Timothy J. Bush

Human Papillomavirus Infection in Women Infected with the Human Immunodeficiency Virus

Background Among women infected with the human immunodeficiency virus (HIV), there is a high prevalence of human papillomavirus (HPV) infections. However, little is known about the natural history of HPV infections in HIV-seropositive women, and persistent HPV infections may explain the increased risk of cervical squamous intraepithelial lesions and invasive cervical cancer in HIV-seropositive women. Methods A total of 220 HIV-seropositive and 231 HIV-seronegative women in the New York City area were evaluated at two or more semiannual gynecologic examinations that included a Pap test, a test for HPV DNA, and colposcopy. Results HPV DNA was detected at the initial examination in 56 percent of the HIV-seropositive and 31 percent of the HIV-seronegative women. After four examinations, the cumulative prevalence of HPV infection was 83 percent in the seropositive women and 62 percent in the seronegative women (P<0.001). Persistent HPV infections were found in 24 percent of the seropositive women but in only 4...

The natural history of transfusion-associated infection with human immunodeficiency virus. Factors influencing the rate of progression to disease

Patients infected by the human immunodeficiency virus (HIV) as a result of blood transfusions are unique in that their dates of infection are well defined and their medical conditions before infection are known. To characterize the natural history of transfusion-associated HIV infection, we studied 694 recipients of blood from 112 donors in whom AIDS later developed and from 31 donors later found to be positive for HIV antibody. Of the recipients tested, 85 were seronegative, 116 were seropositive, and 19 had AIDS. Of 101 HIV-seropositive recipients followed for a median of 55 months after infection, 54 had Centers for Disease Control Class IV disease, including 43 with AIDS. Life-table analysis suggested that AIDS will develop in 49 percent of infected recipients (95 percent confidence limits, 36 to 62 percent) within seven years after infection. As compared with recipients without AIDS, the 43 recipients with AIDS had received more transfusions at the time of infection (median, 21 vs. 7; P = 0.01). HIV-infected blood donors in whom AIDS developed were grouped according to whether AIDS developed within 29 months (the median) after donation (Group 1) or 29 or more months after donation (Group 2). As compared with the 31 recipients of blood from Group 2 blood donors, the 31 recipients of blood from Group 1 donors were more likely to have AIDS four years after infection (49 percent vs. 4 percent; P = 0.005) and illnesses resembling acute retroviral syndrome (14 of 24 vs. 5 of 22; P = 0.03). We conclude that most recipients of HIV-infected blood become seropositive, that AIDS develops in about half these recipients within seven years, and that the risk may be higher when AIDS develops in the blood donor soon after donation.

Correlation of Human Immunodeficiency Virus Type 1 RNA Levels in Blood and the Female Genital Tract

In this study, the correlations of human immunodeficiency virus type 1 (HIV-1) RNA levels in blood plasma, vaginal secretions, and cervical mucus of 52 HIV-1-infected women were determined. The amount of cell-free HIV-1 RNA in blood plasma was correlated with that in vaginal secretions (Spearmans rank correlation coefficient (r) = 0.64, P<.001). In both blood plasma and vaginal secretions, the amounts of cell-free and cell-associated HIV-1 RNA were highly correlated (r=0.76, P<.01 and r=0.85, P<.01, respectively). Cell-free HIV-1 RNA levels in blood plasma and vaginal secretions were negatively correlated with CD4+ T lymphocyte count (r=-0.44, P<.01 and r=-0.40, P<.01, respectively). Similar to the effect observed in blood plasma, initiation of antiretroviral therapy significantly reduced the amount of HIV-1 RNA in vaginal secretions. These findings suggest that factors that lower blood plasma virus load may also reduce the risk of perinatal and female-to-male heterosexual transmission by lowering vaginal virus load.

Low Vitamin D among HIV-Infected Adults: Prevalence of and Risk Factors for Low Vitamin D Levels in a Cohort of HIV-Infected Adults and Comparison to Prevalence among Adults in the US General Population

