Teresa L. Parsons

Hyperosmolar Sexual Lubricant Causes Epithelial Damage in the Distal Colon: Potential Implication for HIV Transmission

BACKGROUND Many sexual lubricants are hyperosmolar. Hyperosmolar enemas induce epithelial damage, and enema use has been associated with an increased risk of HIV infection. To inform the development of rectal microbicide formulation, we evaluated the effects of hyperosmolar gels on the rectal mucosa. METHODS Two commercial lubricants were compounded into iso-osmolar and hyperosmolar mixtures (283 and 3429 mOsm/kg, respectively). Each gel was radiolabeled with 500 micro Ci of (99m)Technetium-diethylene triaminepentaacetic acid, and 10 mL was given rectally to 10 subjects in random sequence. Sigmoidoscopy by an endoscopist blinded to treatment assignment was performed 90 min later to obtain luminal and mucosal samples. Urine radiolabel detection was used to assess mucosal permeability. RESULTS Epithelial denudation 10 cm from the anus occurred to a greater degree with the hyperosmolar gel than with the iso-osmolar formulation (median toxicity grade, 2.50 vs. 1.17 out of 3, respectively; P=.009). The hyperosmolar gel was also associated with lower isotope luminal concentration at 10 cm, compared with the iso-osmolar gel (median, 8.9% vs. 54.6% of administered concentration, respectively). Mucosal permeability measured through 12 h was reduced with the hyperosmolar gel (P=.037). CONCLUSION Rectally applied hyperosmolar gels induce greater epithelial denudation and luminal secretion than iso-osmolar gels. Because denudation plausibly increases the risk of HIV transmission, hyperosmolar gels make poor rectal microbicide formulations, and hyperosmolar sexual lubricants may increase susceptibility to HIV infection.

Marked Intraindividual Variability in Antiretroviral Concentrations May Limit the Utility of Therapeutic Drug Monitoring

BACKGROUND Effective therapeutic drug monitoring for antiretrovirals requires a better understanding of intraindividual variability in pharmacokinetics. METHODS We determined concentrations of human immunodeficiency virus (HIV) protease and nonnucleoside reverse-transcriptase inhibitors for 10 patients with undetectable plasma HIV RNA levels who had been receiving stable regimens for > or = 11 months. Plasma samples were collected at the same time of day 3 times per week for up to 4 months. Patients were instructed to take their antiretrovirals at the same time every day. Plasma protease and nonnucleoside reverse-transcriptase inhibitor concentrations were determined using high-performance liquid chromatographic methods. Pharmacokinetic variability was expressed as intraindividual percentage coefficient of variation (ICV), which was calculated as the patients standard deviation divided by the mean drug concentration for that patient. RESULTS ICV was determined for 6 drugs for 10 patients, for a total of 17 different patient-drug combinations, using 600 total samples. ICV was unexpectedly high for most patients who were receiving protease inhibitors (ICVs for individual patients taking lopinavir/ritonavir were 24%, 33%, 51%, and 92%; for patients taking nelfinavir/M8 metabolite, they were 30%/44% and 39%/54%; for patients taking ritonavir, they were 34% and 43%; for patients taking saquinavir, they were 52% and 55%). ICVs for patients receiving nonnucleoside reverse-transcriptase inhibitors were lower (for patients receiving efavirenz, they were 7%, 13%, 29%, and 51%; for a patient receiving nevirapine, it was 25%). The median ICV for all patients receiving protease inhibitors (n = 12) was 43.5%, and for all patients receiving nonnucleoside reverse-transcriptase inhibitors (n = 5), the median ICV was 25%. CONCLUSIONS Intraindividual variability in concentrations of antiretrovirals was surprisingly high in virologically suppressed patients. Possible contributors include food effects, concomitant use of prescription and herbal medications, assay variability, or medication timing, which was assessed by self-report. High intraindividual pharmacokinetic variability may limit the utility of single measurements in therapeutic drug monitoring for some antiretroviral agents.

