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Abstract

Objectives

Based on cross-sectional studies, the data on protection from Human Papillomavirus (HPV) infections related to using male condoms appear inconsistent. Longitudinal studies are more informative for this purpose. We undertook a systematic review of longitudinal studies on the effectiveness of male condoms in preventing HPV infection and cervical neoplasia.

Methods

We searched PubMed using MeSH terms for articles published until May 2013. Articles were included if they studied a change in non-immunocompromized women’s cervical HPV infection or cervical lesion status along with the frequency of condom use.

Results

In total, 384 abstracts were retrieved. Eight studies reported in 10 articles met the inclusion criteria for the final review. Four studies showed a statistically significantly protective effect of consistent condom use on HPV infection and on regression of cervical neoplasia. In the remaining four studies, a protective effect was also observed for these outcomes, although it was not statistically significant.

Conclusions

Consistent condom use appears to offer a relatively good protection from HPV infections and associated cervical neoplasia. Advice to use condoms might be used as an additional instrument to prevent unnecessary colposcopies and neoplasia treatments in cervical screening, and to reduce the risk of cervical cancer.

Keywords

condom Human Papillomavirus cervical cancer cervical neoplasia infection prevention

Introduction

Persistent infection with sexually transmitted high-risk genotypes of Human Papillomavirus (HPV) is a necessary cause of cervical cancer.¹ Vaccines protect against two of the 13 high-risk HPV genotypes.² Treatment of screen-detected cervical intraepithelial neoplasia (CIN) can reduce the incidence of cervical cancer. However, cervical cancer can still develop after CIN treatment,³ and after normal screening tests.⁴ Screening and vaccination are not used routinely where the burden of cervical cancer is highest.

Use of male condoms (henceforth denoted as “condoms”) has shown a considerable protective effect, when used correctly and consistently, against several sexually transmitted infections (STI), including human immunodeficiency virus, trichomoniasis, chlamydia, and gonorrhea. Data on protective effect from HPV infections and related cervical lesions have been less consistent. In their systematic review from 2002, Manhart and Koutsky identified 20 relevant studies, 19 of them cross-sectional.⁵ The studies showed mixed results. The inconsistency of the evidence regarding a protective effect could suggest that condoms are not a highly effective method of preventing HPV infections.

The findings from Manhart and Koutsky’s review were echoed in a 2004 report on cervical cancer prevention to the USA Congress from the Centers for Disease Control and Prevention (CDC). The report concluded that condoms cannot be recommended for primary prevention of genital HPV infections, although it also stated that evidence suggested effectiveness against cervical cancer.⁶ Also in 2004, the US Food and Drug Administration (FDA) considered changing the labeling of condoms by adding information on the lack of evidence showing protection against HPV infections.⁷ The proposed labeling change could have spillover effects, eg. by undermining condom use to avoid other STI. This took place despite acknowledging Manhart and Koutsky’s cautionary observation that the reviewed studies were not set up to evaluate condom use, did not adequately measure condom use, and, because of cross-sectional design, could not establish the temporal sequence between exposure and outcome.⁵ This debate underscores the importance of a careful assessment of epidemiological evidence used in making public health recommendations.

Compared with cross-sectional studies, longitudinal studies are more reliable in establishing whether non-use of condoms preceded an infection/disease. By 2006, two longitudinal studies had been published showing a protective effect of condoms on HPV infections.^8,9 These studies led, in 2008, to the FDA ruling against the change of condom labeling, and the CDC now also acknowledges that condoms can be useful in preventing HPV infections and related diseases. More relevant longitudinal studies have been published since, and these can potentially give more information on the effectiveness of condoms for the purpose. We undertook a systematic review of longitudinal studies on the use of condoms in preventing HPV infections and cervical neoplasia, assessing in depth their study designs. As developed countries will probably be switching from cytology- to HPV-based primary cervical screening in the near future, we discussed the relevance of the findings in the context of cervical screening.

Methods

A systematic search in PubMed (Appendix) retrieved 384 abstracts. All retrieved reviews and meta-analyses were perused for additional studies. Although a formal ranking of study quality was not made, two authors (JUHL, MR) independently selected relevant studies and abstracted all information on the studies and their quality into pre-specified tables. In case of disagreement, consensus was used. Additional information on the included studies was obtained from related publications.

English, French, Danish, Norwegian, Swedish, German, Chinese, or Dutch-language longitudinal studies on condom use and HPV infections or cervical lesions were included. The studies assessed a change in the woman’s HPV infection (ie. incidence, clearance, persistence), or a change in her cervix uteri diagnosis (ie. incidence, regression, persistence of cytologically or histologically confirmed lesions). It has been hypothesized that regression of CIN might be accelerated by condoms blocking a continuous transmission of HPV infections.⁸ We therefore considered that studies detecting a change in CIN as the outcome are also informative for our purpose.

