Petrie M. Rainey

Cue-dose Training with Monetary Reinforcement: Pilot Study of an Antiretroviral Adherence Intervention

AbstractOBJECTIVE: To assess the feasibility and efficacy of two interventions for improving adherence to antiretroviral therapy regimens in HIV-infected subjects compared with a control intervention. DESIGN: Randomized, controlled, pilot study. SETTING: Department of Veterans Affairs HIV clinic and community-based HIV clinical trials site. PARTICIPANTS: Fifty-five HIV-infected subjects on stable antiretroviral therapy regimens. Subjects were predominantly male (89%) and African American (69%), and had histories of heroin or cocaine use (80%). INTERVENTIONS: Four weekly sessions of either nondirective inquiries about adherence (control group, C), cue-dose training, which consisted of the use of personalized cues for remembering particular dose times, and feedback about medication taking using Medication Event Monitoring System (MEMS) pill bottle caps, which record time of bottle opening (CD group), or cue-dose training combined with cash reinforcement for correctly timed bottle opening (CD+CR). MEASUREMENTS: Opening of the pill bottle within 2 hours before or after a predetermined time was measured by MEMS. RESULTS: Adherence to the medication as documented by MEMS was significantly enhanced during the 4-week training period in the CD+CR group, but not in the CD group, compared with the control group. Improvement was also seen in adherence to antiretroviral drugs that were not the object of training and reinforcement. Eight weeks after training and reinforcement were discontinued, adherence in the cash-reinforced group returned to near-baseline levels. CONCLUSIONS: Cue-dose training with cash reinforcement led to transient improvement in adherence to antiretroviral therapy in a population including mostly African Americans and subjects with histories of drug abuse. However, we were not able to detect any sustained improvement beyond the active training period, and questions concerning the timing and duration of such an intervention require further study. Randomized, controlled clinical studies with objective measures of adherence can be conducted in HIV-infected subjects and should be employed for further evaluation of this and other adherence interventions.

The Protease Inhibitor Lopinavir-Ritonavir May Produce Opiate Withdrawal in Methadone-Maintained Patients

This study examines the pharmacokinetic/pharmacodynamic interactions between (1) lopinavir-ritonavir (L/R), a fixed combination of protease inhibitors used for the treatment of HIV disease, and (2) ritonavir alone at the same dosage as that in the L/R formulation, with methadone, an opiate frequently used in substance abuse pharmacotherapy for opioid (heroin)-dependent injection drug users, many of whom are infected with HIV. L/R was associated with significant reductions in the methadone area under the concentration-time curve (P<.001), maximum concentration (P<.001), and minimum concentration (P<.001), as well as increased methadone oral clearance (P<.001) and increased opiate withdrawal symptoms (P=.013), whereas ritonavir use alone modestly and nonsignificantly increased methadone concentrations. Lopinavir is a potent inducer of methadone metabolism, and treatment with L/R requires clinical monitoring and increased methadone doses in some patients, whereas ritonavir has no significant effect on methadone metabolism.

In vitro antileishmanial properties of tri- and pentavalent antimonial preparations.

To better understand the antileishmanial effects of antimonial agents we synthesized complexes of tri- and pentavalent antimony with mannan. The 50% inhibitory concentrations (IC50s) of these agents, along with those of potassium antimony tartrate [Sb(III)] and sodium stibogluconate [Sb(V)], were determined for promastigotes and intramacrophage amastigotes. The trivalent antimonial agents were more potent than the pentavalent agents. Although the IC50s were 60- to more-than-600-fold higher for promastigotes than for amastigotes, similar intracellular antimony concentrations in both life forms were measured after incubation with all four drugs at their respective IC50s. Macrophages accumulated antimony during a 4-h exposure that was retained intracellularly for at least 3 days. Amastigotes inside macrophages had a higher antimony content 6 days after a single 4-h treatment than they did immediately after treatment, suggesting that macrophages serve as a reservoir for antimonial agents and prolong parasite exposure. Macrophages concentrated antimony from the medium with potassium antimony tartrate, trivalent antimony-mannan, and pentavalent antimony-mannan treatments. N-Acetylcysteine antagonized the antileishmanial effects of these three drugs against intracellular amastigotes; in contrast, it had minimal effects on the action of sodium stibogluconate.

Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262)

Large numbers of injection drug users (IDUs) are infected with HIV and receive both methadone and zidovudine (ZDV) therapy. Pharmacokinetic interactions between these agents may effect drug efficacy, toxicity, and compliance. To confirm and expand previous studies that identified a potential interaction between ZDV and methadone, we performed a within-subject study to determine oral and intravenous ZDV pharmacokinetics in 8 recently detoxified, heroin-addicted patients with HIV disease before and after initiation of methadone treatment. Acute methadone treatment increased oral ZDV in the area under the curve (AUC) by 41% (p = .03) and intravenous ZDV AUC by 19% (p = .06). Clearance was reduced by 21% (p = .007) and 19% (p = .04), respectively. Chronic methadone treatment increased oral ZDV AUC by 29% (p = .15) and intravenous ZDV AUC by 41% (p = .05). Clearance was decreased by 26% for both routes (p = .02). Methadone levels remained in the therapeutic range during ZDV treatment. These effects resulted primarily from inhibition of ZDV glucuronidation, but also from decreased renal clearance of ZDV. This study confirms that methadone-maintained patients receiving standard ZDV doses experience greater ZDV exposure and may be at increased risk for ZDV side effects and toxicity. Increased toxicity surveillance and possibly reduction in ZDV dose are indicated when these two agents are given concomitantly.

Interactions between Buprenorphine and Antiretrovirals. I. The Nonnucleoside Reverse-Transcriptase Inhibitors Efavirenz and Delavirdine

This study examined drug interactions between buprenorphine, an opioid partial agonist medication used in the treatment of opioid dependence, and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs) efavirenz (EFV) and delavirdine (DLV). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per NNRTI) participated in 24-h sessions to determine pharmacokinetics of buprenorphine and of buprenorphine with either EFV or DLV after administration of standard doses of either antiretroviral for 15 or 7 days, respectively. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined before and after antiretroviral administration in opioid-dependent participants. The pharmacokinetics of NNRTIs in healthy control participants were used to determine the effect of buprenorphine on NNRTIs. EFV decreased the buprenorphine area under the concentration-time curve (P<.001). DLV increased buprenorphine concentrations (P<.001). Clinically significant consequences of these interactions were not observed. Buprenorphine did not alter antiretroviral pharmacokinetics. Adjustments of doses of either buprenorphine or EFV or DLV are not likely to be necessary when these drugs are administered for the treatment of opiate dependence and HIV disease.

The effect of fluconazole on the clinical pharmacokinetics of methadone

A randomized, double‐blinded, placebo‐controlled pharmacokinetic and safety trial was conducted to determine the effect of fluconazole on methadone disposition. Volunteers receiving methadone maintenance therapy were randomized to receive either 200 mg/day oral fluconazole (n = 13) or placebo (n = 12). After 14 days there was a 35% average increase in serum methadone area under the curve relative to baseline among patients receiving fluconazole (p = 0.0008). At the same time, mean serum methadone peak and trough concentrations increased by 27% (p = 0.0076) and 48% (p = 0.0023), respectively, and oral clearance of methadone was reduced by 24% (p = 0.0007). In contrast, the pharmacokinetics of methadone were unaltered in the placebo group. Renal clearance of methadone was not significantly affected by fluconazole or placebo therapy. Although exposed to increased concentrations of methadone, patients treated with fluconazole did not exhibit signs or symptoms of significant narcotic overdose.

