Rilpivirine: A second-generation nonnucleoside. reverse transcriptase inhibitors. clinical review

Transcription

1 clinical review Rilpivirine: A second-generation nonnucleoside reverse transcriptase inhibitor Christopher James, Lee Preininger, and Meryn Sweet More than 20 antiretrovirals are approved by the Food and Drug Administration (FDA) for the treatment of human immunodeficiency virus (HIV) infection. Antiretrovirals comprise five types of drugs, including nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, integrase inhibitors, and entry inhibitors. Highly active antiretroviral therapy (HAART) has decreased morbidity and mortality associated with HIV infection. By suppressing the viral load to undetectable HIV type 1 (HIV-1) RNA levels and increasing CD4+ T- lymphocyte counts in HIV-infected patients, treatment has resulted in decreased opportunistic infections and mortality. 1 HAART consists of at least 3 drugs that suppress HIV replication and includes 2 NRTIs plus an NNRTI, a protease inhibitor, an integrase inhibitor, or an entry inhibitor. Four antiretroviral regimens are currently recommended by the U.S. Department of Health and Human Services (DHHS) for HIV-1-infected patients who have not previously received antiretroviral therapy. 2 Purpose. The pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, dosage and administration, and place in therapy of rilpivirine are reviewed. Summary. Rilpivirine is a human immunodeficiency virus type 1 (HIV-1)-specific nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated for use in combination with other antiretroviral agents in adult patients not previously treated with antiretroviral therapy. Rilpivirine is primarily metabolized by the cytochrome P-450 (CYP)3A isoenzyme system. Therefore, providers should be cautious when administering drugs that are inhibitors or inducers of this pathway. Coadministration with CYP 3A inhibitors may lead to increased concentrations of rilpivirine, thereby increasing the risk of adverse effects. Coadministration with inducers of CYP3A isoenzymes or drugs that increase gastric ph may lead to decreased concentrations of rilpivirine, thus promoting virological failure or resistance to rilpivirine. Two Phase III, randomized, double-blind, double-dummy, active-controlled trials compared rilpivirine As more treatment options have become available, HAART has become more efficacious, more potent, more convenient, and better tolerated. However, virological failure is with efavirenz in HIV-infected adults not previously treated with an antiretroviral. The investigators concluded that rilpivirine, when combined with two nucleoside or nucleotide reverse transcriptase inhibitors, was noninferior to efavirenz for reaching the endpoint of confirmed virological response (HIV-1 RNA level of <50 copies/ml) in adults with HIV infection not previously treated with antiretroviral therapy. The most commonly reported adverse effects included depression, insomnia, headache, and rash. Rilpivirine is administered as a single 25-mg tablet given once daily in combination with other antiretroviral drugs in order to optimize efficacy and reduce resistance. Conclusion. Rilpivirine is a viable NNRTI for HIV-infected patients who have not previously received antiretroviral therapy. Index terms: Antiretroviral agents; Blood levels; Dosage; Drug administration; Drug interactions; HIV infections; Mechanism of action; Metabolism; Pharmacokinetics; Rilpivirine; Toxicity Am J Health-Syst Pharm. 2012; 69: still a concern, necessitating continued research for new antiretroviral treatment options. In May 2011, FDA approved rilpivirine (Edurant, Tibotec Therapeutics, Raritan, NJ), an Christopher James, Pharm.D., is Clinical Pharmacy Specialist; and Lee Preininger, Pharm.D., is Clinical Pharmacy Specialist, HIV Community Program, Christiana Care Health System, Wilmington, DE. Meryn Sweet is a pharmacy student, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA. Address correspondence to Dr. James at the HIV Community Program, Christiana Care Health System, P.O. Box 1668, Wilmington, DE (cjames@christianacare.org). The authors have declared no potential conflicts of interest. Copyright 2012, American Society of Health-System Pharmacists, Inc. All rights reserved /12/ $ DOI /ajhp Am J Health-Syst Pharm Vol 69 May 15,

