Assessment of off-label use of denosumab 60 mg injection during the early postmarketing period using health insurance claims data.

UNLABELLED: Off-label use of denosumab 60 milligram (mg) injection was assessed within an administrative claims database. The completeness of claims to assess off-label use was investigated with medical record review. Potential denosumab 60 mg off-label use was observed based on claims, but many had evidence of on-label indications based on medical record review. INTRODUCTION: Denosumab 60 mg injection is approved in the USA to treat patients at high fracture risk due to postmenopausal osteoporosis, male osteoporosis, and hormone therapy for the treatment of prostate and breast cancers. Its RANK ligand-inhibiting effect makes it a candidate for the off-label treatment of other conditions mediated by the rate of bone resorption by osteoclasts. To better understand its utilization patterns, we assessed off-label use of denosumab 60 mg within an administrative claims database. METHODS: Definite, probable, and possible denosumab 60 mg users were identified during the early postmarketing period within a claims database of a US healthcare insurer. Medical record review confirmed a sample of these users. Off-label use among definite and probable users and all chart-confirmed users was classified using claims-derived age, dose interval, and diagnosis and treatment received relative to the administration date. Among chart-confirmed users classified as off-label, patient characteristics related to treatment indication were abstracted from medical records to investigate the completeness of claims to study off-label medication use. RESULTS: Off-label use was identified based on claims in approximately 25 % of definite and probable denosumab 60 mg users and 35 % of chart-confirmed users. Medical record review identified evidence of on-label indications in 81 % of chart-confirmed users classified as off-label in claims. CONCLUSIONS: Many of the off-label denosumab 60 mg users had diagnoses or treatment consistent with on-label indications based on medical record review, suggesting these are under-recorded in claims data. It is warranted to be cautious when using administrative databases to assess off-label medication use.

Comparison of human immunodeficiency virus (HIV)-specific T-cell responses in HIV-1- and HIV-2-infected individuals in Senegal.

Human immunodeficiency virus type 2 (HIV-2) infection is typically less virulent than HIV-1 infection, which may permit the host to mount more effective, sustained T-cell immunity. We investigated antiviral gamma interferon-secreting T-cell responses by an ex vivo Elispot assay in 68 HIV-1- and 55 HIV-2-infected Senegalese patients to determine if differences relate to more efficient HIV-2 control. Homologous HIV-specific T cells were detected in similar frequencies (79% versus 76%, P = 0.7) and magnitude (3.12 versus 3.08 log(10) spot-forming cells/10(6) peripheral blood mononuclear cells) in HIV-1 and HIV-2 infection, respectively. Gag-specific responses predominated in both groups (>/=64%), and significantly higher Nef-specific responses occurred in HIV-1-infected (54%) than HIV-2-infected patients (22%) (P < 0.001). Heterologous responses were more frequent in HIV-1 than in HIV-2 infection (46% versus 27%, P = 0.04), but the mean magnitude was similar. Total frequencies of HIV-specific responses in both groups did not correlate with plasma viral load and CD4(+) T-cell count in multivariate regression analyses. However, the magnitude of HIV-2 Gag-specific responses was significantly associated with lower plasma viremia in HIV-1-infected patients (P = 0.04). CD4(+) T-helper responses, primarily recognizing HIV-2 Gag, were detected in 48% of HIV-2-infected compared to only 8% of HIV-1-infected patients. These findings indicate that improved control of HIV-2 infection may relate to the contribution of T-helper cell responses. By contrast, the superior control of HIV-1 replication associated with HIV-2 Gag responses suggests that these may represent cross-reactive, higher-avidity T cells targeting epitopes within Gag regions of functional importance in HIV replication.

HLA class II DR-DQ and increased risk of cervical cancer among Senegalese women.

