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Director's Report to the National Advisory Council on Drug Abuse - May, 2006

Research Findings - Research on Medical Consequences of Drug Abuse and Infections

Drugs of Abuse and HIV/AIDS

Effect of Long-term Cocaine Use on Regional Left Ventricular Function as Determined by Magnetic Resonance Imaging

Current knowledge about the cardiovascular effects of long-term cocaine use in humans is quite limited. The present study compared the left ventricular (LV) regional mid-wall circumferential strain (Ecc) in long-term cocaine users (the Coc+ group) and controls with no history of cocaine use (the Coc- group). Cardiac tagged magnetic resonance images (MRI) were obtained from 32 study participants in the Coc+ group (average cocaine use: 12.7 8.2 years) and 14 participants in the Coc- group. Regional myocardial Ecc for the standard LV segmentations were obtained through analyzing tagged cardiac images using a harmonic phase MRI processing method. The average systolic or diastolic Ecc measurements of LV segmentations were compared between the Coc- and Coc+ groups with the use of the Student's t test. Compared with their respective counterparts in the Coc- group, the majority of the LV segmentations in the Coc+ group had lower average Ecc measurements: 11 of the 16 ventricular segmentations in the systolic phase, and 15 of the 16 ventricular segmentations in the diastolic phase. Among them, five diastolic average Ecc measurements were significantly lower in the Coc+ group (p < 0.05). The ventricular segmentations with low systolic or diastolic Ecc measurements in the Coc+ group were scattered in LV walls and did not appear to fit into any anatomic pattern. In conclusion, long-term cocaine use may be associated with abnormal cardiac myocardial functions, most prominently in the diastolic phase. The abnormal myocardial segmentations scattering around LV in long-term cocaine users indicate the focal nature of the cocaine-induced myocardial damage. Ren, S., Tong, W., Lai, H., Osman, N.F., Pannu, H. and Lai, S. Am J. Cardiol. 97(7), pp. 1085-1088, April 1, 2006.

Unprotected Sex with Multiple Partners: Implications for HIV Prevention Among Young Men with a History of Incarceration

The objectives of this study were to describe preincarceration risk behaviors of young men and identify correlates of unprotected sex with multiple partners during the 3 months before incarceration. Data on preincarceration risk behaviors were obtained from 550 men, aged 18 to 29 years, in state prisons in California, Mississippi, Rhode Island, and Wisconsin. Correlates of unprotected sex with multiple partners were determined by logistic regression. Of 550 participants, 71% had multiple sex partners, 65.1% had sex with a partner they perceived as risky, and 45.3% engaged in unprotected sex with multiple partners. Men who drank heavily (odds ratio [OR], 1.68; 95% confidence interval [CI], 1.11-2.54) or who had a risky partner (OR, 3.90; 95% CI, 2.60-5.85) were more likely to report unprotected sex with multiple partners. Men who attended religious gatherings (OR, 0.66; 95% CI, 0.46-0.96) or lived in stable housing (OR, 0.69; 95% CI, 0.48-1.00) were less likely to report unprotected sex with multiple partners. Most participants engaged in behaviors that could result in a sexually transmitted disease, including HIV. Prevention programs should address the relationship between heavy alcohol use and risky sexual behavior. Discharge planning should address housing needs. Faith-based community organizations may play an important role for some young men in their transition to the community. Margolis, A.D., MacGowan, R.J., Grinstead, O., Sosman, J., Kashif, I. and Flanigan, T.P. Project START Study Group. Sex Transm Dis. 33(3), pp. 175-180, March 2006.

Commercial Sex Work and Risk of HIV Infection Among Young Drug-Injecting Men Who Have Sex With Men in San Francisco

The objective of this study was to investigate the relationship between sex work and HIV infection among young injection drug-using men who have sex with men (MSM-IDU). This study was a cross-sectional analysis of behavioral and serologic data collected from 227 street-recruited MSM-IDU in San Francisco, California, between January 2000 and November 2001. Sixty-eight percent of participants reported being paid by another man for sex. HIV prevalence was 12% (95% confidence interval, 8-16%); 42% of seropositive participants were unaware of their infection. HIV was independently associated with higher number of paying male partners and history of gonorrhea and inversely associated with number of female partners, education, and syringe-sharing. Consistent condom use overall was 41%, but varied significantly by type of partner. Among MSM-IDU in San Francisco, sex work with men is strongly associated with HIV infection and the prevalence of condom use is low. HIV prevention among MSM-IDU must be tailored to address the excess risk associated with sex work. Bacon, O., Lum, P., Hahn, J., Evans, J., Davidson, P., Moss, A. and Page-Shafer, K. Sex Transm Dis. 33(4), pp. 228-234, April 2006.