Studies were excluded if: they included a substantial proportion of immunocompromized women, used non-cervical HPV samples, studied female condoms, did not include a control group, or did not measure condom use in all sexual partnerships. Studies reporting only baseline measurements of condom use were excluded, as any change in the use during follow-up can be related to the final outcome. Finally, studies were excluded if condom use was categorized broadly, eg. in yes-no or ever-never categories. The “yes” and “ever” categories include an unspecified proportion of inconsistent condom users, making it difficult to interpret the reported outcomes.

Statistical analysis

Reported indicators of relative risk (RR) of HPV infections associated with condom use were collected, regardless of oncogenicity (risk) of the detected genotypes. Although low-risk genotypes do not cause cervical cancer, the risk-based classification has been changing. Also, there is no evidence suggesting that the protection from HPV differs by the genotypes’ oncogenicity.

RR for one study¹⁰ was recalculated by the authors of this review and annotated by square brackets; the 95% confidence interval (CI) was calculated assuming normal distribution for log(RR). Owing to heterogeneity in the designs of the studies, a summary effect measure was not computed. For incidence- and persistence-type outcomes, measures of RR <1 for users v non-users indicated a protective effect of condoms, whereas for clearance- and regression-type outcomes, this was the case with RR >1.

Results

Based on the PubMed search, full texts were retrieved for 33 articles. Eight studies reported in 10 articles met the inclusion criteria.^8–17 For one study, we tabulated the results from the first of three published articles; all three reported the same endpoint with marginally different inclusion criteria.¹⁵

Condom use and HPV infections

Ho et al.¹⁴ followed 399 HPV-negative US students (Tables 1, 2). Their samples, obtained every six months for about two years, were tested with two HPV assays (polymerase chain reaction (PCR) MY09/11, Southern blot hybridization), and the woman was considered HPV-positive if at least one of the two was positive. Information on condom use was collected at each visit. The relative risk (RR) of an incident HPV infection for women always, compared with never, using condoms since the last visit was 0.8 (95% CI: 0.4–1.4; Table 3). The RR was adjusted for several indicators of sexual behavior, including the partners’ risk level.

Table 1.

Study designs of the included studies (in chronological order) focusing on the relationship between condoms, HPV infections, and cervical intraepithelial neoplasia.