To examine Senegalese women to confirm and extend associations between HLA class II types and cervical cancer previously observed among African-American, Caucasian, Hispanic, and Japanese ethnic populations, 55 Senegalese women with invasive cervical carcinoma were compared with age-matched (human papillomavirus) HPV-positive (n = 83) and HPV-negative (n = 107) control women. PCR-based HPV and HLA typing methods were used. Data were analyzed using a global randomization test and conditional logistic regression. Although this study failed to confirm a previously reported association between cervical cancer and DQB1*03 alleles, the DRB1*1101-DQB1*0301 haplotype was detected more frequently among cervical carcinoma cases than among controls (adjusted odds ratio, 2.6; 95% confidence interval, 1.0-7.1). Furthermore, as reported by others, we observed a negative association of borderline statistical significance between DRB1*13 and cervical carcinoma (adjusted odds ratio, 0.5; 95% confidence interval, 0.2-1.1). Observations from this study confirm earlier findings of a negative association between DRB1*13 and cervical cancer and suggest that specific DRB1-DQB1 haplotype combinations, rather than individual DQB1*03 alleles, increase the risk for cervical cancer.

Human papillomavirus and long-term oral contraceptive use increase the risk of adenocarcinoma in situ of the cervix.

We examined United States Surveillance, Epidemiology, and End Results incidence data and conducted a population-based case-control study to examine the role of human papillomavirus (HPV) and oral contraceptive (OC) use in the etiology of adenocarcinoma in situ of the cervix (ACIS). One hundred and fifty women diagnosed with ACIS and 651 randomly selected control women completed in-person interviews. The presence of HPV DNA in archival ACIS specimens was determined by E6 and L1 consensus PCR. Serum samples from case and control subjects were collected at interview, and antibodies to HPV-16 L1 and HPV-18 L1 were detected by virus-like particle capture assays. The overall prevalence of HPV DNA was 86.6%, with 39.0% positive for HPV-16 DNA, 52.4% positive for HPV-18 DNA, and 13.4% positive for more than one HPV type. The age-adjusted relative risk of ACIS associated with HPV-18 seropositivity was 3.3 (95% confidence interval 2.2-4.9). No increased risk was associated with antibodies to HPV-16 L1. Among women born after 1945, the relative risk increased with duration of OC use, with the highest risk for 12 or more years of use (odds ratio, 5.5; 95% confidence interval, 2.1-14.6) relative to nonusers. The detection of HPV DNA in 86.6% of ACIS and the strong association of ACIS with HPV-18 L1 seropositivity underscore the importance of HPV, particularly HPV-18, in the etiology of ACIS. In addition, long-term OC use may contribute to the pathogenesis of these tumors in some women.

Characterization of ciliary activity in distal Fallopian tube biopsies of women with obstructive tubal infertility.

Biopsy specimens were obtained from the distal end of the Fallopian tubes of 62 women with tubal infertility and examined by light and electron microscopy. Ciliary beat frequency (CBF) measurements were obtained using laser light spectroscopy. Neither demographic nor behavioural characteristics nor serological evidence of past chlamydial infection were associated with CBF measurements. In contrast, CBF were significantly lower (P < 0.05) in tissues with oedema compared to tissues without oedema (6.7 versus 12.9) and in tissues with erythema compared to tissues without erythema (9.2 versus 13.7). Furthermore, CBF measurements did vary by chlamydial serotype pattern, with lower values observed among the tissues of women with antibodies to serotype C or E (without D) as compared to the tissues of women with other serotypes (P < 0.04). However, these data must be interpreted with caution as the numbers of subjects with chlamydial antibodies to serotype C (n = 3) or E without D (n = 5) were few in number and serotyping of IgG antibodies in blood is not as accurate as it is in bacterial isolates. Confirmation of the suggested association between chlamydial serotype and risk of adverse sequelae could indicate potential new avenues for vaccine research.

Risk of anal carcinoma in situ in relation to human papillomavirus type 16 variants.

