[Show abstract][Hide abstract] ABSTRACT: GB virus C (GBV-C) may have a beneficial impact on HIV disease progression; however, the epidemiologic characteristics of this virus are not well characterized. Behavioral factors and gender may lead to differential rates of GBV-C infection; yet, studies have rarely addressed GBV-C infections in women or racial/ethnic minorities. Therefore, we evaluated GBV-C RNA prevalence and genotype distribution in a large prospective study of high-risk women in the US.
438 hepatitis C virus (HCV) seropositive women, including 306 HIV-infected and 132 HIV-uninfected women, from the HIV Epidemiologic Research Study were evaluated for GBV-C RNA. 347 (79.2%) women were GBV-C RNA negative, while 91 (20.8%) were GBV-C RNA positive. GBV-C positive women were younger than GBV-C negative women. Among 306 HIV-infected women, 70 (22.9%) women were HIV/GBV-C co-infected. Among HIV-infected women, the only significant difference between GBV-negative and GBV-positive women was age (mean 38.4 vs. 35.1 years; p<0.001). Median baseline CD4 cell counts and plasma HIV RNA levels were similar. The GBV-C genotypes were 1 (n = 31; 44.3%), 2 (n = 36; 51.4%), and 3 (n = 3; 4.3%). The distribution of GBV-C genotypes in co-infected women differed significantly by race/ethnicity. However, median CD4 cell counts and log10 HIV RNA levels did not differ by GBV-C genotype. GBV-C incidence was 2.7% over a median follow-up of 2.9 (IQR: 1.5, 4.9) years, while GBV-C clearance was 35.7% over a median follow-up of 2.44 (1.4, 3.5) years. 4 women switched genotypes.
Age, injection drug use, a history of sex for money or drugs, and number of recent male sex partners were associated with GBV-C infection among all women in this analysis. However, CD4 cell count and HIV viral load of HIV/HCV/GBV-C co-infected women were not different although race was associated with GBV-C genotype.
PLoS ONE 12/2014; 9(12):e114467. DOI:10.1371/journal.pone.0114467 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the MAGI-3 gene and one SNP (rs8031627) in the SMAD3 gene were associated with HR-HPV clearance (p<10-6). A variant (rs1633038) in HLA-G were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.
PLoS ONE 06/2014; 9(6):e99109. DOI:10.1371/journal.pone.0099109 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective. To identify correlates of incident bacterial vaginosis (BV) diagnosed with Nugent scoring among high-risk women.
Study Design. We conducted both cohort and case-crossover analyses, stratified by HIV infection status, based on 871 HIV-infected and 439 HIV-uninfected participants in the HIV Epidemiology Research Study, conducted in 4 US sites in 1993–2000. Results. BV incidence was 21% and 19% among HIV-infected and -uninfected women, respectively. Fewer correlates of BV were found with case-crossover than with cohort design. Reporting frequent coitus (regardless of consistency of condom use) was correlated with BV in cohort analyses but not in case-crossover analyses. The sole correlate of BV in both types of analyses was the detection of spermatozoa on Gram stain, which is a marker of semen exposure. Conclusion. The inconsistent association between condom use and BV in prior studies could be from reporting bias. We found evidence of a relationship between semen exposure and incident BV.
Infectious Diseases in Obstetrics and Gynecology 12/2011; 2011(7204):842652. DOI:10.1155/2011/842652
[Show abstract][Hide abstract] ABSTRACT: The prevalence of Trichomonas vaginalis is higher among incarcerated women than in the general community. We sought to determine whether a history of incarceration itself was independently associated with trichomoniasis.
The HIV Epidemiology Research Study is a prospective cohort study of 871 HIV-seropositive and 439 high-risk seronegative women in 4 urban centers (Bronx, NY; Detroit, MI; Providence, RI; Baltimore, MD). All participants enrolled between April 1993 and January 1995, with interviews and physical examinations conducted at baseline and at follow-up visits every 6 months up to 7 years.
