Michael Moxley

Effects of bacterial vaginosis and other genital infections on the natural history of human papillomavirus infection in HIV-1-infected and high-risk HIV-1-uninfected women.

BACKGROUND Whether the natural history of human papillomavirus (HPV) infection is affected by bacterial vaginosis (BV) or Trichomonas vaginalis (TV) infection has not been adequately investigated in prospective studies. METHODS Human immunodeficiency virus 1 (HIV-1)-infected (n=1763) and high-risk HIV-1-uninfected (n=493) women were assessed semiannually for BV (by Nugents criteria), TV infection (by wet mount), type-specific HPV (by polymerase chain reaction with MY09/MY11/HMB01 HPV primers), and squamous intraepithelial lesions (SIL) (by cytological examination). Sexual history was obtained from patient report at each visit. Risk factors for prevalent and incident HPV infection and SIL were evaluated by use of multivariate models. RESULTS BV was associated with both prevalent and incident HPV infection but not with duration of HPV infection or incidence of SIL. TV infection was associated with incident HPV infection and with decreased duration and lower prevalence of HPV infection. TV infection had no association with development of SIL. Effects of BV and TV infection were similar in HIV-1-infected and high-risk HIV-1-uninfected women. HIV-1 infection and low CD4(+) lymphocyte count were strongly associated with HPV infection and development of SIL. CONCLUSIONS BV and TV infection may increase the risk of acquisition (or reactivation) of HPV infection, as is consistent with hypotheses that the local cervicovaginal milieu plays a role in susceptibility to HPV infection. The finding that BV did not affect persistence of HPV infection and that TV infection may shorten the duration of HPV infection helps explain the lack of effect that BV and TV infection have on development of SIL.

Evolution of cervical abnormalities among women with HIV-1: Evidence from surveillance cytology in the Women's Interagency HIV Study

Objective: To determine incidence, progression, and regression rates for abnormal cervical cytology and their correlates among women with HIV. Methods: In a multicenter prospective cohort study conducted October 1, 1994, through September 30, 1999 at university, public, and private medical centers and clinics, 1639 HIV‐seropositive and 452 seronegative women were evaluated every 6 months for up to 5 years using history, cervical cytology, T‐cell subsets, and quantitative plasma HIV RNA. Human papillomavirus (HPV) typing at baseline was determined by polymerase chain reaction. Cytology was read using the Bethesda system, with any smear showing at least atypia considered abnormal. Poisson regression identified factors associated with incident cytologic abnormalities whereas logistic regression identified those associated with progression and regression after an abnormality. Results: At least one abnormal smear was found during all of follow‐up among 73.0% of HIV‐seropositive patients and 42.3% of seronegatives (p < .001). Only 5.9% of seropositives ever developed high‐grade lesions, and the proportion with high‐grade findings did not rise over time. Incidence of atypical squamous cells of uncertain significance (ASCUS) or more severe lesions among HIV‐seropositive patients and seronegative patients was 26.4 and 11.0/100 woman‐years (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.9‐3.0), whereas that of at least low‐grade squamous intraepithelial lesions (SIL) was 8.9 and 2.2/100 (RR, 4.0; CI, 2.6‐6.1). HIV status, detection of the presence of human papillomavirus (HPV), CD4 lymphocyte count, and HIV RNA level predicted incidence of abnormal cytology (p < .05); HPV detection and HIV RNA level predicted progression (p < .01); and HPV detection, CD4 lymphocyte count, and HIV RNA level predicted regression (p < .001). Rates of incidence, progression, and regression of abnormal cytology did not differ between HIV seronegative women and seropositive women with CD4 lymphocyte counts >200/mm3 and HIV RNA levels <4000/ml of similar HPV status. Conclusions: Although HIV infected women were at high risk for abnormal cytology, high‐grade changes were uncommon. HIV status, HPV detection, CD4 lymphocyte count, and HIV RNA level predicted the incidence of cervical cytologic abnormalities. Progression was significantly increased only among the most immunosuppressed women, while regression was significantly reduced in all HIV seropositive women except those with the best controlled HIV disease.