Infection with human papillomavirus (HPV), especially HPV16, is central to the development of squamous anogenital cancers and their precursor lesions, termed "squamous intraepithelial neoplasias." Men who have sex with men, particularly those who are infected with HIV, are at a high risk for anal infection with HPV16 and for low-grade anal neoplasia; however, only a subset of these men develop anal invasive cancer or its immediate precursor lesion, anal carcinoma in situ (CIS). To examine the hypothesis that certain variants of HPV16 are most strongly associated with development of anal CIS, we followed 589 men who have sex with men whose initial anal cytological smears did not show anal CIS. Anoscopy, anal cytology, and PCR-based assays for detection and classification of HPV types were performed every 4-6 months, with HPV16 further classified by single-stranded conformation polymorphism analysis as being a prototype-like (PL) or non-prototype-like (NPL) variant. Anal CIS was histologically confirmed in 6 of 384 (1.6%) consistently HPV16-negative men, in 12 of 183 (6.6%) men with HPV16 PL variants, and in 4 of 22 (18.2%) men with HPV16 NPL variants. After adjustment for anal cytological diagnoses at study entry, HIV status and CD4 count, and detection of HPV types other than type 16, men with HPV16 NPL variants were 3.2 times (95% confidence interval, 1.0-10.3) more likely to develop anal CIS than were those with PL variants. Neither detection of HPV16 DNA at high levels nor detection of HPV16 DNA for a prolonged period, factors that we previously demonstrated to be associated with risk of high-grade anal squamous intraepithelial neoplasia, was significantly associated with HPV16 NPL variants. The biological mechanism relating to Ihis excess risk remains undetermined.

Effect of HIV infection on the natural history of anal human papillomavirus infection.

OBJECTIVE: To identify risk factors for the detection of prevalent and incident anal human papillomavirus (HPV) infection, and HPV persistence among HIV-seropositive and seronegative homosexual men. DESIGN: Longitudinal study of 287 HIV-seronegative and 322 HIV-seropositive men attending a community-based clinic. METHODS: Subjects underwent an interview and examination; specimens were collected for HIV serology and assessment of anal HPV and HIV DNA. RESULTS: Anal HPV DNA was detected at study entry in 91.6% of HIV-infected men, and 65.9% of men not infected with HIV. HPV detection was associated with lifetime number of sexual partners and recent receptive anal intercourse (HIV-seronegative men), decreased CD4+ lymphocyte count (HIV-seropositive men), and anal warts (all men). Among men negative for HPV at study entry, subsequent detection of HPV was associated with HIV, unprotected receptive anal intercourse, and any sexual contact since the last visit. Among men positive for HPV at study entry, subsequent detection of additional HPV types was more common among HIV-seropositive men. Becoming HPV negative during follow-up was less common among men with HIV or high HPV levels at study entry. Among those with HIV, HPV persistence was associated with presence of anal HIV DNA, but not with CD4+ lymphocyte count. CONCLUSIONS: Risk of anal HPV infection appears to increase with sexual exposure, epithelial trauma, HIV infection and immune deficiency. Incident infection may result from recent sexual exposure or reactivation of latent infection. Further studies are needed to elucidate the mechanism by which HIV DNA in the anal canal increases the risk of HPV persistence.

Determinants of human immunodeficiency virus DNA and RNA shedding in the anal-rectal canal of homosexual men.

To define the determinants of anal-rectal shedding of human immunodeficiency virus (HIV) DNA and RNA, 374 HIV-seropositive homosexual men were tested. Factors independently associated with detection of anal-rectal HIV DNA included anal-rectal inflammation and detection of anal human papillomavirus DNA; predictors of HIV RNA included detection of anal-rectal HIV DNA, anal-rectal inflammation, and high plasma HIV RNA levels. The latter (>10,000 copies/mL) was the main determinant of anal-rectal HIV RNA shedding when HIV DNA (e.g., HIV-infected cells) was not detected in the anal-rectal sample. The local presence of HIV-infected cells and local inflammation were the principal determinants of HIV RNA among those with low (<10,000 copies/mL) plasma HIV RNA load. Among those with anal-rectal HIV DNA present, increased HIV RNA plasma load did not increase the risk of shedding of HIV RNA into the anal-rectal canal.

