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1.  Lack of Pharmacokinetic Interactions Between Pitavastatin and Efavirenz or Darunavir/Ritonavir 
Background
The drug–drug interactions between pitavastatin and darunavir/ritonavir (DRV/r) as well as pitavastatin and efavirenz (EFV) were examined in an open-label, parallel-arm, pharmacokinetic (PK) study in HIV-uninfected healthy volunteers.
Methods
Subjects received a pitavastatin dose of 2 mg for 4 days, followed by either EFV 600 mg (n = 14) or DRV/r 800/100 mg (n = 14) daily for 10 days, and pitavastatin 2 mg coadministered with EFV 600 mg or DRV/r 800/100 mg for 4 days. Full PK profiles were determined for pitavastatin and its lactone metabolite on days 4 and 18 and for EFV or DRV on days 14 and 18.
Results
In the EFV arm, the geometric mean area under the concentration time curve (AUC0-τ) and Cmax of pitavastatin were 85.3 ng·h·mL−1 and 15.6 ng/mL, respectively, when given alone, versus 76 ng·h·mL−1 and 18.8 ng/mL when coadministered with EFV. The geometric mean ratio for pitavastatin with EFV versus alone was 0.89 [90% confidence interval (CI): 0.73 to 1.09] for AUC0-τ and 1.20 (90% CI: 0.79 to 1.83) for Cmax. In the DRV/r arm, AUC0-τ and Cmax were 62.8 ng·h·mL−1 and 24.0 ng/mL, respectively, when pitavastatin was administered alone, versus 56.9 ng·h·mL−1 and 23.2 ng/mL when coadministered with DRV/r. The geometric mean ratio for pitavastatin with DRV/r versus alone was 0.91 (90% CI: 0.78 to 1.06) for AUC0-τ and 0.93 (90% CI: 0.72 to 1.19) for Cmax.
Conclusions
There were no significant PK interactions between pitavastatin and EFV or DRV/r. No significant safety issues or lipid changes were noted.
doi:10.1097/QAI.0000000000000333
PMCID: PMC4404408  PMID: 25202920
pitavastatin; efavirenz; darunavir; ritonavir; HMG-CoA reductase inhibitors; statins; drug interactions
2.  A Randomized Controlled Trial of Palifermin (Recombinant Human Keratinocyte Growth Factor) for the Treatment of Inadequate CD4+ T-Lymphocyte Recovery in Patients with HIV-1 Infection on Antiretroviral Therapy 
Background
Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease.
Methods
In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels ≤200 copies/mL for ≥6 months and CD4 lymphocyte counts <200 cells/mm3 were randomized 1:1:1:1 to receive once daily intravenous administrations of placebo or 20, 40, or 60 µg/kg of palifermin on 3 consecutive days.
Results
The median change in CD4+ T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm3] and the 20-μg/kg dose [11 (2, 32) cells/mm3], the 40-μg/kg dose [12 (−2, 25) cells/mm3], or the 60-μg/kg dose arm [8 (−13, 35) cells/mm3] of palifermin. No significant changes were observed in thymus size or in the number of naïve T cells or recent thymic emigrants.
Conclusions
Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART.
doi:10.1097/QAI.0000000000000195
PMCID: PMC4216663  PMID: 24815851
keratinocyte growth factor; palifermin; HIV; thymus; CD4 T lymphocytes
3.  Differentiation of IL-17-producing effector and regulatory human T cells from lineage-committed naïve precursors1 
A subset of human regulatory T cells (Tregs) secretes IL-17 and thus resembles Th17 effector cells. How IL-17+Treg cells differentiate from naïve precursors remains unclear. Here, we show that IL-17-producing T-cells can differentiate from CCR6+ naïve T cell precursors in the presence of IL-2, IL-1β, TGF-β, and IL-23. CCR6+ naïve T cells are present in adult peripheral and umbilical cord blood and in both conventional T naïve (TN) and FOXP3+ naïve Treg (TNreg) subsets. IL-17+ cells derived from CCR6+ TNreg cells (referred to as IL-17+Treg) express FOXP3, but not HELIOS, another Treg-associated transcription factor, and these cells display suppressor capacity and a surface phenotype resembling memory Tregs. Remarkably, the IL-17+Treg compartment was preferentially reduced relative to the canonical Th17 and Treg compartments in a subset of HIV+ subjects, suggesting a specific perturbation of this subset during the course of disease. Our findings that CCR6+ naïve precursors contain a predetermined reservoir to replenish IL-17-secreting cells, may have implications in balancing the Th17 and IL-17+Treg compartments that are perturbed during HIV infection and potentially in other inflammatory diseases.
doi:10.4049/jimmunol.1302936
PMCID: PMC4108575  PMID: 24958901
4.  High Accuracy of Common HIV-Related Oral Disease Diagnoses by Non-Oral Health Specialists in the AIDS Clinical Trial Group 
PLoS ONE  2015;10(7):e0131001.
