The East Africa Consortium for human papillomavirus and cervical cancer in women living with HIV/AIDS.

The East Africa Consortium was formed to study the epidemiology of human papillomavirus (HPV) infections and cervical cancer and the influence of human immunodeficiency virus (HIV) infection on HPV and cervical cancer, and to encourage collaborations between researchers in North America and East African countries. To date, studies have led to a better understanding of the influence of HIV infection on the detection and persistence of oncogenic HPV, the effects of dietary aflatoxin on the persistence of HPV, the benefits of antiretroviral therapy on HPV persistence, and the differences in HPV detections among HIV-infected and HIV-uninfected women undergoing treatment for cervical dysplasia by either cryotherapy or LEEP. It will now be determined how HPV testing fits into cervical cancer screening programs in Kenya and Uganda, how aflatoxin influences immunological control of HIV, how HPV alters certain genes involved in the growth of tumours in HIV-infected women. Although there have been challenges in performing this research, with time, this work should help to reduce the burden of cervical cancer and other cancers related to HIV infection in people living in sub-Saharan Africa, as well as optimized processes to better facilitate research as well as patient autonomy and safety. KEY MESSAGESThe East Africa Consortium was formed to study the epidemiology of human papillomavirus (HPV) infections and cervical cancer and the influence of human immunodeficiency virus (HIV) infection on HPV and cervical cancer.Collaborations have been established between researchers in North America and East African countries for these studies.Studies have led to a better understanding of the influence of HIV infection on the detection and persistence of oncogenic HPV, the effects of dietary aflatoxin on HPV detection, the benefits of antiretroviral therapy on HPV persistence, and the differences in HPV detections among HIV-infected and HIV-uninfected women undergoing treatment for cervical dysplasia by either cryotherapy or LEEP.

A cross-sectional analysis of factors associated with detection of oncogenic human papillomavirus in human immunodeficiency virus-infected and uninfected Kenyan women.

BACKGROUND: Cervical cancer is caused by oncogenic human papillomaviruses (HPV) and is one of the most common malignancies in women living in sub-Saharan Africa. Women infected with the human immunodeficiency virus (HIV) have a higher incidence of cervical cancer, but the full impact on HPV detection is not well understood, and associations of biological and behavioral factors with oncogenic HPV detection have not been fully examined. Therefore, a study was initiated to investigate factors that are associated with oncogenic HPV detection in Kenyan women. METHODS: Women without cervical dysplasia were enrolled in a longitudinal study. Data from enrollment are presented as a cross-sectional analysis. Demographic and behavioral data was collected, and HPV typing was performed on cervical swabs. HIV-uninfected women (n = 105) and HIV-infected women (n = 115) were compared for demographic and behavioral characteristics using t-tests, Chi-square tests, Wilcoxon sum rank tests or Fisher's exact tests, and for HPV detection using logistic regression or negative binomial models adjusted for demographic and behavioral characteristics using SAS 9.4 software. RESULTS: Compared to HIV-uninfected women, HIV-infected women were older, had more lifetime sexual partners, were less likely to be married, were more likely to regularly use condoms, and were more likely to have detection of HPV 16, other oncogenic HPV types, and multiple oncogenic types. In addition to HIV, more lifetime sexual partners was associated with a higher number of oncogenic HPV types (aIRR 1.007, 95% CI 1.007-1.012). Greater travel distance to the clinic was associated with increased HPV detection (aOR for detection of ≥ 2 HPV types: 3.212, 95% CI 1.206-8.552). Older age (aOR for HPV 16 detection: 0.871, 95% CI 0.764-0.993) and more lifetime pregnancies (aOR for detection of oncogenic HPV types: 0.706, 95% CI, 0.565-0.883) were associated with reduced detection. CONCLUSION: HIV infection, more lifetime sexual partners, and greater distance to health-care were associated with a higher risk of oncogenic HPV detection, in spite of ART use in those who were HIV-infected. Counseling of women about sexual practices, improved access to health-care facilities, and vaccination against HPV are all potentially important in reducing oncogenic HPV infections.

Effect of HSV-2 suppressive therapy on genital tract HIV-1 RNA shedding among women on HAART: a pilot randomized controlled trial.

