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1.  Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257 
In this randomized trial, raltegravir had more of a favorable lipid profile than ritonavir-boosted atazanavir or ritonavir-boosted darunavir–based regimens. Metabolic syndrome rates increased to the same degree for all 3 regimens. There was no relationship between ritonavir exposure and lipid levels.
Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24).
Methods. Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression.
Results. Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1).
Conclusions. Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation.
Clinical Trials Registration. NCT 00811954.
PMCID: PMC4660025  PMID: 25767256
HIV/AIDS; cART; lipids; metabolic syndrome
2.  StudySearch: a web-based application for posting and searching clinical research studies 
Participant accrual into research studies is critical to advancing clinical and translational research to clinical care. Without sufficient recruitment, the purpose of any research study cannot be realized; yet, low recruitment and enrollment of participants persist. StudySearch is a web-based application designed to provide an easily readable, publicly accessible, and searchable listing of IRB-approved protocols that are accruing study participants. The Regulatory, Recruitment and Biomedical Informatics Cores of the Center for Clinical and Translational Science (CCTS) at The Ohio State University developed this research study posting platform. Postings include basic descriptive information: study title, purpose of the study, eligibility criteria and study personnel contact information. Language concerning benefits and/or inducements is not included; therefore, while IRB approval for a study to be listed on StudySearch is required, IRB approval of the posted language is not. Studies are listed by one of two methods; one automated and one manual: (1). Studies registered on are automatically downloaded once a month; or (2). Studies are submitted directly by researchers to the CCTS Regulatory Core staff. In either case, final language is a result of an iterative process between researchers and CCTS staff. Deployed in January 2011 at OSU, this application has grown to approximately 200 studies currently posted and 1500 unique visitors per month. Locally, StudySearch is part of the CCTS recruitment toolkit. Features continue to be modified to better accommodate user behaviors. Nationally, this open source application is available for use.
PMCID: PMC4795181  PMID: 26912012
3.  Pharmacokinetic Interaction between Efavirenz and Dual Protease Inhibitors in Healthy Volunteers 
The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600 mg efavirenz for 10 days with amprenavir 600 mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15–21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CLt/F), volume of distribution at steady state (Vss/F), inter-compartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CLt/F and Vss/F of efavirenz were 0.126 l/h/kg and 4.412 l/kg, respectively. Both AUC and CLt/F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean Vss/F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in Vp/F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically.
PMCID: PMC4307806  PMID: 18041735
pharmacokinetic modeling; drug interactions; non-nucleoside reverse transcriptase inhibitor; efavirenz; HIV-1 protease inhibitors
4.  HIV and asthma, is there an association? 
Respiratory medicine  2012;106(4):493-499.
To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection.
We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data.
HIV-seropositive individuals commonly experience respiratory complaints yet it is unclear if the frequency of these complaints have changed with the initiation of HAART. Changes in pulmonary function testing and serum IgE are seen with HIV infection even in the post-HAART era. An increased prevalence of asthma among HIV-seropositive children treated with HAART has been reported.
The spectrum of HIV-associated pulmonary disease has changed with the introduction of HAART. Current data is limited to determine if asthma and airway hyper-responsiveness are more common among HIV-seropositive individuals treated with HAART.
PMCID: PMC4235227  PMID: 22285768
Asthma; Airway hyper-responsiveness; HIV; Antiretroviral
5.  Phase I/II Trial of the Anti-HIV Activity of Mifepristone in HIV-Infected Subjects ACTG 5200 
Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug’s safety and anti-HIV activity.
A 28-day double-blind, placebo-controlled trial of mifepristone at doses of 75 mg, 150 mg, and 225 mg given daily was conducted in HIV+ persons with CD4+ lymphocyte counts ≥350 cells per cubic millimeter who had no recent antiretroviral therapy.
Fifty-six male and 1 female subjects with a median entry CD4+ lymphocyte count of 555 cells per cubic millimeter and plasma HIV-1 RNA of 15,623 copies per milliliter were accrued. Forty-five subjects (78.9%) were available for endpoint analysis. In each arm, changes from baseline to day 28 in plasma HIV-1 RNA and CD4+ lymphocyte count were not significantly different from zero (no change). There was no relationship between mifepristone trough concentrations and plasma HIV-1 RNA. Day 28 morning plasma cortisol levels were significantly higher in the 150 mg and 225 mg arms compared with placebo, confirming biologic activity, and returned to baseline by day 56. Serum lipids did not change during the trial. Fasting blood sugar was 2.5 mg/dL higher on day 28 in the mifepristone arms, but the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) did not change. Three subjects (7.3%) receiving mifepristone developed a grade 2 rash.
Mifepristone at doses of 75–225 mg daily was safe and well-tolerated, but did not show significant anti-HIV activity.