Of 1310 subjects, 427 (33%) reported being incarcerated on at least one occasion. In addition, 724 (55%) were found to have a sexually transmitted infection on at least one occasion during the study; baseline rates were 21% for T. vaginalis, 4.3% for Chlamydia trachomatis, 0.6% for N. gonorrhea, and 8% for syphilis. Incarceration was associated with the detection of trichomonas infection (between-subject, odds ratio, 2.4; 95% confidence interval: 1.85-3.14; P < 0.01 and within-subject, odds ratio, 1.56; 95% confidence interval: 1.26-1.92; P < 0.01). The association with incarceration remained significant after adjusting for age, race, HIV status, enrollment risk group, number of sexual partners, marital status, education, bacterial vaginosis, vaginal candidiasis, drug use (crack, cocaine, heroin), alcohol use, health insurance, receipt of public assistance, employment status, visit number, and study site.
A history of incarceration was independently associated with the detection of trichomonas infection in a cohort of high-risk women. These data have implications for increased sexually transmitted infection prevention, screening, and treatment upon entry to jail as well as in the communities most affected by incarceration.
[Show abstract][Hide abstract] ABSTRACT: To evaluate associations between common vaginal infections and human papillomavirus (HPV).
Data from up to 15 visits on 756 HIV-infected women and 380 high-risk HIV-uninfected women enrolled in the HIV Epidemiology Research Study (HERS) were evaluated for associations of bacterial vaginosis, trichomoniasis, and vaginal Candida colonization with prevalent HPV, incident HPV, and clearance of HPV in multivariate analysis.
Bacterial vaginosis (BV) was associated with increased odds for prevalent (aOR = 1.14, 95% CI: 1.04, 1.26) and incident (aOR = 1.24, 95% CI: 1.04, 1.47) HPV and with delayed clearance of infection (aHR = 0.84, 95% CI: 0.72, 0.97). Whereas BV at the preceding or current visit was associated with incident HPV, in an alternate model for the outcome of incident BV, HPV at the current, but not preceding, visit was associated with incident BV.
These findings underscore the importance of prevention and successful treatment of bacterial vaginosis.
Infectious Diseases in Obstetrics and Gynecology 08/2011; 2011(11):319460. DOI:10.1155/2011/319460
[Show abstract][Hide abstract] ABSTRACT: Populations of African ancestry continue to account for a disproportionate burden of the human immunodeficiency virus type 1 (HIV-1) epidemic in the United States. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in 2 cohorts: Reaching for Excellence in Adolescent Care and Health (REACH) and HIV Epidemiology Research Study (HERS). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4(+) T cells were examined both separately and combined to represent 3 categories of HIV-1 disease control (76 controllers, 169 intermediates, and 93 noncontrollers). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with 1 or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and nongenetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection cross the boundaries of race and viral subtype, whereas others appear confined within one or the other of those boundaries.
Human immunology 04/2011; 72(4):312-8. DOI:10.1016/j.humimm.2011.01.003 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many studies have chronicled the "epidemiologic synergy" between human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2). HIV adversely affects the natural history of HSV-2 and results in more frequent and severe HSV-2 reactivation. Few longitudinal studies, however, have examined whether HSV-2 is associated with increased HIV plasma viral loads or decreased CD4 counts. The authors estimated the effect of HSV-2 seropositivity on HIV RNA viral load and on CD4 count over time among 777 HIV-seropositive US women not receiving suppressive HSV-2 therapy in the HIV Epidemiology Research Study (1993-2000). Linear mixed models were used to assess the effect of HSV-2 on log HIV viral load and CD4 count/mm(3) prior to widespread initiation of highly active antiretroviral therapy. Coinfection with HSV-2 was not associated with HIV RNA plasma viral loads during study follow-up. There was a statistically significant association between HSV-2 seropositivity and CD4 count over time, but this difference was small and counterintuitive at an increase of 8 cells/mm(3) (95% confidence interval: 2, 14) per year among HSV-2-seropositive women compared with HSV-2-seronegative women. These data do not support a clinically meaningful effect of baseline HSV-2 seropositivity on the trajectories of HIV plasma viral loads or CD4 counts.
American journal of epidemiology 03/2011; 173(7):837-44. DOI:10.1093/aje/kwq432 · 5.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: FIB-4 represents a noninvasive, composite index that is a validated measure of hepatic fibrosis, which is an important indicator of liver disease. To date, there are limited data regarding hepatic fibrosis in women.
FIB-4 was evaluated in a cohort of 1227 women, and associations were evaluated in univariate and multivariate regression models among 4 groups of subjects classified by their human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection status.
