Patricia Barditch-Crovo

Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults.

ABSTRACT Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.

Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients.

The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human immunodeficiency type 1-infected patients. The concentrations of adefovir in serum following the intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose proportional and declined biexponentially, with an overall mean +/- standard deviation terminal half-life of 1.6 +/- 0.5 h (n = 28). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98% was recovered by 24 h postdosing. The overall mean +/- standard deviation total serum clearance of the drug (223 +/- 53 ml/h/kg; n = 25) approximated the renal clearance (205 +/- 78 ml/h/kg; n = 20), which was significantly higher (P < 0.01) than the baseline creatinine clearance in the same patients (88 +/- 18 ml/h/kg; n = 25). Since adefovir is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60% of the clearance of adefovir. The steady-state volume of distribution of adefovir (418 +/- 76 ml/kg; n = 28) suggests that the drug was distributed in total body water. Repeated daily dosing with adefovir at 1.0 mg/kg/day (n = 8) and 3.0 mg/kg/day (n = 4) for 22 days did not significantly alter the pharmacokinetics of the drug; there was no evidence of accumulation. The oral bioavailability of adefovir at a 3.0-mg/kg dose was < 12% (n = 5) on the basis of the concentrations in serum or 16.4% +/- 16.0% on the basis of urinary recovery. The subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102% +/- 8.3% (n = 5) on the basis of concentrations in serum or 84.8% +/- 28.5% on the basis of urinary recovery. These data are consistent with preclinical observations in various species.

Anti-Human Immunodeficiency Virus (HIV) Activity, Safety, and Pharmacokinetics of Adefovir Dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-Infected Patients

A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil, an oral prodrug of adefovir, was conducted in 36 human immunodeficiency virus (HIV)-infected subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Subjects received placebo or one of three dosages of adefovir dipivoxil daily for 14 days. Median decreases in serum p24 antigen of 31% (P = .02), 25% (P = .31), and 30% (P = .01) occurred in each drug-treated group, respectively, compared with an increase of 17% in the placebo group. Median decreases in serum HIV RNA of 0.4-0.6 log10 copies/mL occurred in the drug-treated groups (P = .03), compared with no change in the placebo group. Gastrointestinal complaints and reversible liver transaminase elevations were the most frequently noted adverse events. Decreases in serum free carnitine occurred in each drug-treated group during treatment. After 14 days of dosing, adefovir dipivoxil demonstrated anti-HIV activity and was best tolerated at the lowest dosage studied, 125 mg daily.

Clinic-based treatment of opioid-dependent HIV-infected patients versus referral to an opioid treatment program: A randomized trial.

BACKGROUND Opioid dependence is common in HIV clinics. Buprenorphine-naloxone (BUP) is an effective treatment of opioid dependence that may be used in routine medical settings. OBJECTIVE To compare clinic-based treatment with BUP (clinic-based BUP) with case management and referral to an opioid treatment program (referred treatment). DESIGN Single-center, 12-month randomized trial. Participants and investigators were aware of treatment assignments. (ClinicalTrials.gov registration number: NCT00130819) SETTING HIV clinic in Baltimore, Maryland. PATIENTS 93 HIV-infected, opioid-dependent participants who were not receiving opioid agonist therapy and were not dependent on alcohol or benzodiazepines. INTERVENTION Clinic-based BUP included BUP induction and dose titration, urine drug testing, and individual counseling. Referred treatment included case management and referral to an opioid-treatment program. MEASUREMENTS Initiation and long-term receipt of opioid agonist therapy, urine drug test results, visit attendance with primary HIV care providers, use of antiretroviral therapy, and changes in HIV RNA levels and CD4 cell counts. RESULTS The average estimated participation in opioid agonist therapy was 74% (95% CI, 61% to 84%) for clinic-based BUP and 41% (CI, 29% to 53%) for referred treatment (P < 0.001). Positive test results for opioids and cocaine were significantly less frequent in clinic-based BUP than in referred treatment, and study participants receiving clinic-based BUP attended significantly more HIV primary care visits than those receiving referred treatment. Use of antiretroviral therapy and changes in HIV RNA levels and CD4 cell counts did not differ between the 2 groups. LIMITATION This was a small single-center study, follow-up was only moderate, and the study groups were unbalanced in terms of recent drug injections at baseline. CONCLUSION Management of HIV-infected, opioid-dependent patients with a clinic-based BUP strategy facilitates access to opioid agonist therapy and improves outcomes of substance abuse treatment. PRIMARY FUNDING SOURCE Health Resources and Services Administration Special Projects of National Significance program.