Effects of human immunodeficiency virus on protracted amenorrhea and ovarian dysfunction.

OBJECTIVE: To characterize ovarian failure and prolonged amenorrhea from other causes in women who are both human immunodeficiency virus (HIV) seropositive and seronegative. METHODS: This was a cohort study nested in the Women’s Interagency HIV Study, a multicenter U.S. study of HIV infection in women. Prolonged amenorrhea was defined as no vaginal bleeding for at least 1 year. A serum follicle stimulating hormone more than 25 milli–International Units/mL and prolonged amenorrhea were used to define ovarian failure. Logistic regressions, &khgr;2, and t tests were performed to estimate relationships between HIV-infection and cofactors with both ovarian failure and amenorrhea from other causes. RESULTS: Results were available for 1,431 women (1,139 HIV seropositive and 292 seronegative). More than one half of the HIV positive women with prolonged amenorrhea of at least 1 year did not have ovarian failure. When adjusted for age, HIV seropositive women were about three times more likely than seronegative women to have prolonged amenorrhea without ovarian failure. Body mass index, serum albumin, and parity were all negatively associated with ovarian failure in HIV seropositive women. CONCLUSION: HIV serostatus is associated with prolonged amenorrhea. It is difficult to ascertain whether the cause of prolonged amenorrhea is ovarian in HIV-infected women without additional testing. LEVEL OF EVIDENCE: II-2

Natural history of grade 1 cervical intraepithelial neoplasia in women with human immunodeficiency virus.

OBJECTIVE: We sought to estimate rates of progression and regression of grade 1 cervical intraepithelial neoplasia (CIN 1) among women with human immunodeficiency virus (HIV). METHODS: In a multicenter prospective cohort study, HIV-seropositive and HIV-seronegative women were evaluated colposcopically after receiving an abnormal cytology test result between November 1994 and September 2002. Women with CIN 1 were included, except those who had undergone hysterectomy, cervical therapy, or had CIN 2–3 or cervical cancer. Those women who were included were followed cytologically twice yearly, with colposcopy repeated for atypia or worse. RESULTS: We followed 223 women with CIN 1 (202 HIV seropositive and 21 HIV seronegative) for a mean of 3.3 person-years. Progression occurred in 8 HIV-seropositive women (incidence density, 1.2/100 person-years; 95% confidence interval [CI] 0.5–2.4/100 person-years) and in no HIV seronegative women. Regression occurred in 66 (33%) HIV-seropositive women (13/100 person-years, 95% CI 10–16/100 person-years) versus 14 (67%) seronegative women (32/100 person-years, relative risk 0.40, 95% CI 0.25–0.66; P < .001). In multivariate analysis, regression was associated with human papillomavirus (HPV) detection (hazard ratio [HR] for low risk 0.28, 95% CI 0.13–0.61, P = .001; and for high-risk 0.34, 95% CI 0.20–0.55, P < .001 versus no HPV detected) and Hispanic ethnicity (HR 0.48, 95% CI 0.230.98; P = .04); HIV serostatus was only marginally linked to regression (HR 0.52, 95% CI 0.27–1.03; P = .06), but seropositive women were less likely to regress when analysis was limited to 146 women with HPV detected at CIN 1 diagnosis (HR 0.18, 95% CI 0.05–0.62; P = .006). CONCLUSION: Grade 1 cervical intraepithelial neoplasia infrequently progresses in women with HIV. Thus, observation appears safe absent other indications for treatment. LEVEL OF EVIDENCE: II-1

The occurrence of vaginal infections among HIV-infected and high-risk HIV-uninfected women: longitudinal findings of the women's interagency HIV study.