HIV-related Wasting in HIV-infected Drug Users in the Era of Highly Active Antiretroviral Therapy

A decrease in the rate of human immunodeficiency virus (HIV) infection-related wasting has been reported in the era of highly active antiretroviral therapy (HAART). Authors investigated this concern in a hard-to-reach population of HIV-infected drug users in Miami, Florida. After informed consent was obtained, 119 HIV-infected drug users were administered questionnaires involving demographic, medical history, and food-security information. Blood samples were drawn for immunological and viral studies. HIV-related wasting over a period of >6 months was defined as a body mass index of <18.5 kg/m2, unintentional weight loss of >10% over 6 months, or a weight of <90% of the ideal body weight. The prevalence of HIV-related wasting was 17.6%. A significantly higher proportion of those who experienced wasting (81%) reported that there were periods during the previous month when they went for > or =1 day without eating (i.e., food insecurity), compared with those who did not experience wasting (57%). Although a greater percentage of patients who experienced wasting were receiving HAART, their HIV RNA levels were more than twice as high (mean+/-standard deviation [SD], 166,689+/-238,002 copies/mL; median log HIV RNA level +/- SD, 10.2+/-2.7 log10 copies/mL) as those for the group that did not experience wasting (mean+/-SD, 72,156 +/- 149,080; median log HIV RNA level+/-SD, 9.2+/-2.3 log10 copies/mL). Participants who experienced wasting were more likely to be heavy alcohol drinkers and users of cocaine. In multivariate analysis that included age, sex, food security, alcohol use, cocaine use, viral load, and receipt of antiretroviral therapy, the only significant predictors of wasting were >1 day without eating during the previous month (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.18-3.26; P=.01) and viral load (OR, 1.64; 95% CI, 1.00-2.69; P=.05). HIV-related wasting continues to be common among HIV-infected drug users, even among HAART recipients. Food insecurity and viral load were the only independent predictors of wasting. The social and economic conditions affecting the lifestyle of HIV-infected drug users constitute a challenge for prevention and treatment of wasting. Campa, A., Yang, Z., Lai, S., Xue, L., Phillips, J.C., Sales, S., Page, J.B. and Baum, M.K. Clin Infect Dis. 41(8), pp. 1179-1185, October 2005.

Drugs of Abuse and the Endocrine System

Cortisol Levels and Depression in Men and Women Using Heroin and Cocaine

Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are well documented in men using illicit drugs and/or infected with HIV; however, less is known about HPA function, or the health consequence of HPA dysfunction, in their female counterparts. People with depression exhibit hypercortisolemia, and depression is common in people with HIV or substance use problems. The current study investigated cortisol secretion in 209 demographically matched men and women, stratified by their HIV and drug use status. Self-reported depressive symptoms were evaluated using a standardized, validated questionnaire (CES-D). Women reported more depressive symptoms than men (p=.01). Male and female drug users exhibited higher cortisol concentrations (p=.03), and were more likely to report depressive symptoms (p=.04), than non-users. Depression was related to elevated cortisol concentrations for the study population (p=.03), and women with elevated cortisol concentrations were significantly more depressed than all other participants (p=.05). While it is unknown whether high cortisol concentrations precede depressive symptoms or vice versa, these data indicate that higher cortisol concentrations are associated with depressive symptoms in heroin and cocaine users, and that this association is more pronounced in women than men. HIV status did not act in an additive or synergistic way with drug use for either cortisol or CES-D measures in the current study. Unique therapies to treat the endocrine and mental health consequences of illicit drug use in men and women deserve consideration as depressive symptoms, and high cortisol concentrations associated with depressive symptoms, differ by gender. Wisniewski, A.B., Brown, T.T., John, M., Cofranceso, J.Jr., Golub, E.T., Ricketts, E.P., Wand, G. and Dobs, A.S. Psychoneuroendocrinology. 31(2), pp. 250-255, February 2006.