The median FIB-4 scores were 0.60 in HIV-/HCV- women, 0.83 in HIV-/HCV+ women, 0.86 in HIV+/HCV- women, and 1.30 in HIV+/HCV+ women. In the HIV/HCV co-infected group, multivariate analysis showed that CD4(+) cell count and albumin level were negatively associated with FIB-4 (P <.0001), whereas antiretroviral therapy (ART) was positively associated with FIB-4 score (P =.0008). For the HIV mono-infected group, multivariate analysis showed that CD4(+) cell count (P <.0001) and albumin level (P =.0019) were negatively correlated with FIB-4 score, ART was positively associated with FIB-4 score (P =.0008), and plasma HIV RNA level was marginally associated with FIB-4 score (P =.080). In 72 HIV mono-infected women who were also hepatitis B surface antigen negative, ART naive, and reported no recent alcohol intake, plasma HIV RNA level was associated with increased FIB-4 score (P =.030).
HIV RNA level was associated with increased FIB-4 score in the absence of hepatitis B, hepatitis C, ART, or alcohol use, suggesting a potential relationship between HIV infection and hepatic fibrosis in vivo. A better understanding of the various demographic and virologic variables that contribute to hepatic fibrosis may lead to more effective treatment of HIV infection and its co-morbid conditions.
[Show abstract][Hide abstract] ABSTRACT: Cytomegalovirus (CMV) enters latency following primary infection and can subsequently reactivate. Reinfection with a different viral strain can also occur. During these events, CMV is shed in bodily fluids. This study examined correlates of CMV shedding in specimens obtained from the HIV Epidemiology Research Study, a multicenter cohort study of US women with or at high risk for human immunodeficiency virus (HIV) infection. Among the women studied, 91.4 % (911/997) were CMV IgG seropositive. Of these women, 2.7 % (25/911) were CMV IgM seropositive. CMV DNA was detected via real-time PCR more frequently in cervicovaginal lavage (CVL) specimens (55/764, 7.2 %) than in peripheral blood mononuclear cells (PBMCs) (26/897, 2.9 %). CMV viral loads in 1 ml CVL (median 534; mean 2598; range = 40-74, 844) were higher than in 10⁶ PBMCs (median 264; mean 1287; range = 35-13 ,250). CMV DNA in PBMCs was associated with HIV seropositivity [odds ratio (OR) 13.5; 95 % confidence interval (CI) 1.8-100], increasing HIV viral load (P<0.001 for trend), decreasing CD4 cell counts (P<0.001 for trend) and CMV DNA in CVL (OR 26; 95 % CI 10.7-64). CMV DNA in CVL specimens was associated with CMV IgM seropositivity (OR 4.3; 95 % CI 1.5-12.3), HIV seropositivity (OR 7.3; 95 % CI 2.6-20), increasing HIV viral load (P<0.001 for trend) and decreasing CD4 cell counts (P<0.001 for trend). The positive predictive value of CMV IgM seropositivity for CMV DNA shedding in either PBMCs or CVL was 20 %. In summary, CMV shedding in CVL and PBMCs was highly correlated with each other and with markers of immune suppression.
Journal of Medical Microbiology 03/2011; 60(Pt 6):768-74. DOI:10.1099/jmm.0.027771-0 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug users with HIV infection successfully treated with highly active antiretroviral therapy are now living to older ages. As persons with HIV infection age, they become at risk for comorbidities that occur in any group of aging individuals. However, some of these conditions occur at increased rates, with increasing severity, or pose special problems in older persons with HIV infection. This article discusses the epidemiology of HIV infection in aging drug users, and hormonal, cardiovascular, liver, renal, bone, and cognitive disorders and depression and cancer in these individuals, as well as problems related to taking multiple medications and HIV disease progression.
[Show abstract][Hide abstract] ABSTRACT: HIV infection has been associated with development of prediabetes and diabetes. Optimum screening practices for these disorders in HIV-infected populations remain unclear.
We screened 377 adults, with or at-risk for HIV infection, for incident hyperglycaemia (prediabetes or diabetes) using two oral glucose tolerance tests (OGTTs) a median of 18.6 months apart. We determined proportion of incident cases detected by fasting and 120-min plasma glucose levels. Independent predictors of incident hyperglycaemia were identified using logistic regression.