Objective
Many studies include oral HIV-related endpoints that may be diagnosed by non-oral-health specialists (non-OHS) like nurses or physicians. Our objective was to assess the accuracy of clinical diagnoses of HIV-related oral lesions made by non-OHS compared to diagnoses made by OHS.
Methods
A5254, a cross-sectional study conducted by the Oral HIV/AIDS Research Alliance within the AIDS Clinical Trial Group, enrolled HIV-1-infected adults participants from six clinical trial units (CTU) in the US (San Francisco, New York, Chapel Hill, Cleveland, Atlanta) and Haiti. CTU examiners (non-OHS) received standardized training on how to perform an oral examination and make clinical diagnoses of specific oral disease endpoints. Diagnoses by calibrated non-OHS were compared to those made by calibrated OHS, and sensitivity and specificity computed.
Results
Among 324 participants, the majority were black (73%), men (66%), and the median CD4+ cell count 138 cells/mm3. The overall frequency of oral mucosal disease diagnosed by OHS was 43% in US sites, and 90% in Haiti. Oral candidiasis (OC) was detected in 153 (47%) by OHS, with erythematous candidiasis (EC) the most common type (39%) followed by pseudomembranous candidiasis (PC; 26%). The highest prevalence of OC (79%) was among participants in Haiti, and among those with CD4+ cell count ≤ 200 cells/mm3 and HIV-1 RNA > 1000 copies/mL (71%). The sensitivity and specificity of OC diagnoses by non-OHS were 90% and 92% (for EC: 81% and 94%; PC: 82% and 95%). Sensitivity and specificity were also high for KS (87% and 94%, respectively), but sensitivity was < 60% for HL and oral warts in all sites combined. The Candida culture confirmation of OC clinical diagnoses (as defined by ≥ 1 colony forming unit per mL of oral/throat rinse) was ≥ 93% for both PC and EC.
Conclusion
Trained non-OHS showed high accuracy of clinical diagnoses of OC in comparison with OHS, suggesting their usefulness in studies in resource-poor settings, but detection of less common lesions may require OHS.
doi:10.1371/journal.pone.0131001
PMCID: PMC4492974  PMID: 26148192
5.  Immunogenicity and Safety of the Quadrivalent Human Papillomavirus Vaccine in HIV-1–Infected Women 
This multicenter prospective trial among HIV-1–infected women aged 13–45 years found that the quadrivalent human papillomavirus vaccine was highly immunogenic, but women with CD4 counts <200 cells/µL had lower seroconversion rates compared with women with higher CD4 cell counts.
Background. Women infected with human immunodeficiency virus (HIV) are disproportionately affected by human papillomavirus (HPV)–related anogenital disease, particularly with increased immunosuppression. AIDS Clinical Trials Group protocol A5240 was a trial of 319 HIV-infected women in the United States, Brazil, and South Africa to determine immunogenicity and safety of the quadrivalent HPV vaccine in 3 strata based on screening CD4 count: >350 (stratum A), 201–350 (stratum B), and ≤200 cells/µL (stratum C).
Methods. Safety and serostatus of HPV types 6, 11, 16, and 18 were examined. HPV serological testing was performed using competitive Luminex immunoassay (HPV-4 cLIA). HPV type-specific seroconversion analysis was done for participants who were seronegative for the given type at baseline.
Results. Median age of patients was 36 years; 11% were white, 56% black, and 31% Hispanic. Median CD4 count was 310 cells/µL, and 40% had undetectable HIV-1 load. No safety issues were identified. Seroconversion proportions among women at week 28 for HPV types 6, 11,16, and 18 were 96%, 98%, 99%, and 91%, respectively, for stratum A; 100%, 98%, 98%, and 85%, respectively, for stratum B, and 84%, 92%, 93%, and 75%, respectively, for stratum C.
Conclusions. The quadrivalent HPV vaccine targeted at types 6, 11, 16, and 18 was safe and immunogenic in HIV-infected women aged 13–45 years. Women with HIV RNA load >10 000 copies/mL and/or CD4 count <200 cells/µL had lower rates of seroconversion rates.