Quantitative Imaging and Sigmoidoscopy to Assess Distribution of Rectal Microbicide Surrogates

Understanding the distribution of microbicide and human immunodeficiency virus (HIV) within the gastrointestinal tract is critical to development of rectal HIV microbicides. A hydroxyethylcellulose‐based microbicide surrogate or viscosity‐matched semen surrogate, labeled with gadolinium‐DTPA (diethylene triamine pentaacetic acid) and 99mTechnetium‐sulfur colloid, was administered to three subjects under varying experimental conditions to evaluate effects of enema, coital simulation, and microbicide or semen simulant over 5 h duration. Quantitative assessment used single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI) imaging, and sigmoidoscopic sampling. Over 4 h, radiolabel migrated cephalad in all studies by a median (interquartile range) of 50% (29–102%; P<0.001), as far as the splenic flexure (~60 cm) in 12% of studies. There was a correlation in concentration profile between endoscopic sampling and SPECT assessments. HIV‐sized particles migrate retrograde, 60 cm in some studies, 4 h after simulated ejaculation in our model. SPECT/CT, MRI, and endoscopy can be used quantitatively to facilitate rational development of microbicides for rectal use.

Comparison of Once-Daily versus Twice-Daily Combination Antiretroviral Therapy in Treatment-Naive 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 human immunodeficiency virus (HIV)-positive, treatment-naive patients to lopinavir-ritonavir (LPV/r) administered at a dosage of 400 mg of lopinavir and 100 mg of ritonavir BID (n = 160) or 800 mg of lopinavir and 200 mg of ritonavir QD (n = 161), plus either emtricitabine 200 mg QD and extended-release stavudine at a dosage of 100 mg QD or tenofovir at a dosage of 300 mg QD. Randomization was stratified by screening HIV RNA level <100,000 copies/mL versus > or = 100,000 copies/mL. The primary efficacy end point was sustained virologic response (SVR; defined as reaching and maintaining an HIV RNA level <200 copies/mL) through week 48. RESULTS Subjects were 78% male, 33% Hispanic, and 34% black. A total of 82% of subjects completed the study, and 71% continued to receive the initially assigned dosage schedule. The probability of SVR did not differ significantly for the BID versus QD comparison, with an absolute proportional difference of 0.03 (95% confidence interval [CI], -0.07 to 0.12). The comparison depended on the screening RNA stratum (P=.038); in the higher RNA stratum, the probability of SVR was significantly better in the BID arm than in the QD arm: 0.89 (95% CI, 0.79-0.94) versus 0.76 (95% CI, 0.64-0.84), a difference of 0.13 (95% CI, 0.01-0.25). Lopinavir 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<.001). Conclusions. Although subjects assigned to QD regimens had better adherence, overall treatment outcomes were similar in the QD and BID arms. Subjects with HIV RNA levels > or =100,000 copies/mL had better SVR with BID regimens at 48 weeks, which suggests a possible advantage in this setting for more frequent dosing. Clinical trial registration. ClinicalTrials.gov registration number: NCT00036452.

Possible Differential Induction of Phase 2 Enzyme and Antioxidant Pathways by American Ginseng, Panax quinquefolius

Human immunodeficiency virus (HIV)‐infected patients often take herbal medicines, which may interact with antiretrovirals. American ginseng induces phase 2 and antioxidant enzymes in vitro and might increase the clearance of zidovudine and/or enhance antioxidant activity. Ten healthy volunteers received 300 mg of zidovudine orally before and after 2 weeks of treatment with a ginsenoside‐enriched American ginseng extract 200 mg twice daily. This ginseng extract induced the phase 2 enzyme quinone reductase with an average concentration of doubling of enzyme activity of 190 μg/mL. Total ginsenoside content was 8.5 ± 0.5%. Pharmacokinetic profiles of zidovudine and oxidative stress marker concentrations were measured post‐zidovudine dose. American ginseng does not significantly affect the formation clearance of zidovudine to its glucuronide (ratio post‐ to pre‐American ginseng = 1.17; 90% confidence interval: 0.95–1.45; P = .21), total clearance (ratio = 0.97; 0.82–1.14; P = .70), or plasma zidovudine AUC0–8 (ratio = 1.03; 0.87–1.21; P = .77). Oxidative stress biomarkers are reduced post‐American ginseng (F2‐isoprostane ratio = 0.79; 0.72–0.86; P < .001; 8‐hydroxy‐deoxyguanosine ratio = 0.74; 0.59–0.92; P = .02). Two weeks of American ginseng does not alter zidovudine pharmacokinetics but reduces oxidative stress markers.