RNAi-directed Inhibition of DC-SIGN by Dendritic Cells: Prospects for HIV-1 Therapy

Drug-resistant human immunodeficiency virus (HIV) infections are increasing globally, especially in North America. Therefore, it is logical to develop new therapies directed against HIV binding molecules on susceptible host cells in addition to current treatment modalities against virus functions. Inhibition of the viral genome can be achieved by degrading or silencing posttranslational genes using small interfering (si) ribonucleic acids (RNAs) consisting of double-stranded forms of RNA. These siRNAs usually contain 21-23 base pairs (bp) and are highly specific for the nucleotide sequence of the target messenger RNA (mRNA). These siRNAs form a complex with helicase and nuclease enzymes known as "RNA-induced silencing complex"; (RISC) that leads to target RNA degradation. Thus, siRNA has become a method of selective destruction of HIV now used by various investigators around the globe. However, given the sequence diversity of the HIV genomes of infected subjects, it is difficult to target a specific HIV sequence. Therefore, targeting nonvariable HIV binding receptors on susceptible cells or other molecules of host cells that are directly or indirectly involved in HIV infections may be an interesting alternative to targeting the virus itself. Thus, the simultaneous use of siRNAs specific for HIV and host cells may be a unique, new approach to the therapy of HIV infections. In this article, authors present evidence that siRNA directed at the CD4 independent attachment receptor (DC-SIGN) significantly inhibits HIV infection of dendritic cells (DCs). This effect may be mediated by modulation of p38 mitogen activated protein kinase (MAPK). Nair, M.P., Reynolds, J.L., Mahajan, S.D., Schwartz, S.A., Aalinkeel, R., Bindukumar, B. and Sykes, D. AAPS J. 7(3)pp. E572-E578, October 19, 2005.

Drugs of Abuse and Hepatitis C Infection

Treatment Algorithm for the Management of Hepatitis C in HIV-coinfected Persons

In the era of highly effective antiretroviral therapy (ART), HCV-related liver disease has emerged as a significant cause of morbidity and mortality. Accordingly, expert panels have recommended that coinfected patients undergo medical evaluation for HCV-related liver disease, consideration for HCV treatment and, if indicated, orthotopic liver transplantation. While the treatment of such patients is complicated by medical, and psychiatric comorbidities, HIV disease, and concurrent antiretroviral therapy, randomized controlled trials support the safety, tolerability and efficacy of HCV treatment with peginterferon alfa (PEG-IFN) plus ribavirin (RBV) in HIV-infected persons. Although, the available data has led to consensus among experts regarding the need to medically manage HCV disease in HIV-infected persons, uncertainty remains regarding the best treatment algorithm for coinfected patients. Sulkowski, M.S. J Hepatol. 44(1 Suppl), pp. S49-55, 2006.

Progression of Liver Fibrosis Among Injection Drug Users with Chronic Hepatitis C

Although most hepatitis C virus (HCV) infections are acquired by injection drug use, prospective data on the progression of liver fibrosis are sparse. Baseline liver biopsies were obtained (1996-1998) on a random sample of 210 out of 1667 HCV-positive injection drug users (IDUs). Subjects were followed biannually, with a second biopsy offered to those eligible. Paired biopsies were scored 0 to 6 (modified Ishak score), significant fibrosis was defined as score 3 or greater, and progression of fibrosis was defined as an increase 2 or more units or clinical evidence of end-stage liver disease. Predictive values of blood markers [FibroSURE, aspartate aminotransferase-to-platelet-ratio index (APRI) and alanine aminotransferase (ALT)] were assessed for detection of contemporaneous and future liver fibrosis. Among 119 prospectively followed IDUs, 96% were African American; 97% HCV genotype 1a/b; 27% HIV-infected, and median age was 42 years. Most (90.7%) did not have significant liver fibrosis at first biopsy. Although predictive value for detecting insignificant fibrosis at first biopsy was greater than 95% for FibroSURE, APRI, and ALT, specificities were 88.9%, 72.7%, and 72.7%, respectively. After 4.2 years median follow-up, 21% had progression of fibrosis, which was significantly associated with serum level of HCV RNA and ALT. No serological test had predictive value greater than 40% for contemporaneous or future significant fibrosis. Even initial biopsy result had only a 30.4% value for predicting future significant fibrosis. In conclusion, significant liver fibrosis and progression were detected in some, but not most, IDUs in this cohort. In this setting with low fibrosis prevalence, FibroSURE, ALT, and APRI tests predict insignificant fibrosis; however, further work is needed to find noninvasive markers of significant liver fibrosis. Wilson, L.E., Torbenson, M., Astemborski, J., Faruki, H., Spoler, C., Rai, R., Mehta, S., Kirk, G.D., Nelson, K., Afdhal, N. and Thomas, D.L. Hepatology. 43(4), pp. 788-795, April 2006.