Seroprevalence of human papillomavirus types 6 and 16 capsid antibodies in homosexual men.

Human papillomavirus (HPV) has been implicated in the pathogenesis of anal carcinoma, which is increased in homosexual men. Little is known about the serologic response to HPV in normal or immunosuppressed men; therefore, HIV-infected and -uninfected homosexual men were screened for HPV-6 and -16 capsid antibodies. HIV-infected men had increased HPV DNA detection but did not significantly differ in the prevalence of serum HPV antibodies. HPV-6 DNA detection and the presence of anal warts were significantly correlated with serum antibody overall and in the HIV-infected subgroup. HPV-16 DNA detection was not significantly correlated with serum antibody overall or in either subgroup; however, HIV-infected men with high-grade anal squamous intraepithelial lesions were significantly more likely to have HPV-16 antibodies. HIV-infected men are able to generate an antibody response to HPV, and a lack of serum HPV antibodies cannot explain the increased HPV-associated disease seen in HIV-infected men.

Detection of human immunodeficiency virus type 1 and type 2 in the female genital tract: implications for the understanding of virus transmission.

Risk of perinatal or female to male sexual transmission of HIV is likely to be associated with whether, and at what concentration, the virus is present in the cervical and vaginal secretions of the HIV-infected woman. Examining correlates of cervical and vaginal HIV shedding is, therefore, essential for the development of strategies to interrupt HIV transmission. This article presents the rationale for using detection of HIV in the female genital tract as a marker of infectivity, and briefly describes methods for detecting HIV-1 and HIV-2 in cervical or vaginal fluids. Findings from studies incorporating the measurement of HIV in the female genital tract are reviewed, placing particular emphasis on issues relevant to epidemiological studies of HIV transmission.

HIV-1, HIV-2, human papillomavirus infection and cervical neoplasia in high-risk African women.

OBJECTIVE: To determine the effect of HIV-1 and HIV-2 infection on the prevalence of cervical human papillomavirus (HPV) and squamous intraepithelial lesions (SIL) in a population of high-risk women in Senegal. DESIGN AND PARTICIPANTS: Cross-sectional study among 759 female commercial sex workers, including 68 with HIV-1, 58 with HIV-2, 14 with HIV-1 and 2, and 619 without HIV infection. RESULTS: Overall, HPV was detected in 43% of women by polymerase chain reaction (PCR), and in 7% by Southern transfer hybridization, with 7.4% of all women having SIL. The mean CD4 count was 820, 1205, and 727 x 10(6)/l for those with HIV-1, HIV-2, and dual HIV-1 and 2 infections, respectively, and 1447 x 10(6)/l for those without HIV infection. Both HIV-1 and HIV-2 were associated with HPV, as detected by PCR [HIV-1 odds ratio (OR), 2.9; 95% confidence interval (Cl), 1.7-4.9; HIV-2 OR, 1.7; 95% Cl, 1.0-2.9]. HIV-2 was also associated with cervical SIL, and although the association between HIV-1 and SIL did not attain statistical significance, a trend was apparent (HIV-1 OR, 1.8; 95% Cl, 0.7-4.7; HIV-2 OR, 2.9; 95% Cl, 1.2-7.2). CONCLUSIONS: Despite less immunosuppression with HIV-2, both HIV-1 and HIV-2 were associated with detection of HPV. HIV-2 was also associated with SIL. Further studies are needed to examine the risks of high-grade SIL and invasive cervical cancer with HIV-1 versus HIV-2 infection.