Authors, year of publication	Country	Study design	Inclusion criteria for the study other than the ability to provide informed consent	Sociodemographic characteristics of women at baseline	Definition of condom use
Thomas et al. 1990¹⁰	Australia	Controlled trial (partially random allocation)	Attending dysplasia clinic for investigation of an abnormal smear	Me age: 25 y (18–44), me # of sex partners: 6 (1–30), me period exclusively with current partner: 24 mo (0–168), ≥1 extraneous partner during study 17%, smokers 65% (intervention group) and 60% (control group)	Intervention group: asked to use condoms for every sex act in 6 mo; Control group: asked to avoid condoms for 6 mo; assessed by interview after 3 and 6 mo
Ho et al. 1998¹⁴	USA	Cohort study	First or second y students from a state university and/or planning to stay in the area for ≥2.5 y, not currently pregnant, not planning to become pregnant in 3 y, no prior cervical biopsy or CIN treatment, ≥1 follow-up visit	Me age: 20 y (SD = 3), non-White 43%, 13% no vaginal intercourse^a	Always vs. never in the period since the previous visit; assessed by questionnaire at each visit
Moscicki et al. 2001¹³	USA	Cohort study	13–20 y, attending 1 of 2 family planning clinics and having a pelvic exam for any reason, non-pregnant, not currently using antibiotics, not received or scheduled for cervical ablation, not planning to move in 6 mo, not mentally retarded, English speaking, HPV+ on HPV Profile assay, ≥1 HPV+ result and ≥3 visits, no prevalent LSIL, did not develop HSIL before LSIL	Me age 20 y (SD = 2), non-White 47%, no college 46%, md # sex partners: 5 (IQR = 3–9), chlamydia or gonorrhoea 4%, md length sexually active 3 y, md # new partners in last 2 months 0 (IQR = 0–1)	Always vs. less than always in the period since previous visit; assessed by interview at baseline and interval visits
Hogewoning et al. 2003⁸	The Netherlands	Randomized clinical trial	Referred for colposcopy because of an abnormal smear (≥mild dysplasia) and/or colposcopically or histologically diagnosed CIN, the woman and her partner had no other sexual partners, no CIN treatment at baseline (i.e., CIN2 and CIN3 over ≥2 cervical quadrants), no regular condom use for birth control at baseline	Intervention arm:^b me age 34.1 y (range: 19.1–54.7); colposcopically-confirmed CIN: CIN1 53%, CIN2 45%, CIN3 2%; histologically confirmed CIN: no biopsy 9%, no CIN 13%, CIN1 28%, CIN2 48%, CIN3 2%; smoking 38%,^c users of oral contraceptives 46%;^c me age at first intercourse 16.3 y (range: 13–21);^c history of STI 8%;^c me # of lifetime sex partners 5.6 (range: 1–15);^c other sexual partner last year 8%;^c married/living together 92%;^c me duration of relation 9.7 y (range: 0.6–35);^c me frequency of sexual intercourse per mo 7.2 (range: 0–22.5) ^c Control arm:^b me age 35.1 y (range: 22.5–52.6); colposcopically-confirmed CIN: CIN1 59%, CIN2 39%, CIN3 2%; histologically confirmed CIN: no biopsy 7%, no CIN 18%, CIN1 41%, CIN2 31%, CIN3 3%; smoking 64%,^c users of oral contraceptives 64%;^c me age at first intercourse 16.2 y (range: 13–21);^c history of STI 16%;^c me # of lifetime sex partners 6.3 (range: 1-30);^c other sexual partner last year 0%;^c married/living together 88%;^c me duration of relation 8.7 y (range: 1–28);^c me frequency of sexual intercourse per mo 7.2 (range: 1–22.5)^c	Intervention arm: asked to use condoms during genital-genital contact for at least 3 mo (md duration of use: 6 mo (range: 3.0–53.7), failure to use: 7 women with a md of 2 times (range: 1–5));^b Control arm: no condom use; verbally verified at each visit by asking the frequency of condom use failure
Winer et al. 2006⁹	USA	Cohort study	18–22 y, undergraduate students, never had vaginal intercourse or had first intercourse with one male partner in ≤2 weeks before enrolment, had a cervix, not pregnant, in good general health, had vaginal intercourse during study	Me age: 19.3 y (SD = 0.7)	100% use vs. 50 to 99% use vs. 5–49% use vs. <5% use during 8 mo before HPV testing;^d assessed by web-based diary every 2 weeks
Shew et al. 2006¹²	USA	Cohort study	14–17 y, attending primary care adolescent health clinics, able to understand English, not have any serious psychiatric disturbances or mental handicaps, not pregnant	Me age 15.3 y, African American 85%, prior sexual experience 95%, me age at first coitus 13.2 y (SD = 1.7)	<60% of coital events protected by condom during an HPV infection vs. >60% condom use in the last 3 mo;^e assessed by interview at every clinic visit, and by daily diaries for 12 weeks at a time
Sánchez-Alemán et al. 2011¹¹	Mexico	Cohort study	Sexually active university students	Me age 21.2 y, me age at sexual debut 18.7, me age of partner at woman’s sexual debut 21.6 y, current smoker 36.9%, marijuana use 9.7%, self-reported STI 2.5%, emergency contraceptive pill as regular contraception method 6.8%, consistent condom use 19.8%, ≥2 sex partners 18.1%, same-sex sexual partner 3.4%, casual partners 9.7%	Consistent (always) vs. inconsistent (almost always, half of the time, almost never, never) use over lifetime; assessed by questionnaire
Munk et al. 2012^15–17	Norway	Cohort study	25–40 y, referred to gynecology outpatient clinic for evaluation of atypical cytological cervical smear detected in population-based screening, not pregnant, no immune diseases, not treated for immunosuppression, no previous CIN treatment, biopsy-cone excision interval ≥80 d	Md age 32 y (range: 25–41),¹⁵ had given birth 58% (md age 24 y),¹⁶ smoking 33%, >10 sex partners 54%, ≤15 y at first sexual intercourse 26%¹⁷	Consistent use vs. non-use or inconsistent use in the period between baseline and final visit;^f assessed by interview at baseline and third visit

Abbreviations: # = number, CIN = cervical intraepithelial neoplasia, d = day(s), HPV = Human Papillomavirus, HSIL = high-grade squamous intraepithelial lesions, IQR = interquartile range, LSIL = low-grade squamous intraepithelial lesions, md = median, me = mean, mo = month(s), SD = standard deviation, STI = sexually transmitted infections, y = year(s).

Whole sample of 608 recruited women, among whom 26% were HPV+.

For all 125 randomized women.

Based on 41% of the sample with returned questionnaires.

Calculated by dividing the number of condoms used for vaginal intercourse by the number of instances of vaginal intercourse during the 8-month study period.

Proportion of condom-protected coital events during the duration of a specific HPV infection.

Consistent use defined as partners using condoms for all instances of sexual intercourse.

Table 2.

Description of women included in the studies, and main endpoints.