The baseline OGTT was consistent with diabetes in 7% of participants and with prediabetes in 31%. Among 352 normoglycaemic and prediabetic participants at baseline, 19 (5%) developed diabetes on follow-up. Among participants normoglycaemic at baseline, an additional 38 (16%) developed prediabetes. Overall 52% of incident hyperglycaemia cases were detected by fasting plasma glucose alone, 33% by a 120-min glucose level alone and 15% by both. Factors independently associated with incident hyperglycaemia included age ≥50 years and body mass index ≥30 kg/m(2). Neither HIV infection nor highly active antiretroviral therapy (HAART) use were associated with increased risk of diabetes.
Incident hyperglycaemia is common among older adults with or at-risk for HIV infection. HIV-infected individuals with classic diabetes risk factors should be screened for hyperglycaemia regardless of HAART use. OGTTs might be the preferred screening strategy in HIV-infected individuals at high risk for developing hyperglycaemia.
[Show abstract][Hide abstract] ABSTRACT: To assess the accuracy of clinical diagnosis of bacterial vaginosis (BV) by using Amsel criteria, overall and by human immunodeficiency virus (HIV) infection status.
Women with HIV, or at risk for HIV, participated in the HIV Epidemiology Research Study, a prospective study conducted in 4 US sites. At enrollment and follow-up visits, scheduled at 6-month intervals for ≤ 5 years, participants received gynecologic examinations, had specimens collected, and underwent standardized interviews. We used McNemar test statistic to evaluate agreement between Amsel criteria and Nugent scoring. Using Nugent scoring as the reference standard, we calculated sensitivity and specificity for Amsel criteria and for 3 other classifications of clinical BV. Our results are based on data collected from 9140 study visits by 862 HIV-infected women and 421 HIV-uninfected women.
Amsel criteria and Nugent scoring did not agree in the classification of BV cases (P < 0.01). Amsel criteria had poor sensitivity (60%; 95% confidence interval, 58%-61%) and specificity (90%; 95% confidence interval, 89%-91%) with wide differences in test properties by study site. We found no differences in diagnosing BV by HIV infection status.
The under- and overdiagnosing of BV clinically suggests that the accuracy of Amsel criteria for routine screening of asymptomatic women might be lower than previous estimates; that clinicians need more rigorous training to apply subjective Amsel criteria accurately; or that wide heterogeneity in cases might prevent agreement between clinical and laboratory diagnoses, with future research needed to better understand the criteria or morphotypes associated with specific adverse outcomes.
[Show abstract][Hide abstract] ABSTRACT: To investigate rates and predictors of change in bone mineral density (BMD) in a cohort of aging men with or at risk for HIV infection.
A prospective cohort study among 230 HIV-infected and 159 HIV-uninfected men aged at least 49 years.
Longitudinal analyses of annual change in BMD at the femoral neck, total hip, and lumbar spine.
At baseline, 46% of men had normal BMD, 42% had osteopenia, and 12% had osteoporosis. Of those men with normal BMD, 14% progressed to osteopenia and 86% continued to have normal BMD. Of the men initially with osteopenia, 12% progressed to osteoporosis and 83% continued to have osteopenia. Osteopenia incidence per 100 person-years at risk was 2.6 for HIV-uninfected men and 7.2 for HIV-infected men; osteoporosis incidence was 2.2 per 100 person-years at risk among men with osteopenia, regardless of HIV status. In multivariable analysis of annual change in BMD at the femoral neck, we found a significant interaction between heroin use and AIDS diagnosis, such that the greatest bone loss occurred with both AIDS and heroin use (adjusted predicted mean annual bone loss 0.0196 g/cm). Hepatitis C virus seropositivity was also associated with femoral neck bone loss (P = 0.04). The interaction between AIDS and heroin use also was associated with bone loss at the total hip, as was current methadone use (P < 0.01).
We found an association of heroin use and AIDS with BMD change, suggesting that heroin users with AIDS may be at particular risk for bone loss.
AIDS (London, England) 09/2010; 24(15):2337-45. DOI:10.1097/QAD.0b013e32833d7da7 · 5.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the presence of and estimate risk factors for reactivation of latent high-risk human papillomavirus (HPV) cervical infection in human immunodeficiency virus (HIV)-infected and HIV-uninfected women.