PIP: Between February 1990 and March 1993, 759 female commercial sex workers who attended sexually transmitted disease (STD) clinics in Dakar, Thies, and Mbour, Senegal, were interviewed and underwent a general physical and detailed gynecologic examination so researchers could ascertain the influence of HIV-1 and HIV-2 infection on the prevalence of cervical human papillomavirus (HPV) and squamous intraepithelial lesions (SIL) in this high-risk population. Most lesions were low-grade SIL. 619 had neither HIV-1 nor HIV-2 infection. 9%, 8%, and 2% had HIV-1, HIV-2, and concurrent HIV-1 and HIV-2 infection, respectively. Polymerase chain reaction revealed that 43% had HPV infection, while Southern transfer hybridization found only 7%. HIV-1 infected women faced a significant increased risk for HPV (adjusted odds ratio [AOR] = 2.9) as also did HIV-2 infected women (AOR = 1.7). Both these groups also faced an increased risk for SIL (AOR = 1.8 and 2.9, respectively), but the increased risk was not significant. Similarly, women infected with both HIV-1 and HIV-2 faced an increased risk of HPV and SIL (AOR = 4.9 and 5.2, respectively). Among women with HIV infection, women with HPV had a lower CD4 count and CD4/CD8 ratio (854 vs. 1033 million/l, p = 0.08, and 0.88 vs. 1.17, p = 0.05, respectively) than women with no detectable HPV. HIV-positive women with SIL had a lower CD4/CD8 ratio than HIV-positive women without SIL (0.65 vs. 1.03; p = 0.003). HIV-2 women exhibited lower immunosuppression than HIV-1 women. These findings show that both HIV-1 and HIV-2 infection were associated with HPV and SIL. The researchers expressed interest in longitudinal studies designed to examine the risk of high-grade SIL, the direct precursor of invasive cervical cancer, among HIV-infected women.

Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: influence of HIV infection, immunosuppression and human papillomavirus infection.

OBJECTIVE: To determine the risk of developing high grade anal squamous intraepithelial neoplasia (HG-AIN) in relation to HIV infection and immunosuppression, after controlling for the effects of human papillomavirus (HPV) infection. DESIGN: Prospective cohort study of 158 HIV-seropositive and 147 HIV-seronegative homosexual men presenting to a community-based clinic with initially negative anal cytologic and colposcopic findings. METHODS: Subjects completed self-administered questionnaires, underwent cytologic screening, and standardized unaided and colposcopic examination of the proximal anal canal for presence of abnormalities suggestive of AIN. Anal specimens were screened for HPV DNA. RESULTS: HG-AIN developed in eight (5.4%) and 24 (15.2%) HIV-seronegative and -seropositive men, respectively. Risk of HG-AIN among HIV-seronegative men was associated with detection of anal HPV types 16 or 18 by Southern transfer hybridization (STH), detection of HPV 16 or 18 at the lower levels by polymerase chain reaction but not by STH, and with number of positive HPV tests; HG-AIN risk among HIV-seropositive men was associated with detection of HPV 16 or 18 only by STH, detection of HPV types other than 16 or 18, CD4 count < or = 500 x 10(6)/l, and number of positive HPV tests. HIV-induced immunosuppression remained an independent predictor of HG-AIN after adjusting for type and level of detection of HPV; HIV infection predicted HG-AIN risk after adjustment for number of positive HPV tests. CONCLUSIONS: The association of HG-AIN with HIV, independent of HPV type, level of HPV detection and number of positive HPV tests, suggests that this increased risk cannot be entirely explained by an effect of HIV on HPV detection. Future studies focusing on factors more specific to the local microenvironment in the anal canal should help clarify these issues.

Determinants of cervical ectopia and of cervicitis: age, oral contraception, specific cervical infection, smoking, and douching.