PMCID: PMC3477637  PMID: 20130470
antiretroviral; clinical trial; mifepristone
6.  The Design of Single-Arm Clinical Trials of Combination Antiretroviral Regimens for Treatment-Naive HIV-Infected Patients 
Single-arm clinical trials are useful to evaluate antiretroviral regimens in certain populations of HIV-infected treatment-naive patients for whom a randomized controlled trial is not feasible or desirable. They can also be useful to establish initial estimates of efficacy and safety/tolerability of novel regimens to inform the design of large phase III trials. In this article, we discuss key design considerations for such single-arm studies.
PMCID: PMC3607972  PMID: 23228206
7.  Impact of Chemotherapy for HIV-1 Related Lymphoma on Residual Viremia and Cellular HIV-1 DNA in Patients on Suppressive Antiretroviral Therapy 
PLoS ONE  2014;9(3):e92118.
The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence.
Clinical Trials Registration Unique Identifier:
PMCID: PMC3956871  PMID: 24638072
8.  Human N-acetyltransferase 1 (NAT1) *10 and *11 alleles increase protein expression via distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity 
Pharmacogenetics and genomics  2011;21(10):652-664.
N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared to wild-type NAT1 *4 and to confer cancer risk, via uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.
We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternative splicing, and three 3′-polyadenylation sites in human livers (one of which discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 HIV/AIDS patients treated with the NAT1/NAT2 substrate sulfamethoxazole (SMX), associations were tested between SMX induced hypersensitivity and NAT1 *10 and *11 genotypes, together with known NAT2 polymorphisms.
NAT1*10 and *11 were determined to act as common regulatory alleles accounting for most NAT1 expression variability, both leading to increased translation into active protein. NAT1*11 (2.4% minor allele frequency) affected 3′polyadenylation site usage, thereby increasing formation of NAT1 mRNA with intermediate length 3′UTR (major isoform) at the expense of the short isoform, resulting in more efficient protein translation. NAT1 *10 (19% minor allele frequency) increased translation efficiency without affecting 3′-UTR polyadenylation site usage. Livers and B-lymphocytes with *11/*4 and *10/*10 genotypes displayed higher NAT1 immunoreactivity and NAT1 enzyme activity than the reference genotype *4/*4. Patients who carry *10/*10 and *11/*4 (‘fast NAT1 acetylators’) were less likely to develop hypersensitivity to SMX, but this was observed only in subjects also carrying a slow NAT2 acetylator genotype.
NAT1 *10 and *11 significantly increase NAT1 protein level/enzyme activity, enabling the classification of carriers into reference and rapid acetylators. Rapid NAT1 acetylator status appears to protect against SMX toxicity by compensating for slow NAT2 acetylator status.
PMCID: PMC3172334  PMID: 21878835
N-acetyltransferase; NAT1; polyadenylation; allelic expression imbalance; sulfamethoxazole; cotrimoxazole; protein translation; acetylator phenotype; idiosyncratic drug reactions
9.  Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients 
BMC Medical Genomics  2012;5:32.
Sulfamethoxazole (SMX) is a commonly used antibiotic for prevention of infectious diseases associated with HIV/AIDS and immune-compromised states. SMX-induced hypersensitivity is an idiosyncratic cutaneous drug reaction with genetic components. Here, we tested association of candidate genes involved in SMX bioactivation and antioxidant defense with SMX-induced hypersensitivity.
Seventy seven single nucleotide polymorphisms (SNPs) from 14 candidate genes were genotyped and assessed for association with SMX-induced hypersensitivity, in a cohort of 171 HIV/AIDS patients. SNP rs761142 T > G, in glutamate cysteine ligase catalytic subunit (GCLC), was significantly associated with SMX-induced hypersensitivity, with an adjusted p value of 0.045. This result was replicated in a second cohort of 249 patients (p = 0.025). In the combined cohort, heterozygous and homozygous carriers of the minor G allele were at increased risk of developing hypersensitivity (GT vs TT, odds ratio = 2.2, 95% CL 1.4-3.7, p = 0.0014; GG vs TT, odds ratio = 3.3, 95% CL 1.6 – 6.8, p = 0.0010). Each minor allele copy increased risk of developing hypersensitivity 1.9 fold (95% CL 1.4 – 2.6, p = 0.00012). Moreover, in 91 human livers and 84 B-lymphocytes samples, SNP rs761142 homozygous G allele carriers expressed significantly less GCLC mRNA than homozygous TT carriers (p < 0.05).
rs761142 in GCLC was found to be associated with reduced GCLC mRNA expression and with SMX-induced hypersensitivity in HIV/AIDS patients. Catalyzing a critical step in glutathione biosynthesis, GCLC may play a broad role in idiosyncratic drug reactions.
PMCID: PMC3418550  PMID: 22824134
Idiosyncratic drug reaction; Sulfamethoxazole; Hypersensitivity; Glutamate cysteine ligase catalytic subunit (GCLC); Association; HIV/AIDS
10.  Use of Monoclonal Antibodies Against Two 75,000-Molecular-Weight Glycoproteins Specified by Herpes Simplex Virus Type 2 in Glycoprotein Identification and Gene Mapping 
Journal of Virology  1983;45(3):1223-1227.