Undisclosed Antiretroviral Drug Use in a Multinational Clinical Trial (HIV Prevention Trials Network 052)

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.

Pharmacokinetics and Safety of Tenofovir in HIV-Infected Women During Labor and Their Infants During the First Week of Life

Background:Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking. Methods:The HIV Prevention Trials Network 057 protocol was a phase 1, open-label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV-infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses on days 0, 3, and 5; maternal 900 mg doses/infant 6 mg/kg doses on days 0, 3, and 5; maternal 600 mg doses/infant 6 mg/kg daily for 7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid, and breast milk tenofovir concentrations were determined by liquid chromatographic–tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing. Results:One hundred twenty-two mother–infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 and 900 mg exceeded that in nonpregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults, and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74%–97% of infants receiving daily dosing. Conclusions:A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in the studies of TDF efficacy for HIV prevention of mother-to-child transmission and early infant treatment.

Pharmacokinetic and metabolic effects of American ginseng (Panax quinquefolius) in healthy volunteers receiving the HIV protease inhibitor indinavir

BackgroundComplementary and alternative medicine (CAM) use is prevalent among HIV-infected patients to reduce the toxicity of antiretroviral therapy. Ginseng has been used for treatment of hyperglycemia and insulin resistance, a common side effect of some HIV-1 protease inhibitors (PI). However, it is unknown whether American ginseng (AG) can reverse insulin resistance induced by the PI indinavir (IDV), and whether these two agents interact pharmacologically. We evaluated potential pharmacokinetic interactions between IDV and AG, and assessed whether AG improves IDV-induced insulin resistance.MethodsAfter baseline assessment of insulin sensitivity using the insulin clamp technique, healthy volunteers received IDV 800 mg q8 h for 3 days and then IDV and AG 1g q8h for 14 days. IDV pharmacokinetics and insulin sensitivity were assessed before and after AG co-administration.ResultsThere was no difference in the area-under the plasma-concentration-time curve after the co-administration of AG, compared to IDV alone (n = 13). Although insulin-stimulated glucose disposal per unit of insulin (M/I) decreased by an average of 14.8 ± 5.9% after 3 days of IDV (from 0.113 ± 0.012 to 0.096 ± 0.014 mg/kgFFM/min per μU/ml of insulin, p = 0.03, n = 11), M/I remained unchanged after co-administration of IDV and AG.ConclusionIDV decreases insulin sensitivity, which is unaltered by AG co-administration. AG does not significantly affect IDV pharmacokinetics.

Pharmacokinetics and Placental Transfer of Single-Dose Tenofovir 1% Vaginal Gel in Term Pregnancy

UNLABELLED Tenofovir (TFV) 1% vaginal gel has been found to decrease sexual transmission of human immunodeficiency virus. To initiate investigations during pregnancy, 16 healthy pregnant women scheduled for cesarean delivery received a single application of TFV gel preoperatively. Maternal serum drug concentrations were determined and fetal cord blood, amniotic fluid, placental tissue, and endometrial tissue specimens were collected. The median maternal peak concentration and cord blood TFV concentrations were 4.3 and 1.9 ng/mL, respectively (∼100- and 40-fold lower than after TFV oral dosing, respectively). No adverse events were related to the use of TFV gel. These findings support ongoing and future investigations of TFV gel in pregnancy. CLINICAL TRIAL REGISTRATION NCT00572273. http://www.clinicaltrials.gov/ct2/show/NCT00540605?term=mtn-002&rank=1.

Quantitative assessment of seminal vesicle and prostate drug concentrations by use of a noninvasive method

The male genital tract is a complex collection of anatomically and biochemically distinct compartments that contribute to the ejaculate. Understanding the pharmacokinetics in these compartments should inform rational therapeutics involving these glands.