BACKGROUND we explored serum 25-hydroxyvitamin D (25[OH]D) levels and associated factors for insufficiency or deficiency in an adult human immunodeficiency virus (HIV) cohort and compared 25(OH)D levels with those in the general US population. METHODS using baseline data from the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN), a prospective, observational cohort study of HIV-infected adults enrolled at 7 HIV specialty clinics in 4 US cities from March 2004 to June 2006, we estimated the prevalence of vitamin D insufficiency or deficiency (defined as 25(OH)D levels <30 ng/mL), standardized by age, race, and sex. Using multiple logistic regression, we examined risk factors for vitamin D insufficiency or deficiency. RESULTS among 672 SUN participants with baseline serum 25(OH)D determinations who were not receiving vitamin D supplements, 70.3% (95% confidence interval [CI], 68.1%-74.9%) were vitamin D insufficient or deficient, compared with 79.1% (95% CI, 76.7-81.3) of US adults. Factors associated with vitamin D insufficiency or deficiency included black race (adjusted odds ratio [aOR], 4.51; 95% CI, 2.59-7.85), Hispanic ethnicity (aOR, 2.78; 95% CI, 1.31-5.90), higher body mass index (aOR, 1.04; 95% CI, 1.00-1.09), hypertension (aOR, 1.88; 95% CI, 1.10-3.22), lack of exercise (aOR, 3.14; 95% CI, 1.80-5.47), exposure to efavirenz (aOR, 1.98; 95% CI, 1.18-3.34), higher exposure to ultraviolet light (aOR, .78; 95% CI, .71-.86), renal insufficiency (aOR, .55; 95% CI, .36-.83), and exposure to ritonavir (aOR, .56; 95% CI, .35-0.89). CONCLUSIONS similar to findings in US adults generally, vitamin D insufficiency or deficiency is highly prevalent among HIV-infected adults and is associated with known risk factors. Observed associations of vitamin D levels with renal insufficiency and with use of ritonavir- and efavirenz-containing regimens are consistent with both HIV-related and therapy-mediated alterations in vitamin D metabolism. Clinicians should consider screening all patients for vitamin D insufficiency or deficiency.

Human papillomavirus infection in human immunodeficiency virus-seropositive women

Objective To compare the prevalence of human papillomavirus (HPV) infections in women who are seropositive and seronegative for human immunodeficiency virus (HIV), and to determine if associations between HPV and cervical disease are altered in HIV-seropositive women. Methods In this cross-sectional study, 344 HIV-seropositive and 325 HIV-seronegative women underwent colposcopy and HPV DNA testing. Results Human immunodeficiency virus-seropositive women were more likely than HIV-seronegative women to have HPV DNA of any type detected (60 versus 36%, P < .001). Infections with HPV type 16 (27 versus 17%, P < .05), type 18 (24 versus 9%, P < .05), and more than one type of HPV (51 versus 26%, P < .05) were also more common in HIV-positive women. Although both latent HPV infection and HPV infections associated with cervical intraepithelial neoplasia (CIN) were more prevalent in the HIV-seropositive group, the ratio between these two types of infections was altered markedly in the HIV-seropositive women. Human immunodeficiency virus-seropositive women who were HPV-infected were significantly more likely to have CIN than were HPV-infected HIV-seronegative women, an increase observed at all levels of immunosuppression. Analysis of specific HPV types associated with latent HPV infection and CIN indicated that HIV seropositivity only minimally alters the known associations between specific types of HPV and cervical disease. Conclusion Human papillomavirus infections are more common among HIV-seropositive women at all levels of immunosuppression. However, relationships between HIV and HPV are complex and cannot be explained completely by an increased susceptibility to new HPV infections in the immunosuppressed patient.

HIV-1 infection and risk of vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia: a prospective cohort study

BACKGROUND Information about vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia in women infected with HIV-1 is needed to develop guidelines for clinical care. Our aim was to investigate the incidence of these lesions in HIV-1-positive and HIV-1-negative women and to examine risk factors for disease. METHODS In a prospective cohort study, 925 women had a gynaecological examination twice yearly-including colposcopy and tests for human papillomavirus DNA in cervicovaginal lavage-for a median follow-up of 3.2 years (IQR 0.98-4.87). FINDINGS Vulvovaginal and perianal condylomata acuminata or intraepithelial neoplasia were present in 30 (6%) of 481 HIV-1-positive and four (1%) of 437 HIV-1-negative women (p<0.0001) at enrollment. Women without lesions at enrollment were included in an incidence analysis. 33 (9%) of 385 HIV-1-positive and two (1%) of 341 HIV-1-negative women developed vulvovaginal or perianal lesions, resulting in an incidence of 2.6 and 0.16 cases per 100 person-years, respectively (relative risk 16, 95% CI 12.9-20.5; p < 0.0001). Risk factors for incident lesions included HIV-1 infection (p = 0.013), human papillomavirus infection (p=0.0013), lower CD4 T lymphocyte count (p = 0.0395), and history of frequent injection of drugs (p=0.0199). INTERPRETATION Our results suggest that HIV-1-positive women are at increased risk of development of invasive vulvar carcinoma. Thus, we recommend that, as part of every gynaecological examination, HIV-1-positive women should have a thorough inspection of the vulva and perianal region, and women with abnormalities-except for typical, exophytic condylomata acuminata-should undergo colposcopy and biopsy.