We produced two monoclonal antibodies that precipitate different glycoproteins of similar apparent molecular weight (70,000 to 80,000) from extracts of cells infected with herpes simplex virus type 2. Evidence is presented that one of these glycoproteins is the previously characterized glycoprotein gE, whereas the other maps to a region of the herpes simplex virus type 2 genome collinear with the region in herpes simplex virus type 1 DNA that encodes gC.
PMCID: PMC256538  PMID: 6300459
11.  Antiretroviral drug levels and interactions affect lipid, lipoprotein and glucose metabolism in HIV-1 seronegative subjects: A pharmacokinetic-pharmacodynamic analysis 
HIV-infected patients treated with antiretroviral medications (ARVs) develop undesirable changes in lipid and glucose metabolism that mimic the metabolic syndrome and may be proatherogenic. Antiretroviral drug levels and their interactions may contribute to these metabolic alterations.
Fifty-six HIV-seronegative adults were enrolled in an open-label, randomized, pharmacokinetic interaction study, and received a non-nucleoside reverse transcriptase inhibitor (efavirenz on days 1-21) plus a protease inhibitor (PI; amprenavir on days 11-21), with a second PI on days 15-21 (saquinavir, nelfinavir, indinavir, or ritonavir). Fasting triglycerides, total, LDL- and HDL-cholesterol, glucose, insulin and C-peptide levels were measured on days 0, 14, 21, and 2-3 weeks after discontinuing drugs. Regression models were used to estimate changes in these parameters and associations between these changes and circulating levels of study drugs.
Short-term efavirenz and amprenavir administration significantly increased cholesterol, triglycerides and glucose levels. Addition of a second protease inhibitor further increased triglycerides, total- and LDL-cholesterol levels. Higher amprenavir levels predicted larger increases in triglycerides, total and LDL-cholesterol. Two weeks after all study drugs were stopped, total, LDL- and HDL-cholesterol remained elevated above baseline.
ARV regimens that include a non-nucleoside reverse transcriptase inhibitor plus single or boosted PIs are becoming more common, but the pharmacodynamic interactions associated with these regimens can result in persistent, undesirable alterations in serum lipid/lipoprotein levels. Additional pharmacodynamic studies are needed to examine the metabolic effects of ritonavir-boosted regimens, with and without efavirenz.
PMCID: PMC2078603  PMID: 18007962
12.  Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks▿  
Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.
PMCID: PMC1855557  PMID: 17283195
13.  Amprenavir and Efavirenz Pharmacokinetics before and after the Addition of Nelfinavir, Indinavir, Ritonavir, or Saquinavir in Seronegative Individuals 
Adult AIDS Clinical Trials Group 5043 examined pharmacokinetic (PK) interactions between amprenavir (APV) and efavirenz (EFV) both by themselves and when nelfinavir (NFV), indinavir (IDV), ritonavir (RTV), or saquinavir (SQV) is added. A PK study was conducted after the administration of single doses of APV (day 0). Subjects (n = 56) received 600 mg of EFV every 24 h (q24h) for 10 days and restarted APV with EFV for days 11 to 13 with a PK study on day 14. A second protease inhibitor (PI) (NFV, 1,250 mg, q12h; IDV, 1,200 mg, q12h; RTV, 100 mg, q12h; or SQV, 1,600 mg, q12h) was added to APV and EFV on day 15, and a PK study was conducted on day 21. Controls continued APV and EFV without a second PI. Among subjects, the APV areas under the curve (AUCs) on days 0, 14, and 21 were compared using the Wilcoxon signed-rank test. Ninety-percent confidence intervals around the geometric mean ratios (GMR) were calculated. APV AUCs were 46% to 61% lower (median percentage of AUC) with EFV (day 14 versus day 0; P values of <0.05). In the NFV, IDV, and RTV groups, day 21 APV AUCs with EFV were higher than AUCs for EFV alone. Ninety-percent confidence intervals around the GMR were 3.5 to 5.3 for NFV (P < 0.001), 2.8 to 4.5 for IDV (P < 0.001), and 7.8 to 11.5 for RTV (P = 0.004). Saquinavir modestly increased the APV AUCs (GMR, 1.0 to 1.4; P = 0.106). Control group AUCs were lower on day 21 compared to those on day 14 (GMR, 0.7 to 1.0; P = 0.042). African-American non-Hispanics had higher day 14 efavirenz AUCs than white non-Hispanics. We conclude that EFV lowered APV AUCs, but nelfinavir, indinavir, or ritonavir compensated for EFV induction.
PMCID: PMC1196277  PMID: 16048950
14.  ACTG 260: a Randomized, Phase I-II, Dose-Ranging Trial of the Anti-Human Immunodeficiency Virus Activity of Delavirdine Monotherapy 
ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 μM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance.
PMCID: PMC89281  PMID: 10348755

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