Clinical Trials Registration. NCT00604175.
doi:10.1093/cid/ciu238
PMCID: PMC4305143  PMID: 24723284
HPV vaccine; HIV-infected women; immunogenicity; vaccine safety; anogenital disease
6.  Virologic and Serologic Outcomes of Mono vs. Dual HBV Therapy and Characterization of HIV/HBV Coinfection in a US Cohort 
Objectives
To characterize HIV/HBV coinfection in the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort and compare long-term HBV outcomes between regimens with one (MONO) or two (DUAL) anti-HBV agents.
Design
A retrospective study of coinfected ALLRT subjects who received regimens containing anti-HBV agent(s).
Methods
Stored samples at baseline and weeks 16, 32, 48, 144, and 240 were tested for HBV DNA, HBeAg, HBeAb, and HDV antibody. Resistance and genotype were tested in samples with HBV DNA >600 IU/ml. MONO vs. DUAL analyses were limited to HBV treatment-naïve subjects (Naïve-MONO, Naïve-DUAL).
Results
Of 150 study subjects, median age was 40 years, 96% were male; 57% White, 26% Black, 13% Hispanic. Baseline median CD4 was 224 cells/mm3, HIV RNA 4.48 log10 copies/ml, HBV DNA 6.30 log10 IU/ml; 59% HBeAg positive and 65% HBeAb negative; HBV genotypes A=69%, G=18%, D=7%, <2% for A/G, B, C, F, H. Coinfection with HDV was 2%. There were 49 Naïve-MONO (lamivudine) and 22 Naïve-DUAL (11 lamivudine+tenofovir, 11 emtricitabine+tenofovir) with detectable HBV DNA. In the 240-week follow-up, HBV DNA suppression was not significantly higher in Naïve-DUAL (p=0.14); lower baseline HBV DNA (p<0.01) was associated with suppression. Among 32 Naïve-MONO subjects with detectable HBV DNA at baseline and results at week 48, 41% suppressed; among such 15 Naïve-DUAL subjects, 53% suppressed. HBeAg and HBeAb analyses showed similar trends.
Conclusions
While consistent trends toward increased HBV DNA suppression, HBeAg loss and HBeAb seroconversion were observed in Naïve-DUAL compared to Naïve-MONO, they were not statistically significant. Overall, HDV coinfection was low.
doi:10.1097/QAI.0000000000000149
PMCID: PMC4169110  PMID: 24694927
coinfection; HIV; HBV; HDV; mono-therapy; dual-therapy; lamivudine; tenofovir
7.  Design Aspects of a Case-Control Clinical Investigation of the Effect of HIV on Oral and Gastrointestinal Soluble Innate Factors and Microbes 
PLoS ONE  2014;9(11):e112901.
Introduction
The impaired host defense system in HIV infection impacts the oral and gastrointestinal microbiota and associated opportunistic infections. Antiretroviral treatment is predicted to partially restore host defenses and decrease the oral manifestation of HIV/AIDS. Well-designed longitudinal studies are needed to better understand the interactions of soluble host defense proteins with bacteria and virus in HIV/AIDS. “Crosstalk” was designed as a longitudinal study of host responses along the gastrointestinal (GI) tract and interactions between defense molecules and bacteria in HIV infection and subsequent therapy.
Purpose
The clinical core formed the infrastructure for the study of the interactions between the proteome, microbiome and innate immune system. The core recruited and retained study subjects, scheduled visits, obtained demographic and medical data, assessed oral health status, collected samples, and guided analysis of the hypotheses. This manuscript presents a well-designed clinical core that may serve as a model for studies that combine clinical and laboratory data.
Methods
Crosstalk was a case-control longitudinal clinical study an initial planned enrollment of 170 subjects. HIV+ antiretroviral naïve subjects were followed for 9 visits over 96 weeks and HIV uninfected subjects for 3 visits over 24 weeks. Clinical prevalence of oral mucosal lesions, dental caries and periodontal disease were assessed.
Results
During the study, 116 subjects (47 HIV+, 69 HIV-) were enrolled. Cohorts of HIV+ and HIV- were demographically similar except for a larger proportion of women in the HIV- group. The most prevalent oral mucosal lesions were oral candidiasis and hairy leukoplakia in the HIV+ group.
Discussion
The clinical core was essential to enable the links between clinical and laboratory data. The study aims to determine specific differences between oral and GI tissues that account for unique patterns of opportunistic infections and to delineate the differences in their susceptibility to infection by HIV and their responses post-HAART.
doi:10.1371/journal.pone.0112901
PMCID: PMC4237510  PMID: 25409430
8.  Genetic Predictors of Cervical Dysplasia in African American HIV-Infected Women: ACTG DACS 268 
HIV clinical trials  2013;14(6):292-302.
Objective
To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests.
Design
Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment–naïve studies in the AIDS Clinical Trials Group (ACTG).