Objectives:To evaluate changes over time in rates of bacterial vaginosis (BV), trichomoniasis (TV), and yeast vaginitis (YV) among HIV-infected and similar HIV-uninfected women. Methods:Two thousand fifty-six HIV-infected women and 554 HIV-uninfected women were evaluated semiannually from 1994 until March 2003 in a prospective cohort study. BV was diagnosed by Gram stain, TV by wet mount, and YV by symptoms with microscopically visible hyphae or positive culture. Trends were assessed using Poisson models. Results:At baseline, BV was present in 42.8% and 47.0% of HIV-infected and uninfected women (P = 0.21), TV in 6.1% and 7.8% (P = 0.17), and YV in 10.0% and 3.8% (P < 0.001). Over time, rates of BV and TV decreased significantly in both groups, whereas rates of YV declined only among HIV-infected women. Risk of BV was not associated with HIV status, whereas HIV-infected women had a lower risk of TV. Highly active antiretroviral therapy (HAART) use was associated with decreased risk of all 3 infections. Conclusions:Declines in BV, TV, and YV represent decreased morbidity for HIV-infected women and, potentially, decreased risk of transmission of HIV, because each has been associated with increased genital detection of HIV.

Algorithm for treatment of postoperative incisional groin pain after cesarean delivery or hysterectomy.

OBJECTIVE: Despite the low mortality and morbidity of major obstetric and gynecologic surgeries (including hysterectomy and cesarean delivery), women undergoing these procedures occasionally suffer from intractable postoperative suprapubic and groin pain. We present seven patients whose intractable pain lasted longer than 6 months and was not due to gynecologic disease or other obvious pathology. METHODS: Neuromas of the ilioinguinal, iliohypogastric, and/or genitofemoral nerves were suspected clinically and confirmed intraoperatively. RESULTS: After neuroma resection, all patients reported complete and durable pain relief. CONCLUSION: Intractable pain after obstetric or gynecologic surgery can be due to neuroma formation, and resection is therapeutic. We suggest an algorithm for the management of women with chronic intractable suprapubic or groin pain after major obstetric and gynecologic surgery. LEVEL OF EVIDENCE: II-3

Magnetic resonance imaging of vasa praevia

A 34 year old primigravid woman had an ultrasound examination at 20 weeks of gestation that showed a complete placenta praevia. Follow up transvaginal sonography at 24 weeks of gestation revealed echolucent linear structures overlying the cervix, suggesting a vasa praevia. The placenta appeared to have two lobes, with vessels running over the cervix between them. Pulsed Doppler demonstrated a fetal pulse rate of 140 beats per minute in these vessels. We decided to perform magnetic resonance imaging on the patient in order to determine whether vasa praevia could be diagnosed using magnetic resonance imaging, and also to see whether magnetic resonance imaging could add any further information beyond that which we already had with ultrasound and Doppler. We obtained approval from our Institutional Review Board to perform a magnetic resonance imaging on the patient for further evaluation of the vasa praevia. The patient was counselled, and informed consent was obtained. T2-weighted magnetic resonance imaging revealed three areas of signal void overlying the cervix (Fig. 1). Using two-dimensional time-of-flight sequences, flow was demonstrated through these structures. There was flow through two vessels in one direction (Fig. 2A), and flow through the third vessel in the opposite direction (Fig. 2B), consistent with the expected directions of flow in the umbilical arteries and the vein. The placenta was shown to have an accessory lobe, and these vessels ran between the lobes. The woman was hospitalised in the third trimester and was delivered by elective caesarean section at 351⁄2 weeks of gestation. The diagnosis of vasa praevia was confirmed at delivery; the placenta had two lobes, with communicating vessels running over the cervix between them. The live male infant had Apgar scores of 8 and 9, and was discharged home eight days later. The infant is doing well at 10 months of age.