2 NNRTI, for use in combination with other antiretrovirals for the treatment of HIV-1 infection in adults not previously treated with antiretroviral therapy. 3,4 This article reviews the pharmacology, pharmacokinetics, efficacy, safety, and clinical use of rilpivirine. Chemistry and pharmacology The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2- cyanoethenyl]-2,6-dimethyl phenyl] amino]-2-pyrimidinyl]amino]- benzonitrile monohydrochloride. 4 It has a molecular weight of Da. The genetic material of HIV is positive-sense (5 to 3 ), singlestranded RNA; the virus must transcribe this RNA into double-stranded proviral DNA. 5 HIV transcription is accomplished using reverse transcriptase, which is released with the viral genomic RNA into cytoplasm of the cell after the fusion and uncoating of the viral envelope. 6,7 Rilpivirine is a diarylpyrimidine NNRTI that works through noncompetitive inhibition of HIV-1 reverse transcriptase, thereby stopping replication. It does not inhibit the human cellular DNA polymerases a, b, and g. Rilpivirine demonstrates antiviral activity at a median effective concentration value of 0.73 nm (0.27 ng/ml). 4 Pharmacokinetics Rilpivirine exhibited linear pharmacokinetics after the administration of a single dose and multiple doses, up to a dosage of 150 mg daily in healthy volunteers. 8,9 While the absolute bioavailability is unknown, the maximum rilpivirine plasma concentration is achieved within four to five hours after oral administration. 4 Rilpivirine is most bioavailable when taken with a normal meal, ideally containing 533 kcal. Rilpivirine s absorption decreases by 40% when taken in a fasted state or when taken with a high-fat, high-calorie meal (928 kcal) compared with a normal meal. In addition, rilpivirine absorption decreases by 50% when it is taken with a protein-rich meal or nutritional drink. 4,10 Rilpivirine requires a low gastric ph for adequate absorption. Concomitant administration with acid-suppressive agents can significantly reduce its absorption and oral bioavailability. Caution should be used when administering rilpivirine concomitantly with antacids and histamine H 2 -receptor antagonists. The area under the concentration time curve (AUC) for rilpivirine was reduced by 76% when given 2 hours after famotidine administration, but no effect was found when rilpivirine was administered 12 hours after famotidine administration in healthy volunteers. 4,11 Coadministration with proton pump inhibitors is contraindicated. Rilpivirine s AUC was reduced by 40% when administered with omeprazole 20 mg daily in healthy volunteers. 12 Rilpivirine is more than 99% bound to plasma proteins in a concentration-dependent manner. 13 The exact volume of distribution in humans has not been examined. In vitro studies have indicated that rilpivirine is primarily metabolized by oxidative metabolism through the cytochrome P-450 (CYP) 3A isoenzyme system. 4 Eighty-five percent of an oral dose of rilpivirine is excreted in the feces, with 25% remaining as unchanged drug. Approximately 6% of the dose is excreted in the urine, with only trace amounts remaining unchanged. Rilpivirine s half-life is approximately 50 hours. 4 Dose exposure is higher in patients with mild-to-moderate hepatic impairment (Child-Pugh classes A and B); however, no dosage adjustment is required in this population. 4 Rilpivirine has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment is required for patients with mild-to-moderate renal insufficiency. 4 Caution and increased monitoring are recommended when using rilpivirine in patients with severe renal insufficiency; however, because it is highly bound to plasma proteins, rilpivirine is not likely to be significantly removed by hemodialysis or peritoneal dialysis. The safety and effectiveness of rilpivirine in pediatric patients have not been established. 4 Rilpivirine is a pregnancy category B drug. While data on rilpivirine in pregnant women are lacking, studies of pregnant or lactating rats taking rilpivirine dosages of up to 400 mg/kg daily approximately 40 times higher than the exposure in humans with the approved 25-mg daily dose revealed maternal toxicity but no effect on fertility and no embryonic or fetal toxicity. 