Authors, year of publication	Baseline cervical status (HPV or cervical lesions)	Main study endpoint(s)	Assessment of endpoint	HPV assay (# of detectable genotypes)	Planned follow-up duration (interval)	Loss to follow-up
Thomas et al. 1990¹⁰	Histologically confirmed and adjudicated CIN1^a	Histologically confirmed regression of untreated CIN1	Biopsy at study entry, and at 3 (if indicated by cytology and/or colposcopy) and 6 mo	Not relevant for definition of outcome	6 mo (every 3 mo)	None
Ho et al. 1998¹⁴	HPV-	Non-type-specific incident HPV infection	Cervicovaginal lavage at each visit	PCR MY09/MY11 and HMB01, Southern blot hybridization (16 HR + 22 LR genotypes)	3 y (every 6 mo, range: 3–24)^b	Me follow-up time 2.2 y, max 3.4 y, md # of visits 5 ^b
Moscicki et al. 2001¹³	Normal cytology and HPV- on a PCR assay at baseline and first follow-up, HPV+ at baseline on the HPV Profile assay	Incident LSIL on cytology after prior HPV infection	Cytology and colposcopy;^c at baseline and interval visits	Not relevant for definition of outcome	NR (every 4 mo if HPV+, or 6 mo if HPV-)	Md # of visits 10 (IQR: 5–16), md follow-up time 56 (IQR: 27–82); those with <3 visits had fewer sex partners at baseline and lower SES than women with ≥3 visits and ≥1 HPV + result
Hogewoning et al. 2003⁸	Colposcopically confirmed CIN 1 or CIN2/3 smaller than 2 cervical quadrants; Intervention arm: 87% HPV+ at baseline, Control arm: 80% HPV+ at baseline^d	Colposcopic regression of CIN (2 consecutive normal colposcopic diagnoses); clearance of HPV (2 consecutive negative HPV tests)	CIN regression: smears and colposcopy; biopsy only if suspected CIN progression; colposcopic diagnoses were adjudicated from photographs; HPV clearance: HPV testing	PCR GP5 + /6 + EIA (14 HR + 6 LR genotypes)	NR (at 3, 6, and 12 months after baseline, and subsequently every 12 months until CIN treatment if any)	Intervention arm: md follow-up time 16.4 mo (range: 3.0–85.4); Control group: 12.8 mo (3.1–63.0)^d
Winer et al. 2006⁹	HPV-	Genotype-specific incident HPV infection, and incident cervical squamous intraepithelial lesions on cytology^e	HPV testing (clinician- and self-collected) and cytology at every visit	PCR PGMY09/MY11, reverse line-blot (19 HR + 18 LR genotypes)	NR (every 4 mo, md = 4.1 mo)	Me follow-up time: 33.9 mo (SD = 11.8), me # of visits: 8.6 (SD = 2.9)
Shew et al. 2006¹²	HPV + at baseline or during follow-up^f	Genotype-specific HPV clearance^g	HPV testing: clinican-collected every 3 mo, self-collected every week for 12 weeks at a time	PCR/reverse blot strip assay with non-degenerate primers (19 HR + 8 LR genotypes)	27 mo (every 3 mo at the clinic, and weekly at home for 12 weeks at a time)	Me follow-up time: 2.2 y (range: 2.0–2.4)
Sánchez-Alemán et al. 2011¹¹	HPV-	Incident HPV infection	Self-collected HPV testing	Hybrid Capture 2 (13 HR genotypes)	NR^h	Me follow-up duration: 1.71 y
Munk et al. 2012^15–17	Histologically confirmed CIN2/3 (22% CIN2, 78% CIN3)	Histologically confirmed regression of untreated CIN (95% HPV+)ⁱ	Colposcopy at the second visit, colposcopy + cone excision at the third visit; histology was adjudicated	Not relevant for definition of outcome	≥3 visits (second visit 7–9 weeks after baseline, third visit 12–24 weeks after baseline, md 113 d (range: 84–171)	No loss to follow-up by design

Abbreviations: # = number, CIN = cervical intraepithelial neoplasia, HPV = Human Papillomavirus, HPV-/+ = HPV negative/positive, HR = high-risk genotypes (classification of high-risk genotypes as defined by authors of studies), HSIL = high-grade squamous intraepithelial lesions, IQR = interquartile range, LR = low-risk genotypes (classification of low-risk genotypes as defined by authors of studies), LSIL = low-grade squamous intraepithelial lesions, max = maximum, md = median, me = mean, mo = month(s), NR = not reported, PCR = polymerase chain reaction, SES = socioeconomic status, STI = sexually transmitted infections, y = year(s).

34 out of 42 (81%) patients in whom the distribution of HPV on initial colposcopy was fully charted had vulval and/or vaginal involvement.

Whole sample of 608 recruited women, among whom 26% were HPV+.

Majority of women with LSIL also underwent biopsy to rule out HSIL.

For all 125 randomized women.

Events detected during visits at which no instances of vaginal intercourse were recorded during the previous 8 months were excluded.

HPV infection defined as ≥2 positive specimens for a specific HPV genotype.

Defined as ≥2 negative specimens for the genotype before end of follow-up.

The interval was not clearly specified. Women were recruited in 2001, 2002 and 2003, and follow-up was carried out during the years 2002, 2003 and 2005.

Defined as ≤CIN1 in the subsequent cone. HPV testing based on formalin fixed paraffin embedded cervical biopsies, using the Linear Array assay (37 HR + LR genotypes) on all samples, and the AMPLICOR assay (13 HR genotypes) on samples negative on Linear Array.

Table 3.

Summary of study outcomes.