OBJECTIVE: Our purpose was to assess determinants of cervical ectopia and cervicitis, specifically after adjustment for cervical infection. STUDY DESIGN: A cross-sectional study was conducted with colposcopic, cytologic, and microbiologic examination of 764 randomly selected women attending a sexually transmitted disease clinic and 819 consecutive college students undergoing routine annual examination. RESULTS: After we controlled for potential confounders, cervical ectopia was positively associated with oral contraception and Chlamydia trachomatis infection and negatively associated with aging in both populations, with recent vaginal douching in patients with sexually transmitted diseases, and with current smoking in college students. Oral contraception wa also associated with the radius of ectopia, and among users of oral contraception ectopia was associated with duration of oral contraception. Cervicitis (evaluated by Gram stain, Papanicoloau smear, and colposcopy) was associated with cervical infection by C. trachomatis and cytomegalovirus (both populations) and with gonorrhea and cervical herpes simplex virus infection (patients with sexually transmitted diseases). Cervicitis was independently associated with ectopia but not with oral contraception after we adjusted for these four cervical infections. However, oral contraception was associated with edema and erythema of the zone of ectopia among women without cervical infection. CONCLUSIONS: Oral contraception, aging, cervical infection, smoking, and douching have effects on cervical ectopia that may influence the acquisition, transmission, or effects of sexually transmitted agents. Ectopia is associated with young age, oral contraception, and cervical infection; cervicitis is associated with ectopia and cervical infection by C. trachomatis, Neisseria gonorrhoeae, herpes simplex virus, and cytomegalovirus. In women without cervical infection, edema and erythema of the zone of ectopia are associated with oral contraception.

Cervical intraepithelial neoplasia and human papillomavirus infection among Senegalese women seropositive for HIV-1 or HIV-2 or seronegative for HIV.

Studies in various regions of the world have shown that women infected with HIV-1 are at increased risk for cervical human papillomavirus (HPV) infection as well as for cervical cancer precursor lesions. HIV infection and cervical cancer are both widespread in West Africa, but little is known about the relationship between HPV and HIV-2, which is the predominant type of HIV in the general population of many West African countries. To address this issue, we collected cervical samples for cytology and HPV analysis from 93 women presenting to the University of Dakar Infectious Disease Service (18 women with HIV-1 infection, 17 with HIV-2 infection, and 58 HIV seronegative controls). Compared to those without HIV infection, HIV seropositive women were 13.1 (95% CI = 2.4, 128) and 11.0 (95% CI = 3.5, 35.8) times more likely to have HPV detected using Southern transfer hybridization (STH) and the polymerase chain reaction (PCR) respectively. Detection of high and intermediate risk HPV types were significantly associated with HIV-1 and HIV-2 infection. Among HPV positive women, those with, as compared to those without HIV infection were more likely to harbour high risk HPV types (OR = 9.2, 95% CI = 0.97, 433). HIV-1 and HIV-2 seropositive women were 23.3 (95% CI = 2.9, 209) and 9.3 (95% CI = 1.1, 79) times more likely to have cytological diagnosis of dysplasia, respectively, than were HIV seronegative women. Biopsy-proven CIN 3 was found in one woman with HIV-1 and invasive cancer was found in one woman with HIV-2.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Studies in various regions of the world have shown that women infected with HIV-1 are at increased risk for cervical human papillomavirus (HPV) infection as well as for cervical cancer precursor lesions. HIV infection and cervical cancer are both widespread in West Africa, but little is known about the relationship between HPV and HIV-2, the predominant type of HIV in the general population of many West African countries. The authors report findings from their collection of cervical samples for cytology and HPV analysis from 93 women presenting to the University of Dakar Infectious Disease Service; 18 women infected with HIV-1, 17 with HIV-2, and 58 HIV seronegative controls. Compared to those without HIV infection, HIV seropositive women were 13.1 and 11.0 times more likely to have HPV detected using Southern transfer hybridization and the polymerase chain reaction, respectively. The detection of high and intermediate risk HPV types was significantly associated with HIV-1 and HIV-2 infection. Among HPV-positive women, those infected with HIV were more likely to harbor high-risk HPV types. HIV-1 and HIV-2 seropositive women were 23.3 and 9.3 times more likely to have a cytological diagnosis of dysplasia, respectively, than were HIV-seronegative women. Biopsy-proven cervical intraepithelial neoplasia (CIN) 3 was found in one woman with HIV-1 and invasive cancer was found in one woman with HIV-2. It remains unclear, however, whether HIV-1 and HIV-2 confer similar risks of developing CIN 2-3 and the potential of invasive cervical cancer.