4 Clinical efficacy The product labeling for rilpivirine was based on the results of a Phase IIb dose-finding study, as well as two Phase III trials. Phase IIb trial. A Phase IIb trial of rilpivirine was conducted with 368 patients with HIV-1 infection who had not previously been treated with antiretroviral therapy. In this trial, patients were randomized to receive regimens of two NRTIs with rilpivirine 25 mg daily, rilpivirine 75 mg daily, rilpivirine 150 mg daily, or efavirenz 600 mg daily (randomization was done in a 1:1:1:1 fashion). 14 Rilpivirine dosing was blinded, while efavirenz was administered open label as an active control. The primary efficacy endpoint was the proportion of patients with confirmed HIV-1 RNA levels of <50 copies/ml at 48 weeks, analyzed by the time to loss of virological response (TLOVR) algorithm. TLOVR is an intent-to-treat algorithm, so premature treatment discontinuation, regardless of the reason, is considered treatment failure. Virological response was achieved with all rilpivirine dosages, as well as with efavirenz, at 48 weeks (78.9% for rilpivirine versus 80.9% for efavirenz) and was sus- 858 Am J Health-Syst Pharm Vol 69 May 15, 2012

3 tained during the 96-week extension period (73.1% for rilpivirine versus 70.8% for efavirenz). The median CD4+ T-lymphocyte counts also increased for the rilpivirine-treated and efavirenz-treated groups by week 48 ( cells/µl for the rilpivirine groups versus cells/µl for the efavirenz group) and continued to increase through the 96-week extension period ( cells/ µl for the rilpivirine groups versus cells/µl for the efavirenz group). No significant difference was seen among treatment groups with regard to virological response or CD4+ T-cell count. Based on the similar efficacy observed with the three rilpivirine dosages, the 25-mg daily dose was further developed and studied in Phase III trials due to its favorable risk:benefit profile. 14 Phase III clinical trials. Two Phase III, randomized, double-blind, double-dummy, active-controlled trials, ECHO and THRIVE, further compared rilpivirine with efavirenz in HIV-infected adults not previously treated with an antiretroviral. 15,16 Both trials enrolled patients in 21 different countries, including the United States, Canada, South Africa, and countries in Europe, Asia, and Latin America. In the ECHO trial, patients were randomized to receive rilpivirine (n = 346) or efavirenz (n = 344). 15 All patients received a background regimen of tenofovir plus emtricitabine. In the THRIVE trial, patients were randomized to receive either rilpi virine or efavirenz, with 340 patients in each group. 16 The background regimen consisted of two investigator-selected NRTIs: tenofovir plus emtricitabine (60%), zidovudine plus lamivudine (30%), or abacavir plus lamivudine (10%). Both trials were performed in adults with HIV-1 RNA levels of 5000 copies/ml, no NNRTI-resistant mutations at baseline, and sensitivity to NRTIs. 15,16 Demographics and baseline characteristics were balanced between the rilpivirine and efavirenz groups. Randomization was stratified by screening HIV-1 RNA levels. In THRIVE, randomization was further stratified by NRTI background regimen. 16 Pooled results of the trials showed that at week 48, mean CD4+ T- lymphocyte counts had increased in the rilpivirine- and efavirenz-treated groups by 192 and 176 cells/ml, respectively. 4 Both groups also demonstrated comparable virological response rates (HIV-1 RNA levels of <50 copies/ml). As in the Phase IIb trial, the primary endpoint was assessed by the intent-to-treat TLOVR algorithm. Rilpivirine was found to be noninferior, with a virological response rate of 84.3%, compared with 82.3% for efavirenz (p < ). However, patients who received rilpivirine with an HIV-1 RNA level of >100,000 copies/ml had a somewhat reduced response rate when compared with patients with a an HIV-1 RNA level of 100,000 copies/ml (77% versus 90%). Patients in the efavirenz-treated group maintained a similar virological response rate across the HIV-1 RNA viral load strata (81% for HIV-1 RNA levels of >100,000 copies/ml versus 84% for HIV-1 RNA levels of 100,000 copies/ml). Rilpivirine s most common adverse effects were psychological in nature, with rash being the second most common adverse effect. However, the frequency of adverse effects was lower than that seen in the efavirenz-treated group. The adverse effects observed in the rilpivirinetreated group were associated with fewer treatment discontinuations compared with the efavirenz-treated group. 