Introduction
Approximately 1.2 million U.S. residents are infected with human immunodeficiency virus type-1 (HIV-1), an enveloped, single-stranded RNA retrovirus of the subfamily Orthoretrovirinae. In high-income countries, HIV-1 is transmitted from person to person primarily through sexual activity and contact with blood (e.g., sharing of needles by people who inject drugs). In lower-income countries, maternal-to-child transmission is also a concern. HIV-1 infection can cause the death of T-cells (CD-4) and severe immune suppression; if untreated, the infection progresses over time to AIDS, a range of immune-related opportunistic infections and related diseases, including cancer. These diseases, including three types of cancer—Kaposi sarcoma, non-Hodgkin lymphoma, and cervical carcinoma—are referred to as AIDS-defining conditions.
Methods
The National Toxicology Program (NTP) conducted a cancer hazard evaluation of HIV-1 infection and 12 types of cancer. The evaluation included the findings from studies reported in the IARC monograph in Volume 100B, as well as from human cancer studies and mechanistic reviews published after 2008. For each cancer site, the evidence from human and mechanistic studies was integrated considering the following guidelines: Hill’s characteristics of causality, multicausality epidemiology considerations, and concepts of direct and indirect carcinogenesis proposed several virus experts. Finally, NTP applied the Report on Carcinogens (RoC) listing criteria to its assessment to reach an overall cancer hazard conclusion.
Results and discussion
Epidemiological studies demonstrated consistent evidence of a causal association between HIV-1 infection and nine types of cancer and limited evidence of an association with three types of cancer. Most cancers are related to coinfection with both HIV-1 and another cancer-causing virus. In coinfected individuals, HIV-1 impairs their immune system’s ability to suppress or destroy cancer-causing viruses, resulting in an increased risk of cancer from those viruses.
Nine infection-related cancers
NTP concluded there was sufficient evidence of the carcinogenicity of HIV-1 from studies in humans for seven cancers—Kaposi sarcoma, non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, cervical cancer, invasive anal cancer, vaginal/vulvar cancer, and penile cancer—based on consistent findings of statistically significant increased risk in numerous epidemiological studies in different populations. Limited evidence was found for liver and oral cancers because confounding and other biases could not be reasonably excluded. Kaposi sarcoma-associated herpesvirus was a covirus for Kaposi sarcoma and NHL; Epstein-Barr virus for NHL and Hodgkin lymphoma; hepatitis B virus and hepatitis C virus for liver cancer; and human papilloma viruses for the three reproductive cancers, anal cancer, and oral cancer. Mechanistic studies, especially those evaluating CD-4 cell counts, support the evidence from epidemiological studies.
Three noninfection-related cancers
NTP concluded there was sufficient evidence of the carcinogenicity of HIV-1 from studies in humans for two cancers—conjunctival eye cancer and nonmelanoma skin cancer—based on consistent findings of statistically significant increased risks in numerous epidemiological studies in different populations. Although most studies have reported a positive association between HIV-1 infection and lung cancer, it is not clear whether tobacco smoking can explain the excess risk, and the evidence was considered limited. Mechanistic studies provide some evidence for a direct carcinogenic effect of HIV-1 and its proteins.
NTP hazard conclusion and significance
The conclusion of the cancer hazard evaluation was that HIV-1 should be listed as known to be a human carcinogen in the RoC. The Secretary of Health and Human Services approved the listing of HIV-1 in the 14th RoC. The rationale for the listing was sufficient evidence from studies in humans (human cancer and mechanistic) for nine types of cancer. In the United States, HIV-1 was estimated to be responsible for approximately 3,900 cancers in 2010.
National Toxicology Program (NTP). 2016. Report on Carcinogens monograph on human immunodeficiency virus type 1. Research Triangle Park, NC: National Toxicology Program. RoC Monograph 08. https://doi.org/10.22427/ROC-MGRAPH-08