In Vitro Comparison of Topical Microbicides for Prevention of Human Immunodeficiency Virus Type 1 Transmission

ABSTRACT A standardized protocol was used to compare cellular toxicities and anti-human immunodeficiency virus type 1 (HIV-1) activities of candidate microbicides formulated for human use. The microbicides evaluated were cellulose acetate phthalate (CAP), Carraguard, K-Y plus nonoxynol-9 (KY-N9), PRO 2000 (0.5 and 4%), SPL7013 (5%), UC781 (0.1 and 1%), and Vena Gel, along with their accompanying placebos. Products were evaluated for toxicity on cervical and colorectal epithelial cell lines, peripheral blood mononuclear cells (PBMCs), and macrophages (MΦ) by using an ATP release assay, and they were tested for their effect on transepithelial resistance (TER) of polarized epithelial monolayers. Anti-HIV-1 activity was evaluated in assays for transfer of infectious HIV-1 from epithelial cells to activated PBMCs and for PBMC and MΦ infection. CAP, Carraguard, PRO 2000, SPL7013, and UC781 along with their placebos were 20- to 50-fold less toxic than KY-N9 and Vena Gel. None of the nontoxic product concentrations disrupted the TER. Transfer of HIV-1Ba-L from epithelial cells to PBMCs and PBMC and MΦ infection with laboratory-adapted HIV-1Ba-L and HIV-1LAI isolates were inhibited by all products except Carraguard, KY-N9, and Vena Gel. KY-N9, Vena Gel, and Carraguard were not effective in blocking PBMC infection with primary HIV-1A, HIV-1C, and HIV-1CRF01-AE isolates. The concordance of these toxicity results with those previously reported indicates that our protocol may be useful for predicting toxicity in vivo. Moreover, our systematic anti-HIV-1 testing provides a rational basis for making better informed decisions about which products to consider for clinical trials.

Increased prevalence of vulvovaginal condyloma and vulvar intraepithelial neoplasia in women infected with the human immunodeficiency virus

Objective To compare the prevalence of human papilloma-virus (HPV)-associated vulvovaginal lesions in human immunodeficiency virus (HIV)-positive and HIV-negative women. Methods For this cross-sectional study, all participants received a complete gynecologic examination including colposcopic evaluation and a structured interview about sociodemographic characteristics and risk factors for vulvovaginal disease. In addition, HPV DNA was assayed for in cervicovaginal lavages using polymerase chain reaction. Results Vulvar and/or vaginal condyloma acuminata were detected in 22 of 396 (5.6%) HIV-positive and in 3 of 375 (0.8%) HIV-negative women (odds ratio [OR] 7.3, P < .001). High-grade vulvar intraepithelial neoplasia (VIN) was present in two of the HIV-positive and none of the HIV-negative women. Human immunodeficiency virus-positive women with condyloma or VIN were significantly more likely to have cervical intraepithelial neoplasia (33%) than those without vulvovaginal lesions (17%) (OR 2.9, 95% confidence interval [CI] 1.1, 74). In multivariate logistic regression analysis, both HIV seropositivity (adjusted OR 5.3, 95% CI 1.3, 35.3) and HPV infection (adjusted OR 6.1, 95% CI 1.7, 39.4) were associated with vulvovaginal condyloma. Conclusion The prevalence of vulvovaginal condyloma was increased in HIV-positive women even when controlling for HPV infection. Human papillomavirus-associated disease was more likely to be multicentric and involve the vulva, vagina, and cervix in HIV-positive than HIV-negative women. Detection of high-grade VIN in two of the HIV positive women suggests that they may also be at risk for developing invasive vulvar carcinoma.

Ongoing sexually transmitted disease acquisition and risk-taking behavior among US HIV-infected patients in primary care: implications for prevention interventions.

Background: To better understand the factors associated with HIV- and sexually transmitted disease (STD)-transmitting behavior among HIV-infected persons, we estimated STD prevalence and incidence and associated risk factors among a diverse sample of HIV-infected patients in primary care. Methods: We analyzed data from 557 participants in the SUN Study, a prospective observational cohort of HIV-infected adults in primary care in 4 US cities. At enrollment and 6 months thereafter, participants completed an audio computer-assisted self-interview about their sexual behavior, and were screened for genitourinary, rectal, and pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis infections by nucleic acid amplification testing, and for serologic evidence of syphilis. Women provided cervicovaginal samples and men provided urine to screen for Trichomonas vaginalis by polymerase chain reaction. Results: Thirteen percent of participants had a prevalent STD at enrollment and 7% an incident STD 6 months later. The most commonly diagnosed infections were rectal chlamydia, oropharyngeal gonorrhea, and chlamydial urethritis among the men and trichomoniasis among the women. Other than trichomoniasis, 94% of incident STDs were identified in men who have sex with men. Polysubstance abuse other than marijuana, and having ≥4 sex partners in the 6 months before testing were associated with diagnosis of an incident STD. Conclusions: STDs were commonly diagnosed among contemporary HIV-infected patients receiving routine outpatient care, particularly among sexually active men who have sex with men who used recreational drugs. These findings underscore the need for frequent STD screening, prevention counseling, and substance abuse treatment for HIV-infected persons in care.

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.