Drug-Drug Interactions

Effect of Buprenorphine and Antiretroviral Agents on the QT Interval in Opioid-Dependent Patients

Cardiac arrhythmias have been linked to treatment with methadone and levacetylmethadol. HIV-positive patients often have conditions that place them at risk for QT interval prolongation including HIV-associated dilated cardiomyopathy, coronary artery disease as a consequence of highly active antiretroviral (ARV) therapy-associated metabolic syndrome, and uncorrected electrolyte abnormalities. As of February 14, 2006, no cases of adverse events related to QT interval prolongation have been reported in patients receiving buprenorphine, an opioid partial agonist and the newest drug approved for the treatment of opioid dependence. The objective of this study was to evaluate the effects of buprenorphine/naloxone alone and in combination with 1 of 5 ARV agents (efavirenz, nelfinavir, delavirdine, ritonavir, lopinavir/ritonavir) on the QT interval. This study was prospective, open-label, and within-subject in design, with subjects serving as their own controls. In 50 HIV-negative, opioid-dependent subjects, electrocardiogram recordings were obtained at baseline, after receiving buprenorphine/naloxone for 2 weeks, and then following buprenorphine/naloxone plus ARV administration for 5-15 days at steady-state. QTc interval measurements were compared using mixed-model, repeated-measures ANOVA. Recent cocaine use and gender were considered covariates. Buprenorphine/naloxone alone and often in the presence of evidence for recent use of cocaine did not significantly alter the QT interval (p = 0.612). Buprenorphine/naloxone in combination with ARVs caused a statistically, but not clinically, significant increase (p = 0.005) in the QT interval. Subjects receiving buprenorphine/naloxone in combination with either delavirdine or ritonavir had the greatest increase in QTc intervals. Prolonged QT intervals were not observed in opioid-dependent subjects receiving buprenorphine/naloxone alone. QT interval increases were observed with buprenorphine/naloxone in combination with either delavirdine or ritonavir, which inhibit CYP3A4. Baker, J.R., Best, A.M., Pade, P.A. and McCance-Katz, E.F. Ann Pharmacother. 40(3), pp. 392-396, April 2006.

Drug Interactions Between Opioids and Antiretroviral Medications: Interaction Between Methadone, LAAM, and Delavirdine

Understanding the drug interactions between antiretrovirals and opioid therapies may decrease toxicities and enhance adherence with improved HIV outcomes in opioid-dependent individuals. The authors report the results of a clinical pharmacology study designed to determine whether significant pharmacokinetic and/or pharmacodynamic interactions occur between the non-nucleoside reverse transcriptase inhibitor, delavirdine (DLV), and either methadone or levo-alpha acetyl methadol (LAAM) (n = 40). DLV significantly decreased methadone clearance (p = .018) and increased the methadone elimination half-life (p<.001) with a resultant increase in AUC of 19% and C(min)of 29%. The combined effect of DLV on the total concentration of LAAM and its active metabolites, norLAAM and dinorLAAM, was to significantly increase AUC by 43% (p<.001), C(max) by 30% (p = .013), and C(min) by 59% (p = .004) while decreasing T(max) (p = .05). Cognitive deficits over the seven-day study period as measured by the Mini-Mental State Examination, opioid withdrawal symptoms as measured by the Objective Opioid Withdrawal Scale, or complaints of adverse symptoms were not observed. Methadone and LAAM did not affect DLV concentrations. The findings from this study show that DLV treatment in methadone- or LAAM-maintained individuals results in altered opioid pharmacokinetics with an increased exposure and potential risk for opioid toxicity with methadone or LAAM treatment and an increased risk of cardiac toxicity with concomitant LAAM and DLV administration. McCance-Katz, E.F., Rainey, P.M., Smith, P., Morse, G.D., Friedland, G., Boyarsky, B., Gourevitch, M. and Jatlow, P. Am J Addict. 5(1), pp. 23-34, Jan-Feb 2006.

