Triin Umbleja

Harvard Medical School, Boston, Massachusetts, United States

Are you Triin Umbleja?

Claim your profile

Publications (13)65.08 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background. HIV-infected women are disproportionately affected by human papillomavirus (HPV)-related anogenital disease, particularly with increased immunosuppression. A5240 was a trial of 319 HIV-infected women in US, Brazil and South Africa to determine immunogenicity and safety of the quadrivalent HPV vaccine in 3 strata based on screening CD4: >350 (A), >200to350 (B), ≤200 cells/mm(3) (C). Methods. Safety and serostatus of HPV types 6, 11, 16, and 18 were examined. HPV serological testing was performed using competitive Luminex Immuno-Assay (HPV-4 cLIA). HPV type-specific seroconversion analysis was on participants who were seronegative for the given type at baseline. Results. Median age was 36 years, 11% were white, 56% black, 31% Hispanic. Median CD4 was 310 cells/mm(3), 40% had undetectable HIV-1 viral load. No safety issues were identified. Seroconversion proportions at week 28 among women in CD4 stratum A were 96%, 98%, 99%, and 91% for HPV types 6, 11,16, and 18 respectively; in stratum B 100% 98%, 98%, and 85% and in stratum C 84%, 92%, 93%, 75% for each type respectively. Conclusion. Quadrivalent HPV vaccine targeted at types 6, 11, 16, and 18 was safe and immunogenic in HIV-infected women 13-45 years old. Women with HIV viral load >10,000 copies/mL and/or CD4 counts <200 cells/mm&sup3; had lower seroconversion.
    Clinical Infectious Diseases 04/2014; · 9.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: We hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coinfected persons. Methods: Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to historical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR). Results: Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%-75.3%), cEVR in 38.8% (28.8%-49.6%). and SVR in 32.8% (23.4%-43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated. Conclusion: Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.
    HIV Clinical Trials 01/2013; 14(6):274-283. · 2.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The effect of peginterferon alpha/ribavirin (PEG-IFN/RBV) and hepatitis C virus (HCV) clearance on lipid and insulin resistance (IR) profiles in HCV/human immunodeficiency virus (HIV) coinfection is unknown. We measured fasting total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoproteins (HDL-C), triglycerides (TG), glucose, and insulin at defined intervals in the A5178 study (N = 329), a prospective treatment trial in HCV/HIV coinfection. Changes from baseline and the relation between baseline values of these variables to sustained virologic response (SVR) were determined. Of 182 subjects with metabolic data, 98 achieved early virologic response (EVR) and continued PEG-IFN/RBV. Among those, median pretreatment HCV RNA was 6.6 log(10 )IU/mL; 73% had HCV genotype 1. Median pretreatment TC was 176 mg/dL (interquartile range [IQR],150-205]; median LDL-C was 99 mg/dL (IQR, 79-123); median HDL-C was 40 mg/dL (IQR, 31-47); and median TG was 147 mg/dL (IQR, 101-221). Median homeostasis model assessment of IR (HOMA-IR) was 3.3 (IQR, 1.7-5.3). The EVRs demonstrated a decline in TC, LDL-C, and HDL-C, whereas TG increased on treatment but returned to near baseline 24 weeks after end of treatment (EOT). The HOMA-IR decline from entry to 24 weeks after EOT was significant among non-sustained virologic responders and nonsignificant among sustained virologic responders; this difference was offset after adjusting for higher HOMA-IR at baseline among the former. Among all 182 subjects, entry LDL-C was associated with SVR in a joint logistic model adjusted for HCV genotype, race, and prior IFN (odds ratio, 1.17 per 10 mg/dL increase; 95% confidence interval, 1.03-1.32), but TC, HDL, TG, and IR were not. Peginterferon alpha and RBV can significantly affect lipid profile and IR in HCV/HIV-coinfected persons. Although the lipid profile returns to near pretreatment levels after completion of treatment, our data suggest persistent modest improvement in IR with treatment. Clinical Trials Registration. NCT00078403.
