In populations with broad access to antiretroviral therapy (ART), AIDS-related cancers have declined, along with other AIDS-related illnesses, however all cancer mortality, including types not traditionally classified as AIDS-related, exceeds cardiovascular and liver mortality in most analyses of HIV-related deaths in high-income countries.
Rates of many cancers are increased in HIV when compared with the HIV-uninfected population. The increase is attributable in part to aging and higher rates of cancer risk factors such as smoking and alcohol use in the HIV population.
Increased cancer incidence is most striking for the infection-related cancers Kaposi’s sarcoma, Hodgkin’s and non-Hodgkin’s lymphoma (NHL), cervical, anal, and head and neck cancer, and hepatocellular cancer, suggesting an important role for immune dysfunction in cancer pathogenesis in HIV.
Since ART initiation preserves immune function, early ART use should help decrease the excess cancer risk seen in HIV. An analysis of cancer in the START trial presented at the Conference on Retroviruses and Opportunistic Infections (CROI) 2016 addressed this issue.
The START trial randomly assigned individuals with a baseline CD4 above 500 to immediate or deferred initiation of ART. The trial proved that immediate ART conferred protection against AIDS- or non-AIDS-related clinical events or death.1 Cancer was an important component of that composite clinical endpoint.
Borges et al analyzed the START trial to determine factors associated with the effect of ART on cancer risk.2 There were 6 vs. 23 cases of infection-related cancer and 8 vs.16 cases of non-infection-related cancer in the immediate and deferred ART arms, respectively. The reduction in infection-related cancers was highly significant (HR 0.26, p=0.003). The trend toward fewer non-infection-related cancers was not significant (HR 0.49, p=0.1), but longer follow-up may have been needed to realize the full effect. Multivariable models adjusting for most recent CD4 and HIV RNA appeared to attenuate the effect of immediate ART more for non-infection related cancers, which suggested that other mechanisms not captured by viral load and CD4 measurement may be present and affect these categories of cancer differently.
Cancer mortality appears to increase substantially when it occurs in HIV-infected individuals. Coghill et al used data from the National Center for Health Statistics and the HIV/AIDS Cancer Match Study from 1996-2010 to determine mortality rates for specific types of cancer with or without HIV.3 Excess mortality in HIV was seen in some or all demographic groups with lung, colorectal, breast and anal cancer. No excess mortality was seen for prostate cancer. Large excesses in the range of 500/1000 person-years occurred in men below the age of 50 for HIV/lung cancer. The researchers noted excess mortality in all demographics for HIV/NHL and was more than 200/1000 person-years for men and women younger than 50. Excess mortality for breast cancer was seen only in non-white women and for colorectal cancer only in younger men.
Although tuberculosis and other infections cause the predominant burden of HIV-related illness in low-income countries, cancer is also important. In Botswana, a low-income country where ART coverage rates over 90% have been achieved, cancer is overtaking tuberculosis as the leading cause of AIDS-related deaths.4 Using data from the Botswana National Cancer Registry, cancer survival rates for HIV-infected patients were estimated. During the study period cancer mortality increased 1.2%/year. Cervical cancer mortality increased the most (13%/year). During the same period, tuberculosis mortality declined precipitously. Mortality for Kaposi’s sarcoma declined by 4%/year and was the only cancer studied with a 5 year survival above 50%.
Prevention of anal cancer is one of the most difficult management problems in HIV care. Compared to the general population, where it is a rare disease, the incidence of this HPV-related malignancy is markedly elevated in men whom have sex with men. Other groups may also be at risk. Screening with anal cytology yields frequent abnormal results and the optimal management is not known. Current treatment options are difficult for patients to undergo and must often be repeated.
A highly effective HPV vaccine is approved only for use in males and females age 9-26, since younger individuals are less likely to have already been infected by HPV. The development of this vaccine raised the hope that it could be useful therapeutically in HIV. Immunization of individuals already infected by HPV might prevent acquisition of additional oncogenic HPV types or boost HPV-specific immune responses in individuals with anal dysplasia, clearing HPV and preventing progression to cancer.
Wilkins et al presented the results of a clinical trial conducted in 575 HIV-infected men reporting receptive anal intercourse and women (20% of the study population) who were 27 years of age or older.5 Participants were randomly assigned to 3 doses of the quadrivalent HPV vaccine or placebo. Abnormal anal cytology, including high-grade intraepithelial lesions (HSIL) were common at study entry, as was detection of vaccine HPV types. After 2.6 years, the study was stopped for futility. The vaccine was highly immunogenic but compared to placebo, failed to reduce persistent detection of anal HPV, improve clearance of vaccine HPV types, or reduce abnormal cytology or the detection of HSIL.
Summary and Clinical Applications
Cancer has emerged as a major comorbidity in HIV-infected individuals living longer lives on ART. With better preservation of immune function as a result of the worldwide trend toward earlier diagnosis and initiation of ART, the classical AIDS-related cancers should continue to decline, but non-AIDS cancers, both infection-related and non-infection-related, will likely be the greatest cause of mortality, not only high-income countries but also in low-income countries that have high rates of ART.
The excess mortality that occurs when cancer complicates HIV may be due residual immune dysfunction, reduced access to or increased toxicity with treatment, or patient and health care provider attitudes towardcancer treatment The causes need to be understood and addressed. Much of the excess cancer risk in HIV is attributable to smoking.
Cancer prevention efforts for patients with HIV should focus on smoking cessation and appropriate screening based on recommendations for the general population. Prevention of anal cancer continues to be an unmet need. It does not appear that adjunctive vaccination will help.
1. The INSIGHT START study group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807.
2. Borges AH, Neuhaus J, Babiker A, et al. Immediate ART initiation reduces risk of infection-related cancer in HIV infection. Abstract 160.
3. Coghill A, Pfeiffer R, Shiels M, Engles E. Excess Mortality Rates Among HIV-Infected Cancer Patients in the United States. Abstract 616.
4. Dryden-Peterson S, Suneja G, Medhin H, et al. Cancer versus tuberculosis mortality among HIV-infected individuals in Botswana. Abstract 615.
5. Wilkin T, Chen H, Cespedes M, et al. ACTG A5298: A phase 3 trial of the quadrivalent HPV vaccine in older HIV+ adults. Abstract 161. All presented at: CROI 2016, Feb. 22-25, 2016, Boston, MA. .