Data from 898 women in the HIV Epidemiology Research Study (HERS) were used to evaluate cervical HPV latency and reactivation. Prior exposure to HPV types (16, 18, 31, 35, and 45) was determined by serologic testing at enrollment, and cervical shedding of HPV was detected by polymerase chain reaction at 6-month intervals. Human papillomavirus cervical shedding and sexual history were used to estimate rates of reactivation and recurrence. Repeated measures survival analysis was used to estimate hazard ratios and 95% confidence intervals for reactivation and recurrence. Rates of total HPV shedding (recurrence and reactivation) during follow-up were assessed by HIV status and rate ratios were calculated.
Reactivation of latent HPV infections was observed in HIV-infected women, but few reactivation events were identified in HIV-uninfected women. Factors consistently associated with reactivation in HIV-infected women included CD4 count less than 200/mm and age younger than 35 years. Women infected with HIV had 1.8 to 8.2 times higher rates of viral shedding (reactivation plus recurrence) compared with HIV-uninfected women.
Women with a history of cervical HPV infection may be at risk of reactivation of latent viral infection even in the absence of sexual activity, and this risk is higher in women with HIV infection.
Obstetrics and Gynecology 06/2010; 115(6):1150-8. DOI:10.1097/AOG.0b013e3181e00927 · 5.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of human leukocyte antigen (HLA) class I supertypes in controlling human immunodeficiency virus type 1 (HIV-1) infection in African Americans has not been established. We examined the effects of the HLA-A and HLA-B alleles and supertypes on the outcomes of HIV-1 clade B infection among 338 African American women and adolescents. HLA-B58 and -B62 supertypes (B58s and B62s) were associated with favorable HIV-1 disease control (proportional odds ratio [POR] of 0.33 and 95% confidence interval [95% CI] of 0.21 to 0.52 for the former and POR of 0.26 and 95% CI of 0.09 to 0.73 for the latter); B7s and B44s were associated with unfavorable disease control (POR of 2.39 and 95% CI of 1.54 to 3.73 for the former and POR of 1.63 and 95% CI of 1.08 to 2.47 for the latter). In general, individual alleles within specific B supertypes exerted relatively homogeneous effects. A notable exception was B27s, whose protective influence (POR, 0.58; 95% CI, 0.35 to 0.94) was masked by the opposing effect of its member allele B*1510. The associations of most B supertypes (e.g., B58s and B7s) were largely explained either by well-known effects of constituent B alleles or by effects of previously unimplicated B alleles aggregated into a particular supertype (e.g., B44s and B62s). A higher frequency of HLA-B genotypic supertypes correlated with a higher mean viral load (VL) and lower mean CD4 count (Pearson's r = 0.63 and 0.62, respectively; P = 0.03). Among the genotypic supertypes, B58s and its member allele B*57 contributed disproportionately to the explainable VL variation. The study demonstrated the dominant role of HLA-B supertypes in HIV-1 clade B-infected African Americans and further dissected the contributions of individual class I alleles and their population frequencies to the supertype effects.
