The introduction of highly active antiretroviral therapy (HAART) has significantly improved the morbidity and mortality of HIV-infected patients.1,2 However, the incidence of non-AIDS defining cancer has increased with prolongation of life expectancy of HIV-infected patients.3–6
Colorectal cancer is the third most commonly diagnosed cancer in male patients and the second in female patients, and a major cause of death worldwide.7 To prevent the development of colorectal cancer and death, removal of premalignant lesion, adenoma, is effective, and screening is recommended in patients aged 50 years and older.8–11 Recent studies from western countries have suggested that higher incidence of colonic adenoma in patients with HIV infection compared with the general population.12–14 Furthermore, HIV-infected patients are at high risk of oncogenic human papillomavirus (HPV) infection, and the potential role of HPV infection in the development of colorectal cancer has been suggested.15–17 However, little is known about the risk of adenoma in HIV-infected patients compared with the general population.
In the past, the incidence of colorectal cancer was lower in Asia compared with Western countries.18 However, the incidence has increased lately in Asian countries, including Japan, and is currently comparable with that in western countries.18,19 Nevertheless, all previous studies on colorectal adenoma in HIV-infected patients were only from the United States, and there are no available data in Asia.12–14 This study reports the findings of a prospective cross-sectional colonoscopic study that compared the prevalence of colorectal adenoma in HIV-infected patients with HIV-negative patients in Japan.
Study Design, Setting, and Participants
We conducted a prospective cross-sectional single-center study in adults who underwent colonoscopy between September 2009 and July 2012 at the endoscopy unit of the National Center for Global Health and Medicine (NCGM). NCGM has one of the largest clinics for patients with HIV infection in Japan with more than 3500 registered patients as of May 2013. The institutional review board at NCGM approved this study. The study was conducted according to the principles expressed in the Declaration of Helsinki.
The following inclusion criteria were used in this study: (1) aged 18 years or older, (2) independent in activities of daily living, (3) able to understand written documents and to write, and (4) asymptomatic but desired screening for colorectal cancer, or presented with continuous or intermittent lower gastrointestinal (GI) symptoms. The following exclusion criteria were used in this study: (1) contraindication or patient refusal of total colonoscopy, (2) colonoscopy for follow-up evaluation during the study period, and (3) previous diagnosis of either adenoma or adenocarcinoma. All inclusion and exclusion criteria were fulfilled before patients were enrolled in the study. Each HIV-infected patient was matched with 1 HIV-negative patient based on age in 5-year age-bands and sex.
A detailed questionnaire was completed at the endoscopy unit on the same day of colonoscopy. Patients were asked about their (1) lifestyle habits (smoking history and alcohol consumption), (2) medications [nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin], and (3) comorbidities (hypertension, diabetes mellitus, and coronary heart disease) in a face-to-face interview with the medical staff. With regard to medication history, prescriptions and medical records were reviewed in addition to information provided by the patients to avoid omissions. The survey form included photographs of all these oral drugs, which are approved in Japan. Regular use of medication was defined as oral administration starting at least 1 year before the interview. The smoking index was evaluated among ever and daily smokers and was defined as the number of cigarettes per day multiplied by the number of smoking years. Then, smoking index was categorized into nil, <400, 400–799, and >800. Alcohol consumption was calculated and categorized into nondrinker, light (1–180 g/wk), moderate (181–360 g/wk), and heavy drinker (>360 g/wk). To evaluate lower GI symptoms, the GI symptom rating scale rating on a 7-graded Likert scale was used.20,21 The GI symptom rating scale consists of 15 questions covering lower GI symptoms: increased flatus, decreased passage of stools, increased passage of stools, loose stools, hard stools, urgent need for defecation, and feeling of incomplete evacuation. Positive symptoms were defined as score ≥ 3.
