Infectious Agents: Public Health Advances

Human Papillomavirus (HPV)

The Changing Epidemiology of HPV and Cervical Cancer with Mark Schiffman

Starting in the 1980s, DCEG investigators carried out landmark studies on the natural history of cervical cancer that firmly established HPV as the necessary cause of this malignancy [1,2]. Their efforts laid the groundwork for vaccine development and improved strategies for screening.

Negative HPV Test Result is Better Predictor of Low Cervical Cancer Risk than Negative Pap Test

Human papillomavirus (HPV) is the cause of nearly all cervical cancers. Newer approaches to cervical cancer screening test for DNA (or RNA) of HPV at the cervix, whereas the Pap test detects abnormal cell changes associated with the development of cancer. Co-testing is now recommended for most women but clinicians were still unsure of the reassurance from a negative HPV test. Based on a study that included more than one million women, DCEG investigators determined that a negative test for HPV infection compared to a negative Pap test provides greater safety, or assurance, against future risk of cervical cancer [3]. These findings provide evidence to support the currently recommended cotesting strategy with HPV and Pap, as well as the possibility of primary HPV testing as another alternative for cervical screening. Read more about this study.

Spotlight on Population Research: Aimée Kreimer, Ph.D.

Efficacy of HPV Vaccines – Reduced Dose Regimens

The licensure of prophylactic HPV vaccines in 2009 created the opportunity to reduce a large fraction of the disease burden of cervical cancer and other HPV-caused cancers. However, the cost and logistical challenges of administering a three-dose regimen created a barrier to countries including HPV vaccines in their national vaccine programs and vaccinating their adolescents. DCEG investigators reported that one or two doses of an HPV 16/18 vaccine may prevent cervical cancer just as effectively as three doses [4]. Such an approach could lower the cost of vaccination and result in greater accessibility, affordability, and thus global update of the vaccine.

In 2016, the U.S. Food and Drug Administration (FDA) approved a two-dose regimen of the nonavalent HPV vaccine for adolescents aged 9–14. Shortly after, the Centers for Disease Control and Prevention (CDC) recommended a two-dose regimen for all prophylactic HPV vaccines given to children aged 9–14, while maintaining the three-dose recommendation for those 15 or older. This decision was based on a review of evidence from randomized clinical trials and other studies, including research conducted by DCEG investigators. Read more about the two-dose CDC recommendation at Cancer.gov.

Controlling Cervical Cancer: DCEG’s Ongoing Commitment to Improving Women’s Health

Scientists in DCEG are among the leaders of a growing global effort to greatly reduce deaths from cervical cancer

In 2022, the World Health Organization’s Strategic Advisory Group of Experts on Immunization (SAGE) issued an off-label, alternative single-dose HPV vaccine schedule recommendation for use in the primary target of girls aged 9–14 years, and even up to age 20 years. The recommendation was based on the evaluation of available evidence regarding single-dose HPV vaccination schedules, including data from the Costa Rica HPV Vaccine Trial (CVT) conducted by DCEG investigators in collaboration with Costa Rican investigators [5]. SAGE’s alternative single-dose recommendation could dramatically improve accessibility to HPV vaccination in countries that otherwise may not implement HPV vaccination and could simplify vaccine delivery. Single-dose HPV vaccination is especially relevant in resource-constrained settings that are struggling to vaccinate the WHO’s recommended target cohort of girls aged 9–14-years, as well as for countries trying to catch up after the SARS-CoV-2 pandemic disruptions and past HPV vaccine supply shortages.

Read more about HPV vaccine studies.  

Efficacy of HPV Vaccines – Non-Cervical Sites

DCEG investigators also reported that the HPV 16/18 vaccine provides strong protection against anal, vulvar, and oral HPV infections in women [6,7].

HPV-based Screening for Cervical Cancer

In 2012, the U.S. Preventive Services Task Force and a coalition of health organizations published new guidelines for cervical cancer screening. DCEG studies into the use of HPV DNA testing and cytology to stratify women into accurate and precise risk categories have informed these revised guidelines [8].