Interactions between Buprenorphine and Antiretrovirals. II. The Protease Inhibitors Nelfinavir, Lopinavir/Ritonavir, and Ritonavir

We examined drug interactions between buprenorphine, an opioid partial agonist available by prescription for treatment of opioid dependence, and the protease inhibitors (PIs) nelfinavir (NFV), ritonavir (RTV), and lopinavir/ritonavir (LPV/R). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per PI) participated in 24-h pharmacokinetic studies, before and after administration of each PI. Symptoms of opiate withdrawal and excess were determined before and after PI administration. PI pharmacokinetics were determined and compared between opiate-dependent participants and healthy control participants (n=15 per PI). Administration of RTV, but not of NFV or LPV/R, resulted in a significant increase in the buprenorphine area under the concentration-time curve (AUC). Symptoms of opiate excess, however, were not observed. Buprenorphine had no significant effects on PI AUC. Adjustments of doses of either buprenorphine or NFV, LPV/R, or RTV are not likely to be necessary when these drugs are administered for the treatment of opioid dependence and HIV disease.

Interaction of methadone with didanosine and stavudine.

For opiate-dependent injection drug users infected with HIV, methadone therapy may facilitate adherence to complex highly active antiretroviral therapy (HAART) regimens. Current HAART regimens include one or more nucleoside analogues. We investigated the effects of methadone on the pharmacokinetics of the tablet formulation of didanosine (ddI) and of stavudine (d4T) in 17 study subjects on stable methadone therapy and in 10 untreated controls. Methadone treatment reduced the measured areas under the time-concentration curve (AUC0-6) by 63% for ddI (p =.04) and by 25% for d4T (p =.005) and the extrapolated AUCs for the full dosing interval (AUC0-12) by 57% for ddI (p =.11) and by 23% for d4T (p =. 02). Peak drug concentrations (Cmax) were reduced by 66% (p =.007) and 44% (p =.001) for ddI and d4T, respectively. The effects on AUC and Cmax appeared to result primarily from decreases in bioavailability. Methadone also delayed drug absorption. Trough levels for methadone did not differ significantly from those in historical controls, suggesting that ddI and d4T did not substantially alter methadone disposition. The results suggest that larger doses of the tablet formulation or an alternate formulation may be needed when didanosine is given to study subjects treated with methadone.

Drug Interactions between Opioids and Antiretroviral Medications: Interaction between Methadone, LAAM, and Nelfinavir

Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.

The Clinical Pharmacokinetics of Rifampin and Ethambutol in HIV-Infected Persons with Tuberculosis

BACKGROUND The pharmacokinetics of rifampin and ethambutol in HIV-infected patients with tuberculosis (TB) are incompletely characterized. We examined the pharmacokinetics of rifampin and ethambutol in a cohort of patients with HIV-related TB who were treated in the United States. METHODS Serum drug concentrations were determined 2, 6, and 10 h after dosing in 36 HIV-infected patients with TB who were taking rifampin and in 49 who were taking ethambutol. Observed serum concentrations were compared with published normal ranges and published data. RESULTS With daily dosing of rifampin (600 mg), 26 (77%) of 34 patients (95% confidence interval [CI], 59%-89%]) had a low maximum concentration of rifampin (<8 microg/mL), and 12 (35%; 95% CI, 20%-54%) had a very low maximum concentration (<4 microg/mL). With intermittent rifampin dosing (600 mg), 13 (68%) of 19 patients (95% CI, 44%-85%) had a low maximum concentration of rifampin, and 5 (26%; 95% CI, 11%-50%) had a very low maximum concentration. With daily ethambutol dosing (20 mg/kg), 33 (69%) of 48 patients (95% CI, 55%-81%) had a low maximum concentration of ethambutol (<2 microg/mL), and 18 (38%; 95% CI, 24%-53%) had a very low maximum concentration (<1 microg/mL). With intermittent ethambutol dosing (50 mg/kg twice weekly or 30 mg/kg thrice weekly), 13 (72%) of 18 patients (95% CI, 47%-88%) had a low maximum concentration of ethambutol (<4 microg/mL), and 5 (28%; 95% CI, 12%-54%]) had a very low maximum concentration (<2 microg/mL). CONCLUSIONS In HIV-infected patients with TB who are receiving rifampin and ethambutol, low maximum concentrations of rifampin and ethambutol were common. For patients with HIV-related TB, therapeutic monitoring of rifampin and ethambutol levels may help clinicians achieve target serum concentrations.