    Clinical Infectious Diseases 05/2012; 55(5):631-8. · 9.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It is unknown whether extended treatment with pegylated interferon (PEG) and weight-based ribavirin (WBR) results in higher rates of sustained viro-logic response (SVR) among HCV-HIV coinfected patients compared with standard duration therapy. The study aimed to measure rates of SVR among coinfected patients who received extended therapy with PEG plus WBR.Methods: HCVHIV coinfected subjects were treated with PEG and WBR, and those who achieved early virologic response (EVR; ≥ 2 log decrease in HCV RNA from baseline or HCV RNA<600 IU/mL) at week 12 were eligible to continue treatment for 72 weeks. SVR (HCV RNA<60 IU/mL) was measured 24 weeks after treatment discontinuation. Predictors of SVR were assessed in simple and multivariate logistic regression. A total of 329 subjects enrolled at 36 sites. Of 184 subjects who achieved EVR, 169 entered Step 3: 89% male, 52% White, 29% Black, and 71% HCV treatment naïve. The overall SVR rate was 27% (95% CI, 22%-32%) among all subjects, and 33% (95% CI, 27%-40%) among the 223 who were HCV treatment naïve. In exploratory analyses, among 120 treatment-naïve subjects who entered Step 3, the SVR rate was 62% (95% CI, 52%-70%). In this subgroup, predictors of SVR were HCV genotype 2 or 3 (P = .03), HCV RNA <800,000 IU/mL at study entry (P = .05), and achievement of complete EVR (HCV RNA<600 IU/mL at week 12;P < .0001). Among all subjects, we observed a comparable overall SVR rate to prior studies of subjects treated for 48 weeks. Extended treatment with PEG and WBR may be beneficial to subsets of coinfected patients, specifically those who are treatment naïve and achieve complete EVR.
    HIV Clinical Trials 01/2012; 13(2):70-82. · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The association of anaemia with outcomes in the HCV/HIV coinfected persons undergoing HCV treatment remains unclear. To study the incidence, predictors and management of anaemia, and its association with outcomes among persons treated with pegylated interferon and weight-based ribavirin. Retrospective analysis of a prospective controlled treatment trial of HCV/HIV coinfection. Among 329 subjects enrolled, 40% developed anaemia during the first 12-18 weeks of treatment (median haemoglobin decrease at week 4: 2.2 g/dL). Among 169 subjects who achieved early virological response and received therapy for 72 weeks, 55% eventually developed anaemia. However, median haemoglobin levels stayed stable after 12-18 weeks of initial therapy. Among these 169 subjects, 45% were prescribed an erythropoiesis stimulating agent (ESA), with 17% receiving it prior to a drop in haemoglobin meeting protocol definition of anaemia. Only 27% completed the study without any ribavirin dose modification. Age >40 years, lower BMI, zidovudine use and lower entry haemoglobin were significant predictors of anaemia in the multi-covariate model. Among all 329, sustained virological response (SVR) rate was similar in those with or without anaemia (23% vs. 30%; P=0.17) with no evidence of association between anaemia or ESA use and treatment response. Anaemia is common in HCV/HIV coinfected persons undergoing HCV treatment, and only a minority of them are able to maintain ribavirin dose. Persons with age >40 years, lower baseline haemoglobin and lower baseline BMI should be monitored carefully. Prescription of erythropoiesis stimulating agent is common, but anaemia or erythropoiesis stimulating agent use is not associated with SVR.
    Alimentary Pharmacology & Therapeutics 06/2011; 33(11):1234-44. · 4.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated immunologic predictors of response to HBV vaccine administered in the presence or absence of GM-CSF in HIV infected individuals. We measured peripheral blood hematopoietic progenitor, monocyte and myeloid-derived suppressor cell (MDSC) frequencies, and expression of GMCSF receptor on monocytes and MDSCs, at baseline and 4weeks after immunization in relation to antibody response. We observed higher baseline progenitor and lower monocyte frequencies among week 16 antibody responders. Week 4 decline in MDSC frequency was associated with week 16 antibody response, while administration of GM-CSF was associated with preservation of these cells. No significant differences in GM-CSF receptor expression were observed in the presence vs. absence of GM-CSF. These findings are consistent with a positive role of progenitor cells and a potential negative role of monocytes in vaccine response. Additionally, GM-CSF augmented the preservation of peripheral blood MDSC, which may contribute to the lack of improved vaccine responses.
