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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
11.  HIV: primary and secondary prophylaxis for opportunistic infections 
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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  COMPARISON OF ONCE-DAILY VERSUS TWICE-DAILY COMBINATION ANTIRETROVIRAL THERAPY IN TREATMENT-NAÏVE PATIENTS: RESULTS OF AIDS CLINICAL TRIALS GROUP (ACTG) A5073, A 48-WEEK RANDOMIZED CONTROLLED TRIAL 
Background
Dosing frequency is an important determinant of regimen effectiveness.
Methods
To compare efficacy of once-daily (QD) versus twice-daily (BID) antiretroviral therapy, we randomized HIV-1 positive, treatment-naïve, patients to lopinavir/ritonavir (LPV/r) 400/100 mg BID (n=160) or LPV/r 800/200 mg QD (n=161), plus either emtricitabine 200 mg QD and extended-release stavudine (d4T-XR) 100 mg QD, or tenofovir 300 mg QD. Randomization was stratified by screening HIV-1 RNA
Results
Subjects were 78% male, 33% Hispanic, and 34% black. 82% of subjects completed the study, and 71% remained on initially assigned dose schedule. Probability of SVR did not differ significantly for the BID vs. QD comparison, with an absolute proportional difference (95% confidence interval [CI]) of 0.03 (−0.07, 0.12). The comparison depended on the screening RNA stratum (p=0.038); in the higher RNA stratum, the probability (95% CI) of SVR was significantly better in the BID arm: 0.89 (0.79, 0.94) compared to 0.76 (0.64, 0.84) in the QD arm; difference of 0.13 (0.01, 0.25). LPV trough plasma concentrations were higher with BID dosing. Adherence to prescribed doses of LPV/r was 90.6% in the QD arm versus 79.9% in the BID arm (p<0.001).
Conclusions
Although subjects assigned to QD regimens had better adherence, overall treatment outcomes were similar to the BID regimens. Subjects with HIV-1 RNA ≥100,000 copies/mL had better SVR on BID regimens at 48 weeks, suggesting a possible advantage in this setting for more frequent dosing.
doi:10.1086/651118
PMCID: PMC2833234  PMID: 20192725
HIV; clinical trials; adherence; lopinavir; pharmacokinetics
The Open Virology Journal  2011;5:109-113.
Background:
Hepatitis B (HBV) vaccination is an important preventive intervention for HIV-infected population. Data regarding booster HBV vaccine for persons with low HBV surface antibody (sAb) titers after vaccination in this immunocompromised population is lacking.
Methods:
We randomized 60 HIV-infected subjects lacking HBV protection after completion of 3 doses of HBV vaccine to receive a booster dose of HBV vaccine with 250mcg GM-CSF as an adjuvant or booster vaccine alone.
Results:
GM-CSF was safe with expected side effects. However, only 35% of persons receiving GM-CSF developed protective sAb while 50% in vaccine only arm developed protection (P = 0.47). Overall, only 28% of subjects maintained protective sAb 1 year after vaccination.
Conclusions:
GM-CSF failed to improve responses to the booster HBV vaccination. Overall, response was poor with only 42% of persons responding at one month post-vaccination confirming booster vaccination with the current HBV vaccine has poor immunogenicity among HIV-infected persons. Further research is needed to develop optimal vaccination strategies in HIV-infected persons.
doi:10.2174/1874357901105010109
PMCID: PMC3201215  PMID: 22043256
HIV; HBV vaccination; GM-CSF; adjuvant.
The Journal of infectious diseases  2010;201(3):315-317.
doi:10.1086/649898
PMCID: PMC2945522  PMID: 20039805
Introduction
Fish oil has been shown to reduce serum triglyceride (TG) concentrations. In HIV-infected patients on antiretroviral therapy, high TG concentrations likely contribute to increased risk of cardiovascular disease. AIDS Clinical Trials Group A5186 examined the safety and efficacy of fish oil plus fenofibrate in subjects not achieving serum TG levels ≤200 mg/dL with either agent alone.
Methods
One hundred subjects on highly active antiretroviral therapy with serum TG concentrations ≥400 mg/dL and low-density lipoprotein cholesterol ≤160 mg/dL were randomized to 3 g of fish oil twice daily or 160 mg of fenofibrate daily for 8 weeks. Subjects with a fasting TG level >200 mg/dL at week 8 received a combination of fish oil and fenofibrate in the same doses from week 10 to week 18.
Results
Median baseline TG was 662 mg/dL in the fish oil group and 694 mg/dL in the fenofibrate group (P = not significant). Fish oil reduced TG levels by a median of 283 mg/dL (46%), fenofibrate reduced them by 367 mg/dL (58%), and combination therapy reduced them by 65.5%. Combination therapy achieved TG levels of ≤200 mg/dL in 22.7% subjects. Fish oil had no measurable effect on immunologic parameters or the pharmacokinetics of lopinavir.
Conclusions
Fish oil was safe when administered alone or combined with fenofibrate and significantly reduced TG levels in HIV-infected subjects with hypertriglyceridemia.
doi:10.1097/QAI.0b013e31815bace2
PMCID: PMC2788607  PMID: 17971707
fenofibrate; fish oil; hypertriglyceridemia; low-density lipoprotein cholesterol; omega-3 fatty acids
Background
Lack of functional CCR5 increases the severity of certain viral infections, including West Nile virus and tickborne encephalitis. In a phase II trial of the investigational CCR5 antagonist vicriviroc (AIDS Clinical Trials Group protocol A5211), 4 lymphomas occurred in study patients who received vicriviroc. Because of the known association between unregulated Epstein-Barr virus (EBV) replication and lymphoma in immunocompromised patients, we evaluated whether vicriviroc exposure was associated with lymphoma EBV antigen positivity and/or had an effect on plasma levels of EBV DNA.
Methods
Clinical findings for all 4 patients enrolled in the A5211 study who developed lymphoma (2 Hodgkin and 2 non-Hodgkin) were reviewed, and tumor specimens were assessed for evidence of ongoing EBV replication. Longitudinal plasma samples from 116 patients in the A5211 study were analyzed, and EBV DNA was quantified by real-time polymerase chain reaction.
Results
Plasma EBV DNA was not detected in the 2 patients with non-Hodgkin lymphoma; both patients with Hodgkin lymphoma who had samples tested had EBV DNA levels <3200 copies/mL. One patient with Hodgkin lymphoma had a lymph node core biopsy specimen that was strongly positive for EBV; the other 3 lymphomas were histochemically EBV negative. None of the 116 patients with available samples experienced sustained increases in plasma EBV levels.
Conclusions
CCR5 antagonism by vicriviroc treatment in treatment-experienced patients was not associated with reactivation of EBV infection.
doi:10.1086/597007
PMCID: PMC2756462  PMID: 19191652
doi:10.1016/j.ecl.2008.11.009
PMCID: PMC2753589  PMID: 19217520
HIV-related dyslipidemia; Hypertriglyceridemia; Drug interactions; Statins; Fibrates

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