Alcohol consumption and persistent infection of high-risk human papillomavirus

Epidemiol. Infect. (2015), 143, 1442–1450. © Cambridge University Press 2014

                   Alcohol consumption and persistent infection of high-risk
                   human papillomavirus

                   H. Y. OH 1 , M. K. KIM 1 *, S. SEO 2 , D. O. LEE 2 , Y. K. CHUNG 3 , M. C. LIM 2 ,
                   J. KIM 2 , C. W. LEE 3 AND S. PARK 2
                     Translational Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center,
                   Gyeonggi-do, Korea
                     Center for Uterine Cancer, National Cancer Center, Gyeonggi-do, Korea
                     Center for Cancer Prevention and Detection, Hospital, National Cancer Center, Gyeonggi-do, Korea

                   Received 26 January 2014; Final revision 2 July 2014; Accepted 9 August 2014;
                   first published online 4 September 2014

                   Alcohol consumption is a possible co-factor of high-risk human papillomavirus (HR-HPV)
                   persistence, a major step in cervical carcinogenesis, but the association between alcohol and
                   continuous HPV infection remains unclear. This prospective study identified the association
                   between alcohol consumption and HR-HPV persistence. Overall, 9230 women who underwent
                   screening during 2002–2011 at the National Cancer Center, Korea were analysed in multivariate
                   logistic regression. Current drinkers [odds ratio (OR) 2·49, 95% confidence interval (CI)
                   1·32–4·71] and drinkers for 55 years (OR 2·33, 95% CI 1·17–4·63) had a higher risk of 2-year
                   HR-HPV persistence (HPV positivity for 3 consecutive years) than non-drinkers and drinkers for
Alcohol and persistent HPV infection                          1443

          contraceptive use [9] have also been reportedly asso-                               DNA data, cytology findings (Pap smear), and ques-
          ciated with HPV persistence, but the results related to                             tionnaires about detailed alcohol consumption be-
          these epidemiological factors are highly controversial.                             haviours, sociodemographics, smoking history,
             Alcohol is a potential risk factor of oral, oeso-                                parity, menopausal status, and oral contraceptive
          phageal, colorectal, and liver cancers [10] and has                                 use for these 9230 women. Among them, 1284 and
          been reported to increase the risk of breast, endome-                               543 women with a cytological result of low-grade
          trial, and ovarian cancers by enhancing oestrogen                                   squamous intraepithelial lesion (LSIL) or less for the
          levels and metabolism [11]. However, epidemiological                                study period were available for 1- and 2-year follow-
          evidence for cervical cancer is lacking and contro-                                 up studies, respectively, after excluding six subjects.
          versial [12]. Alcohol is known to be a potential risk                               Five subjects and one subject had cytology findings
          factor of HPV infection (acquisition), but there are                                of high-grade squamous intraepithelial lesion (HSIL)
          few studies on the association of alcohol consumption                               or worse in the 1- and 2-year follow-up, respectively.
          and HPV persistence [2, 13]. Furthermore, no studies                                   Two definitions of HR-HPV persistence were used
          have reported on specific alcohol consumption beha-                                  in this study. First, 1-year HPV persistence was
          viours such as frequency, duration, and specific                                     defined as HR-HPV positivity in the enrolment year
          types of alcoholic beverages consumed, relative to                                  and the 1-year follow-up study year, and 2-year
          HPV persistence.                                                                    HPV persistence was defined as HR-HPV positivity
             The aim of our prospective study was to investigate                              in the enrolment year and both the 1- and 2-year
          the alcohol consumption characteristics (drinking sta-                              follow-up study years. One- and 2-year HPV negatives
          tus, frequency, duration of drinking, and the amount                                were defined as HPV negativity in the 1-year follow-
          of alcoholic beverages consumed) in association with                                up study year and as HPV negativity in both the 1-
          a high risk (HR)-HPV persistence according to the                                   and 2-year follow-up study years, respectively, after
          subjects’ health screening data.                                                    enrolment with HPV negativity. According to these
                                                                                              definitions, 10·1% of the 9230 women were HPV posi-
                                                                                              tive (negative, 8301; positive, 929) at enrolment. In the
          METHODS                                                                             follow-up study, 127 and 46 women were included in
                                                                                              the 1- and 2-year HPV-persistence categories, and
          Study design and population                                                         949 and 373 women were included in the 1- and 2-year
          A total of 10 444 Korean women who underwent                                        HPV-negative categories, respectively.
          health-screening examinations at the National Can-                                     An additional analysis was performed to compare
          cer Center from 2002 to 2011 and provided signed                                    the statuses of those cleared of HR-HPV and those
          informed consent were included in this study. This                                  still infected by HR-HPV for the two follow-up
          health screening examinee study is part of the                                      years. Two-year consecutive or alternate HR-HPV
          Korean Prospective Study for the Transition of                                      persistence was defined as HPV positivity/HPV posi-
          Human Papillomavirus into Cervical Carcinoma                                        tivity, as HPV positivity/HPV negativity, or as HPV
          (KOVIC). KOVIC is the prospective study established                                 negativity/HPV positivity in both the next year and
          to identify host and environmental co-factors in the                                the subsequent year, respectively, after enrolment
          persistent HPV infection and its transformation into                                with HPV positivity. Two-year consecutive HR-HPV
          cervical carcinoma in Korean women. KOVIC is                                        clearance was defined as HPV negativity in both the
          composed to two studies, a health examinee-based                                    next year and the subsequent year after enrolment
          prospective study and a patient-based prospective                                   with HPV positivity. By this definition, 140 women
          study. There is an ongoing follow-up investigation.                                 (2-year consecutive or alternate persistence: 89,
          The study protocol was approved by the Insti-                                       2-year consecutive clearance: 51) were included in
          tutional Review Boards and Ethics Committee of                                      the second analysis.
          the National Cancer Center in Korea (NCCNCS-
          11-433). After excluding 558 women who did not
                                                                                              Questionnaires related to alcohol consumption
          participate in HR-HPV deoxyribonucleic acid
          (DNA) testing and 656 women who did not complete
          the questionnaire about detailed alcohol consumption                                General characteristics were analysed with the ques-
          behaviours, a total of 9230 women were available                                    tionnaire that included age, height, weight, marital
          for HPV infection analysis. We collected HPV                                        status, number of children, menopausal status, oral