Methods
Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 × 10−8 for genome-wide associations.
Results
No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively).
Conclusions
These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infected women. Given the small sample size, the results need to be validated in a separate cohort.
doi:10.1310/hct1406-292
PMCID: PMC4118741  PMID: 24334182
cervical dysplasia; GWAS; risk markers
9.  Aspirin Attenuates Platelet Activation and Immune Activation in HIV-1-Infected Subjects on Antiretroviral Therapy: A Pilot Study 
Background
Mechanisms for increased cardiovascular risk in HIV-1-infected adults are incompletely understood, but platelet activation and immune activation leading to a prothrombotic state have been proposed as significant contributors. Aspirin has antiplatelet and immunomodulatory properties. We explored whether 1 week of low-dose aspirin attenuates platelet activation and immune activation in HIV-1-infected and virologically suppressed adults on antiretroviral therapy.
Methods
Platelet activation and immune activation were measured in HIV-1-infected subjects virologically suppressed on antiretroviral therapy and controls before and after 1 week of low-dose aspirin.
Results
Compared with control subjects, HIV-1-infected subjects had increased platelet activation, as measured by spontaneous platelet aggregation and aggregation in response to adenosine diphosphate, collagen, and arachidonic acid. After aspirin therapy, percent aggregation decreased similarly in both HIV-1-infected and control subjects to all platelet agonists tested except aggregation in response to arachidonic acid, which remained elevated in the HIV-1-infected group. HIV-1-infected subjects exhibited increased markers of T-cell activation (CD38 and HLA-DR) and monocyte activation (sCD14), which decreased after 1 week of aspirin therapy. Moreover, leukocyte responses to Toll-like receptor stimulation were enhanced after 1 week of aspirin therapy. In vitro studies showed that HIV-1 plasma could activate healthy platelets, which in turn activated monocytes, implicating a direct role for activated platelets in immune activation.
Conclusions
Our data demonstrate that heightened platelet activation and immune activation in treated HIV-1 disease are attenuated by 1 week of aspirin therapy. Aspirin should be further studied for its antithrombotic and immunomodulatory benefits in treated HIV-1 disease.
doi:10.1097/QAI.0b013e31828a292c
PMCID: PMC3756489  PMID: 23406976
platelets; HIV-1; aspirin; immune activation; aggregation
10.  Steady-State Pharmacokinetics, Cord Blood Concentrations, and Safety of Ritonavir-Boosted Fosamprenavir in Pregnancy 
Steady-state pharmacokinetics in pregnant women prescribed ritonavir boosted fosamprenavir (FPV/RTV) to prevent HIV transmission were assessed in the second trimester, third trimester, and postpartum. Compared to postpartum, geometric mean amprenavir (APV, FPVs active metabolite) area under the plasma concentration-time curves (AUC) were 35% lower in the second trimester and 25% lower in the third trimester. Maternal APV concentrations were 9 – 15-fold above the mean APV protein-adjusted 50% inhibitory concentration for wild-type HIV. Median ratio of cord blood/maternal APV levels was 0.27 and all infants were HIV negative. FPV/RTV during pregnancy was well tolerated and led to virologic suppression.
doi:10.1097/QAI.0b013e318285d918
PMCID: PMC3683080  PMID: 23314414
Fosamprenavir; pharmacokinetics; pregnancy; HIV
11.  Clash of the microbes: let’s bring back the good guys 
A 38-year-old man with a history of HIV infection virologically suppressed on antiretroviral therapy presents to his gastroenterologist for evaluation of iron deficiency anemia and weight loss. A diagnostic colonoscopy demonstrates a two-centimeter ulcerated mass in the cecum. Biopsies of the lesion return moderately differentiated adenocarcinoma that is wild type for the KRAS mutation by real-time PCR.