Comparison of dot filter hybridization, Southern transfer hybridization, and polymerase chain reaction amplification for diagnosis of anal human papillomavirus infection.

The detection and classification of human papillomavirus (HPV) by a consensus primer polymerase chain reaction (PCR) technique were compared with detection and classification by dot filter hybridization (DFH) and Southern transfer hybridization (STH). PCR detected HPV in 87% of specimens; the detection rates for DFH and STH were 51% and 49%, respectively. The specific HPV types detected by STH were also detected by PCR in 90% of specimens. However, 75% of the samples positive for unclassified HPV by STH were typed by PCR. PCR results were reproducible, as assessed by repeat analysis (96% agreement), by analysis of paired same-day specimens (89% agreement), and by interlaboratory analysis (88% agreement). PCR is a sensitive, specific, and reproducible test for HPV detection and classification in clinical and epidemiologic studies.

Association of anal dysplasia and human papillomavirus with immunosuppression and HIV infection among homosexual men.

OBJECTIVE: To examine and quantify the association between anal squamous intraepithelial lesions (ASIL), anal human papillomavirus (HPV) infection and immunosuppression among HIV-seropositive and HIV-seronegative homosexual men. DESIGN: Cross-sectional study among homosexual men presenting at a community-based clinic for HIV serologic screening. RESULTS: Anal HPV DNA was detected in 55 and 23% of 285 HIV-seropositive and 204 HIV-seronegative men, respectively, by Southern transfer hybridization (STH) [odds ratio (OR), 4.0; 95% confidence interval (CI), 2.7-6.2], and in 92 and 78% by polymerase chain reaction (PCR) (OR, 3.1; 95% CI, 1.6-5.8). ASIL was noted in 26% of HIV-seropositive men and in 8% of HIV-seronegative men (compared with men with negative cytologic findings: OR, 5.6; 95% CI, 3.0-10.5), with high-grade lesions noted in 4% of HIV-seropositive and in 0.5% of HIV-seronegative men. Among HIV-infected men, ASIL, detection of specific anal HPV types, and detection of high levels of anal HPV DNA (i.e., levels of HPV DNA detectable by both STH and PCR) were all associated with immunosuppression. Nevertheless, HIV-seropositive men with CD4 counts > 500 x 10(6)/l had a higher prevalence of both anal HPV and ASIL than men without HIV infection. Overall, detection of HPV at high levels was associated with ASIL. However, after adjustment for level of detectable HPV DNA, the risk of ASIL among HIV-seropositive men with CD4 counts < 500 x 10(6)/l was increased 2.9-fold (95% CI, 1.4-6.2) over that of HIV-seropositive men with CD4 counts > 500 x 10(6)/l. CONCLUSION: Given the high rates of ASIL in HIV-seronegative and both immunosuppressed and non-immunosuppressed HIV-seropositive homosexual men, natural history studies are now needed to assist in the development of strategies for the detection and management of such lesions. The increased prevalence of ASIL seen among immunosuppressed HIV-seropositive men may be the result of both a non-specific increase in productive HPV infection and HIV-induced immune alterations of HIV-related neoplasia.

A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection.