Study endpoint	Authors, year of publication	Condom use: exposure vs. reference group (n of women in analysis, or by condom use if reported)	Estimate of the relative risk (95% CI)	Adjustments	Conclusion regarding effectiveness of condoms in preventing cervical dysplasia
Regression of untreated histologically-confirmed CIN	Thomas et al. 1990¹⁰	54% condom use in all sex acts, 38% some use, 8% no coitus (n = 26) vs. 95% non-use, 5% some use (n = 20)	[RR = 0.77 (95% CI: 0.47–1.27)^a]	None	Not significantly protective
Incident HPV infection	Ho et al. 1998¹⁴	Always vs. never use (n = 399)	RR = 0.8 (95% CI: 0.4–1.4)^b	Age, race, alcohol consumption, # of sex partners in prior 6 and 7–12 mo, anal sex, frequency of vaginal sex, male partner’s # of lifetime partners, main partner currently in school, income, lifestyle, smoking, recreational drugs, oral contraceptives, # of casual sex partners, frequency of oral sex, sex with alcohol or drugs, postcoital bleeding, sex during menstruation, douching^b	Not significantly protective
Incident LSIL	Moscicki et al. 2001¹³	Always vs. less than always (n = 496)	HR = 0.82 (95% CI: 0.48–1.41)	None	Not significantly protective
Regression of untreated colposcopically confirmed CIN	Hogewoning et al. 2003⁸	Intervention arm (n = 50) vs. control arm (n = 48)^c	HR = 3.1 (95% CI: 1.4-7.1)	HPV status at baseline, histologic CIN grade at baseline, age at baseline	Significantly protective
Clearance of HPV infection	Hogewoning et al. 2003⁸	Intervention arm (n = 48) vs. control arm (n = 36)^d	HR = 12.1 (95% CI: 1.5–97.2)	HPV status at baseline, histologic CIN grade at baseline, age at baseline	Significantly protective
Incident HPV infection	Winer et al. 2006⁹	<5% (36.9 wy) vs. 5–49% (31.3 wy) vs. 50–99% (43.4 wy) vs. 100% (31.7 wy) use (n = 82)	All genotypes 5–49% vs. <5%: HR = 1.0 (95% CI: 0.5–1.8) 50–99% vs. < 5%: HR = 0.5 (95% CI: 0.3–0.9) 100% vs. <5%: HR = 0.3 (95% CI: 0.1–0.6) High-risk genotypes: 5–49% vs. <5%: HR = 1.0 (95% CI: NR) 50–99% vs. <5%: HR = 0.3 (95% CI: NR) 100% vs. <5%: HR = 0.3 (95% CI: NR) Low-risk genotypes: 5–49% vs. <5%: HR = 1.0 (95% CI: NR) 50–99% vs. <5%: HR = 0.8 (95% CI: NR) 100% vs. <5%: HR = 0.3 (95% CI: NR)	# of new sex partners, # of previous partners of sex partner	Significantly protective
Incident cervical squamous intraepithelial lesions	Winer et al. 2006⁹	<5% (37.0 wy) vs. 5–49% (24.8 wy) vs. 50–99% (35.0 wy) vs. 100% (32.1 wy) use (n = 82)	All genotypes 5–49% vs. <5%: HR = 0.5 (95% CI: 0.1–3.2) 50–99% vs. <5%: HR = 0.9 (95% CI: 0.2–3.6) 100% vs. <5%: HR = 0.0 (95% CI: 0–1.8)	# of new sex partners, # of previous partners of sex partner (in 8 months before HPV testing)	Not significantly protective
Clearance of HPV infection	Shew et al. 2006¹²	<60% use vs. >60% use (n = 49)	HR = 0.58 (95% CI: 0.35–0.97)^e	# of partners during an HPV infection, # of coital events during an HPV infection, oncogenic HPV type, C trachomatis / T vaginalis coinfection	Significantly protective
Incident HPV infection	Sánchez-Alemán et al. 2011¹¹	Inconsistent (321.9 wy) vs. consistent use (73.8 wy) (n = 237)	Inconsistent, 1 partner vs. consistent, 1 partner: HR = 2.1 (95% CI: 0.8–5.3) Consistent, ≥2 partners vs. consistent, 1 partner: HR = 4.8 (95% CI: 0.5–42.9) Inconsistent, ≥2 partners vs. consistent, 1 partner: HR = 3.8 (95% CI: 1.4–10.2)^f	Current tobacco consumption, marijuana use, self-reported STI, emergency contraceptive pill	Not significantly protective
Regression of untreated CIN	Munk et al. 2012¹⁵	Consistent (n = 18) vs. inconsistent or non-use of condoms (n = 144)	OR = 5.28 (95% CI: 1.68–16.62)	pRb, CIN length, CD4+ stroma	Significantly protective

Abbreviations: RR = relative risk, HR = hazard ratio, = number, wy = woman-years at risk, STI = sexually transmitted infections, OR = odds ratio.

Calculated as 0.70 (95% CI: 0.38–1.31) for comparing histologically confirmed regression in women with 100% use of condoms or no coitus (n = 16) vs. women with non-use of condoms (n = 19).