doi:10.1172/JCI66736
PMCID: PMC3561820  PMID: 23321673
12.  Hyperparathyroidism and Complications Associated with Vitamin D Deficiency in HIV-Infected Adults in New York City, New York 
Abstract
Although recent studies report a high prevalence of vitamin D deficiency in HIV-infected adults similar to that in the general population, metabolic complications of vitamin D deficiency may be worsened with HIV infection and remain insufficiently characterized. We conducted a retrospective cross-sectional cohort study to determine prevalence and correlates of vitamin D deficiency and hyperparathyroidism among HIV-infected patients attending an urban clinic. Vitamin D deficiency was defined as 25(OH)-vitamin D <20 ng/ml and insufficiency as 20 to <30 ng/ml, and hyperparathyroidism as parathyroid-hormone >65 pg/ml. We used the X2 test to compare proportions and logistic regression to assess for associations. Among 463 HIV-infected patients, the prevalence of vitamin D deficiency was 59%. The prevalence of hyperparathyroidism was 30% among patients with vitamin D deficiency, 23% among those with insufficiency, and 12% among those with sufficient vitamin D levels. Vitamin D deficiency was associated with increased odds of hyperparathyroidism. Severe vitamin D deficiency was associated with elevated alkaline phosphatase, a marker for increased bone turnover. Although efavirenz use was associated with vitamin D deficiency, and protease inhibitor use with decreased odds of vitamin D deficiency, there was no statistical difference in rates of hyperparathyroidism stratified by combination antiretroviral therapy (cART) use. Given the increased risk of osteopenia with HIV infection and cART use, vitamin D supplementation for all HIV-infected patients on cART should be prescribed in accordance with the 2011 Endocrine Society guidelines. In HIV-infected patients with severe vitamin D deficiency or hyperparathyroidism, screening for osteomalacia and osteopenia may be warranted.
doi:10.1089/aid.2011.0325
PMCID: PMC3423777  PMID: 22220755
13.  Risk factors for tuberculin skin test conversion among HIV-infected patients in New York City 
Summary
Background
We assessed the incidence of and risk factors for tuberculin skin test (TST) conversion among HIV-infected adults at a New York City clinic.
Methods
All adult HIV-infected patients were eligible for inclusion if they had a negative baseline TST result and at least one subsequent documented TST test result.
Results
A total of 414 HIV-infected patients had a negative baseline TST result; 288 (69.6%) were male. Among 348 patients who had a place of birth documented, 50% were born outside of mainland USA. Twenty-two (5.3%) of 414 patients had documented TST conversions, giving a crude incidence rate of 1.77 per 100 person-years. Being a foreign-born Asian individual (p = 0.02), having lived in a shelter (p = 0.004), and having an increase in CD4 cell count (p = 0.02) while under care were independent risk factors for TST conversion.
Conclusions
We found a high TST conversion rate among HIV-infected patients attending an urban clinic. Annual TST testing is particularly important for patients who are foreign-born from high-endemic countries, those with a history of homelessness, and those with an increase in CD4 cell count since the baseline negative TST test.
doi:10.1016/j.ijid.2012.03.002
PMCID: PMC3378789  PMID: 22542005
HIV; Latent tuberculosis infection; Diagnosis; Tuberculin skin test
14.  Glycated Hemoglobin A1c as Screening for Diabetes Mellitus in HIV-Infected Individuals 
AIDS Patient Care and STDs  2012;26(4):197-201.
Abstract
The American Diabetes Association now recommends hemoglobin A1c (HbA1c) screening for the diagnosis of diabetes. It has been reported that HbA1c levels underestimate glycemic levels in HIV-infected persons. We examined the performance of HbA1c as a screening test for diabetes in a group of HIV-infected people without diabetes. We conducted a retrospective cross-sectional cohort study among HIV-infected patients determining the sensitivity and specificity of HbA1c as a screening test compared to fasting blood glucose (FBG). The effect of treatment regimen on the relationship between HbA1c and FBG was assessed by multiple linear regressions. Twenty-two of the 395 patients included in the study were newly diagnosed with diabetes based on FBG≥126 mg/dL. Using a cutoff of HbA1c≥6.5%, HbA1c had a sensitivity of 40.9% and specificity of 97.5% for identification of incident diabetes. At an HbA1c level of 5.8% the product of sensitivity and specificity was maximized, with values of 88.8% and 77.5% respectively. Higher mean cell volume (MCV) values (p=0.02) and current use of a non-nucleoside reverse transcriptase inhibitors (NNRTIs; p=0.02) significantly increased the slope, while PI use significantly decreased the slope (p<0.001), of the linear regression of HbA1c compared to FBG. Tenofovir use did not significantly alter the slope or y-intercept of the line. Among HIV-infected nondiabetic patients, HbA1c is insensitive, although highly specific for diagnosing diabetes. Current antiretroviral (ART) use has significant and variable influence on the relationship between HbA1c and FBG. The use of HbA1c in conjunction with FBG may be the best modality to screen for diabetes.
doi:10.1089/apc.2011.0379
PMCID: PMC3317391  PMID: 22324292
15.  Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks 
AIDS Research and Human Retroviruses  2012;28(10):1184-1195.
Abstract
We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4+ cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, –0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.
doi:10.1089/aid.2011.0327
PMCID: PMC3448095  PMID: 22352336
17.  HIV: primary and secondary prophylaxis for opportunistic infections 
BMJ Clinical Evidence  2010;2010:0908.