BACKGROUND: The role of suppressive HSV therapy in women coinfected with HSV-2 and HIV-1 taking highly active antiretroviral therapy (HAART) is unclear. METHODS: 60 women with HIV-1/HSV-2 coinfection on HAART with plasma HIV-1 viral load (PVL) ≤75 copies/mL were randomized to receive acyclovir (N = 30) or no acyclovir (N = 30). PVL, genital tract (GT) HIV-1, and GT HSV were measured every 4 weeks for one year. RESULTS: Detection of GT HIV-1 was not significantly different in the two arms (OR 1.23, P = 0.67), although this pilot study was underpowered to detect this difference. When PVL was undetectable, the odds of detecting GT HIV were 0.4 times smaller in the acyclovir arm than in the control arm, though this was not statistically significant (P = 0.07). The odds of detecting GT HSV DNA in women receiving acyclovir were significantly lower than in women in the control group, OR 0.38, P < 0.05. CONCLUSIONS: Chronic suppressive therapy with acyclovir in HIV-1/HSV-2-positive women on HAART significantly reduces asymptomatic GT HSV shedding, though not GT HIV shedding or PVL. PVL was strongly associated with GT HIV shedding, reinforcing the importance of HAART in decreasing HIV sexual transmission.

Association of HIV viral load and CD4 cell count with human papillomavirus detection and clearance in HIV-infected women initiating highly active antiretroviral therapy.

OBJECTIVES: The extent to which highly active antiretroviral therapy (HAART) affects human papillomavirus (HPV) acquisition and clearance in HIV-infected women is not well understood. We sought to describe high-risk HPV detection and clearance rates over time since HAART initiation, based on time-varying HIV viral load (VL) and CD4 T-cell count, using novel statistical methods. METHODS: We conducted a retrospective analysis of data from the completed AIDS Clinical Trials Group (ACTG) A5029 study using multi-state Markov models. Two sets of high-risk HPV types from 2003 and 2009 publications were considered. RESULTS: There was some evidence that VL>400 HIV-1 RNA copies/mL was marginally associated with a higher rate of HPV detection [P=0.068; hazard ratio (HR) =4.67], using the older set of high-risk HPV types. Such an association was not identified using the latest set of HPV types (P=0.343; HR=2.64). CD4 count >350 cells/µL was significantly associated with more rapid HPV clearance with both sets of HPV types (P=0.001, HR=3.93; P=0.018, HR=2.65). There was no evidence that HPV affects VL or CD4 cell count in any of the analyses. CONCLUSIONS: High-risk HPV types vary among studies and can affect the results of analyses. Use of HAART to improve CD4 cell count may have an impact on the control of HPV infection. The decrease in VL may also have an effect, although to a lesser degree.

Discrete-time semi-Markov modeling of human papillomavirus persistence.

Multi-state modeling is often employed to describe the progression of a disease process. In epidemiological studies of certain diseases, the disease state is typically only observed at periodic clinical visits, producing incomplete longitudinal data. In this paper we consider fitting semi-Markov models to estimate the persistence of human papillomavirus (HPV) type-specific infection in studies where the status of HPV type(s) is assessed periodically. Simulation study results are presented indicating that the semi-Markov estimator is more accurate than an estimator currently used in the HPV literature. The methods are illustrated using data from the HIV Epidemiology Research Study.

Factors associated with prevalent abnormal anal cytology in a large cohort of HIV-infected adults in the United States.