Cervical Cancer Screening for Women with HIV

In 2021, findings from the HIV/AIDS Cancer Match Study were used to inform an important revision to cervical cancer screening guidelines among women with HIV [9]. 

Learn more about public health advances in cervical cancer prevention.

Helicobacter pylori (H. pylori)

Evidence H. pylori Treatment Reduces Gastric Cancer Incidence and Mortality

Infection with Helicobacter pylori (H. pylori) —a bacterium found in the stomach—is a major cause of gastric cancer. Approximately two-thirds of the world’s population harbors the bacterium, with infection rates much higher in developing countries. Treatment of the infection with antibiotics had been shown in intervention trials to lower gastric cancer incidence when compared to placebo [10]. Lowered gastric cancer mortality was also suggested, though benefits in older people and those with advanced precancerous lesions were unknown. DCEG investigators and collaborators found that a two-week course of H. pylori treatment given 15 years earlier was associated with lower gastric cancer incidence and mortality in older adults (aged 55 years and older at the beginning of the study) [11,12]. Incidence, but not mortality, was also statistically significantly reduced in subjects with advanced precancerous lesions initially. H. pylori treatment can benefit an entire population, not just the young or those with mild precancerous lesions in the stomach.

Human Immunodeficiency Virus (HIV)

DCEG research provided the initial assessment of the specificity, sensitivity, and appropriate applications of the first-generation human immunodeficiency virus (HIV) antibody testing system for diagnosis of HIV infection [13]. As a result of this work, those tests became standard care in the routine clinical practice of diagnosing individuals thought to have contracted HIV.

DCEG biostatisticians applied novel statistical methods to derive early estimates of HIV prevalence in the U.S. population [20, 21, 22]. A prospective study of HIV infection and the development of AIDS in people with hemophilia showed that a much larger proportion of people living with HIV would develop AIDS than previously thought [14], a finding with broad impact for public health prevention programs and clinical practice.

DCEG research led to the recognition that CD4 count and HIV viral load predict risk for the development of AIDS and mortality [15, 16, 17, 18].  These biomarkers are now the standard measures used to inform routine clinical care of people living with HIV, including counseling, screening, and medication management.

New worker safety recommendations for the handling of concentrated HIV samples in the laboratory were influenced by a DCEG study of HIV infection among laboratory workers [19] . 

DCEG’s HIV/AIDS Cancer Match Study has provided important information on cancer risk among people living with HIV. Researchers described the enormous increase in risk for cancers associated with immunosuppression early in the AIDS epidemic [23], and declines over time in these cancers with the introduction of effective antiretroviral therapy [24]. The study documented a strongly increased risk for a rare skin cancer, Merkel cell carcinoma [25], which led other investigators to focus on this cancer and the eventual discovery of a novel cancer virus, Merkel cell polyomavirus. With prolonged survival, people with HIV are aging, which has led to a dramatic increase in the burden of some cancers [26].

Learn about current research in the HIV/AIDS Cancer Match Study.

Other Infectious Agents

U.S. poliovirus vaccines were accidentally contaminated with simian virus 40 (SV40). These contaminated doses were widely administered from 1955 through 1962. The public was alarmed by the possible risks from exposure to this oncogenic virus. DCEG investigators published results from a study of newborns who received SV40-contaminated polio vaccine showing no increased risk of cancer [27, 28, 29].

The Food and Drug Administration (FDA) recommended screening all blood donations for human T-cell leukemia virus type I and II (HTLV-I/II) antibodies, based on DCEG research that demonstrated increased risks of HTLV-1 and associated complications following exposure to HTLV-I/II in contaminated blood [30, 31]. 

The FDA decided not to screen the U.S. blood supply for human herpesvirus 8 (HHV-8) after DCEG research demonstrated that serological tests for HHV-8 had poor reproducibility [32].