The use of condoms during vaginal sex was reported by authors as not significant in multivariate time-dependent proportional-hazards analysis; however, no RR estimate was shown. The RR estimate shown in this table was reported by Manhart and Koutsky after obtaining additional data from the investigators.⁵

Of the 125 randomized women, 17 were excluded due to lack of follow-up data after they showed a normal colposcopy once.

Of the 125 randomized women, 34 were excluded because they were HPV- at baseline, had cervical scrapes that were inadequate for HPV testing at baseline and/or during follow-up, or there was no available follow-up data on HPV after they were HPV- once. From the remaining 91 women, HR was based on 84 women.

Limited to periods during which sexual intercourse occurred.

Number of sexual partners during the past year.

In the study by Winer et al.,⁹ 82 initially virginal women were tested for HPV every four months. Samples were analyzed using PCR PGMY09/MY11 assay, and genotyped with a reverse line-blot assay. Every two weeks, these women were asked to complete web-based diaries (91% complete) detailing sexual acts including condom use. Consistent users during eight months before HPV testing had a substantially lower risk of acquiring HPV compared with women using condoms in <5% of sexual acts, Hazards ratio (HR) = 0.3 (95% CI: 0.1–0.6). Frequent but inconsistent condom use, defined as use in 50–99% of sexual acts, was also associated with a lower frequency of incident HPV infections, HR = 0.5 (95% CI: 0.3–0.9). Infrequent users (5–49% of sexual acts) had the same risk of HPV infections as women using condoms <5% of the time, HR = 1.0 (95% CI: 0.5–1.8). All estimates were adjusted for indicators of sexual behaviour, including the partners’ risk level. No consistent user had incident squamous intraepithelial lesions on cytology, but the numbers were too small to reach statistical significance.

In the study by Shew et al.¹² 49 adolescents were asked every three months to keep daily diaries on sexual activity, including condom use. Every week the girls obtained an HPV self-sample (HPV evaluation was undertaken using PCR/reverse blot strip assay), and every three months they underwent sampling performed by a clinician. Adjusted for indicators of sexual behaviour, HPV infections cleared faster in girls who used condoms in >60% of sexual acts (sample median) compared with those who used condoms less frequently, HR = 0.6 (95% CI: 0.4–1.00).

In a study by Sánchez-Alemán et al.¹¹ 237 women appeared to have been tested for HPV yearly, and their use of condoms was assessed over their lifetime. Samples were analyzed using the high-risk probe on the Hybrid Capture 2 assay. The risk of HPV infections increased with the number of sexual partners, and the use of condoms was not significantly protective when adjusting for this number, HR = 1.9 (95% CI: 0.8–4.4). Among women with one sexual partner, inconsistent users had a higher risk of HPV infections, but not significantly so, HR = 2.1 (95% CI: 0.8–5.3). No protective effect was found among women with two or more sexual partners, with similar relative risks for consistent and inconsistent condom use, HR = 4.8 (95% CI: 0.5–42.9) and HR = 3.8 (95% CI: 1.4–10.2), respectively. The estimates were adjusted for several lifestyle indicators.

Condom use and CIN lesions

Thomas et al.¹⁰ followed 46 women with untreated CIN1, and asked them either to consistently use condoms in the next six months (intervention group), or to avoid using condoms (control group). Women were assessed by cytology and colposcopy at three and six months, when compliance with condom use was also assessed in an interview. In the intervention group, only 54% of women used condoms consistently, while 38% reported some use. Histologically-confirmed CIN regression was not statistically significantly more frequent in the intervention than in the control group, [unadjusted RR = 0.8 (95% CI: 0.5–1.3)].

Moscicki et al.¹³ followed 496 women aged 13–20 in intervals of 4–6 months. Women were initially free of cytological abnormalities but tested positive for HPV at least once during the follow-up. Condom use was assessed at all visits. Consistent users had an unadjusted HR = 0.8 (95% CI: 0.5–1.4) of developing cytologically-confirmed low-grade squamous intraepithelial lesions compared with women who did not always use condoms. Women were selected into the study if they tested positive on the HPV Profile assay, but (twice) negative on a PCR HPV assay. Hence, we did not consider the reported results for incident HPV infections representative, as some of the infections considered incident on a PCR assay may have actually been persistent infections, originally detected by the HPV Profile assay.

In a randomized clinical trial by Hogewoning et al.⁸ 125 women with a colposcopic impression of CIN1 or CIN2/3 not stretching over more than one cervical quadrant and not using condoms for contraception were either recommended to use condoms for at least three months (intervention arm), or were not recommended to use condoms (control arm). Compliance with condom use was further stimulated by provision of free Durex fetherlite condoms. Women were assessed colposcopically at three and six months, and thereafter every six months. Consistency of condom use was verified verbally at each visit. Compliance in the intervention arm was high, with seven out of 64 women reporting on average two failures in condom use throughout the whole study. Actual use of condoms in the control group was not reported. After two years, the intervention group had a higher rate of regression of colposcopically-determined CIN than the control group, HR = 3.1 (95% CI: 1.4–7.1), and also more frequently cleared the baseline HPV infection, HR = 12.1 (95% CI: 1.5–97.2; tested using the PCR GP5 + /6 + assay). All estimates were adjusted for HPV status, CIN grade, and age at baseline.