17 The mean serum creatinine concentration of patients receiving rilpivirine increased slightly from baseline (mean change, 0.09 mg/dl; range, 0.20 to 0.62 mg/dl), but no significant change from baseline was observed in the efavirenz-treated group. Despite this increase, the glomerular filtration rate remained in a healthy range for all patients, and no grade 3 or 4 serum creatinine concentration changes were noted. Changes in the lipid profile were noted in both treatment groups, but abnormalities of grade 3 and 4 were less common in patients receiving rilpivirine than in those receiving efavirenz. 17 The investigators of both the ECHO and THRIVE studies concluded that rilpivirine, when combined with two NRTIs, was noninferior to efavirenz for reaching the endpoint of confirmed virological response (HIV-1 RNA level of <50 copies/ml) in adults with HIV infection not previously treated with antiretroviral therapy. 17 The rilpivirinetreated groups had a high virological response rate, a durable increase in CD4+ T-lymphocyte counts, and fewer adverse effects than observed with efavirenz. However, virological failure, particularly in patients with a baseline HIV-1 RNA level of 100,000 copies/ml, was more frequently observed with rilpivirine, which led to more frequent antiretroviral resistance. 17 Resistance and cross-resistance The most common NRTI and NNRTI mutations associated with virological failure in rilpivirine-treated patients were M184I and E138K, respectively. 17 Other frequently observed mutations that cause decreased susceptibility to rilpivirine include L100I, K101E, V106I/A, V108I, E138G/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. 4 Patients who displayed phenotypic resistance were also shown to have cross-resistance to etravirine, efavirenz, and nevirapine, which affects future therapy. Due to similarities in chemical structure, approximately 90% of people who were resistant to rilpi virine were also resistant to etravirine. In addition, NRTI- and Am J Health-Syst Pharm Vol 69 May 15,

4 resistance-associated substitutions were more frequently associated with rilpivirine virological failure than with efavirenz virological failures in the ECHO (70% versus 31%) and THRIVE (64% versus 33%) trials. 15,16 The most common NRTI mutation observed was M184I/V, which is associated with resistance to lamivudine and emtricitabine. This mutation was seen in 26 of 28 patients in the ECHO trial and 12 of 14 patients with NRTI resistance in the THRIVE trial. 15,16 Safety The ECHO and THRIVE trials compared the safety of rilpivirine and efavirenz. Pooled analysis of the two trials revealed that an adverse effect occurred in 90% of patients receiving rilpivirine and 92% of patients receiving efavirenz. 17 Grade 2 4 adverse effects occurred in 16% of rilpivirine-treated patients and 31% of efavirenz-treated patients (p < ). Discontinuation rates due to these adverse effects were 3% and 8% for the rilpivirine- and efavirenz-treated groups, respectively. The most common adverse events reported in ECHO and THRIVE were insomnia, headache, nausea, dizziness, rash, and abnormal dreams or nightmares. 15,16 However, a comparison to efavirenz in a pooled analysis of the clinical trials demonstrated that rash (3% versus 14%, p < ), adverse psychiatric events (15% versus 23%, p = ), and adverse neurologic events (17% versus 38%, p < ) were observed less frequently with rilpivirine. 17 Of the 1368 patients involved in the trials, discontinuation rates due to any adverse event from rilpivirine and efavirenz were 3% and 8%, respectively. When compared to efavirenz, there were no significant differences between the groups in regards to change in the Q-Tc interval. 