BACKGROUND: The prevalence of and risk factors for abnormal anal cytology among men and women with human immunodeficiency virus (HIV) infection have not been extensively investigated. METHODS: The Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN study) is a prospective cohort study of HIV-infected patients in 4 US cities. Baseline questionnaires were administered and anal samples for cytology and human papillomavirus (HPV) detection and genotyping were collected. RESULTS: Among 471 men and 150 women (median age, 41 years), 78% of participants were receiving combination antiretroviral therapy, 41% had a CD4(+) cell count of ≥500 cells/µL, and 71% had an HIV RNA viral load of <400 copies/mL. The anal cytology results were as follows: 336 participants (54%) had negative results, 96 participants (15%) had atypical squamous cells, 149 participants (24%) had low-grade squamous intraepithelial lesions, and 40 participants (6%) had high-grade squamous intraepithelial lesions. In a multivariate analysis, abnormal anal cytology was associated with number of high-risk and low-risk HPV types (adjusted odds ratio [AOR] for both, 1.28; P < .001), nadir CD4(+) cell count of <50 cells/µL (AOR, 2.38; P = .001), baseline CD4(+) cell count of <500 cells/µL (AOR, 1.75; P = .004), and ever having receptive anal intercourse (AOR, 2.51; P < .001). CONCLUSION: HIV-infected persons with multiple anal HPV types or a nadir CD4(+) cell count of <50 cells/µL have an increased risk for abnormal anal cytology.

HIV-1 cord-blood seroprevalence of parturient women in Sihanoukville, Cambodia.

Facing a 1.2% HIV-1 seroprevalence amongst its adult female population, Cambodia recently established national guidelines for the expansion of services to prevent mother-to-child transmission. Anticipating this expansion, Sihanoukville Hospital performed an anonymous HIV-1 cord-blood serosurvey of 600 consecutive deliveries from May 2001 through June 2002. Laboratory analysis utilizing ELISA and Western blot techniques yielded a 4.2% seroprevalence; a value resembling previous reports from other Sihanoukville antenatal clinics (3.9%) but exceeding the national ANC clinic average of 2.3%. Demographic information was confidentially collected and analysed for co-variation to HIV-1 status. One hundred percent of HIV positive mothers (P =0.013) self-reported the occupation of housewife, consistent with previous documentations suggesting the shift in infection burden from high-risk groups into the general female population. A substantial proportion received no prenatal care, suggesting that interventions addressing mother-to-child transmission will need to prepare for the management of pregnant women presenting at or near the time of delivery.

Human immunodeficiency virus in plasma and cervicovaginal secretions in Filipino women.

This study examined 30 HIV-infected women in Manila to assess the relationship between cervicovaginal and plasma HIV-1 viral load. An interview and gynaecologic examination was conducted and cervicovaginal lavage (CVL) and venous blood specimens were collected. HIV-1 RNA was detected in plasma samples of 24 patients (80%) and in CVL samples of 18 women (60%); 16 patients (53%) had detectable levels in both. CVL HIV-1 RNA was detectable in 75% of women (6/8) with plasma viral loads between 10,000 and 100,000 copies/mL and in 77% of women (10/13) with plasma viral loads higher than 100,000 copies/mL (P =0.0086). Among women with CD4 cell counts of less than 200, 200-500, and greater than 500/mm(3), CVL HIV-1 RNA was detected in 73%, 69%, and 17% of women, respectively (P =0.1428). HIV-1 RNA shedding in the genital tract was significantly associated with plasma viral load.

Variation of human immunodeficiency virus type 1 viral RNA levels in the female genital tract: implications for applying measurements to individual women.

The short-term detection and variability of human immunodeficiency virus type 1 (HIV-1) RNA level was assessed in the blood plasma and genital tracts of 55 HIV-1-infected women. Specimens were collected weekly for 8 weeks from the endocervical canal with wicks and cytobrushes and from the ectocervix and vagina with cervicovaginal lavage. In all, 48 women (87.3%) had detectable genital tract HIV-1 RNA at > or =1 collection times. HIV-1 RNA levels varied least in specimens from endocervical canal wick and most in cervicovaginal lavage samples. The within-subject variation for genital-tract virus level was greater than that for blood. Overall, the odds for viral RNA detection in the genital tract approximately tripled for each 10-fold increase in plasma viral RNA concentration (P<.001) or with concomitant genital tract infection (P=.003). Endocervical canal wicks should be considered as an adjunct to cervicovaginal lavage, to improve the sensitivity and precision of HIV-1 RNA detection.

Longitudinal analysis of bacterial vaginosis: findings from the HIV epidemiology research study.