Insulin-Like Growth Factor Axis and Oncogenic Human Papillomavirus Natural History

High serum levels of insulin-like growth factor-I (IGF-I) are reported to be a risk factor for several common cancers, and recent cross-sectional data suggest a possible additional association of IGF-I with cervical neoplasia. To prospectively assess whether circulating IGF-I levels influence the natural history of oncogenic human papillomavirus (HPV), the viral cause of cervical cancer, we conducted a pilot investigation of 137 women who underwent semiannual type-specific HPV DNA PCR testing and cervical cytology. Total IGF-I and IGF binding protein-3 (IGFBP-3), the most abundant IGFBP in circulation, were measured using baseline serum specimens. Having a high IGF-I/IGFBP-3 ratio was associated with increased persistence of oncogenic HPV infection [that is, a lower rate of clearance; adjusted hazard ratio (AHR), 0.14; 95% confidence interval (95% CI), 0.04-0.57], whereas IGFBP-3 was inversely associated with both the incident detection of oncogenic HPV (AHR, 0.35; 95% CI, 0.13-0.93) and the incidence of oncogenic HPV-positive cervical neoplasia (that is, squamous intraepithelial lesions at risk of progression; AHR, 0.07; 95% CI, 0.01-0.66). These prospective data provide initial evidence that the IGF axis may influence the natural history of oncogenic HPV. (Cancer Epidemiol Biomarkers Prev 2008;17(1):245–8)

Outcome after negative colposcopy among human immunodeficiency virus-infected women with borderline cytologic abnormalities

Objective: To estimate the risk of and risk factors for progression among human immunodeficiency virus (HIV)-seropositive women with abnormal cervical cytology but negative colposcopy. Methods: In a prospective cohort study, 391 HIV-seropositive and 103 seronegative women with cervical cytology read as atypical squamous cells (ASC) or low-grade squamous intraepithelial lesion (LSIL) but negative colposcopy were followed up for a mean of 4.0 years with cytology at 6-month intervals. Colposcopy was prescribed for any epithelial abnormality. Results: Progression to CIN2, CIN3, high-grade SIL/severe dysplasia, or cancer occurred in 47 (12%) HIV-seropositive women and 4 (4%) HIV-seronegative women (P = .02). Progression to CIN1 was seen in an additional 12 HIV-seropositive women and 1 seronegative woman. In multivariate analysis, high-risk but not low-risk HPV detection (hazard ratio [HR] 2.46–95% confidence interval [CI] 1.18–5.12, P = .02 for high risk, HR 1.41, 95% CI 0.62–3.21, P = .42 for low risk), satisfactory colposcopy (HR 2.01, 95% CI 1.11–3.65, P = .02), and non-Hispanic African-American ethnicity (HR 5.08, 95% CI 1.72–14.98, P = .003) were the only factors associated with progression, while HIV serostatus was marginally significant (HR 2.53, 95% CI 0.85–7.50, P = .09). Conclusion: Human immunodeficiency virus–seropositive women with negative colposcopy after borderline cytology face a higher risk of progression than seronegative women, but the absolute risk is low and becomes nonsignificant after controlling for HPV risk type, ethnicity, and colposcopic findings. Observation is appropriate. Level of Evidence: II-2

Marijuana Use is Not Associated with Cervical Human Papillomavirus Natural History or Cervical Neoplasia in HIV-Seropositive or HIV-Seronegative Women

Marijuana use was recently reported to have a positive cross-sectional association with human papillomavirus (HPV)–related head and neck cancer. Laboratory data suggest that marijuana could have an immunomodulatory effect. Little is known, however, regarding the effects of marijuana use on cervical HPV or neoplasia. Therefore, we studied the natural history (i.e., prevalence, incident detection, clearance/persistence) of cervical HPV and cervical neoplasia (i.e., squamous intraepithelial lesions; SIL) in a large prospective cohort of 2,584 HIV-seropositive and 915 HIV-seronegative women. Marijuana use was classified as ever/never, current/not current, and by frequency and duration of use. No positive associations were observed between use of marijuana, and either cervical HPV infection or SIL. The findings were similar among HIV-seropositive and HIV-seronegative women, and in tobacco smokers and nonsmokers. These data suggest that marijuana use does not increase the burden of cervical HPV infection or SIL. Cancer Epidemiol Biomarkers Prev; 19(3); 869–72