For HIV-infected patients, CD4 cell count, HIV viral load, history of HAART, and sexual behavior were also obtained. CD4 cell counts within 1 week and HIV-RNA viral load within 1 month were used in the analysis, and positive result for real-time HIV-RNA was defined as ≥40 copies per milliliter. Sexual behavior was defined as men who have sex with men or heterosexuality. Furthermore, immediately following colonoscopy, rectal swabs (DNAPAP cervical sampler; Qiagen, Gaithersburg, MD) were obtained. Rectal samples were analyzed for HPV-DNA and genotyping by means of polymerase chain reaction-invader assay as described previously.22 HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 were defined as oncogenic HPV.23
Diagnosis of Colorectal Adenoma, Adenocarcinoma, and Non-Neoplastic Polyps
After intestinal lavage with 2 L of solution containing polyethylene glycol, colonoscopy was performed by experienced gastroenterologists by using an electronic high-resolution video endoscope (model CFH260; Olympus Optical, Tokyo, Japan). The location of all lesions was recorded in electronic endoscopic database (Olympus Medical Systems; Solemio Endo). All visualized lesions were biopsied and histologically assessed by experienced pathologists.
Baseline characteristics were compared using the unpaired Student t test or χ2 test (Fisher exact test) for quantitative or qualitative variables, respectively. To estimate the effect of HIV infection on adenoma, multivariate logistic regression analysis was performed adjusted for age, sex, and possible risk factors for adenoma (these included smoking and alcohol consumption, diabetes mellitus, coronary artery diseases, and NSAIDs and aspirin use). In addition, we conducted uni- and multivariate logistic regression analysis in HIV-infected patients to elucidate the impact of other factors on adenoma related to HIV-infected patients (CD4 count, HIV-RNA, history of HAART, sexual behavior, and oncogenic HPV infection).
Statistical significance was defined at 2-sided P values < 0.05. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs). All statistical analyses were performed using the Statistical Package for Social Sciences version 17.0 (SPSS, Chicago, IL).
A total of 177 HIV-infected patients and 177-HIV-negative controls were selected for analysis after the application of the aforementioned exclusion criteria and age matching (Fig. 1). The baseline characteristics are listed in Table 1. The study subjects were mostly men, Asians, and comparatively young. HIV-infected patients were more likely to be smokers and on treatment with NSAIDs. In contrast, aspirin was mostly used by the control subjects. All other major background parameters were similar in the 2 groups. With regard to the clinical symptoms, there was no difference in GI symptom scores other than increased passage of stools but there was no difference in the proportion of asymptomatic patients between the 2 groups. In patients with HIV infection, the median CD4 count was 371/μL (interquartile range, 121–579), 29.4% of the patients were treatment naive, 75.4% had HPV infection, and 71.5% were infected with oncogenic HPV. The most frequently identified HPV types were type 16 (41%), followed by type 58 (35%), 59 (33%), 52 (27%), 31 (25%), 33 (25%), 51 (19%), 18 (18%), 35 (14%), 39 (13%), 56 (11%), and type 45 (7%).
Prevalence of Colorectal Adenoma, Adenocarcinoma, Non-Neoplastic Polyps, and Other Tumors
Adenomas were identified in 29 (16.4%) patients with HIV infection and in 40 (22.6%) control subjects, and the incidence was not significantly different between the 2 groups (Table 2). Classification of the adenoma according to size (<5, 5–9, and ≥10 mm) showed that HIV-negative subjects tended to have mainly adenomas measuring <5 mm (P = 0.08) although this difference did not reach statistical significance. The incidences of adenocarcinoma and hyperplastic polyps were higher in patients without HIV infection, although the differences in the rates were not statistically significant (P > 0.05). In contrast, Kaposi’s sarcoma was diagnosed only in HIV-infected patients (P = 0.03).
Uni- and multivariate analyses showed that HIV infection did not correlate with higher prevalence of adenoma (Table 3, adjusted OR = 0.66; 95% CI: 0.37 to 1.18; P = 0.16). Multivariate analysis identified age as an independent and significant factor associated with increased risk of adenoma (adjusted OR = 1.72; 95% CI: 1.29 to 2.29; P < 0.01). All other factors did not correlate with adenoma by multivariate analysis.