    Vaccine 03/2011; 29(19):3558-63. · 3.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In HIV/ hepatitis C virus (HCV) coinfection, adverse events (AEs) during HCV therapy account for 12%-39% of treatment discontinuations. It is unknown whether sex influences complications. Meta-analysis to study the effect of sex and other predictors of AEs in 3 randomized trials, ACTG 5071, APRICOT, and ANRSHCO2-RIBAVIC of Interferon (IFN) and Pegylated IFN (PEG), both with and without Ribavirin, in HIV/HCV coinfection. Primary endpoints were AEs requiring treatment discontinuation (AETD) or first dose modification (AEDM). Multi-covariate stratified logistic regression was used to study predictors and assess interactions with sex. Twenty-one percent of 1376 subjects were women; 61% had undetectable HIV RNA; 14% were antiretroviral (ARV) therapy naive at entry; median CD4 was 485 cells per cubicmillimeter. Seventeen percent had an AETD and 50% AEDM; women had more AETD than men (24% vs. 16% P = 0.003) and AEDM (61% vs. 48% P < 0.0001). AETD and AEDM occurred earlier in women; but the types of AETD and AEDM were similar between sexes. Seventy-four percent of AETDs and 49% of AEDMs involved constitutional AEs; 18% of AETD depression; and 26% of AEDM neutropenia. We identified interactions with sex and body mass index (BMI) (P = 0.04, continuous) and nonnucleoside reverse transcriptase inhibitor (P = 0.03); more AETDs were seen in men with lower BMI (P = 0.01) and in women on nonnucleoside reverse transcriptase inhibitors (P = 0.009). More AEDMs were seen with PEG [odds ratio (OR) = 2.07]; older age (OR = 1.48 per 10 years); decreasing BMI (OR = 1.04 per kg/m); HCV genotype 1, 4 (OR = 1.31); Ishak 5, 6 (OR = 1.42); decreasing Hgb (OR = 1.23 per g/dL); and decreasing absolute neutrophil count (1.04 per 500 cells/mm). Interactions between sex and ARV-naive status (P = 0.001) and zidovudine (P = 0.001) were identified: There were more AEDMs in ARV-naive women (P = 0.06) and ARV-experienced men (P = 0.001) and higher AEDMs in women with zidovudine (P = 0.0002). Although there was no difference in type of AE, AETD and AEDM were more frequent and occurred earlier in women. In women, ARV regimen may be an important predictor of AETDs during HCV therapy and should be explored as a predictor of AEs in HIV/HCV coinfection trials.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2010; 55(2):170-5. · 4.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV)/HIV coinfection treatment is suboptimal with low sustained viral response rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated interferon maintenance therapy was performed by the National Institutes of Health-funded AIDS Clinical Trials Group network. HCV treatment-naive and nonresponding interferon-experienced subjects with confirmed HCV and HIV, CD4 >200 cells per cubic millimeter, and at least stage 1 fibrosis were enrolled and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg per week (PEG) + weight-based ribavirin to determine response status. Nonresponder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist. Three hundred thirty subjects were enrolled; median age was 48 years; 43% white, 37% black, non-Hispanic; 83% male; CD4+ 498 cells per cubic millimeter; 32% were interferon experienced; 74% had entry HIV RNA <50 copies per milliliter. early virologic responder was observed in 55.9% and 42.5% achieved complete Early Viral Response (cEVR). A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm. Lack of fibrotic progression in the control arm was unexpected and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression, and use of antiretroviral regimens that may be less toxic than prior generations of therapy.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2010; 55(5):597-605. · 4.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV-infected persons are at risk for HBV co-infection which is associated with increased morbidity and mortality. Unfortunately, protective immunity following HBV vaccination in HIV-infected persons is poor. This randomized, phase II, open-label study aimed to evaluate efficacy and safety of 40 mcg HBV vaccine with or without 250 mcg GM-CSF administered at day 0, weeks 4 and 12. HIV-infected individuals >or=18 years of age, CD4 count >or=200 cells/mm(3), seronegative for HBV and HCV, and naïve to HBV vaccination were eligible. Primary endpoints were quantitative HBsAb titers and adverse events. The study enrolled 48 subjects. Median age and baseline CD4 were 41 years and 446 cells/mm(3), 37 were on ART, and 26 subjects had undetectable VL. Vaccination was well tolerated. Seven subjects in the GM-CSF arm reported transient grade >or=2 signs/symptoms (six grade 2, one grade 3), mostly aches and nausea. GM-CSF had no significant effect on VL or CD4. Four weeks after vaccination, 26 subjects (59%) developed a protective antibody response (HBsAb >or=10 mIU/mL; 52% in the GM-CSF arm and 65% in the control arm) without improved Ab titer in the GM-CSF vs. control arm (median 11 mIU/mL vs. 92 mIU/mL, respectively). Response was more frequent in those with CD4 >or=350 cells/mm(3) (64%) than with CD4 <350 cells/mm(3) (50%), though not statistically significant. GM-CSF as an adjuvant did not improve the Ab titer or the development of protective immunity to HBV vaccination in those receiving an accelerated vaccine schedule. Given the common routes of transmission for HIV and HBV, additional HBV vaccine research is warranted.