Novel Metabolites of Buprenorphine Detected in Human Liver Microsomes and Human Urine

The in vitro metabolism of buprenorphine was investigated to explore new metabolic pathways and identify the cytochromes P450 (P450s) responsible for the formation of these metabolites. The resulting metabolites were identified by liquid chromatography-electrospray ionization-tandem mass spectrometry. In addition to norbuprenorphine, two hydroxylated buprenorphine (M1 and M2) and three hydroxylated norbuprenorphine (M3, M4, and M5) metabolites were produced by human liver microsomes (HLMs), with hydroxylation ccurring at the tert-butyl group (M1 and M3) and at unspecified site(s) on the ring moieties (M2, M4, and M5). Time course and other data suggest that buprenorphine is N-dealkylated to form norbuprenorphine, followed by hydroxylation to form M3; buprenorphine is hydroxylated to form M1 and M2, followed by N-dealkylation to form M3 and M4 or M5. The involvement of selected P450s was investigated using cDNA-expressed P450s coupled with scaling models, chemical inhibition, monoclonal antibody (MAb) analysis, and correlation studies. The major enzymes involved in buprenorphine elimination and norbuprenorphine and M1 formation were P450s 3A4, 3A5, 3A7, and 2C8, whereas 3A4, 3A5, and 3A7 produced M3 and M5. Based on Mab analysis and chemical inhibition, the contribution of 2C8 was higher in HLMs with higher 2C8 activity, whereas 3A4/5 played a more important role in HLMs with higher 3A4/5 activity. Examination of human urine from subjects taking buprenorphine showed the presence of M1 and M3; most of M1 was conjugated, whereas 60 to 70% of M3 was unconjugated. Chang, Y., Moody, D.E. and McCance-Katz, E.F. Drug Metab Dispos. 34(3), pp. 440-448, March 2006.

Medical Illness and Comorbidities in Drug Users: Implications for Addiction Pharmacotherapy Treatment

Providing effective medical care to those with substance use disorders can be a challenge to clinicians. In this article, the authors briefly summarize issues that occur frequently in the medical treatment of substance users. The focus of this article is twofold. The first is to briefly summarize common co-occurring medical illnesses in those manifesting substance use disorders with an emphasis on issues related to providing effective treatment for these diseases in this population. Using specific examples of frequently occurring comorbid medical illness in substance users, including infectious diseases (hepatitis C and HIV disease), sexually transmitted diseases, and pregnancy as examples, the complexities of medical care for this population is demonstrated. Second, this article addresses some of the difficulties encountered in pharmacotherapy aimed specifically at treatment of substance use disorders. For example, difficulties in managing concomitant opiate therapy in those requiring medications for medical illness that may have strong and adverse interactions with opiates are addressed. Adverse events reported for some substance use disorder pharmacotherapies are also highlighted. The authors conclude with a brief review of models of care that have been effective in addressing the needs of this challenging population that can provide additional means for enhancing the clinical care of substance users. Draper, J.C. and McCance-Katz, E.F. Subst Use Misuse. 40(13), pp. 1899-1921, 2005.

Treatment of Opioid Dependence and Coinfection with HIV and Hepatitis C Virus in Opioid-dependent Patients

The occurrence of human immunodeficiency virus (HIV) disease and hepatitis C is common in injection drug users, most of whom are opioid dependent. Methadone pharmacotherapy has been the most widely used treatment for opioid addiction in this population. Methadone has significant, adverse drug-drug interactions with many antiretroviral therapeutic agents that can contribute to nonadherence and poor clinical outcomes in this high-risk population. The present article summarizes current knowledge about interactions between methadone and antiretroviral medications. Buprenorphine is the newest agent available for the treatment of opioid dependence and may have fewer adverse interactions with antiretroviral agents. Buprenorphine has a significant pharmacokinetic interaction with efavirenz but no pharmacodynamic interaction; therefore, simultaneous administration of these drugs is not associated with opioid withdrawal, as has been observed with methadone. This promising finding may simplify the treatment of opioid-dependent patients with HIV disease and should also improve clinical outcomes for persons coinfected with HIV and hepatitis C virus. McCance-Katz, E.F. Clin Infect Dis. 41 Suppl 1, pp. S89-95, July 1, 2005.