BACKGROUND: Human papillomavirus (HPV) has been associated with cervical intraepithelial neoplasia, but the temporal relation between the infection and the neoplasia remains unclear, as does the relative importance of the specific type of HPV, other sexually transmitted diseases, and other risk factors. METHODS: We studied prospectively a cohort of 241 women who presented for evaluation of sexually transmitted disease and had negative cervical cytologic tests. The women were followed every four months with cytologic and colposcopic examinations of the uterine cervix and tests for HPV DNA and other sexually transmitted diseases. RESULTS: Cervical intraepithelial neoplasia grade 2 or 3 was confirmed by biopsy in 28 women. On the basis of survival analysis, the cumulative incidence of cervical intraepithelial neoplasia at two years was 28 percent among women with a positive test for HPV and 3 percent among those without detectable HPV DNA: The risk was highest among those with HPV type 16 or 18 infection (adjusted relative risk as compared with that in women without HPV infection, 11; 95 percent confidence interval, 4.6 to 26; attributable risk, 52 percent). All 24 cases of cervical intraepithelial neoplasia grade 2 or 3 among HPV-positive women were detected within 24 months after the first positive test for HPV. After adjustment for the presence of HPV infection, the development of cervical intraepithelial neoplasia was also associated with younger age at first intercourse, the presence of serum antibodies to Chlamydia trachomatis, the presence of serum antibodies to cytomegalovirus, and cervical infection with Neisseria gonorrhoeae. CONCLUSIONS: Cervical intraepithelial neoplasia is a common and apparently early manifestation of cervical infection by HPV, particularly types 16 and 18.

Association of human immunodeficiency virus and anal human papillomavirus infection among homosexual men.

BACKGROUND: A previous study of men with proctitis, proctocolitis, or enteritis showed an association of anal human papillomavirus (HPV) infection with human immunodeficiency virus (HIV) infection. Because anorectal abnormalities may confound an observed association between anal HPV DNA and HIV seropositivity, the present study was undertaken among consecutive homosexual men seeking HIV serologic testing who were unselected for anorectal symptoms. METHODS: Consecutive homosexual men underwent a standardized interview, physical examination, and collection of specimens for HIV serologic testing and detection of anal HPV DNA. RESULTS: Anal HPV DNA was detected in eight (31%) of 26 HIV-seropositive men and in 10 (8%) of 119 HIV-seronegative men (odds ratio, 5.8; 95% confidence interval, 1.1 to 30.1, adjusted for history of sexually transmitted disease, current anorectal symptoms, and age). When men with anorectal symptoms were excluded from the analysis, anal HPV DNA was detected in 27% of seropositive men compared with 8% of seronegative men (odds ratio, 4.4; 95% confidence interval, 1.4 to 13.4). There was no difference between HIV-seropositive and HIV-seronegative men with respect to distribution of type of HPV DNA. Men with group II or III and group IV HIV disease were 4.1 and 10.9 times, respectively, more likely than HIV-seronegative men to have anal HPV DNA detected. CONCLUSIONS: Because HIV-seropositive men appear to be at increased risk for the detection of anal HPV DNA, the natural course of anal HPV infection should be compared among HIV-seropositive and HIV-seronegative homosexual men.

Prevalence and cytologic manifestations of human papilloma virus (HPV) types 6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, and 56 among 500 consecutive women.

The prevalence and associated cytologic manifestations of cervical infection with human papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, and 56 were studied among 500 consecutive women attending the Harborview Medical Center Sexually Transmitted Diseases (STD) Clinic in Seattle, WA. Using radiolabeled-probes without prior amplification of DNA, HPV DNA was detected in cervical specimens from 120 (24%) of the women and was found to be more prevalent than Chlamydia trachomatis (13%), Neisseria gonorrhoeae (12%), or mucopurulent cervicitis (20%). High-risk HPV types 16 or 18 were present alone in 5% of the women; intermediate-risk types 31, 33, 35, 45, 51, 52, or 56 in 3%; and low-risk types 6, 11, 42, 43, and 44 in 5%. In an additional 8% HPV DNA was detected but could be characterized only as being type 6, 11, 16, 18, 31, 33, or 35. Each grouping of HPV types was equally associated with squamous intraepithelial lesions (SILs) of the cervix. In the absence of SIL and koilocytosis, the cytologic changes associated with HPV infection included frequent binucleation and variation in nuclear size and chromatin distribution. Parakeratosis and hyperkeratosis without nuclear atypia were not associated with HPV DNA. The natural history and clinical significance of these HPV-associated lesions remain to be defined.