References

1. Schiffman MH et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993.  
2. Schiffman et al. Human papillomavirus and cervical cancer. Lancet 2007.  
3. Gage JC et al. Reassurance against future risk of precancer and cancer conferred by a negative HPV test. J Natl Cancer Inst 2014.  
4. Kreimer AR et al. Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine. J Natl Cancer Inst 2011. 
5. Kreimer AR. Efficacy of fewer than three doses of an HPV 16/18 AS04-adjuvanted vaccine: Combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials. Lancet Oncology 2015.
6. Kreimer et al. Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: A nested analysis within the Costa Rica Vaccine Trial. Lancet Oncology 2011.  
7. Beachler DC, et al. Multisite HPV 16/18 vaccine efficacy against cervical, anal, and oral HPV infection. J Natl Cancer Inst 2015.  
8. Katki HA et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: A population-based study in routine clinical practice. Lancet Oncology 2011. 
9. Stier EA et al. Cervical cancer incidence stratified by age in women living with HIV compared with the general population in the United States, 2002-2016. AIDS 2021. 
10. You WC et al. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J Natl Cancer Inst 2006. 
11. Ma JL et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality.  J Natl Cancer Inst 2012. 
12. Li WQ et al. Effects of Helicobacter pylori treatment on gastric cancer incidence and mortality in subgroups. J Natl Cancer Inst 2014. 
13. Weiss SH et al. Screening test for HTLV-III (AIDS agent) antibodies. Specificity, sensitivity, and applications.  JAMA 1985.
14. Goedert JJ et al. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia.  N Engl J Med 1989.  
15. Goedert JJ et al. Effect of T4 count and cofactors on the incidence of AIDS in homosexual men infected with human immunodeficiency virus.  JAMA 1987. 
16. Engels EA et al. Plasma HIV viral load in patients with hemophilia and late-stage HIV disease: A measure of current immune suppression. Multicenter Hemophilia Cohort Study. Ann Intern Med 1999. 
17.  Ehmann WC et al. Relationship of CD4 lymphocyte counts to survival in a cohort of hemophiliacs infected with HIV. Multicenter Hemophilia Cohort Study.  J Acquir Immune Defic Syndr 1994.  
18. O'Brien TR et al. Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study. JAMA 1996.
19. Weiss SH et al. Risk of human immunodeficiency virus (HIV-1) infection among laboratory workers. Science 1988. 
20. Rosenberg PS et al. Backcalculation of the number with human immunodeficiency virus infection in the United States.  Am J Epidemiol 1991. 
21. Rosenberg PS.  Scope of the AIDS epidemic in the United States. Science 1995. 
22. Rosenberg PS et al. Trends in HIV incidence among young adults in the United States.  JAMA 1998. 
23. Engels EA et al. AIDS-Related opportunistic illness and potent antiretroviral therapy. JAMA 2000. 
24. Hernandez-Ramirez RU et al. Cancer risk in HIV-infected people in the USA from 1996 to 2012: A population-based, registry-linkage study. Lancet HIV 2017. 
25. Engels EA et al. Merkel cell carcinoma and HIV infection. Lancet 2002. 
26. Shiels MS et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst 2011.
27. Fraumeni JF Jr et al. An evaluation of the carcinogenicity of simian virus 40 in man.  JAMA 1963.
28. Fraumeni JF Jr, et al. Simian virus 40 in polio vaccine: Follow-up of newborn recipients. Science 1970. 
29. Mortimer EA Jr, et al. Long-term follow-up of persons inadvertently inoculated with SV40 as neonates. N Engl J Med 1981.
30. Blattner WA et al. The human type-C retrovirus, HTLV, in Blacks from the Caribbean region, and relationship to adult T-cell leukemia/lymphoma. Int J Cancer 1982. 
31. Blayney DW et al. The human T-cell leukemia/lymphoma virus associated with American adult T-cell leukemia/lymphoma. Blood 1983. 
32. Rabkin CS et al. Interassay correlation of human herpesvirus 8 serologic tests. HHV-8 Interlaboratory Collaborative Group. J Infect Dis 1998.