Evaluating the association of single-nucleotide polymorphisms with tenofovir exposure in a diverse prospective cohort of women living with HIV.

Higher exposure to tenofovir (TFV) increases the risk for kidney function decline, but the impact of genetic factors on TFV exposure is largely unknown. We investigated whether single-nucleotide polymorphisms (SNPs, n=211) in 12 genes are potentially involved in TFV exposure. Participants (n=91) from the Women's Interagency HIV Study, underwent a 24 h intensive pharmacokinetic sampling of TFV after witnessed dose and TFV area under the time-concentration curves (AUCs) were calculated for each participant. SNPs were assayed using a combination of array genotyping and Sanger sequencing. Linear regression models were applied to logarithmically transformed AUC. Those SNPs that met an a priori threshold of P<0.001 were considered statistically associated with TFV AUC. ABCG2 SNP rs2231142 was associated with TFV AUC with rare allele carriers displaying 1.51-fold increase in TFV AUC (95% confidence interval: 1.26, 1.81; P=1.7 × 10-5). We present evidence of a moderately strong effect of the rs2231142 SNP in ABCG2 on a 24 h TFV AUC.

Relation of HLA class I and II supertypes with spontaneous clearance of hepatitis C virus.

Human leukocyte antigen (HLA) genotype has been associated with the probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; P=0.004) was associated with HCV persistence, whereas DR8 (PR=1.8; P=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became nonsignificant in analysis that included supertypes, whereas B*57:03 (PR=1.9; P=0.008) and DRB1*07:01 (PR=1.7; P=0.005) retained their significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance.

Effects of depot-medroxyprogesterone acetate on the immune microenvironment of the human cervix and endometrium: implications for HIV susceptibility.

Depot-medroxyprogesterone acetate is a commonly used injectable contraceptive that has been associated with an increased risk of HIV acquisition. This study compares effects of depot-medroxyprogesterone acetate on immune parameters from several upper reproductive tract compartments relevant to HIV-1 susceptibility in repetitive samples from 15 depot-medroxyprogesterone acetate users and 27 women not on hormonal contraceptives. Compared with samples from unexposed women in the mid-luteal phase, depot-medroxyprogesterone acetate use was associated with: increased endocervical concentrations of MCP1 and IFNalpha2; decreased endocervical concentrations of IL1beta and IL6; increased proportions of endometrial CD4+ and CD8+ cells expressing the activation marker HLADR; increased density of endometrial macrophages; and decreased density of endometrial regulatory T cells. Unlike previous reports with samples from the vagina, we did not observe increased expression of the HIV co-receptor CCR5 on CD4+ T cells in the endocervix or endometrium. Our results indicate important differences in anatomic compartments regarding mechanisms by which depot-medroxyprogesterone acetate could be associated with increased risk of HIV acquisition, including increased recruitment of macrophages to the endometrium, decreased levels of pro-inflammatory cytokines in the endocervix possibly leading to enhanced susceptibility to viral infection, and activation of endometrial T cells.

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.

Selective inhibition of precursor incorporation into ribosomal RNA in gamma-irradiated Tetrahymena pyriformis.

Sublethal doses of gamma radiation are known to inhibit total RNA synthesis in the ciliate protozoan Tetrahymena. To determine if the synthesis of a particular class of RNA is preferentially inhibited, pulse-labeled RNA was isolated from normal exponentially growing cells, irradiated cells, and cells in which total RNA synthesis had recovered to the pre-irradiation level. The RNAs were analyzed by SDS-polyacrylamide gel electrophoresis and oligo(dT)-cellulose column chromatography. Inhibition of RNA synthesis primarily involves ribosomal RNA. However, radiation does not cause a delay in the processing of precursor rRNA or a preferential loss of either of the mature rRNAs. Following irradiation, poly(A)-containing RNA [poly(A+)RNA] is synthesized at a rate up to three times greater than the control rate. The elevated poly(A+)RNA synthesis occurs during the period of depressed rRNA synthesis and even after rRNA synthesis has recovered to its pre-irradiation rate. While the sizes of the total cellular ribonucleoside triphosphate pools are depressed in the irradiated cells, these pools probably do not represent the actual compartments containing the precursors for RNA synthesis, and the observed changes cannot explain the modifications in macromolecular synthesis in irradiated Tetrahymena.

Genital ulceration as a risk factor for human immunodeficiency virus infection.