OBJECTIVE: To determine the natural history of bacterial vaginosis in women with or at risk for human immunodeficiency virus (HIV). METHODS: A cohort of 854 HIV-infected women and 434 HIV-uninfected women from four US sites was followed prospectively with gynecologic exams every 6 months over a 5-year period. The prevalence, incidence, persistence, and severity of bacterial vaginosis, which was defined using a Gram-staining scoring system, were calculated using generalized estimating equation methods. RESULTS: In adjusted analyses, HIV-infected women had a higher prevalence of bacterial vaginosis than HIV-uninfected women (adjusted odds ratio [OR] 1.29; 95% confidence interval [CI] 1.08, 1.55). Although HIV-infected women were not more likely to have incident infections, they were more likely to have persistence of their infections (adjusted OR 1.49; 95% CI 1.18, 1.89). Similarly, immunocompromised women (CD4+ cell count less than 200 cells/microL) were more likely than HIV-infected women with higher CD4+ cell counts (more than 500 cells/microL) to have prevalent (adjusted OR 1.29; 95% CI 1.03, 1.60) and persistent (adjusted OR 1.38; 95% CI 1.01, 1.91) bacterial vaginosis infections, but not more likely to have incident infections. Immunocompromised women had more severe bacterial vaginosis by both clinical criteria (adjusted OR 1.40; 95% CI 1.08, 1.82) and by Gram-staining criteria (adjusted OR 1.50; 95% CI 1.12, 2.00). CONCLUSIONS: Bacterial vaginosis is more prevalent and persistent among HIV-infected women, particularly among those who are immunocompromised. Immunocompromised women are more likely than HIV-infected women with higher CD4+ cell counts to have severe bacterial vaginosis.

Association between bacterial vaginosis and expression of human immunodeficiency virus type 1 RNA in the female genital tract.

We assessed the effect of lower genital tract infections on human immunodeficiency virus type 1 (HIV-1) RNA shedding in the female genital tract. Bacterial vaginosis was significantly associated with HIV-1 RNA expression in the female genital tract of HIV-infected women.

A menstrual cycle pattern for cytokine levels exists in HIV-positive women: implication for HIV vaginal and plasma shedding.

OBJECTIVES: To evaluate the effect of the menstrual cycle in HIV-positive women on plasma and genital cytokine levels, interrelationships between vaginal and plasma cytokines, CD4 and CD8 T cell fluctuations, and genital and plasma viral loads. METHODS: Plasma and cervicovaginal lavage specimens were collected from 55 HIV-positive women with CD4 cell counts < 350 cells/microl during phases of the menstrual cycle. Samples were assayed for IL-1beta, IL-6, IL-4, IL-8, IL-10, TGFbeta, TNFalpha, INFgamma, MIP1alpha, MIP1beta, RANTES, and TNFR-II using enzyme-linked immunosorbent assays. CD4 and CD8 T cell expression was evaluated by flow cytometry. Repeated measures regression models were used to assess the effect of the menstrual cycle on cytokines and viral load. Multivariate repeated regression models were used to assess the correlation among selected cytokines and between selected cytokines and HIV viral load. RESULTS: Vaginal IL-1beta, IL-4, IL-6, IL-8, IL-10, MIP1beta, RANTES, TGFbeta, and TNFR-II were significantly elevated during menses but were not altered during other phases. Plasma cytokine levels were not altered during the menstrual cycle. A positive Candida culture increased vaginal IL-8 during menses, whereas vaginal discharge was associated with a reduction in vaginal IL-4, IL-10, and RANTES. CD4 and CD8 cell numbers did not vary with the menstrual cycle. Vaginal cytokine levels correlated only with vaginal viral load, in a sampling method-dependent manner. CONCLUSION: We provide evidence of elevated vaginal cytokine levels during menses, which appear to regulate vaginal and not plasma HIV shedding, suggesting that a menstrual cycle pattern exists for cytokine production in HIV-positive women impacting vaginal shedding of HIV.

A multicenter study of bacterial vaginosis in women with or at risk for human immunodeficiency virus infection.

