Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection.

The effect of highly active antiretroviral therapy (HAART) on the natural history of anal squamous intraepithelial lesions (ASIL)-the likely anal cancer precursor-and anal human papillomavirus (HPV) infection is unknown. ASIL severity and level of anal HPV DNA were evaluated among HIV-positive men who have sex with men (MSM) for at least 6 months before initiation of HAART. The results were compared with those from a 6-month period after initiation of HAART. Anal swabs for cytology and HPV studies were obtained, followed by high-resolution anoscopy and biopsy. Among men whose most severe pre-HAART diagnosis was atypical squamous cells of undetermined significance or low-grade ASIL, 18% (confidence interval [CI], 6-31%, 7 of 38) progressed and 21% (CI, 8-34%, 8 of 38) regressed 6 months after starting HAART. Seventeen percent (CI, 0-38%, 2 of 12) of study subjects who began with a normal diagnosis developed ASIL. Only 4% (CI, 0-10%, 1 of 28) of study subjects with high-grade ASIL regressed to normal. There was no reduction in the proportion of study subjects who tested positive for HPV DNA or HPV DNA levels after HAART initiation. The ASIL and HPV data were similar to those of the pre-HAART comparison period. These results indicate that HAART has little effect on either ASIL or HPV in the first 6 months after HAART initiation.

Prevalence and risk factors for anal squamous intraepithelial lesions in women.

BACKGROUND: Anal cancers are thought to arise from squamous intraepithelial lesions in the anal canal, and women infected with human immunodeficiency virus-1 (HIV) may be at higher risk of anal cancer. Our aim was to determine the prevalence of human papillomavirus (HPV)-related abnormalities of the anal canal in women and to characterize risk factors for these lesions. METHODS: We evaluated HPV-related abnormalities in 251 HIV-positive and in 68 HIV-negative women. We completed physical examinations and obtained questionnaire data on medical history and relevant sexual practices. Univariate and adjusted relative risks (RRs) and 95% confidence intervals (CIs) were computed using the Mantel-Haenszel procedure and regression techniques. All statistical tests were two-sided. RESULTS: Abnormal anal cytology, including atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, or high-grade squamous intraepithelial lesions (HSILs), was diagnosed in 26% of HIV-positive and in 8% of HIV-negative women. HSILs were detected by histology or cytology in 6% of HIV-positive and in 2% of HIV-negative women. HIV-positive women showed increased risk of anal disease as the CD4 count decreased (P<.0001) and as the plasma HIV RNA viral load increased (P =.02). HIV-positive women with abnormal cervical cytology had an increased risk of abnormal anal cytology at the same visit (RR = 2.2; 95% CI = 1.4 to 3.3). Abnormal anal cytology in HIV-positive women was associated with anal HPV RNA detected by the polymerase chain reaction and by a nonamplification-based test (RR = 4.3; 95% CI = 1.6 to 11). In a multivariate analysis, the history of anal intercourse and concurrent abnormal cervical cytology also were statistically significantly (P =.05) associated with abnormal anal cytology. CONCLUSIONS: HIV-positive women had a higher risk of abnormal anal cytology than did HIV-negative women with high-risk lifestyle factors. These data provide strong support for anoscopic and histologic assessment and careful follow-up of women with abnormal anal lesions.

Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women.

Little is known about the epidemiology of anal human papillomavirus (HPV) infection in women. We studied 251 human immunodeficiency virus (HIV)-positive and 68 HIV-negative women for the presence of anal HPV by use of polymerase chain reaction (PCR) and hybrid capture. Medical and behavioral risk factors were evaluated; 76% of HIV-positive and 42% of HIV-negative women were found to have anal HPV DNA via analysis by PCR (relative risk [RR], 1.8; 95% confidence interval [CI], 1.3-2.5). Among 200 women for whom there were concurrent anal and cervical HPV data, anal HPV was more common than cervical HPV in both HIV-positive (79% vs. 53%) and HIV-negative women (43% vs. 24%). By multivariate analysis of HIV-positive women, CD4(+) cell counts 500 cells/mm(3) (RR, 1.4; 95% CI, 1.1-1.5), and cervical HPV infection (RR, 1.3; 95% CI, 1.1-1.4) were associated with anal HPV infection. Women >45 years old had reduced risk, compared with women <36 years old (RR, 0.80; 95% CI, 0.50-0.99), as did African American women (RR, 0.86; 95% CI, 0.72-1.0), compared with white women. Anal HPV infection is underrecognized in HIV-positive and high-risk HIV-negative women.

Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men.

Anal cancer may be preceded by anal squamous intraepithelial lesions (ASIL), but the natural history of ASIL is poorly understood. In this report, we characterize the 2-year incidence and progression of low-grade SIL (LSIL) and high-grade SIL (HSIL) in a cohort study in 346 HIV-positive and 262 HIV-negative homosexual or bisexual men. Subjects were studied at defined intervals using anal cytology, anoscopy with biopsy of visible lesions, human papillomavirus (HPV) testing, HIV serostatus, CD4 level, and data on medical history and lifestyle. The incidence of HSIL within 2 years was 20% in HIV-positive men and 8% in HIV-negative men who were normal at baseline. In total, 62% of HIV-positive and 36% of HIV-negative men with LSIL at baseline progressed to HSIL. The relative risk (RR) for anal disease progression in HIV-positive men was 2.4 (95% confidence interval [CI], 1.8-3.2) when compared with HIV-negative men. The RR increased to 3.1 (95% CI, 2.3-4.1) in HIV-positive men with CD4 counts <200/mm3. Infection with multiple HPV types was a risk factor for anal disease progression in both HIV-positive (RR = 2.0; 95% CI, 1.0-4.1) and HIV-negative (RR = 5.1; 95% CI, 2.3-11) men. The incidence of anal HSIL and progression of LSIL to HSIL within 2 years of follow-up is high in HIV-positive homosexual or bisexual men and to a lesser extent, in HIV-negative men. Men with the above risk factors may be at increased risk of developing anal cancer.

Anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual and bisexual men: prevalence and risk factors.

Anal cancer is more commonly found in homosexual and bisexual men than cervical cancer is in women. Invasive anal cancer may be preceded by anal squamous intraepithelial lesions (ASIL), and treatment of ASIL may prevent the development of anal cancer. We characterized the prevalence and risk factors for ASIL in 346 HIV-positive and 262 HIV-negative homosexual men. Anal cytology, biopsy of visible anal lesions, and human papillomavirus (HPV) tests were performed, and data on HIV serostatus, CD4 count, and medical and lifestyle history were collected. ASIL was diagnosed in 36% of HIV-positive men and 7% of HIV-negative men (relative risk [RR] = 5.7; 95% confidence interval [CI], 3.6-8.9). Among HIV-positive men, the RR for ASIL increased with lower CD4 levels but was elevated even in men with CD4 levels >500/mm3 (RR = 3.8; 95% CI, 2.1-6.7) when compared with HIV-negative men. High-level HPV infection, as measured by detection of both hybrid capture (HC) group A and group B types, was another significant risk factor for ASIL in both HIV-positive men (RR = 8.8; 95% CI, 2.3-35) and HIV-negative men (RR = 20; 95% CI, 5.5-71) when compared with HC-negative men. HIV-negative men with anal HPV infection and HIV-positive men, regardless of CD4 level, are at high risk for ASIL.

High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men.

OBJECTIVE: The incidence of anal cancer among homosexual men exceeds that of cervical cancer in women, and HIV-positive homosexual men may be at even higher risk than HIV-negative men. Cervical cancer is preceded by high-grade squamous intra-epithelial lesions (HSIL) and anal HSIL may similarly be the precursor to anal cancer. In this study, we describe the incidence of and risk factors for HSIL in HIV-positive and HIV-negative homosexual and bisexual men. DESIGN: Prospective cohort study of HIV-positive and HIV-negative homosexual men. SETTING: The University of California, San Francisco. PATIENTS: 346 HIV-positive and 262 HIV-negative men enrolled at baseline, 277 HIV-positive and 221 HIV-negative homosexual men followed after baseline. STUDY DESIGN: A questionnaire was administered detailing lifestyle habits, medical history and sexual practices. Anal swabs for cytology and human papillomavirus studies were obtained, followed by biopsies of visible lesions. Human papillomavirus testing was performed using polymerase chain reaction (PCR) and 'hybrid capture'. Blood was obtained for HIV testing and measurement of CD4 levels. MAIN OUTCOME MEASURES: Incident HSIL. RESULTS: HIV-positive men were more likely to develop HSIL than HIV-negative men relative risk (RR), 3.7; 95% confidence interval (CI), 2.6-5.7. Life-table estimates of the 4-year incidence of HSIL was 49% (95% CI, 41-56) among HIV-positive men and 17% (95% CI, 12-23) among HIV-negative men. Among HIV-positive men, those with lower baseline CD4 counts (P = 0.007) and persistent infection with one or more human papillomavirus types, determined using PCR (P = 0.0001), were more likely to develop HSIL. CONCLUSIONS: HIV infection, lower CD4 levels and human papillomavirus infection were associated with high rates of incident HSIL among homosexual men. However, high rates were found at all CD4 levels among HIV-positive men and among HIV-negative men.

Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men.

One of the groups at highest risk of anal cancer is homosexual and bisexual men. Like cervical cancer, anal cancer is associated with human papillomavirus (HPV) infection. Anal HPV infection was characterized in a study of 346 human immunodeficiency virus (HIV)-positive and 262 HIV-negative homosexual and bisexual men. Anal HPV DNA was detected in 93% of HIV-positive and 61% of HIV-negative men by polymerase chain reaction. The spectrum of HPV types was similar in HIV-positive and HIV-negative men, with HPV-16 the most common type. Infection with multiple HPV types was found in 73% of HIV-positive and 23% of HIV-negative men. Among HIV-positive men who were positive by hybrid capture for group B HPV types (16/18/31/33/35/39/45/51/52/56/58) or group A types (6/11/42/43/44), lower CD4 cell levels were associated with higher levels of group B DNA (P = .004) but not group A DNA. These data suggest increased replication of the more oncogenic HPV types with more advanced immunosuppression.

Anal cytological abnormalities and anal HPV infection in men with Centers for Disease Control group IV HIV disease.

OBJECTIVE: To characterise risk factors for abnormal and cytology and anal human papilloma virus (HPV) infection in homosexual/bisexual men with advanced HIV related immunosuppression. DESIGN: Cross sectional study of men with Centers for Disease Control group IV HIV disease. SETTING: The University of California San Francisco, AIDS Clinic. PATIENTS: 129 homosexual or bisexual men with group IV HIV disease. METHODS: A questionnaire was administered detailing tobacco, alcohol and recreational drug use, medical history, and sexual practices. Anal swabs for cytology and HPV studies were obtained, as was blood for CD4 levels. MAIN OUTCOME MEASURES: Abnormal anal cytology and anal HPV infection. RESULTS: Abnormal anal cytology was detected in 39% of subjects and anal HPV infection in 93% as measured by polymerase chain reaction (PCR). Risk factors for abnormal cytology in multivariate analysis included HPV 16/18 infection (measured by PCR, RR = 2.1, 95% CI = 1.2-3.5) and intravenous drug use (RR = 1.8, 95% CI = 1.2-2.7). Infection with HPV 6/11 also had significantly elevated RRs in a separate model. Cigarette smoking, alcohol use, recreational drug use, and low CD4 level were associated with abnormal anal cytology in univariate analysis, as was infection with multiple HPV types and high levels of hybrid capture group B viral DNA. CONCLUSIONS: Anal cytological abnormalities and HPV infection are common among homosexual/bisexual men with group IV HIV disease. In this study population, the main risk factors for abnormal cytology were HPV infection and intravenous drug use.

Inhibition of gene expression in transformed plants by antisense RNA.

We report the successful suppression of nopaline synthase (EC 1.5.1.19) enzymatic activity in the leaves of tobacco plants via the overproduction of RNAs complementary to the nopaline synthase (nos) mRNA. Several different regions of the nos gene were fused, in antisense orientation, to the promoter from a strongly expressed petunia chlorophyll a/b-binding protein gene. These constructions were directly introduced into a tobacco line which contained a single copy of the wild-type nos gene and transgenic plants were regenerated. The degree of nopaline synthase suppression in the leaves of the double transformants ranged up to 85% and was dependent on the particular region of the nos gene present in the antisense RNA. The most effective nos antisense sequences were derived from the 3' half of the nos gene transcript. In addition, we report a new sensitive method for the detection and quantitation of nopaline synthase activity in crude plant extracts.