Introduction
Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylaxis for Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis? What are the effects of antituberculosis prophylaxis in people with HIV infection? What are the effects of prophylaxis for disseminated Mycobacterium avium complex (MAC) disease for people with, and without, previous MAC disease? What are the effects of prophylaxis for cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV)? What are the effects of prophylaxis for invasive fungal disease in people with, and without, previous fungal disease? What are the effects of discontinuing prophylaxis against opportunistic pathogens in people on highly active antiretroviral treatment (HAART)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aciclovir; antituberculosis prophylaxis; atovaquone; azithromycin (alone or plus rifabutin); clarithromycin (alone, or plus rifabutin and ethambutol); discontinuing prophylaxis for CMV, MAC, and PCP; ethambutol added to clarithromycin; famciclovir; fluconazole; isoniazid; itraconazole; oral ganciclovir; rifabutin (alone or plus macrolides); trimethoprim–sulfamethoxazole; and valaciclovir.
Key Points
Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment (HAART). HAART has reduced the rate of Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, and other opportunistic infections, so the absolute benefits of prophylactic regimens for opportunistic infections are probably smaller in people with HIV who are also taking HAART, and even smaller for those whose HIV is suppressed.
Primary prophylaxis with trimethoprim–sulfamethoxazole may reduce the risk of PCP, and has been found to be more effective than pentamidine or dapsone. Atovaquone may prevent PCP in people who cannot tolerate trimethoprim−sulfamethoxazole.We don't know whether these drugs prevent toxoplasmosis as we found few RCTs, but there is consensus that standard trimethoprim–sulfamethoxazole prophylaxis or dapsone should offer adequate coverage for toxoplasmosis.
Tuberculosis can be prevented by standard primary prophylaxis in people who are tuberculin skin test positive. Short-term combination treatment has similar efficacy to long-term isoniazid monotherapy, but is associated with a greater risk of adverse effects.
Azithromycin or clarithromycin reduce the risk of disseminated Mycobacterium avium complex (MAC) disease as primary prophylaxis for people without prior MAC disease. Adding rifabutin may also be beneficial in this population, but is also associated with an increased risk of adverse effects. There is consensus that secondary prophylaxis with clarithromycin plus ethambutol decreases the risk of relapse in people with previous MAC disease. It remains unclear whether adding rifabutin to the dual drug regimen confers additional benefit as secondary prophylaxis, and the three-drug combination increases adverse effects.
Aciclovir as secondary prophylaxis reduces the risk of herpes simplex virus (HSV) and varicella zoster virus infection (VZV) and all-cause mortality. Valaciclovir may reduce the risk of recurrent HSV infection, but it may be associated with serious adverse effects.There is consensus that famciclovir is effective as secondary prophylaxis against HSV or VZV and that ganciclovir is effective as secondary prophylaxis against CMV, HSV, or VZV.
Fluconazole and itraconazole as primary prophylaxis may reduce the risk of invasive fungal infections, but azoles have been associated with potentially serious interactions with other drugs. As secondary prophylaxis, itraconazole seems effective in reducing relapse of Penicillium marneffei, but seems less effective than fluconazole at reducing recurrence of cryptococcal meningitis.
In people who have responded to HAART and have a CD4 cell count greater than 100/mm3 to 200/mm3 (depending on the condition), discontinuation of primary or secondary prophylactic treatment for PCP, toxoplasmosis, MAC, herpes virus, or invasive fungal disease infection seems safe.
PMCID: PMC3217757  PMID: 21418688
18.  Management of dyslipidemia in HIV-infected patients 
Clinical lipidology  2011;6(4):447-462.
Antiretroviral therapy has dramatically increased survival for HIV-infected individuals. As this population lives longer, coronary heart disease has become an important comorbid condition. Dyslipidemia in HIV-infected individuals is a complex condition, with multiple contributing factors including the HIV virus itself, individual genetic characteristics and antiretroviral therapy-induced metabolic changes. Effective management of dyslipidemia in this population is essential to reduce cardiovascular risk but presents multiple challenges due to interactions between antiretroviral therapy agents and lipid-lowering medications.
doi:10.2217/CLP.11.25
PMCID: PMC3249059  PMID: 22216062
drug interactions; fibrates; fish oil; guidelines; HIV-associated dyslipidemia; hypertriglyceridemia; niacin; statins
19.  Uridine supplementation in the treatment of HIV lipoatrophy: Results of ACTG 5229 
AIDS (London, England)  2010;24(16):2507-2515.
BACKGROUND
Lipoatrophy is prevalent on thymidine NRTIs (tNRTI). A pilot trial showed that uridine (NucleomaxX®) increased limb fat.