BACKGROUND: Bacterial vaginosis is a common gynecologic infection that has been associated with a variety of gynecologic and obstetric complications, including pelvic inflammatory disease, postabortal infection and premature delivery. Recent studies suggest that bacterial vaginosis may increase a woman's risk for human immunodeficiency virus (HIV). We undertook this study to assess whether the prevalence and characteristics of bacterial vaginosis differed according to HIV status in high-risk US women. METHODS: Prevalence of bacterial vaginosis was assessed by Gram's stain and clinical criteria for 854 HIV-infected and 434 HIV-uninfected women enrolled in the HIV Epidemiology Research (HER) Study. Multiple logistic regression techniques were used to determine whether HIV infection independently predicted bacterial vaginosis. RESULTS: Almost half (46%) the women had bacterial vaginosis by Gram's stain. The prevalence of bacterial vaginosis was 47% in the HIV-positive women compared with 44% in the HIV-negative women; this difference was not statistically significant (p = 0.36). After adjustment for other covariates, HIV-positive women were more likely than HIV-negative women to have bacterial vaginosis (odds ratio (OR) 1.31; 95% confidence interval (CI) 1.01-1.70) by Gram's stain but not by clinical criteria (OR 1.16; CI 0.87-1.55). Among HIV-positive women, use of antiretroviral drugs was associated with a lower prevalence of bacterial vaginosis (adjusted OR 0.54; Cl 0.38-0.77). CONCLUSIONS: In this cross-sectional analysis of high-risk US women, HIV infection was positively correlated with bacterial vaginosis diagnosed by Gram's stain.

Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women.

Human immunodeficiency virus (HIV) infection and related immunosuppression are associated with excess risk for cervical neoplasia and human papillomavirus (HPV) persistence. Type-specific HPV infection was assessed at 6-month intervals for HIV-positive and HIV-negative women (median follow-up, 2.5 and 2.9 years, respectively). The type-specific incidence of HPV infection was determined, and risk factors for HPV persistence were investigated by statistical methods that accounted for repeated measurements. HIV-positive women were 1.8, 2.1, and 2.7 times more likely to have high-, intermediate-, and low-risk HPV infections, respectively, compared with HIV-negative women. In multivariate analysis, high viral signal, but not viral risk category, was independently associated with persistence among HIV-positive subjects (odds ratio [OR], 2.5; 95% confidence interval [CI], 2.1-2.9). Furthermore, persistence was 1.9 (95% CI, 1.5-2.3) times greater if the subject had a CD4 cell count <200 cells/microL (vs. >500 cells/microL). Thus, HIV infection and immunosuppression play an important role in modulating the natural history of HPV infection.

Attitudes towards prenatal HIV testing and treatment among pregnant women in southern India.

During June and July 1999, oral interviews were conducted on 666 women seeking prenatal care at 9 medical facilities in Chennai and Mysore, India, to assess their attitudes towards prenatal HIV testing and antiretroviral prophylaxis for preventing perinatal HIV transmission if needed. Seventy-eight per cent were aware of the risk of perinatal HIV transmission and 36% knew that intervention could reduce the chances of such transmission. Eighty-six per cent would agree to undergo prenatal HIV testing but only 21% of all respondents would make this decision independently while 46% said their husband would have to decide. Of those women who would not agree to testing, 21% would agree if testing were compulsory. Ninety-seven per cent of respondents would undergo antiretroviral prophylaxis to prevent vertical transmission, and 94% would consider alternatives to breastfeeding if HIV positive. Considering its widespread acceptability, prenatal voluntary counselling and testing may be an affordable method of HIV prevention for this population.

High-risk behaviors and the prevalence of sexually transmitted diseases among women prisoners at the women state penitentiary in Metro Manila.

Women prisoners in the Philippines are particularly vulnerable to HIV infection. The economic and social disadvantages that women endure in mainstream society are magnified once they are committed to penitentiaries where control over one's own life is even more restricted and limited. Outside prison, impoverished and uninformed about the ways of protecting their health, women have engaged in unprotected sex with their male partners, many of whom have had casual sex or extra-marital affairs. Within prison, it is therefore not surprising that over 25% of women were already infected with sexually transmitted diseases (STDs). None were infected with HIV. The presence of STDs among female inmates highlights the importance of addressing health needs while at the correctional facility. It also raises the need for educational and prevention programs and health services that will help reduce women's vulnerability to HIV, AIDS and STDs.

