People living with HIV remain at risk of Aids-defining cancers in the era of effective antiretroviral therapy, and also have higher rates of several non-Aids cancers than the general population, including lung, anal and liver cancer, according to findings from a study of more than 86,000 HIV-positive people.
Since the advent of effective combination antiretroviral therapy (ART) in the mid-1990s, rates of the three Aids-defining cancers – Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer – have fallen among people with HIV. These cancers are caused by opportunistic viruses that can take hold when the immune system is damaged and CD4 T-cell counts are low, though human papillomavirus (HPV) also causes cervical and anal cancer in otherwise healthy people.
Most studies, however, have found that HIV-positive people have a higher overall risk for other non-Aids-related cancers compared to HIV-negative populations, although data have been inconsistent about specific cancer types. In fact, cancer rates among people with HIV have risen over time as they live long enough to develop malignancies.
Michael Silverberg of Kaiser Permanente Northern California and fellow investigators evaluated trends in cumulative incidence of common cancer types by HIV status among participants in the large North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).
This study included 86,620 people with HIV from 16 cohorts in the US and Canada, as well as 196,987 HIV-negative adults from five cohorts selected to be similar in terms of age, sex and race/ethnicity. Participants were followed between 1996 – when effective ART started to become widely available – and 2009.
About 85% of the HIV-positive NA-ACCORD participants were men, about 40% were white and 40% were black, and the median age was approximately 45 years. About 40% were men who have sex with men and about 20% had a history of injection drug use. Approximately 20% were co-infected with hepatitis C virus (HCV) while 4% also had hepatitis B virus (HBV). The proportion on ART increased from 39% during 1996-1999 to 74% during 2005-2009 and the median CD4 count rose from 309 to 382 cells/mm3.
The researchers looked at cumulative incidence (new cases) for nine types of cancer by age 75, as well as calendar trends in cumulative incidence and hazard rates, according to HIV status and taking into account the competing risk of death due to other causes. All-cause mortality decreased over time for the HIV-positive group, falling from 5,140 per 100,000 person-years during 1996-1999 to 2,844 during 2005-2009. But it remained more than three times higher than that of the HIV-negative group, at 863 per 100,000 person-years during 2005-2009.
Cumulative incidence by age 75 of the two Aids-related cancers remained higher for people with HIV compared to the HIV-negative cohorts: Kaposi sarcoma: 4.4% vs 0.01%; and non-Hodgkin lymphoma: 4.5% vs 0.7%. Some of the non-Aids cancers had higher rates among HIV-positive people compared to HIV-negative people, while others were about the same: lung cancer: 3.4% vs 2.8%; anal cancer: 1.5% vs 0.05%; colorectal cancer: 1.0% vs 1.5%; liver cancer: 1.1% vs 0.4%; Hodgkin lymphoma: 0.9% vs 0.09%; oral cavity or mouth and throat cancer: 0.8% vs 0.8%; and melanoma: 0.5% vs 0.6%.
Anal, colorectal and liver cancer showed increasing cumulative incidence over time, but hazard rate trends were stable, so the researchers attributed the increase in cancer to decreased overall mortality, allowing more opportunity to be diagnosed with cancer. Lung cancer, Hodgkin lymphoma and melanoma, in contrast, showed decreasing hazard rate trends, but cumulative incidence trends were not seen due to the counterbalancing effect of declining mortality.
“In the era before antiretroviral therapy, people who were infected with HIV were dying of Aids. Now that use of this therapy is greatly increasing the lifespan of HIV-infected patients, their risk of developing other diseases, such as cancer, has increased,” Silverberg said. “These patients have a higher burden of cancer compared with the general population due to impaired immune function and chronic inflammation, as well as a higher prevalence of risk factors including smoking and viral co-infections.”