Factors Associated With Colorectal Adenoma in Patients With HIV Infection
Age was an independent factor associated with increased risk of adenoma by uni- and multivariate analysis (adjusted OR = 2.28; 95% CI: 1.37 to 3.80; P < 0.01; Table 4). High CD4 count, low HIV-RNA, and history of HAART were associated with prevalence of adenoma by univariate analysis, although these factors were not significant on multivariate analysis. Oncogenic HPV infection was not associated with adenoma.
This study demonstrated that HIV infection was not an independent risk for colorectal adenoma after adjustment for variables known to be related to adenoma. In HIV-infected patients, only age was associated with increased risk of colorectal adenoma, whereas CD4 count, HIV-RNA, and HPV infection were not associated with adenoma by multivariate analysis. To our knowledge, this is the first study that compared the prevalence of colorectal adenoma between patients with and without HIV infection in Asia.
Previous reports suggested possible relation between HIV infection and increased risk of colorectal adenoma.12–14 Bini et al12 investigated the prevalence of adenoma in 2382 patients (165 HIV-infected patients and 2217 controls) who underwent screening sigmoidoscopy. Their study identified a high incidence of adenoma in HIV-infected patients and that the risk of such lesion was higher in patients with low CD4 count and long-term HIV infection. The same group also conducted a prospective study of 408 patients who underwent total colonoscopy in the United States.13 They included only asymptomatic patients aged 50 years or older and found a high rate of colonic neoplasm, including adenoma, in HIV-infected patients. They also reported that patients with HIV infection who were not on treatment with HAART and those with a positive family history of colorectal cancer were at higher risk for colonic neoplasm. In contrast, the study of Kothari et al,14 which included 130 HIV-infected patients and 779 controls who underwent screening colonoscopy, did not find significant difference in the prevalence of adenoma between the 2 groups. Similarly, our study showed similar prevalence of adenoma in patients with and without HIV infection. These differences may be explained by differences in sample size, populations, and different inclusion criteria. The abovementioned previous studies included only asymptomatic patients whereas this study included many patients with GI symptoms. Taken together, these results suggest lack of consensus on this issue. Thus, it is still unclear whether HIV infection is truly associated with increased risk of colorectal adenoma. Bini et al12 suggested that the low immune status associated with HIV infection may enhance the development of adenoma; however, CD4 count did not correlate with adenoma in our study. Furthermore, HIV itself is also suggested to play a role in oncogenesis.24 There is limited information on this issue, and further studies are needed to clarify the association between HIV infection and colorectal adenoma.
In this study, advanced age correlated with increased risk of adenoma in HIV-infected patients. Excision of adenoma prevents colon cancer and screening colonoscopy is recommended for individuals aged 50 years or older.8,10,11 However, it has been suggested that colorectal cancer screening is underused in HIV-infected patients.25 In addition, patients with HIV infection are at higher risk for other GI malignancies such as Kaposi’s sarcoma, anal cancer, and GI lymphoma than general population,26–28 and these patients are sometimes asymptomatic.28–31 Therefore, we believe that screening colonoscopy is important in HIV-infected patients, especially those aged 50 years or older.
The association between HPV infection and colorectal cancer is controversial.32 Although 2 recent studies argued against such association, a recent meta-analysis study demonstrated increased risk of colorectal cancer with HPV infection.17,33,34 Because previous reports suggested increased prevalence of colorectal adenoma in HIV-infected patients, in whom the prevalence of HPV infection is known to be higher than that in the general population,15 we hypothesized that oncogenic HPV infection may be a risk factor for adenoma in patients with HIV. However, our results did not find such association.
Fecal occult blood test is a useful screening tool for the detection of colorectal cancers.10 However, fecal blood test is also positive in various GI diseases such as asymptomatic colitis and Kaposi’s sarcoma.35,36 Thus, the diagnostic accuracy of fecal occult blood test may be less than ideal in HIV-infected patients and accordingly was not used in all subjects in this study. Instead, we assessed the clinical symptoms because we hypothesized that differences in GI symptoms might affect the prevalence of colorectal adenoma. Nevertheless, the proportion of asymptomatic patients was not different between the 2 groups.