Among 115 heterosexual men who presented with genital ulcers to a sexually transmitted disease clinic in Nairobi, Kenya, the prevalence of serum antibody to HIV was 16.5%. A past history of genital ulcers was reported by 12 (63%) of 19 men with antibody to HIV versus 30 (31%) of 96 without antibody (P = 0.008). HIV infection was also positively associated with lack of circumcision, but was not associated with the etiology of the current genital ulcer. Logistic regression analysis (adjusted for age, number of recent sex partners, recent prostitute contact, circumcision, tribal ethnic identity, past history of urethritis, and current diagnoses) confirmed only the association between prior history of genital ulcer disease and HIV infection; (P = 0.04, odds ratio 2.35, 95% confidence limits, 1.01-5.47). The incidence of genital ulcers, particularly chancroid, is much higher in parts of Africa than in Europe or North America. This may contribute to the increased risk of heterosexual transmission of HIV in Africa. Aggressive control of chancroid and syphilis may offer one very feasible approach to reducing transmission of HIV in this region.

Polypharmacy among patients attending an AIDS clinic: utilization of prescribed, unorthodox, and investigational treatments.

The objective of this study was to describe the utilization and characteristics associated with the use of prescribed, over-the-counter, investigational, and unorthodox treatments among AIDS clinic patients. This report is derived from cross-sectional data obtained using structured telephone surveys. Study participants (n = 197) were recruited from the University of California, San Francisco, Medical Center AIDS clinic. One hundred eighty-nine participants (96%) received 1-24 prescription medications during the 3 months prior to interview. Those with an AIDS diagnosis received a relatively greater number of prescription drugs (p = 0.0001); an average of 5.6 prescribed medications were used by AIDS patients versus 4.8 among AIDS-related complex and 2.3 among asymptomatic patients. Thirty-one percent participated in drug trials during the 3 months before interview, including 18% who were in multiple studies. Twenty-nine percent used unorthodox treatments. Seventy-five (40%) received prescription medication from a provider other than their primary provider. A more advanced stage of illness was associated with the use of unorthodox treatments (p = 0.003): users of these treatments had a greater educational attainment than nonusers (p = 0.03) and were significantly less likely to report that their primary provider was aware of all the treatments they used (odds ratio = 2.1, p less than 0.03). We conclude that use of polypharmacy among some AIDS clinic patients is common, could create an increased risk for adverse drug reactions, and may affect clinical drug trials. Despite having decided to obtain care at a university-based clinic, many of the participants of this study also chose to receive unorthodox therapies and care from nonprimary medical providers.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of chancroid with ciprofloxacin. A prospective, randomized clinical trial.

Chancroid is a major sexually transmitted disease in many developing countries. Although single-dose and short-course treatment of chancroid have been described, the increasing resistance of Hemophilus ducreyi to antimicrobial agents requires continuing evaluation of new therapies. Ciprofloxacin is a new quinolone antimicrobial agent with excellent in vitro efficacy against H. ducreyi. A double-blind, randomized clinical trial was conducted comparing a single-dose ciprofloxacin regimen (500 mg) and a three-day regimen of ciprofloxacin (500 mg twice daily) with a three-day regimen of trimethoprim-sulfamethoxazole (160 and 800 mg, respectively, twice daily) for the treatment of chancroid. The three-day ciprofloxacin regimen successfully eradicated H. ducreyi, and resulted in rapid clinical improvement in all 40 patients followed, with no failures. The other two regimens were also effective, but bacteriologic and clinical failure occurred in two and three patients following treatment with single-dose ciprofloxacin and three days of trimethoprim-sulfamethoxazole, respectively. All patients with buboes had resolution of lesions. There were no significant adverse effects associated with ciprofloxacin or trimethoprim-sulfamethoxazole. All three regimens are effective therapy for chancroid and H. ducreyi infections. If resistance to trimethoprim-sulfamethoxazole becomes widespread, ciprofloxacin may become a first-line therapy for chancroid. This study also demonstrates the efficacy of ciprofloxacin in soft tissue infection.

Kaposi's sarcoma and human herpesvirus-8.

KS is a major cause of morbidity and mortality among AIDS patients and a treatment problem in the sporadic cases that are not associated with HIV. All four forms of the disease are linked to a newly described herpesvirus, HHV-8 or KSHV, via strong epidemiologic associations and biologic plausibility as a causal agent. HHV-8 is also epidemiologically associated with body cavity-based lymphomas, which are almost unique to AIDS, and Castleman's disease. Existing radiation and chemotherapeutic treatments of KS are only partially effective and cause significant adverse effects. New preventive approaches and therapies aimed at inhibiting HHV-8 may be effective. New treatments that interfere with the molecular mechanisms that drive KS may, in the future, provide the best opportunities to control the disease.

Prevalence of human herpesvirus-8 salivary shedding in HIV increases with CD4 count.