17 Rilpivirine was associated with fewer grade 3 or 4 lipid abnormalities. 17 Drug interactions Rilpivirine is primarily metabolized by the CYP3A isoenzyme system. Therefore, providers should be cautious when administering drugs that are inhibitors or inducers of this pathway. Coadministration with CYP3A inhibitors may lead to increased concentrations of rilpivirine, thereby increasing the risk of adverse effects. Coadministration with inducers of CYP3A isoenzymes or drugs that increase gastric ph may lead to decreased concentrations of rilpivirine, thus promoting virological failure or resistance to rilpivirine. 4 Rilpivirine is contraindicated in patients taking carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifamycins, proton pump inhibitors, or St. John s wort. 4 Caution is also advised in patients taking rilpivirine concomitantly with antacids, histamine H 2 -receptor antagonists, clarithromycin, erythromycin, azole antifungal agents, and methadone. 4,11,18 A complete listing of drug interactions with rilpivirine is Table 1. Drug Pricing for Nonnucleoside Reverse Transcriptase Inhibitors Drug Regimen Price Per Tablet or Capsule ($) Average Wholesale Price for 1-Mo Supply 19 ($) Place in therapy Rilpivirine is a viable option in the NNRTI antiretroviral drug class for adults with HIV-1 infection not previously treated with an antiretroviral. As with any new medication therapy, the risks and benefits should be considered before its use. Rilpivirine was recently deemed an al- Rilpivirine 25 mg daily Efavirenz 600 mg daily Nevirapine IR a 200 mg twice daily b Etravirine 200 mg twice daily a IR = immediate release. b Initial recommended adult dosage is 200 mg daily for first 14 days of therapy. included in the manufacturer s prescribing information. 4 Economic considerations Compared with the monthly cost of therapy with other NNRTIs, the cost of rilpivirine is generally comparable and not expected to affect prescribing decisions. Comparative drug pricing, as the average wholesale price, for NNRTIs is listed in Table Future directions The labeling for a single fixed-dose combination tablet of rilpivirine with tenofovir and emtricitabine (Complera, Gilead Sciences, Foster City, CA) was recently approved by FDA. 3,20 Recruitment has begun for a trial comparing this combination tablet with efavirenz plus emtricitabine or tenofovir. 1,21 Rilpivirine was briefly studied in patients who were not responding to antiretroviral therapy during a proof-of-principle trial. 22 Rilpivirine was studied in patients with at least one NNRTI mutation, and significant reductions in viral load were observed after seven days of therapy. However, additional studies are needed to investigate the efficacy of rilpivirine in this patient population. In addition, the results of a small study by Crauwels and colleagues 23 indicated that the effect of efavirenz on the induction of rilpivirine metabolism may persist for longer than three weeks after efavirenz has been discontinued. This effect would limit clinicians ability to switch patients from an efavirenz-based regimen to one including rilpivirine. 860 Am J Health-Syst Pharm Vol 69 May 15, 2012

5 ternative NNRTI by the DHHS treatment guidelines, with efavirenz remaining the preferred NNRTI. 1,24 Rilpivirine s recent availability in a combination tablet and less-frequent adverse effects, especially psychological and neurologic adverse effects, make it a welcome alternative to efavirenz. However, providers should be mindful of decreased response rates in patients with baseline HIV- 1 RNA levels of >100,000 copies/ ml. Patients with virological failure were more likely to exhibit crossresistance to etravirine, efavirenz, and nevirapine, which may affect future therapy options. Conclusion Rilpivirine is a viable NNRTI for HIV-infected patients who have not previously received antiretroviral therapy. References 1. Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998; 338: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. January 10, ContentFiles/AdultandAdolescentGL.pdf (accessed 2011 Sep 1). 3. Food and Drug Administration. Drugs@FDA: label and approval history for rilpivirine. index.cfm?fuseaction=search.label_ ApprovalHistory#apphist (accessed 2011 Jun 1). 