At baseline, Munk et al.^15–17 asked 162 women with histologically-confirmed CIN2/3 to continue using their usual form of contraception, and to return for colposcopy two months, and again about three to six months after the baseline. Condom use was determined from interviews at baseline and final visits. Consistent condom use was associated with significantly more frequent regression of CIN2/3 compared with inconsistent use or non-use, odds ratio (OR) = 5.3 (95% CI: 1.7–16.6), adjusted for clinical variables. In inconsistent users, CIN2/3 regressed as frequently (13%) as in non-users (17%), p = 0.9. However, the protective effect of consistent use was only seen in women who, at baseline, were not infected with HPV16.

Discussion

Four out of eight longitudinal studies showed a statistically significant protective effect of condoms in prevention of HPV infections and cervical neoplasia. This means that consistent users had: a significantly lower risk of becoming infected with HPV, a higher chance to clear the existing infections, or a higher chance of high-grade CIN regression without surgical intervention. In the remaining four studies, a protective effect was also observed for these outcomes, although it was not statistically significant. This is a substantially more positive message compared with that from an earlier systematic review including predominantly cross-sectional studies.⁵

Nevertheless, there are several reasons to suggest that the effectiveness of condoms may be underestimated, even in these longitudinal studies. As in vitro studies showed that condoms are a nearly impermeable barrier for transmission of small viruses like HPV,¹⁸ why is it that the observed protective effect is not higher in in vivo studies? Several design weaknesses of the currently available studies, discussed below, may have contributed to this.

HPV can be transmitted by skin contact,^19;20 and is found in male genital areas not covered by a condom.²¹ Furthermore, errors and problems such as breakage, slippage, or late application are also common.²² Hence, infection pathways and incorrect use, that are unaccounted for in studies, make condoms appear less protective against HPV infections.²³ In the study by Winer et al, the association between HPV infections and condom use was not changed after accounting for correctness of use in consistent users.⁹ Other studies did not verify that condoms were used correctly.

The risk of acquiring HPV is strongly related to the number of sexual partners.^{11,12,14,24,25} Condom use appears to be higher among casual and new sexual partners than among regular ones.^5,26–29 Hence, exposure to infections is often imbalanced between condom users and non-users, and would need to be accounted for in the analyses. Although several studies attempted to control this by, for example, adjusting for the number of sexual partners, or history of STI, some residual confounding is likely to have remained.²⁶ Differences in host characteristics between condom users and non-users, eg. their immunological status, which could explain the variation in HPV clearance rates, were not studied.

Cultural norms play an important role in how truthfully sensitive information is disclosed to researchers. As use of condoms is socially desirable, it might be reported more frequently than justified by reality,^30,31 thereby diluting the observed protective effect of condoms. Other reasons for misclassification of condom use have been discussed in the literature. For example, long recall periods may be associated with more frequently inaccurate reporting of use.^23,30,32,33 Correct recall may be a particular challenge for women who frequently engage in sexual acts,³² which is in itself a risk factor for acquiring an HPV infection. It has been argued that validity of self-reports increases when questionnaires or electronic diaries are used, instead of face-to-face interviews,^31,34 but the latter were still frequently used in the reviewed studies.

It should also be noted that the life-time protective effect of condoms is smaller than that observed in epidemiological studies. Even per sexual act, condoms are not 100% effective. Therefore, the proportion of women without an HPV infection will gradually decrease with an increasing number of sexual acts.^18,35 In epidemiological studies typically covering a relatively short period, only a certain proportion of life-time infections can be observed. The length of the reviewed studies varied, however, only two^12,14 adjusted for the frequency of sexual intercourse during follow-up.

When the outcome of interest is detection of HPV infections, differences in condom quality and instructions for use, sampling methods, and the utilized HPV assays should be taken into account. Only one study⁸ reported which brand of condoms was distributed to women to increase compliance. Sampling methods varied across studies. For example, Ho et al. used a lavage sample.¹⁴ Lavage sampling returns varying volumes for HPV testing, and this variability might affect the HPV positivity rate. Sampling for HPV has developed tremendously since that study was undertaken; contemporary utensils and media secure a more uniform result for the subsequent HPV analysis. Finally, the time span between the publications in this systematic review (1990–2012), also highlights the technical progress in HPV detection technologies. Whereas earliest studies detected HPV using PCR and southern blotting methods, later studies used MY09/11 or GP5 + /6 + consensus primers with line blot detection, and, finally, the FDA-approved Hybrid Capture 2 assay. If these studies were redone today, modern HPV sampling and testing technologies would probably lead to a higher degree of reproducibility of study results.