“Our approach allowed us to disentangle the effects of longevity from other factors on the risk of cancer,” Silverberg explained. “For example, we found that longevity was the main contribution to the increased risk over time for anal, colorectal and liver cancers. The risk for other cancers, such as lung cancer, melanoma, and Hodgkin’s lymphoma, did not appear to increase over time. This was because the increased risk with longevity was compensated for by other factors, such as decreases in smoking or adverse sun exposure behaviours.”
The non-Aids cancers in this study were a mix of those caused by viruses – including anal cancer (HPV) and liver cancer (HBV and HCV) – as well as those with no confirmed viral cause, such as melanoma and lung cancer. Many HIV/HCV co-infected people are reaching the age at which HCV-related hepatocellular carcinoma, a type of liver cancer, typically develops.
The reasons for increased risk of non-infectious cancers in HIV-positive people on ART is not fully understood, but residual immune system damage that does not reverse with treatment and chronic inflammation due to persistent low-level HIV infection may play a role.
“The high cumulative incidences by age 75 years for Kaposi sarcoma, non-Hodgkin lymphoma, and lung cancer support early and sustained antiretroviral therapy and smoking cessation,” the study authors concluded. In their discussion the researchers suggested that HIV-positive smokers may benefit from new guidelines for annual lung cancer screening with low-dose computed tomography, as well as targeted smoking cessation efforts. Lung cancer incidence fell over time among both HIV-positive and HIV-negative people, presumably due to a decline in smoking. People with HIV may also need more frequent colorectal cancer screening.
Regarding the infectious cancers, they emphasised the importance of universal HBV vaccination, expanded HPV vaccination and antiviral treatment for hepatitis B and hepatitis C – the latter of which can now be cured using effective and well-tolerated interferon-free therapy.
The increased anal cancer risk highlights the need for further research on the harms and benefits of anal dysplasia screening (pap smears). Early and sustained antiretroviral treatment is the only known approach to prevent Kaposi sarcoma and non-Hodgkin lymphoma, and it may also play a role in reducing other cancers linked to immuno-suppression or inflammation.
Background: Cancer is increasingly common among persons with HIV.
Objective: To examine calendar trends in cumulative cancer incidence and hazard rate by HIV status.
Design: Cohort study.
Setting: North American AIDS Cohort Collaboration on Research and Design during 1996 to 2009.
Participants: 86 620 persons with HIV and 196 987 uninfected adults.
Measurements: Cancer type–specific cumulative incidence by age 75 years and calendar trends in cumulative incidence and hazard rates, each by HIV status.
Results: Cumulative incidences of cancer by age 75 years for persons with and without HIV, respectively, were as follows: Kaposi sarcoma, 4.4% and 0.01%; non-Hodgkin lymphoma, 4.5% and 0.7%; lung cancer, 3.4% and 2.8%; anal cancer, 1.5% and 0.05%; colorectal cancer, 1.0% and 1.5%; liver cancer, 1.1% and 0.4%; Hodgkin lymphoma, 0.9% and 0.09%; melanoma, 0.5% and 0.6%; and oral cavity/pharyngeal cancer, 0.8% and 0.8%. Among persons with HIV, calendar trends in cumulative incidence and hazard rate decreased for Kaposi sarcoma and non-Hodgkin lymphoma. For anal, colorectal, and liver cancer, increasing cumulative incidence, but not hazard rate trends, were due to the decreasing mortality rate trend (−9% per year), allowing greater opportunity to be diagnosed. Despite decreasing hazard rate trends for lung cancer, Hodgkin lymphoma, and melanoma, cumulative incidence trends were not seen because of the compensating effect of the declining mortality rate.
Limitation: Secular trends in screening, smoking, and viral co-infections were not evaluated.
Conclusion: Cumulative cancer incidence by age 75 years, approximating lifetime risk in persons with HIV, may have clinical utility in this population. The high cumulative incidences by age 75 years for Kaposi sarcoma, non-Hodgkin lymphoma, and lung cancer support early and sustained antiretroviral therapy and smoking cessation.