The role of protective HCP5 and HLA-C associated polymorphisms in the control of HIV-1 replication in a subset of elite suppressors.

Elite suppressors (ES) are untreated HIV-1-infected patients who maintain undetectable viral loads. A recent whole-genome analysis identified two independent polymorphisms associated with low viral loads in untreated HIV-1 infection. We screened 16 ES; none were positive for the protective HLA complex 5 gene polymorphism, and only four were positive for the protective polymorphism associated with the HLA-C gene. These results suggest that some ES control viremia by mechanisms independent of the newly-identified genetic factors.

A Phase I/II Evaluation of Oral L‐2‐Oxothiazolidine‐4‐Carboxylic Acid in Asymptomatic Patients Infected with Human Immunodeficiency Virus

A randomized double‐blind, placebo‐controlled study was conducted in 37 asymptomatic HIV‐infected individuals (mean CD4 count 707 cells/mm3) to characterize the safety, pharmacokinetics, and effect on blood thiols of three dosage levels of a cysteine prodrug, L‐2‐oxothiazolidine‐4‐carboxylic acid (OTC; Procysteine; Clintec Technologies, Deerfield, IL). Single‐dose administration of OTC resulted in measurable plasma levels at all dosages, with a mean peak plasma concentration of 734 ± 234 nmol/mL at the highest dosage studied. After 4 weeks of administration three times daily, a statistically significant increase was seen in whole blood glutathione in the 1,500 mg and 3,000 mg dose groups compared with the placebo group. A significant increase in whole blood cysteine and peripheral blood mononuclear cell (PBMC) glutathione was not seen during the study period.

Beneficial pharmacokinetic interaction between atazanavir and lopinavir/ritonavir

Background:The combination of lopinavir/ritonavir (LPV/r) and atazanavir (ATV) with nucleoside reverse transcriptase inhibitors has been used as a salvage regimen in HIV-infected patients. Because these agents, to various degrees, are substrates, inducers, and inhibitors of CYP450 3A4, there is concern for alterations in the pharmacokinetics (PK) of these combined agents. Objective:To determine the steady-state PK interactions between ATV, ritonavir (RTV), and LPV when coadministered at various doses. Methods:HIV-negative subjects (n = 15) received a combination of ATV, RTV, and LPV in the following sequence: period I (days 1-10), ATV/r at a dose of 300/100 mg once daily; period II (days 11-24), ATV at a dose of 300 mg once daily plus LPV/r at a dose of 400/100 mg twice daily; and period III (days 25-34), ATV/r at a dose of 300/100 mg once daily plus LPV/r at a dose of 400/100 mg twice daily. Intensive PK analysis was performed on days 10, 24, and 34. A paired t test was used for pairwise comparison of log-transformed PK parameters of ATV and LPV. Results:In period II, the ATV minimum concentration (Cmin) geometric mean (GM) was higher compared with period I (GM: 0.75 vs. 0.51 μg/mL, geometric mean ratio (GMR) = 1.45, 90% confidence interval [CI]: 1.19 to 1.77; P = 0.006). The ATV area under the concentration-time curve from dosing to 24 hours after the dose (AUC0-24; GM: 36.40 vs. 39.62 μg·h/mL, GMR = 0.92, 90% CI: 0.80 to 1.05; P = 0.28) did not differ, however. The addition of 100 mg of RTV in period III did not significantly increase the ATV Cmin (GM: 0.84 vs. 0.75 μg/mL, GMR = 1.13, 90% CI: 0.91 to 1.40; P = 0.34) or ATV AUC0-24 (GM: 39.59 vs. 36.40 μg·h/mL, GMR = 1.09, 90% CI: 0.99 to 1.20; P = 0.14) compared with period II. The additional RTV in period III resulted in a higher LPV Cmin (GM: 5.12 vs. 3.99 μg/mL, GMR = 1.28, 90% CI: 1.15 to 1.43; P = 0.001), but the LPV areas under the concentration-time curve from dosing to 12 hours after the dose and maximum concentration were not significantly different. LPV PK parameters in period II were comparable to those of historical control subjects receiving LPV/r at a dose of 400/100 mg twice daily. All studied regimens were well tolerated. Indirect hyperbilirubinemia was the only grade 3 and 4 abnormality reported, which was expected given that ATV competitively inhibits UGTIA1 and has not been shown to result in other hepatic abnormalities. Conclusions:The combination of ATV at a dose of 300 mg once daily plus LPV/r at a dose of 400/100 mg twice daily resulted in an appropriate PK profile for ATV and LPV and could be further evaluated in treatment-experienced patients requiring a dual-boosted protease inhibitor-containing regimen.