    Vaccine 08/2010; 28(34):5597-604. · 3.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adherence to antiretroviral therapy (ART) in pregnancy is crucial to optimize its efficacy and minimize mother-to-child transmission. Our objective was to examine adherence patterns to ART and health behaviors during and after pregnancy among HIV-positive women enrolled in A5084, a prospective, observational, multisite study. Between 2002-2005, HIV-infected women between 20 and 34 weeks'gestation completed at least 1 self-reported adherence questionnaire antepartum (AP), and were followed through 12 weeks' postpartum (PP). Questionnaires also addressed tobacco, alcohol, and illicit drugs use. Adherence was defined as reporting not having missed any doses for more than 3 months. Exact McNemar's tests were used for paired binary data and exact logistic regression was used for predictors of nonadherence. We report on 149 women (55% black, 26% Hispanic, 32% less than 25 years, 9% with AIDS, 100% on ART). PP, 31 (21%) women stopped ART and 18 (12%) withdrew from the study. AP, 57% reported adherence to ART and PP, 45% (p = 0.03, n = 87). AP, 11% reported ongoing alcohol use and 23% tobacco use compared to 37% and 30% PP (p < 0.0001, n = 103; p = 0.07, n = 99, respectively). Although 39% ever used marijuana (n = 116) and 25% used illicit drugs (n = 107), few participants reported use during the study. In multivariate analyses, those who had ever used illicit drugs had 5.95 times higher odds (p = 0.002) and those who missed prenatal vitamins had 4.84 times higher odds (p = 0.001) of ART nonadherence. Women reporting a history of illicit drug use and/or having missed prenatal vitamins should be targeted for programs to enhance adherence to ART during pregnancy.
    AIDS patient care and STDs 02/2008; 22(1):29-40. · 2.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the effect of protease inhibitors on lipid and lactate levels and gastrointestinal symptoms in pregnancy. Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) A5084 was an observational cohort study of human immunodeficiency virus (HIV)-infected pregnant women. Women recruited between 20 and 34 weeks of gestation were required to be on a stable, highly active antiretroviral therapy (HAART) regimen, stratified by protease inhibitor compared with no protease inhibitor regimens. Interval history was assessed, and lipid and lactate levels were drawn every 8 weeks during pregnancy and 12 weeks postpartum, with levels closest to delivery and postpartum used for analysis. Statistical comparisons used Kruskal-Wallis and Fisher exact tests. One-hundred fifty-eight women were evaluated. Total cholesterol levels (median 230 mg/dL, interquartile range [197, 259], compared with 212 [179, 246] mg/dL, P=.042) and triglycerides (median 224 mg/dL, interquartile range [187, 288], compared with 185 [142, 230] mg/dL, P<.001] were elevated in the protease inhibitor group during pregnancy and remained higher in this group after delivery (total cholesterol 185 [163, 224] mg/dl compared with 171 [140, 190] mg/dL, P<.004; triglycerides 122 [87, 175] mg/dL compared with 89 [66, 150] mg/dL, P=.02). No difference was seen in lactate levels or rates of gastrointestinal symptoms between groups. Obstetric outcomes were similar between the two groups. A higher number of low birth weight infants were born to women in the highest twentieth percentile of triglycerides compared with the lowest across medication groups. Cholesterol and triglycerides were higher in protease inhibitor-treated women in pregnancy. Lactate and gastrointestinal symptoms were not different. A higher number of low birth weight infants were noted in women with high triglycerides, but other elevated lipid levels did not affect pregnancy outcomes. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00017797 II.