Human herpesvirus-8 (HHV-8) is the etiologic agent of Kaposi's sarcoma (KS), which occurs in epidemic form in human immunodeficiency virus(HIV)-infected individuals. Saliva is the only mucosal fluid in which infectious HHV-8 has been identified, although factors associated with HHV-8 salivary shedding remain unclear. Our study performed PCR analysis for HHV-8 DNA in saliva (and other body fluids) in 66 HIV- and HHV-8-co-infected women without KS so that we could examine predictors for HHV-8 DNA detection. CD4 count was the most significant predictor of HHV-8 salivary shedding, with increased prevalence of HHV-8 salivary DNA at higher CD4 counts. The odds of salivary HHV8 shedding at CD4 counts > = 350 cells/microL was 63 times the odds of shedding at CD4 < 350 (95%CI, 1.3-3078), with an increase in effect size when the analysis was restricted to those with a CD4 nadir > 200. Analysis of these data suggests an increased potential for HHV-8 transmission early in HIV infection, with implications for HHV-8 prevention.

Effectiveness of highly active antiretroviral therapy among HIV-1 infected women.

STUDY OBJECTIVE: To describe the impact of highly active antiretroviral therapy (HAART) on mortality, morbidity, and markers of HIV disease progression in HIV infected women. DESIGN: Data collected from the Women's Interagency HIV Study, a prospective cohort study that enrolled women between October 1994 and November 1995. SETTING: Six clinical consortia based in five cities in the United States (New York, NY; Washington, DC; Los Angeles, CA; San Francisco, CA; and Chicago, IL). PARTICIPANTS: A total of 1691 HIV seropositive women with a study visit after April 1996. MAIN RESULTS: Beginning in April 1996, the self reported use of HAART increased over time, with more than 50% of the cohort reporting HAART use in 1999. There was a 23% decline per semester in the incidence of AIDS from April 1996 (95% confidence intervals (CI) -29% to -16%). Furthermore, there was a 21% decline of the semiannual mortality rates among those with AIDS at baseline (95% CI -27% to -14%) and an 11% decline among those AIDS free at baseline (95% CI -3% to -18%). CD4+ lymphocyte counts either increased (women with baseline AIDS) or stabilised (women without baseline AIDS) after April 1996, and HIV RNA levels dramatically declined in both groups, although the percentage of women with HIV RNA above 4000 cps/ml remained stable at approximately 40% since mid-1997. CONCLUSIONS: Despite concerns regarding the use of antiretroviral therapies in this population, the use of therapies led to improved immunological function, suppressed HIV disease activity, and dramatic declines in morbidity and mortality.

Self-disclosure experience of people with HIV infection in dedicated and mainstreamed dental facilities.

OBJECTIVES: People infected with HIV choose dental care in dedicated or mainstreamed facilities. In this study, people with HIV were asked whether they sought care in dedicated or mainstreamed dental facilities, their reasons for choosing this source of care, their HIV disclosure experiences, and what, if any, consequences the disclosure had on access to dental care. METHODS: Patients in a dedicated AIDS medical clinic (n = 84) responded to questions in a telephone survey. The sample was predominantly gay, white males with symptomatic HIV infection, from randomly chosen clinic appointments. RESULTS: The study found that 67.6 percent of respondents who had seen a dentist since their HIV diagnosis chose mainstreamed dental facilities. The majority of study participants (70%) disclosed their HIV status. Of those subjects who chose disclosure, discrimination was minimal (2.7%). CONCLUSIONS: Results suggest support for public policy encouraging people with HIV to go to any dentist with whom they feel most comfortable and with whom they will receive the best possible care, regardless of whether the dentist practices in a dedicated or mainstreamed facility.

Dental care experience of HIV-positive patients.

Three studies were conducted to assess the experiences of persons with acquired immune deficiency syndrome (AIDS) or risk factors for the disease in seeking dental care in Los Angeles; San Francisco; Seattle; and Tacoma, WA. Given previous reports from surveys of dentists that they would be reluctant to provide care to people from these groups, widespread denial of care was expected. Our two surveys conducted in San Francisco, however, showed that only 1.3% and 10.8% had been denied care by a dentist. These data suggest that dentist reactions to people with AIDS are more favorable than has previously been suggested, although denial of care is still a problem to some extent.

Effect of tuberculosis on the survival of women infected with human immunodeficiency virus.

Evidence regarding the effect of tuberculosis (TB) disease on progression of human immunodeficiency virus (HIV) disease is inconclusive. The authors estimated the effect of time-varying incident TB on time to acquired immunodeficiency syndrome (AIDS)-related mortality using a joint marginal structural Cox model. Between 1995 and 2002, 1,412 HIV type 1 (HIV-1)-infected women enrolled in the Women's Interagency HIV Study were followed for a median of 6 years. Twenty-nine women incurred incident TB, and 222 died of AIDS-related causes. Accounting for age, CD4 cell count, HIV-1 RNA level, serum albumin level, and non-TB AIDS at study entry, as well as for time-varying CD4 cell count, CD4 cell count nadir, HIV-1 RNA level, peak HIV-1 RNA level, serum albumin level, HIV-related symptoms, non-TB AIDS, anti-Pneumocystis jiroveci prophylaxis, antiretroviral therapy, and household income, the hazard ratio for AIDS-related death comparing time after incident TB with time before incident TB was 4.0 (95% confidence interval (CI): 1.2, 14). The effect of incident TB on mortality was similar among highly active antiretroviral therapy (HAART)-exposed women (hazard ratio = 4.3, 95% CI: 0.9, 22) and non-HAART-exposed women (hazard ratio = 3.9, 95% CI: 0.9, 17; interaction p = 0.91). Although results were imprecise because few women incurred TB, irrespective of HAART exposure, incident TB increases the hazard of AIDS-related death among HIV-infected women.