METHODS
A5229 was a multicenter trial in which HIV-infected individuals with lipoatrophy on tNRTI-regimens were randomized to NucleomaxX or placebo. Primary endpoint was change in limb fat from baseline to week-48. The study was powered to detect 400-gram difference between arms at week-48. A stratified Wilcoxon rank-sum test was used to assess between-arm differences.
RESULTS
The 165 subjects were 91% male, 62% white; median age 49 years, CD4 506 cells/mm3, and limb fat 3037 grams; 81% had HIV-1 RNA ≤50 copies/mL; 76% were on AZT. Baseline characteristics were similar between groups. Only 59% completed 48-weeks of treatment, however only 3 subjects (1 on uridine) discontinued due to toxicity (diarrhea). In intent-to-treat, there was no difference for changes in limb fat between treatments at week-24 or week-48. On as-treated analysis, uridine resulted in an increase in %limb fat vs. placebo (3.4% vs. −0.8%, p=0.01) at week-24 but not at week-48 (1.8% vs.3.8%, p=0.93). Similar results were seen when limiting the analysis to subjects with ≥80% adherence. The results were not related to severity of lipoatrophy or type of tNRTI. No changes were found in facial-anthropometrics, fasting lipids, trunk-fat, CD4, or HIV-RNA.
CONCLUSIONS
We found a modest transient improvement in limb fat after 24 weeks of uridine. The lack of sustained efficacy at week-48 was not due to changes in adherence or reduction in sample size. Uridine was safe and did not impair virologic control.
doi:10.1097/QAD.0b013e32833ea9bc
PMCID: PMC2956768  PMID: 20827170
20.  A Pilot Study to Determine the Impact on Dyslipidemia of Adding Tenofovir to Stable Background Antiretroviral Therapy: ACTG 5206 
AIDS (London, England)  2010;24(11):1781-1784.
Summary
Several studies have reported improvements in lipids after antiretroviral therapy (ART) switches to tenofovir disoproxil fumarate (TDF)-containing regimens. We assessed lipid-lowering effects of TDF by adding it to a stable ART regimen in this double-blind, placebo-controlled crossover study. We demonstrated that non-HDL-C, LDL-C and TC improved significantly over TDF vs. placebo treatment in HIV-infected individuals with dyslipidemia. Adding TDF to stable, virologically-suppressive ART regimens improved lipid parameters, supporting a lipid-lowering effect of TDF.
doi:10.1097/QAD.0b013e32833ad8b4
PMCID: PMC2913151  PMID: 20495438
Dyslipidemia; Tenofovir; Complications of Antiretroviral therapy
21.  Global Pharmacovigilance for Antiretroviral Drugs: Overcoming Contrasting Priorities 
PLoS Medicine  2011;8(7):e1001054.
Jur Strobos and colleagues describe the deliberations of a recent multi-stakeholder meeting discussing the creation of a sustainable global pharmacovigilance system for antiretroviral drugs that would be applicable in resource limited settings.
doi:10.1371/journal.pmed.1001054
PMCID: PMC3130019  PMID: 21750668
22.  Treatment with pravastatin and fenofibrate improves atherogenic lipid profiles but not inflammatory markers in ACTG 5087 
Journal of clinical lipidology  2010;4(4):279-287.
Objectives
Statins and fibrates alter lipids, apolipoproteins and inflammatory markers in persons without HIV. The objective of this study was to evaluate changes in lipoproteins, apolipoproteins and other markers of inflammation with the use of pravastatin and fenofibrate.
Design
Evaluation of participants in ACTG A5087, a randomized trial of pravastatin 40 mg/day or fenofibrate 200 mg/day for the treatment of dyslipidemia. Participants that failed single-agent therapy at week 12 were given the combination.
Methods
Participants with available specimens were tested for apolipoproteins A1 and B, adiponectin, plasminogen-activator inhibitor type 1 (PAI-1), P-selectin, and high-sensitivity C-reactive protein (hs-CRP).
Results
74 participants (37 per randomized arm) received either pravastatin or fenofibrate for 12 weeks with 60 receiving combination treatment from weeks 12–48. There were no significant changes in hs-CRP, PAI-1, and P-selectin. From baseline to week 12, the median Apo B levels (−8 mg/dL, P=0.01 for fenofibrate and −27 mg/dL, P<0.01 for pravastatin) and ApoB/A1 ratios (−0.16, P<0.01 for both arms) significantly decreased. From baseline to week 48, median adiponectin (−1 ng/dL, P<0.01), Apo B (−22 mg/dL, P<0.01) and Apo B/A1 ratios (−0.2, P<0.01) all decreased in those who went on combination therapy, whereas Apo A1 (9.5 mg/dL, P=0.01) levels increased.