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1444         H. Y. Oh and others

                   contraceptive use, education level, income level, and                               (vs. HR-HPV clearance) associated with the charac-
                   cigarette smoking status. A detailed questionnaire                                  teristics related to alcohol consumption after adjust-
                   about alcohol consumption included drinking status                                  ment for age, BMI, parity and education level as
                   (current, former, never), the frequency of alcohol con-                             categorical variables. The risk estimates were calcu-
                   sumption (once/month, 2–3 times/month, once/week,                                   lated using the non-drinkers or non-alcoholic charac-
                   2–3 times/week, 4–5 times/week, every day, twice/                                   teristics as the non-exposure category. The statistical
                   day), duration of drinking habit (
Alcohol and persistent HPV infection                          1445

          Table 1. General characteristics of study subjects at baseline (n = 9230)

                                                               Non-drinkers                                     Drinkers
                                                               (N = 4652, 50·4%)                                (N = 4578, 49·6%)

          Characteristics                                      n                        %                       n                        %                         P value

          Age, years mean (S.E.)                               49·9 (0·14)                                      45·3 (0·13)
1446         H. Y. Oh and others

                   Table 2. Odds ratios for persistent infection of high risk-human papillomavirus (HPV)

                                                                                                 Odds ratios (95% confidence intervals)

                                                                   Subjects at                   Enrolment HPV                   1-year follow-up              2-year follow-up
                   Alcohol-related characteristics                 enrolment n (%)               Infection*                      Persistence†                  Persistence†

                   Alcohol consumption
                     Non-drinker                                   4652 (50·4)                   1 (ref.)                        1 (ref.)                      1 (ref.)
                     Drinker (former)                               390 (4·2)                    0·96 (0·68–1·35)‡               1·23 (0·55–2·74)              0·37 (0·05–2·96)
                     Drinker (current)                             4188 (45·4)                   1·21 (1·07–1·41)                1·56 (1·09–2·24)              2·49 (1·32–4·71)
                   Frequency of alcohol consumption
                     Non-drinker                                   4652 (65·8)                   1 (ref.)                        1 (ref.)                      1 (ref.)
                     Once/month                                     758 (10·7)                   0·85 (0·60–1·21)                1·40 (0·60–3·23)              0·62 (0·08–5·17)
                     2–4 times/month                                806 (11·4)                   1·28 (1·04–1·56)                1·64 (0·90–3·02)              2·00 (0·73–5·42)
                     ∼2 times/week                                  855 (12·1)                   1·31 (1·04–1·64)                1·80 (1·01–3·36)              1·83 (0·58–5·85)
                     P value                                                                        0·049§                       0·603                         0·669
                   Duration of alcohol habit
Alcohol and persistent HPV infection       1447

                                                                    Drinking of twice a month

                              Alcohol consumption characteristics

                                                                        Drinkers for ≥5 years

                                                                     ≥2 Glasses (beer, soju)

                                                                             Alcohol drinkers

                                                                                                0   2             4             6             8             10   12

                                                                                                    OR for 2 year consective or alterative HR-HPV persistance

                              Note. odds ratios are shown with 95 % confidence intervals and reference is HR-HPV clearance