4. Edurant (rilpivirine) package insert. Raritan, NJ: Tibotec Therapeutics; 2011 May. 5. Fletcher CV, Kakuda TN. Human immunodeficiency virus infection. In: DePiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiological approach. 6th ed. New York: McGraw-Hill; 2005: James CW, Sabundayo BP. Immunology of HIV infection and AIDS. In: Smith BT, ed. Concepts in immunology and immunotherapeutics. 4th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2008: Sabundayo BP, James CW. HIV treatment strategies. In: Smith BT, ed. Concepts in immunology and immunotherapeutics. 4th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2008: Hoetelmans R, van Heeswijk R, Kestens D et al. Effect of food and multiple-dose pharmacokinetics of TMC278 as an oral tablet formulation. Paper presented at Third International AIDS Society Conference of HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil; 2005 Jul. Poster TuPe3.1B Goebel F, Yakovlev A, Pozniak AL et al. Short-term antiviral activity of TMC278 a novel NNRTI in treatment-naive HIV-1 infected subjects. AIDS. 2006; 20: Crauwels HM, van Heeswijk R, Bollen A et al. The effect of different types of food on the bioavailability of TMC278, an investigational NNRTI. Paper presented at the Ninth International Workshop of Pharmacology of HIV Therapy. New Orleans, LA; 2008 Apr. 11. Van Heeswijk R, Hoetelmans R, Kestens D et al. The pharmacokinetic interaction between famotidine and TMC278, a next generation NNRTI, in HIVnegative volunteers. Paper presented at the Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Sydney, Australia; 2007 Jul. 12. Crauwels HM, van Heeswijk RP, Kestens D et al. The pharmacokinetic interaction between omeprazole and TMC278, an investigational NNRTI. Paper presented at the Ninth International Congress on Drug Therapy in HIV Infection (HIV9). Glasgow, United Kingdom; 2008 Nov. 13. Janssen PA, Lewi PJ, Arnold E et al. In search of a novel anti-hiv drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6- dimethylphenyl]amino]-2-pyrimidinyl] amino]benzo-nitrile (R278474, rilpivirine). J Med Chem. 2005; 48: Pozniak AL, Morales-Ramirez J, Katabira E et al. Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS. 2010; 24: Molina JM, Cahn P, Grinsztejn B et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011; 378: Cohen CJ, Andrade-Villanueva J, Clotet B et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011; 378: Cohen C, Molina JM, Cahn P et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomized, phase III trials comparing TMC278 versus efavirenz in treatmentnaïve, HIV-1 infected patients. Paper presented at the XVIII International AIDS Conference. Vienna, Austria; 2010 Jul Van Heeswijk RP, Hoetelmans RM, Kestens D et al. The pharmacokinetic interaction between ketoconazole and TMC278, an investigational NNRTI, in healthy HIV-negative volunteers. Paper presented at the 16th International AIDS Conference. Toronto, Canada; 2006 Aug. 19. McKesson. Online McKesson database. (accessed 2011 Jun 23). 20. Complera (emtricitabine rilpivirine tenofovir disoproxil fumarate) package insert. Foster City, CA: Gilead Sciences; 2011 Aug. 21. Aidsbeacon.com. Phase 3 clinical trial tests Truvada plus rilpivirine combination pill versus Atripla in previously untreated HIV-positive adult. (accessed 2011 Jun 3). 22. Arastéh K, Rieger A, Yeni P et al. Shortterm randomized proof-of-principle trial of TMC278 in patients with HIV type-1 who have previously failed antiretroviral therapy. Antivir Ther. 2009; 14: Crauwels H, Vingerhoets J, Ryan R et al. Pharmacokinetic parameters of oncedaily TMC278 following administration of EFV in healthy volunteers. Paper presented at the 18th Conference on Retroviruses and Opportunistic Infections. Boston, MA; 2011 Feb Panel on Antiretroviral Guidelines for Adults and Adolescents. DHHS adult and adolescent antiretroviral treatment guidelines panel releases supplemental information regarding the role of rilpivirine as initial therapy. August 16, NNRTI_One_Page_Info-RPV.pdf (accessed 2011 Sep 1). Am J Health-Syst Pharm Vol 69 May 15,

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