Safety and tolerability of BufferGel, a novel vaginal microbicide, in women in the United States.

BufferGel (ReProtect, LLC) is a vaginal gel with an acidic buffering action that was designed to prevent vaginal neutralization by semen. The purpose of this study was to evaluate the safety and tolerability of BufferGel (ReProtect, Limited Liability Company) applied vaginally either once or twice daily by 27 women who were at low risk for acquisition of human immunodeficiency virus (HIV). Participants initially used the product once daily for 14 days and then twice daily for 14 days; they underwent colposcopy before and after product exposure. BufferGel was well tolerated, although two-thirds of the participants reported at least 1 mild or moderate adverse experience. The most common adverse events were irritative genitourinary symptoms. Product use was discontinued after 3 adverse events. BufferGel was well tolerated in women at low risk for acquisition of HIV; toxicity was limited and occurred at frequencies similar to those in women who did not use any vaginal product and at levels lower than in women who used detergent-based microbicides.

Multicenter review of protease inhibitors in 89 pregnancies.

CONTEXT: Despite the success of highly active antiretroviral therapy, the optimal approach for preventing perinatal HIV-1 transmission is not known. OBJECTIVE: A retrospective survey was conducted at six centers in the United States and Puerto Rico from January 1997 to October 1998 to evaluate the effects of protease inhibitor use during pregnancy on maternal and infant safety, prematurity rate, and frequency of perinatal HIV-1 transmission. RESULTS: In the study, 91 live infants, including 3 sets of twins, and 1 neonate who died shortly after birth were born to 89 women. HIV perinatal transmission rate in this series was 0 (95% confidence interval [CI], 0%-3%). Prematurity rate was 19.1%, comparable to rates in earlier reports of HIV-1-infected women. In multiple regression analysis, only cocaine use and premature rupture of membranes were associated with prematurity (p =.03 and.008, respectively). The gestational week during which the protease inhibitors were initiated was not found to be significantly associated with prematurity. Adverse maternal, obstetric, and infant events possibly related to protease inhibitors were uncommon. CONCLUSIONS: Protease inhibitors appeared generally safe in mothers and infants in this series. No perinatal HIV-1 transmission occurred. Further prospective, controlled studies are needed to define the optimal management of HIV-1 in pregnancy.

Hormonal levels among HIV-1-seropositive women compared with high-risk HIV-seronegative women during the menstrual cycle. Women's Health Study (WHS) 001 and WHS 001a Study Team.

There is a paucity of normative data on hormonal levels among HIV-infected women. Hormonal levels may influence fertility and HIV-related immunological and virological factors. The objective of this study was to determine progesterone and estradiol levels during the menstrual cycle in HIV-seropositive women compared with high-risk seronegative women. The study enrolled 55 HIV-infected and 10 high-risk uninfected women with self-reported regular menstrual cycles (25-30-day cycles). Progesterone and estradiol levels were determined on a weekly basis for 8 weeks. The analysis included evaluations from the first complete menstrual cycle for the 54 HIV-infected and 9 uninfected women who had at least one complete cycle. The median age was 35 years for HIV-infected women and 36 years for uninfected women. The median CD4+ count for HIV-seropositive women was 210 cells/mm3. The median menstrual cycle length was 28 days (range 22-49 days) for HIV-infected women and 25 days (range 24-44 days) for uninfected women. The maximum progesterone level during the luteal phase was normal (>3.0 ng/ml) for 52 (96%) of 54 HIV-seropositive women and 7 (78%) of 9 HIV-seronegative women (p = 0.09, Fisher's exact test). The median maximum progesterone level was 12.2 ng/ml in HIV-seropositive women and 7.2 ng/ml in HIV-seronegative women (p = 0.07, Wilcoxon test). The median maximum estradiol value during the follicular phase was 148 pg/ml for HIV-seropositive women and 111 pg/ml for HIV-seronegative women (p = 0.04, Wilcoxon test). Among HIV-infected women, there were no significant differences in progesterone and estradiol levels by antiretroviral therapy, baseline plasma viral load, or median CD4+ cell count. We conclude that HIV-infected women with self-reported normal menstrual cycles have normal levels of progesterone and estradiol during the menstrual cycle.