Conclusion
Treatment with pravastatin or fenofibrate improves the atherogenic lipid profile within the first 12 weeks and is sustained through 48 weeks with combination therapy. Adiponectin levels decrease with lipid-lowering therapy. However, markers of inflammation and platelet activation were not appreciably changed suggesting that the biologic properties of these agents differ in persons with HIV infection.
doi:10.1016/j.jacl.2010.04.003
PMCID: PMC2932453  PMID: 20824151
Dyslipidemia; Inflammation; Lipoproteins; Apolipoproteins; HIV; Antiretroviral therapy; Pravastatin; Fenofibrate
23.  Virologic Outcome of Using Tenofovir/Emtricitabine to Treat Hepatitis B in HIV-Coinfected Patients 
ISRN Gastroenterology  2011;2011:405390.
Goal. To study the effect of combination antiviral therapy with tenofovir and emtricitabine or lamivudine with and without prior monotherapy with lamivudine. Study. We reviewed charts of 31 HIV-/HBV-coinfected patients. Twelve 3TC-naïve patients initially received tenofovir plus emtricitabine. Nineteen epivir experienced patients who had previously failed epivir were given tenofovir plus emtricitabine. Results. Baseline median HBV DNA was similar in the epivir-naïve (5.8×107 copies/mL) and experienced group (7.3×107 copies/mL, P = .65). The median time to complete suppression of HBV was 466 days in the naïve group and 877 days in the experienced (P = .001). After 12 months, 6/10 (60%) naïve patients and 3/14 (21%) experienced patients had HBV DNA below the detectionlimit (P = .067). After 24 months, 5/5 (100%) naïve patients and 4/13 (31%) experienced patients had an undetectable HBV DNA level (P = .015). Conclusions. The median time to suppression of HBV DNA was significantly shorter among treatment naïve patients. There was a significantly greater proportion of naïve patients with suppressed HBV DNA at 24 months. Our results support using initial dual therapy in those with HIV/HBV coinfection.
doi:10.5402/2011/405390
PMCID: PMC3168392  PMID: 21991507
24.  The virologic and immunologic effects of Cyclosporine A as an adjunct to antiretroviral therapy in patients treated during acute and early HIV-1 infection 
The Journal of infectious diseases  2010;201(9):1298-1302.
Acute HIV-1 infection is characterized by high levels of immune activation. Immunomodulation with Cyclosporin A combined with antiretroviral therapy (ART) in the setting of acute and early HIV-1 infection has been reported to result in enhanced immune reconstitution. Fifty-four individuals with acute and early infection were randomized to receive ART with 4 weeks of Cyclosporine A versus ART alone. In 48 subjects who completed the study, there were no significant differences between treatment arms in levels of proviral DNA or CD4+ T cell counts. Adjunctive therapy with Cyclosporine A in this setting does not provide apparent virologic or immunologic benefit.
doi:10.1086/651664
PMCID: PMC2851487  PMID: 20235838
25.  Health Needs of HIV-Infected Women in the United States: Insights from The Women Living Positive Survey 
AIDS Patient Care and STDs  2011;25(5):279-285.
Abstract
The objective of this study was to describe attitudes, opinions, and perceived health needs of HIV-infected women in the United States. In this cross-sectional study, women were invited to participate in the Women Living Positive survey, a structured interview instrument with 45 questions. Collected data were deidentified and the margin of error was calculated as four percentage points. Incoming toll-free phone interviews were conducted from December 21, 2006, through March 14, 2007 among subjects recruited from a U.S. national network of AIDS counseling centers. Seven hundred HIV-infected women (43% African American, 28.5% Hispanic, 28.5% Caucasian; median age, 42.5 years) receiving combination antiretroviral therapy for 3 years or more replied to recruitment flyers. Overall, 55% of survey participants had never discussed gender-specific HIV treatment issues with their HIV care providers. Of the 45% who did discuss these issues, almost all (96%) were satisfied. On average, one-third of the women had seen three or more providers since beginning HIV treatment; 43% indicated they had switched providers because of communication issues. Among women who had been or were pregnant at the time of the survey (n=159), more than half (57%) had not had pre-pregnancy discussions with their HIV provider about the most appropriate HIV regimens for women attempting to become pregnant. Significant communication gaps exist between HIV-infected women and their providers when discussing gender-specific treatment issues. These data highlight a need for U.S. health care providers to incorporate discussion of gender-specific issues, including preconception and reproductive counseling, into management strategies for HIV-infected women.
doi:10.1089/apc.2010.0228
PMCID: PMC3085953  PMID: 21446785

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