Important strengths of this study includes its prospective study design, detailed assessment of GI symptoms and other GI tumors, first study in Asia, and conducting total colonoscopy in all subjects. However, there are several limitations to our study. First, because our study population was younger than those in previous studies, the prevalence might have been underestimated compared with other studies. It is well known that the risk of colorectal cancer increases with age.37 Thus, the young age of our study subjects and the small sample size of our study could have masked any association between HIV infection and colorectal adenoma. Similar to the study by Bini et al,13 which examined the relation between HIV infection and colorectal adenoma, larger studies on patients aged 50 years or older will be needed in Asia. Second, because we included both symptomatic and asymptomatic patients who underwent diagnostic colonoscopy, a selection bias could not be ruled out in our study. As a result, it is possible that the control group could have included patients suspected to have colon cancer, whereas HIV-infected patients tended to include those who were referred for colonoscopy based on the suspicion of opportunistic infections, which might have led to the higher prevalence of adenoma in the control group. However, the background characteristics and proportion of asymptomatic patients were similar between the 2 groups. Third, although we collected detailed information on risk factors of adenoma, we could not collect data on factors such as obesity and family history of colon cancer as reported previously,38,39 and these might have influenced the results.
In conclusion, the incidence of adenoma was not significantly different between patients with and without HIV infection. However, it should be noted that 16.4% HIV-infected patients had adenoma and its risk increased with age. As the issue of aging in patients with HIV infection is growing, the results of this study carry certain significance. Thus, HIV-infected patients should not miss screening opportunities for colorectal adenoma and other HIV-related malignancies.
The authors are grateful to Hisae Kawashiro (Clinical Research Coordinator) for help with data collection. The authors thank all other clinical staff at the AIDS Clinical Center and all the staff of the endoscopy unit.
1. Palella FJ Jr, Delaney KM, Moorman AC, et al.. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853–860.
2. Murphy EL, Collier AC, Kalish LA, et al.. Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. Ann Intern Med. 2001;135:17–26.
3. Crum-Cianflone N, Hullsiek KH, Marconi V, et al.. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. AIDS. 2009;23:41–50.
4. Shiels MS, Cole SR, Kirk GD, et al.. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr. 2009;52:611–622.
5. Sackoff JE, Hanna DB, Pfeiffer MR, et al.. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med. 2006;145:397–406.
6. Palella FJ Jr, Baker RK, Moorman AC, et al.. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006;43:27–34.
7. Jemal A, Bray F, Center MM, et al.. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
8. Winawer SJ, Zauber AG, Ho MN, et al.. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med. 1993;329:1977–1981.
9. Zauber AG, Winawer SJ, O’Brien MJ, et al.. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012;366:687–696.
10. Levin B, Lieberman DA, McFarland B, et al.. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008;58:130–160.
11. Calonge N, Petitti DB, DeWitt TG, et al.. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:627–637.
12. Bini EJ, Park J, Francois F. Use of flexible sigmoidoscopy to screen for colorectal cancer in HIV-infected patients 50 years of age and older. Arch Intern Med. 2006;166:1626–1631.
13. Bini EJ, Green B, Poles MA. Screening colonoscopy for the detection of neoplastic lesions in asymptomatic HIV-infected subjects. Gut. 2009;58:1129–1134.
14. Kothari ND, Engelson ES, Drake V, et al.. Effect of HIV infection on the prevalence of colorectal adenomas during screening colonoscopy. J Clin Gastroenterol. 2010;44:77–78.
15. Mbulawa ZZ, Marais DJ, Johnson LF, et al.. Impact of human immunodeficiency virus on the natural history of human papillomavirus genital infection in South African men and women. J Infect Dis. 2012;206:15–27.
16. Burnett-Hartman AN, Newcomb PA, Potter JD. Infectious agents and colorectal cancer: a review of Helicobacter pylori
, Streptococcus bovis
, JC virus, and human papillomavirus. Cancer Epidemiol Biomarkers Prev. 2008;17:2970–2979.