    Obstetrics and Gynecology 08/2007; 110(2 Pt 1):391-7. · 4.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whole body and abdominal obesity are associated with increased risk of diabetes mellitus and heart disease. The effects of testosterone therapy on whole body and visceral fat mass in HIV-infected men with abdominal obesity are unknown. The objective of this study was to determine the effects of testosterone therapy on intraabdominal fat mass and whole body fat distribution in HIV-infected men with abdominal obesity. IN this multicenter, randomized, placebo-controlled, double-blind trial, 88 HIV-positive men with abdominal obesity (waist-to-hip ratio > 0.95 or mid-waist circumference > 100 cm) and total testosterone 125-400 ng/dl, or bioavailable testosterone less than 115 ng/dl, or free testosterone less than 50 pg/ml on stable antiretroviral regimen, and HIV RNA less than 10,000 copies per milliliter were randomized to receive 10 g testosterone gel or placebo daily for 24 wk. Fat mass and distribution were determined by abdominal computerized tomography and dual energy x-ray absorptiometry during wk 0, 12, and 24. We used an intention-to-treat approach and nonparametric statistical methods. Baseline characteristics were balanced between groups. In 75 subjects evaluated, median percent change from baseline to wk 24 in visceral fat did not differ significantly between groups (testosterone 0.3%, placebo 3.1%, P = 0.75). Total (testosterone -1.5%, placebo 4.3%, P = 0.04) and sc (testosterone-7.2%, placebo 8.1%, P < 0.001) abdominal fat mass decreased in testosterone-treated men, but increased in placebo group. Testosterone therapy was associated with significant decrease in whole body, trunk, and appendicular fat mass by dual energy x-ray absorptiometry (all P < 0.001), whereas whole body and trunk fat increased significantly in the placebo group. The percent of individuals reporting a decrease in abdomen (P = 0.01), neck (P = 0.08), and breast size (P = 0.01) at wk 24 was significantly greater in testosterone-treated than placebo-treated men. Testosterone-treated men had greater increase in lean body mass than placebo (testosterone 1.3%, placebo -0.3, P = 0.02). Plasma insulin, fasting glucose, and total high-density lipoprotein and low-density lipoprotein cholesterol levels did not change significantly. Testosterone therapy was well tolerated. Testosterone therapy in HIV-positive men with abdominal obesity and low testosterone was associated with greater decrease in whole body, total, and sc abdominal fat mass and a greater increase in lean mass compared to placebo. However, changes in visceral fat mass were not significantly different between groups. Further studies are needed to determine testosterone effects on insulin sensitivity and cardiovascular risk.
    Journal of Clinical Endocrinology &amp Metabolism 04/2007; 92(3):1049-57. · 6.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Reduced energy intake is a primary factor in HIV-associated wasting. Megestrol acetate (MA) stimulates appetite and weight gain. However, much of the weight gained is fat, possibly as a result of MA-induced hypogonadism. The objective of the study was to determine whether coadministration of testosterone with MA could enhance lean body mass (LBM) accrual and evaluate the effects of MA, alone or combined with testosterone, on sexual functioning and the hypothalamic-pituitary-adrenal axis. This was a randomized, double-blind, placebo-controlled, multicenter trial. Fourteen AIDS Clinical Trials Units in the United States participated in the study. Seventy-nine HIV-positive men with 5% or more weight loss or body mass index less than 20 kg/m2 took part in the study. Subjects were randomized to receive MA (800 mg daily) plus testosterone enanthate (200 mg; MA/TE; n = 41) or placebo (MA/PL; n = 38) biweekly for 12 wk. Weight, body composition (bioelectric impedance analysis), adrenal and gonadal hormones, and sexual functioning (questionnaire) were measured. Both groups experienced robust increases in weight (median 5.3 and 7.3 kg in MA/TE and MA/PL, respectively), LBM (3.3 and 3.3 kg), and fat (3.0 and 3.8 kg). There were no significant differences between groups in the magnitude or composition of weight gain (P = 0.44, 0.90, and 0.11 for weight, LBM, and fat, respectively). Trough testosterone concentrations decreased to a greater extent in MA/PL (-12.3 vs. -6.1 nmol/liter in MA/TE; P = 0.04). Cortisol levels became nearly undetectable in subjects with plasma MA levels greater than 150 ng/ml. Sexual functioning was preserved with MA/TE but worsened in MA/PL. MA produced robust weight gain. Coadministration of testosterone preserved sexual functioning but did not enhance LBM accrual.
    Journal of Clinical Endocrinology &amp Metabolism 03/2007; 92(2):563-70. · 6.43 Impact Factor