          Fig. 1. Odds ratios for 2-year consecutive or alternate high-risk human papillomavirus persistence associated with the
          characteristics related to alcohol consumption such as ‘alcohol drinkers’ (non-drinkers vs. drinkers); ‘usual amount of
          alcoholic beverages’ [2 glasses (50 ml/glass) of beer or soju vs. 52 glasses]; ‘duration of drinking’ (
1448         H. Y. Oh and others

                   years, who were recruited from Hawaii, but cervical                                 alcohol activates cytochrome P450 2E1 which leads
                   HPV clearance did not correlate with alcohol con-                                   to the production of reactive oxygen species (ROS)
                   sumption [13]. In contrast to the lack of studies on al-                            [28], and various antioxidant enzymes and detoxifying
                   cohol and HPV persistence, several cervical cancer                                  pathways are consistently associated with HPV-
                   cohort studies have been conducted with respect to                                  transformed cells [29]. As reported in several studies,
                   alcoholics or alcoholism [15–17]. A single large-scale                              cervical ROS could contribute to a divergent host
                   population-based cohort study assessed the associ-                                  response against the viral infection because of highly
                   ation between moderate alcohol intake and the total                                 variable concentrations of amines and amine oxidases
                   incidence of cancer among women in the UK, but                                      in the cervical mucus [30]. Moreover, women with high
                   no significant association was found with cervical                                   ferritin levels were less likely to clear HR-HPV due to
                   cancer [18].                                                                        the increased generation of ROS than those with
                      A critical point is that the drinkers in our cohort                              lower levels [31]. The immune system is important in
                   had a light-to-moderate level of alcohol consumption;                               viral disease, but the mechanisms that influence specific
                   the mean daily alcohol amount consumed by the                                       host immunity against HPV remain unclear [32].
                   drinkers (6·0 ± 9·5 g/day) was within the range of                                     In our study, the frequency of current drinkers in
                   light-to-moderate alcohol consumption for Korean                                    the subjects (45·4%) was higher than the overall fre-
                   women (1·0–14·9 g/day [19]). Additionally, drinking                                 quency of drinkers (20·3%) among Korean women
                   of beer, a mild type of alcohol (the rates of pure al-                              [19]. The reason for the higher rate of light-to-
                   cohol in beer and soju are 4·5% and 21%, respectively)                              moderate alcohol drinkers in this study might be the
                   showed the highest risk of HPV persistence with a reg-                              higher socioeconomic status of our subjects, as
                   ular consumption of 53 glasses of beer. Daily alcohol                               determined by factors such as household income.
                   consumption had a relatively high level in our sub-                                 Compared to the mean monthly household income
                   jects, but this is included in a moderate alcohol con-                              in Korea (about 199 and 386 million won in 2001
                   sumption level. The benefits of moderate alcohol                                     and 2011, respectively) [33], our subjects had a higher
                   consumption have been suggested by several health out-                              income level (about 390 million won). It is a known
                   comes, but to date, controversies and inconsistent                                  fact that lower socioeconomic groups are at a higher
                   findings exist [20]. As reported in a recent meta-analysis                           risk of binge- or heavy drinking, while higher socio-
                   that investigated the relationship between alcohol                                  economic groups are associated with a higher fre-
                   consumption and the mortality risk of all cancers,                                  quency of light drinking [34, 35]. Furthermore, the
                   a J-shaped association was found in men but not in                                  drinkers in our subject cohort were characterized as
                   women [21]. In a large-scale prospective study of                                   younger, more likely to smoke, and more likely to
                   Korean men and women, light-to-moderate alcohol                                     use oral contraceptives compared to non-drinkers.
                   consumption was associated with lower mortality                                     Although a regression analysis was performed after
                   risks from all causes and from cancer in men, but did                               sufficiently adjusting for these characteristics, undis-
                   not show favourable effects on the risks in women                                   closed social factors of the moderate drinkers or the
                   [19]. Members of Asian populations frequently present                               complex natures of these factors could influence the
                   with a slow-metabolizing acetaldehyde dehydrogenase                                 risk of HPV persistence.
                   variant [22]. Furthermore, there are gender differences                                This study has some limitations. Sexual activity
                   in alcohol pharmacokinetics and alcohol-related                                     could not be considered as a confounding factor for
                   comorbidities [23]. Therefore, the genetic susceptibility                           HPV infection because of the absence of sexual
                   of Asian women to alcohol might differ from that of                                 behaviour-related questions in the health screening
                   other populations with respect to defence against viral                             questionnaire. The mean age of our study subjects
                   infection or viral clearance.                                                       was 48 years (540 years: 81%). A reduced sexual
                      There are potential direct mechanisms to support a                               interest and desire along with a reduced frequency of
                   positive association between alcohol and HPV persist-                               sexual intercourse have been reported among
                   ence. Alcohol can induce folate deficiency by reducing                               middle-aged women [36]. About 89% and 71% of
                   the absorption of folate in the colon and thus induce                               Korean women aged 40–49 and 50–59 years, respect-
                   DNA hypomethylation [24]. In fact, folate is a plaus-                               ively, reported having an inactive sexual life and the
                   ible protective factor against cervical cancer [25] and                             highest sexual intercourse frequency was once/month
                   high levels have potential effects against the initiation                           in those aged 40–49 years [37]. However, the incidence
                   of HPV-related dysplasia [26, 27]. Additionally,                                    of cervical cancers in Korea was highest in

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Alcohol and persistent HPV infection                          1449

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