17. Damin DC, Ziegelmann PK, Damin AP. Human papillomavirus infection and colorectal cancer risk: a meta-analysis. Colorectal Dis. 2013;15:e420–e428.
18. Center MM, Jemal A, Ward E. International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev. 2009;18:1688–1694.
19. Sung JJ, Lau JY, Goh KL, et al.. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol. 2005;6:871–876.
20. Svedlund J, Sjodin I, Dotevall G. GSRS—a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci. 1988;33:129–134.
21. Revicki DA, Wood M, Wiklund I, et al.. Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res. 1998;7:75–83.
22. Tadokoro K, Akutsu Y, Tanaka K, et al.. Comparative quantitative analysis of 14 types of human papillomavirus by real-time polymerase chain reaction monitoring Invader reaction (Q-Invader assay). Diagn Microbiol Infect Dis. 2010;66:58–64.
23. Doorbar J, Quint W, Banks L, et al.. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30(suppl 5):F55–F70.
24. Deeken JF, Tjen-A-Looi A, Rudek MA, et al.. The rising challenge of non-AIDS-defining cancers in HIV-infected patients. Clin Infect Dis. 2012;55:1228–1235.
25. Reinhold JP, Moon M, Tenner CT, et al.. Colorectal cancer screening in HIV-infected patients 50 years of age and older: missed opportunities for prevention. Am J Gastroenterol. 2005;100:1805–1812.
26. Franceschi S, Lise M, Clifford GM, et al.. Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Br J Cancer. 2010;103:416–422.
27. Machalek DA, Poynten M, Jin F, et al.. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol. 2012;13:487–500.
28. Beck PL, Gill MJ, Sutherland LR. HIV-associated non-Hodgkin's lymphoma of the gastrointestinal tract. Am J Gastroenterol. 1996;91:2377–2381.
29. Nagata N, Shimbo T, Yazaki H, et al.. Predictive clinical factors in the diagnosis of gastrointestinal Kaposi’s sarcoma and its endoscopic severity. PLoS One. 2012;7:e46967.
30. Abbas A, Yang G, Fakih M. Management of anal cancer in 2010. Part 1: overview, screening, and diagnosis. Oncology (Williston Park). 2010;24:364–369.
31. Heise W, Arasteh K, Mostertz P, et al.. Malignant gastrointestinal lymphomas in patients with AIDS. Digestion. 1997;58:218–224.
32. Lorenzon L, Ferri M, Pilozzi E, et al.. Human papillomavirus and colorectal cancer: evidences and pitfalls of published literature. Int J Colorectal Dis. 2011;26:135–142.
33. Khoury JD, Tannir NM, Williams MD, et al.. Landscape of DNA virus associations across human malignant cancers: analysis of 3,775 cases using RNA-Seq. J Virol. 2013;87:8916–8926.
34. Burnett-Hartman AN, Feng Q, Popov V, et al.. Human papillomavirus DNA is rarely detected in colorectal carcinomas and not associated with microsatellite instability: the Seattle colon cancer family registry. Cancer Epidemiol Biomarkers Prev. 2013;22:317–319.
35. Okamoto M, Kawabe T, Ohata K, et al.. Amebic colitis in asymptomatic subjects with positive fecal occult blood test results: clinical features different from symptomatic cases. Am J Trop Med Hyg. 2005;73:934–935.
36. Nagata N, Nakashima R, Nishiumura S, et al.. Gastrointestinal Kaposi’s sarcoma: diagnosis and clinical features. In: Butler EJ, ed. Sarcoma. New York, NY: Nova Science Publishers; 2012:153–165.
37. Eddy DM. Screening for colorectal cancer. Ann Intern Med. 1990;113:373–384.
38. Imperiale TF, Ransohoff DF. Risk for colorectal cancer in persons with a family history of adenomatous polyps: a systematic review. Ann Intern Med. 2012;156:703–709.
39. Renehan AG, Tyson M, Egger M, et al.. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–578.
Keywords:© 2014 by Lippincott Williams & Wilkins
colorectal cancer; colorectal adenoma; oncogenic HPV infection; Japan; gastrointestinal malignancy