Efficacy of Dose and Contingency Management Procedures in LAAM-maintained Cocaine-dependent Patients

Opioid- and cocaine-dependent participants (N=140) were randomly assigned to one of the following in a 12-week clinical trial: LAAM (30, 30, 39 mg/MWF) with contingency management (CM) procedures (LC); LAAM (30, 30, 39 mg/MWF) without CM (LY); LAAM (100, 100, 130 mg/MWF) with CM (HC); LAAM (100, 100, 130 mg/MWF) without CM (HY). Urine samples were collected thrice-weekly. In CM, each urine negative for both opioids and cocaine resulted in a voucher worth a certain monetary value that increased for consecutively drug-free urines. Subjects not assigned to CM received vouchers according to a yoked schedule. Vouchers were exchanged for mutually agreed upon goods and services. Groups generally did not differ on retention and baseline characteristics. Overall opioid use was least in the HC and HY groups; opioid use decreased most rapidly over time in the HC group relative to the HY, LC and LY groups. Overall cocaine use was least in the HC group relative to the HY, LC, and LY groups; cocaine use decreased over time most rapidly in the HC and LY groups. Abstinence from both was greatest in the HC group. Opioid withdrawal symptoms decreased most rapidly in the high-dose groups relative to the low-dose groups. These results suggest that an efficacious maintenance dose is necessary for contingencies to be effective in facilitating both opioid and cocaine abstinence. Oliveto, A., Poling, J., Sevarino, K.A., Gonsai, K.R., McCance-Katz, E.F., Stine, S.M. and Kosten, T.R. Drug Alc Depend. 79(2), pp. 157-165, August 1, 2005.

Effect of Extended Exposure to Grapefruit Juice on Cytochrome P450 3A Activity in Humans: Comparison with Ritonavir

Acute ingestion of usual quantities of grapefruit juice produces inhibition of enteric cytochrome P450 (CYP) 3A enzymes, causing pharmacokinetic interactions with a number of drugs. However, the effect of extended exposure to grapefruit juice on CYP3A activity is not established. Triazolam, a CYP3A index compound, was administered to 3 cohorts of volunteers (n = 6-7 per group) on 4 occasions (trials 1-4), as follows: 1 day prior to cotreatment initiation, at the beginning and end of cotreatment, and 3 days after cotreatment discontinuation. The 3 cotreatments (daily administration for 10 consecutive days) were: 300 mL grapefruit juice, 400 mg ritonavir, or 300 mL water. Grapefruit juice cotreatment (trial 2) increased the triazolam area under the plasma concentration curve by 50% compared to the trial 1 control (15.1 +/- 7.6 ng/mL.h versus 10.0 +/- 3.5 ng/mL.h, p<.05), but the half-life was not changed. Effects of acute and extended exposure to grapefruit juice (trials 2 and 3) were similar, and produced augmentation in benzodiazepines agonist effects measured by the Digit Symbol Substitution Test and electroencephalographic beta amplitude. Kinetic and dynamic effects reverted to baseline (trial 1) values at 3 days after grapefruit juice discontinuation (trial 4). Ritonavir caused a more than 20-fold increase in the triazolam area under the plasma concentration curve during trial 2 (553 +/- 422 ng/mL.h) and trial 3 (287 +/- 299 ng/mL.h) compared to the trial 1 control (13.3 +/- 16.3 ng/mL.h) (p<.05 for both comparisons); Digit Symbol Substitution Test and electroencephalographic pharmacodynamics increased in parallel. During trial 4, triazolam kinetics reverted close to trial 1 values, with no evidence of induction. Triazolam kinetics were not altered by water cotreatment. Acute and extended exposure to grapefruit juice produces quantitatively similar inhibition of enteric, but not hepatic, CYP3A. Recovery is complete within 3 days after grapefruit juice discontinuation. Ritonavir greatly inhibits both enteric and hepatic CYP3A. With extended exposure to ritonavir, inhibition is the predominant effect, and recovery to baseline is nearly complete 3 days after ritonavir dis-continuation. Culm-Merdek, K.E., von Moltke, L.L., Gan, L., Horan, K.A., et al., Clin Pharmacol Ther. 79(3), pp. 243-254, March 2006.


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