Journal of Virology 03/2010; 84(5):2610-7. DOI:10.1128/JVI.01962-09 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The utility of certain 5-alkynyloxy-, 5-alkynylthio, and 5-alkynylsulfinyl-pyrimidines as precursors of 7-substituted furo[3,2-d]- and thieno[3,2-d]pyrimidines has been examined. When treated with sodium methoxide in warm methyl sulfoxide, 1,3-dimethyl-5-(2-propynyloxy)uracil (6) cyclizes to afford 1,3,7-tri-methylfuro[3,2-d]pyrimidine-2,4-(1H,3H)-dione (12) in 52% yield, possibly via the allenic ether 9 (R = H). The corresponding 5-(2-butynyloxy)pyrimidine (7), obtained in good yield by treating 6 with methyl iodide and sodium hydride in methyl sulfoxide, fails to undergo an analogous cyclization. However, compound 7 does undergo a normal alkynyl Claisen rearrangement and cyclization when heated at 130°, giving the 8-methylpyrano[3,2-d]pyrimidine 8 in methyl sulfoxide and the 6,7-dimethylfuro[3,2-d]pyrimidme 11 in dimethylformamide. The 5-(2-propynylthio)pyrimidine 15 affords the allene 19 and the 1-propyne 22 when treated with various bases, but none of the 7-methylthieno[3,2-d]pyrimidine 16. At 145° in methyl sulfoxide, 15 undergoes a thio-Claisen rearrangement process to afford the 6-methylthieno[3,2-d]pyrimidine 17 together with substantial amounts of a product 20 that bears a 7-thiomethoxymethyl substituent derived from the solvent. Heating the 5-(2-propynylsulfinyl)pyriniidine 23 at 105° in methyl sulfoxide, followed by acidification of the reaction mixture, affords 1,3-dimethyl-7-formylthieno[3,2-d]pyrimidine-2,4-(1H,3H)-dione (29) in 47% yield. Deuterium labelling studies established that the aldehyde proton of 29 is derived from the 3′-proton of 23. This finding is consistent with a mechanism that involves sequential [2,3] and [3,3] sigma-tropic rearrangements, and the intermediacy of a dihydrothieno[3,2-d]pyrimidine such as compound 30.
[Show abstract][Hide abstract] ABSTRACT: Tumors produce multiple proangiogenic factors, making it unlikely that agents targeting a single angiogenic pathway will be sufficient to treat the spectrum of tumors that occur clinically. Platelet-derived endothelial cell growth factor has angiogenic activity in vitro and in vivo and is overexpressed in most human cancers, where its expression has been correlated with increased microvessel density, more aggressive tumors, and poorer patient prognosis. Platelet-derived endothelial cell growth factor is identical to the enzyme thymidine phosphorylase (TP), and unlike other angiogenic factors, the proangiogenic actions of TP are dependent on its enzyme activity.
A potent and specific small-molecule inhibitor of the catalytic activity of TP, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), was tested for antiangiogenic and antitumor activity in human cancer xenografts in vivo.
Oral administration of AEAC caused 40% to 50% reductions in the growth of A549 non-small cell lung cancer and PANC-1 pancreatic cancer xenografts, but it was not active against a second pancreatic tumor, BxPC-3. AEAC reduced the microvessel density in the tumors, providing evidence for an antiangiogenic action. Equal or better activity was seen when the mice were treated with the vascular endothelial growth factor (VEGF)-Trap, a soluble VEGF decoy receptor, and the combination of AEAC and VEGF-Trap produced additive antitumor activity that was significantly greater than the VEGF-Trap alone. In the A549 tumors, the combination produced tumor regressions.
These studies show antitumor activity for a drug targeting TP and suggest that inhibitors of TP could be used to augment the clinical efficacy of drugs targeting the VEGF pathway.
Clinical Cancer Research 09/2009; 15(16):5136-44. DOI:10.1158/1078-0432.CCR-08-3203 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Persons who use illicit drugs are at increased risk of new tuberculosis (TB) infection. We conducted a prospective cohort study to assess rates and risk factors for tuberculin skin test (TST) conversion among persons with a history of illicit drug use, who were enrolled in a methadone program and had a negative baseline 2-step TST (eligible participants).
TST and standardized interviews were administered to 401 eligible participants from 1995 through 1999, every 6 months for a 2-year follow-up time. Analyses were conducted in 2006.
A total of 1,447 repeat TSTs were performed during 843 person-years of follow-up (median: 2.0 years). The TST conversion rate was 3.7 per 100 person-years. In multivariate analysis, participants who converted were more likely to report ever having been homeless (HR, 2.4; 95% CI, 1.2-5.0) or ever having lived in a homeless shelter (HR, 2.4; 95% CI, 1.2-4.9) at the baseline interview, and less likely to have reported receiving public assistance since the last study visit (RR, 0.15; 95% CI, 0.07-0.32).
This is the first study utilizing 2-step TST at baseline to measure the incidence of TST conversion among persons who use illicit drugs. Controlling for homelessness, persons with a lack of current public assistance was identified as a risk factor for TST conversion. These individuals may most benefit from annual tuberculin skin testing.
Journal of Addiction Medicine 09/2009; 3(3):172-7. DOI:10.1097/ADM.0b013e31819eac4c · 1.76 Impact Factor