The impact of HIV-related illness on employment.

We used structured telephone interviews to determine the extent of work loss following onset of symptoms, the interval between onset of symptoms and cessation of work, and the risk factors for work loss among 193 persons with symptoms of human immunodeficiency virus (HIV)-related illness attending the AIDS Clinic at the University of California, San Francisco, between October 1, 1988, and September 30, 1989. Estimates of the duration of time between onset of HIV-related symptoms and work loss derive from the life table method of Kaplan and Meier. A Cox proportional hazards model is used to estimate the effect of risk factors on the probability of withdrawing from work in each time interval. Eighty-six percent of the respondents worked prior to onset of the first symptom of HIV-related illness; 40 percent were working at the time of the most recent interview, a mean of 958 days later. The total number of hours worked declined by 59 percent during this time. Kaplan-Meier analysis indicates that 50 percent who worked prior to onset of HIV-related illness stopped working within two years and all had stopped within 10 years after onset of the first symptom.

Impact of the ovulatory cycle on virologic and immunologic markers in HIV-infected women.

An individual's sex influences plasma human immunodeficiency virus type 1 (HIV-1) RNA level and rate of CD4 cell decline, but the mechanism for this effect is currently unknown. To determine the effect of the ovulatory cycle on HIV-1 RNA level and lymphocyte subsets in HIV-infected women, blood specimens were obtained weekly from 14 women infected with HIV. Participants reported regular menses and were not using hormonal medications or narcotics. The occurrence of ovulation was verified by use of endocrine criteria. Ovulation occurred in 10 of the 14 women. Among women who ovulated, median HIV-1 RNA level fell by a median of 0.16 log10 from the early follicular phase to the midluteal phase (P=.03, Wilcoxon signed-rank test). When women who did not ovulate were included in the analysis, no significant fluctuation in plasma HIV RNA level was identified. Thus, the ovulatory cycle influenced circulating HIV-1 RNA levels, a finding that is plausible because of the known effect of sex hormones on lymphocyte function and cytokine production.

Access to and utilization of primary care services among HIV-infected women.

OBJECTIVES: To identify factors associated with the use of medical services, and to test a model of access to care, among HIV-infected women. METHODS: A cross-sectional telephone survey was administered to 213 HIV-infected women. Outcomes were having a primary care provider, and use of primary care and emergency health services. Predictors included characteristics of the population-at-risk and of the health care system. RESULTS: Ninety-three percent of respondents had a primary care provider. Linear regression found age >45 years (p = .002), perceiving greater barriers to getting to a clinic (p = .04) and greater benefits from medications (p = .03), lack of problems with appointment times (p = .02), having AIDS (p = .01), shorter appointment waiting times (p = .0003), and greater cost of travel to care (p = .001) were associated with a greater number of primary care visits. Thirty-seven percent missed at least 1 primary care appointment. In logistic regression, lack of insurance (odds ratio [OR] = 2.76), current injection drug use (OR = 2.89) and difficulty remembering appointments (OR = 2.36) were associated with having missed any appointments. CONCLUSIONS: Characteristics of the population-at-risk and of the health care system both make important contributions to primary care service use.

Dental care access and use among HIV-infected women.

OBJECTIVES: This study sought to identify predictors of dental care use in HIV-infected women. METHODS: In a cross-sectional survey of HIV-infected women enrolled in the northern California site of the Women's Interagency HIV Study, dental care use and unmet need were assessed in relation to selected variables. RESULTS: Among 213 respondents, who were predominantly Black and younger than 45 years, 43% had not seen a dentist and 53% (among dentate women) reported no dental cleaning in more than a year (although 67% had dental insurance coverage, mainly state Medicaid). Nine percent were edentulous. Among nonusers of dental care, 78% reported that they wanted care but failed to get it. Barriers included fear of and discomfort with dentists, not getting around to making an appointment, and not knowing which dentist to visit. Multivariate analysis showed that lack of past-year dental care was associated mainly with unemployment, a perception of poor oral health, and edentulism. CONCLUSIONS: HIV-positive women appear to be underusing dental care services. Fear and lack of information regarding available resources, in addition to unemployment and perception of poor oral health, may be important barriers.

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.