Coronary artery endothelial dysfunction is present in HIV positive individuals without significant coronary artery disease

Objective: HIV-positive (HIV+) individuals experience an increased burden of coronary artery disease (CAD) not adequately accounted for by traditional CAD risk factors. Coronary endothelial function (CEF), a barometer of vascular health, is depressed early in atherosclerosis and predict future events but has not been studied in HIV+ individuals. We tested whether CEF is impaired in HIV+ patients without CAD as compared with an HIV-negative (HIV−) population matched for cardiac risk factors. Design/methods: In this observational study, CEF was measured noninvasively by quantifying isometric handgrip exercise-induced changes in coronary vasoreactivity with MRI in 18 participants with HIV but no CAD (HIV+CAD−, based on prior imaging), 36 age-matched and cardiac risk factor-matched healthy participants with neither HIV nor CAD (HIV−CAD−), 41 patients with no HIV but with known CAD (HIV−CAD+), and 17 patients with both HIV and CAD (HIV+CAD+). Results: CEF was significantly depressed in HIV+CAD− patients as compared with that of risk-factor-matched HIV−CAD− patients (P < 0.0001) and was depressed to the level of that in HIV− participants with established CAD. Mean IL-6 levels were higher in HIV+ participants (P < 0.0001) and inversely related to CEF in the HIV+ patients (P = 0.007). Conclusion: Marked coronary endothelial dysfunction is present in HIV+ patients without significant CAD and is as severe as that in clinical CAD patients. Furthermore, endothelial dysfunction appears inversely related to the degree of inflammation in HIV+ patients as measured by IL-6. CEF testing in HIV+ patients may be useful for assessing cardiovascular risk and testing new CAD treatment strategies, including those targeting inflammation.

Quantitation of vaginally administered nonoxynol-9 in premenopausal women

A feasibility study was performed in 11 healthy nonpregnant premenopausal women to determine a method for collection and recovery of vaginally administered nonoxynol-9. We also determined if nonoxynol-9 could be quantitated in vaginal lavage fluid obtained 2 h after instillation of a standard precoitol dose of a foam formulation of nonoxynol-9. Samples were analyzed in batch using a validated normal phase high-performance liquid chromatography (HPLC) method. Two hours after instillation of one dose of Delfen Contraceptive Foam (100 mg), the quantity of nonoxynol-9 collected ranged from 10.8 to 67.8 mg (mean: 35.4 mg). This corresponds to a recovery of 11.70%, of the administered dose. Quantitation of vaginally administered nonoxynol-9 is both practical and feasible. These data represent a critical first step in the evaluation of the safety and effectiveness of nonoxynol-9-containing products in the prevention of sexually transmitted diseases.

Hydroxyurea does not enhance the anti-HIV activity of low-dose tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate (DF) is an adenosine analogue with significant activity against HIV-1. Hydroxyurea decreases the intracellular concentrations of deoxyadenosine triphosphate, the active metabolite of adenosine. We therefore tested the hypothesis that hydroxyurea could enhance the anti-HIV activity of low-dose tenofovir in vivo. Eight patients received tenofovir DF, 75 mg, plus hydroxyurea, 500 mg bid, for 28 days. Changes in plasma HIV RNA levels were compared with a previously studied cohort of patients treated with tenofovir DF, 75 mg once daily ( n = 8), or tenofovir placebo ( n = 12). The median change in HIV RNA levels after 28 days of continuous treatment was -0.01 log(10) copies/ml for tenofovir placebo, -0.33 log(10) copies/ml for tenofovir 75 mg once daily, and -0.22 log(10) copies RNA/ml for tenofovir plus hydroxyurea. The difference between placebo and tenofovir-treated groups was significant ( p <.05); however, the difference between the tenofovir and tenofovir plus hydroxyurea groups was not significant ( p =.90). We conclude that hydroxyurea does not significantly enhance the antiviral activity of low-dose tenofovir.