johns Hopkins HIV Clinical Cohort and the mostly HIV-negative general population represented in the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database.

To date, there has been limited research on disease progression and outcomes among HIV-positive people with cancer. Some studies suggest that people with HIV are diagnosed with cancer later, are less likely to be treated and have poorer survival, but data have been inconsistent, they noted as background. Greater immune suppression may result in more aggressive cancer and may make cancer treatment less tolerable. HIV-positive people are also more likely to have risk factors such as smoking and viral co-infections that affect cancer risk and outcomes.

The researchers compared 254 people newly diagnosed with their first cancer (excluding Kaposi sarcoma) between 1997 and 2014 and nearly 1.9m people diagnosed with first cancers of the same types in the SEER database between 2000 and 2014.

In the Johns Hopkins cohort, 69% were men, 78% were black and the median age at diagnosis was 50 years. The most common cancers were non-Hodgkin lymphoma (21%), lung cancer (17%), liver cancer (9%), Hodgkin lymphoma (7%), prostate cancer (7%), breast cancer (6%) and anal cancer (6%).

People in the Johns Hopkins cohort were substantially more likely than those in the SEER database to be diagnosed with localised cancer (30% vs 6%, for a probability difference of 24%), after adjusting for age, sex, race/ethnicity, year of diagnosis and cancer type. Localised cancer generally indicates that it is at an early stage, though some cancers progress slowly and can still be localised years after they develop.

Likewise, the chances of having cancer spread to distant parts of the body were also higher in the HIV-positive group (45% vs 9%, for a probability difference of 36%). Distant metastasis is typically an indication of late-stage cancer, though some cancers progress rapidly and can spread throughout the body soon after they arise.

Overall, people in the Johns Hopkins cohort and those in the SEER database had a similar likelihood of receiving any kind of cancer treatment (83% vs 87%, respectively). This remained the case when looking at people with CD4 counts above or below 200 cells/mm3, the latter indicating substantial immune suppression.

HIV-positive people with cancer had overall shorter survival – by 5.4 months – than those in the general population within the first 5 years after a cancer diagnosis when adjusting for demographic factors, year of diagnosis and cancer type. However, the difference was no longer statistically significant after accounting for cancer stage and treatment.

The difference in survival was more pronounced – a reduction of 11.7 months – among HIV-positive people with a low CD4 count. This difference was smaller (a reduction of 6.8 months) but remained significant after adjusting for cancer stage and treatment.
Notably, there was no difference in survival among HIV-positive people with CD4 counts above 200 cells/mm3, which should now be the status of almost everyone taking modern antiretroviral therapy.

“People with HIV are more likely to be diagnosed with cancer at earlier and later stages than the general US population, suggesting that HIV may contribute to faster progression and that engagement in HIV care may improve earlier detection,” the researchers concluded.

Abstract
The effect of HIV on cancer stage, treatment, and survival is unclear and differences may be driven by immune suppression and/or access to care. We compared cancer outcomes among people with HIV (PWH) enrolled in care to the general US population, with a sub-analysis stratified by CD4 count.
We compared cancer stage at diagnosis, receipt of any cancer treatment, and restricted mean survival time (RMST) between 255 cancer cases in PWH enrolled in the Johns Hopkins HIV Clinical Cohort (JHHCC) and similar cases sampled from the NCI’s Surveillance, Epidemiology and End Results Program (SEER), presumed to be largely HIV negative. We performed G-computation using random forest methods to estimate the effect of HIV on stage and treatment risk differences (RD) and on RMST differences, adjusting for demographic and cancer covariates. We also stratified the JHHCC by CD4 cell count ≤200 and >200 cells/mm[sup]3[/sup], to examine effect modification by immune status at cancer diagnosis.
The probability of localized cancer was 0.30 among PWH in JHHCC, while it was 0.07 in SEER (Risk difference (RD)= 0.24 [95% CI= 0.17, 0.31]). Similarly, the probability of distant cancer was 0.45 in JHHCC versus 0.07 in SEER (RD=0.38 [95% CI= 0.31, 0.43]). Among those in JHHCC with ≤CD4 200, 74% received any cancer treatment compared to 80% of SEER (RD=-0.06 [95% CI= -0.24, -0.02]), but there was no difference in cancer treatment overall or at higher CD4 levels. Table 1 provides a comparison of mortality after cancer diagnosis between JHHCC and SEER. Model 1 accounted for age, sex, race, year of diagnosis, and cancer type; while model 2 also adds CD4 count at cancer diagnosis. PWH had evidence of reduced survival of all cancers after adjusting for the model 1 covariates (RMST Difference= -3.4 months [95% CI= -7.1, -0.2]). The observed difference was larger when examining PWH with CD4 ≤200 adjusting for the model 2 covariates (-10.6 months [95% CI=-18.3, -4.9]). Differences in survival were no longer significant when stage and treatment were added to the models.
PWH are more likely to be diagnosed with cancer at earlier and later stages than the general US population, suggesting that HIV may contribute to faster progression and that engagement in HIV care may improve earlier detection. Survival differences were largely explained by cancer stage and treatment, although there is some evidence of lower rates of cancer treatment and higher mortality in those with low CD4 counts.

Authors
Keri Calkins, Geetanjali Chander, Corinne Joshu, Anthony T Fojo, Richard D Moore, Bryan Lau

Aidsmap material
CROI 2018 abstract


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