Implications for cervical screening

Substantial proportions of younger cohorts are now vaccinated against HPV genotypes 16/18. As demonstrated by the reviewed studies, the benefit of continuing condom use could derive either from partial primary prevention of infections⁹ or from partial prevention of re-infections.^8,12,15 Consistent use of condoms in real life would be difficult to maintain over the entire sexually active life. However, the frequency of regular condom use could be increased by innovations that would make the condom less cumbersome,³⁶ whereas their effectiveness could perhaps be improved by increasing awareness about correct use.

For decades, cervical cancer has been successfully controlled by cytology-based cervical screening.³⁷ Because HPV testing is more sensitive in detecting high-grade CIN and preventing cervical cancers,³⁸ many countries are now considering replacing cytology with HPV testing. However, one of the main concerns with HPV-based screening is a high number of infected women with no underlying high-grade CIN or cervical cancer (false-positive tests), even among those aged ≥30 years.³⁹ Although the hypothesis has not been formally studied, what the data from the reviewed longitudinal studies seem to suggest is that (a more consistent) use of condoms might potentially reduce the number of women with (false-)positive primary screening HPV tests who would need further clinical management.

There are other implications of the reviewed condom studies that are relevant in cervical screening. Firstly, treatment of CIN is sometimes associated with pain, bleeding, and possibly a higher frequency of severe obstetric outcomes.⁴⁰ Studies in women with CIN lesions included in this review showed that condoms could be used to prevent unnecessary surgical CIN treatments. In those studies, the beneficial effect was already seen after relatively short periods of consistent use. However, it remains to be determined whether this effect can be maintained over a longer period. In the context of the generally short study durations, a reason for cautiousness is that the tissue prone to infections and cancerous growths is removed by CIN treatment; when lesions regress spontaneously as a consequence of condom use, this tissue remains intact and susceptible to new disease processes.

Secondly, condom users appeared to clear HPV infections faster than non-users, possibly by reducing continuous transmission of the virus between sexual partners.¹² In HPV-based cervical screening, many women are expected to test HPV-positive without having cervical abnormalities.⁴¹ As these women have a substantial risk of future high-grade CIN, they will be referred for colposcopy if their infections persist. The persistence of these infections, and with it the need for colposcopy referral, could perhaps be reduced if women used condoms consistently throughout the waiting period. Finally, another possible indication for recommending consistent and correct condom use could be in women after surgical treatment of CIN. Women with untreated CIN3 have a 30% chance of developing cervical cancer in 30 years,⁴² but with treatment this risk decreases by approximately 95%.⁴³ Nevertheless, women treated for CIN continue having a higher incidence of cervical cancer than the general population³, possibly because of a higher frequency of new or repeated HPV infections. These two indications for use of condoms in supplementing the effect of cervical screening have not yet been formally studied.

Conclusion

Consistent use of condoms appears to offer relatively good, though partial, protection from HPV infections and associated cervical diseases, although many aspects of this protection remain to be elucidated. Even in longitudinal studies, the protective effect of correct condom use is probably underestimated. Carefully undertaken prospective cohort studies or randomized controlled trials are warranted to further determine the potential role of condoms in prevention of HPV infections and related cervical lesions.

Declaration of conflicting interests

JUHL, PAD, and MEC declare no competing interests.

MR, JB and EL are currently undertaking a comparative study of four HPV assays, involving collaboration with the following assay manufacturers: Qiagen, Roche, Genomica, and Hologic/Gen-Probe.

MR and her employer received honoraria from Qiagen for lectures.

JB has served as a paid advisor to Roche Molecular Systems and Genomica, and received honoraria from Hologic/Gen-Probe, Roche, Qiagen, Genomica, and BD Diagnostics for lectures. He has received funding and/or consumables to carry out assay evaluations from Hologic/Gen-Probe, Genomica, Qiagen, Roche, and BD Diagnostics.

EL served as an unpaid advisor to Hologic/Gen-Probe and Norchip.

None of the authors was compensated for their work on this project, holds stock, or received bonuses from any of the manufacturers.

Financial disclosure

This work was supported by the Danish Strategic Research Council [grant number: 10–092793 to MR] and the University of Copenhagen [to PAD].

None of the funders had a role in the study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the article for publication. The researchers worked independently of the funders.

Previous presentations

This work was presented as an oral communication at Eurogin 2013, 3–6 November 2013, Florence, Italy (abstract number: OC11–1).

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgments

The authors thank Lene Borrits (Royal Danish Library) for help with the search strategy, and Bryan Howard Goldman (Department of Public Health, University of Copenhagen) for statistical help.

Appendix

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Condom use in prevention of Human Papillomavirus infections and cervical neoplasia: systematic review of longitudinal studies

Abstract

Objectives

Methods

Results

Conclusions

Keywords

Introduction

Methods

Statistical analysis

Results

Condom use and HPV infections

Condom use and CIN lesions

Discussion

Implications for cervical screening

Conclusion

Declaration of conflicting interests

Financial disclosure

Previous presentations

Footnotes

Funding

Acknowledgments

Appendix

References