Presentazione sul tema: "Stefano Bonora Università di Torino 12 Aprile 2013"— Transcript della presentazione:
1Stefano Bonora Università di Torino 12 Aprile 2013 L’importanza delle interazioni farmacologiche nella gestione dell’HIV/AIDS, delle comorbosità e della co-infezione HCVStefano BonoraUniversità di Torino12 Aprile 2013
2PremessaUn farmaco introdotto nell’organismo (per via orale, parenterale, ecc.) può subire varie trasformazioni, in funzione delle sue caratteristiche fisico-chimiche, ed essere eliminato per vie diverse, in varie forme molecolari.Può accadere che un farmaco non venga quasi per nulla modificato e sia eliminato come tale, oppure che subisca numerose trasformazioni verso forme che possono essere ancora farmacologicamente attive (o anche più attive rispetto alla molecola originale) oppure del tutto inerti (non attive) per quanto concerne l’effetto desiderato.
3PremessaLe interazioni possono avere differenti meccanismi (non solo inibizione o induzione del metabolismo).Le interazioni possono alterare la quantità di farmaco disponibile nell’organismo con potenziale impatto su efficacia e tossicità.L’effetto di un farmaco interagente nel tempo è diverso in funzione del meccanismo di interazione.
4OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of informationInterpretation and management of DDIs
5OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of informationInterpretation and management of DDIs
6Considerations in Management of the Older HIV Patient Earlier appearance of co-morbidities supports an earlier ‘older’ age designation in HIV patients, ie 55 vs 65 years!
7Drug Interactions will be greater as patients age 102030405060cardiovascular drugsCNS agentsanti-infectivesanalgesicsgastrointestinal drugsmethadonehormonesantilipidemicsantiplatelets/anticoagulantsACE inhibitorsBeta blockersangiotensin II inhibitorsdiureticsinsulin/antidiabeticscalcium channel inhibitorspatients (%)< 50 years?50 yearsB******10203040501234567>8number of co-medicationspatients (%)< 50 years?50 yearsANumber of co-medicationsPatients (%)>50 years> 50 yearsMarzolini C et al J Antimicrob Chemother 2011;66:2107
8Failure to Recognise Drug Interactions HIV drugs amongst the most therapeutically risky% patients on ARVs at risk of clinically significant interactionsPIs > NNRTIs >> MVC/RAL > NRTIs- PIs associated with 5-fold prevalence risk of significant DDIs compared to raltegravir, and 10-fold risk compared to NRTIsPhysicians recognise only around a third correctly- Pharmacist pre-screening of 200 HIV clinic patients told physicians something they did not know about medication history (20%), adherence (31%) or drug interactions (38%), and changed patient management in 13.6%Patel et al. Ann Pharmacother 2011, Miller et al Pharmacother 2007;27:1379, Evans-Jones et al. CID 2010;50:1419, de Maat et al. Ann Pharmacother 2002;36: Mok et al. Am J Health Sys Pharm 2008;65:55, Seden et al. Int J STD AIDS 2012 (in press) Seden et al (unpublished)
9QuindiIl rischio di interazione è funzione del numero di farmaci assunti dal paziente.Tale rischio è probabilmente sottostimato nella pratica clinica.Alcune classi di farmaci hanno un rischio di interazione significativamente ridotto rispetto ad altre (per es. INI, inibitori dell’integrasi vs. NNRTI o IP).
10OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of informationInterpretation and management of DDIs
11Drug Interaction Data for RPV (Rilpivirina) GILEAD_EP_4x3_TEMPLATE_v01.ppt3/27/2017Drug Interaction Data for RPV (Rilpivirina)Change in RPV exposure (AUC)Change in other drug’s exposure (AUC)TDF1+23%LPV/r2+52% (CYP inhibition)DRV+RTV3+130% (CYP inhibition)MaravirocRaltegravirKetoconazole4,5+ 49% (CYP inhibition)- 24%Acetaminophen6Rifampicin4-80% (CYP induction)Rifabutin7-46% (CYP induction)Ethinylestradiol8 or norethindrone8Atorvastatin9Famotidine10« (if separated by 4 hrs)¯-16%Methadone11, 12«, «Chlorzoxazone4Omeprazole13-40% (pH increase)Sildenafil14Crauwels H, et al. ACTHIV 2011; Denver. Colorado. #TPOI-4Presentation Name1111
12Rilpivirine Drug Interaction: Rationale for Contraindication & Spacing GILEAD_EP_4x3_TEMPLATE_v01.ppt3/27/2017Rilpivirine Drug Interaction: Rationale for Contraindication & SpacingH2 antagonists must be taken 12 hours before or 4 hours after RPV since when taken 2 hours before RPV resulted in 85% reduction in RPV exposuresPPIs are contraindicated with RPV due to significant 40% reduction in RPV exposureAntacids should be given ≥ 2h before or ≥ 4h after RPVParameterMean % Change (90% CI)CmaxAUCFamotidine40 mg single dose taken 2 hours before rilpivirine 85% ( 88 to 81) 76% ( 80 to 72)Omeprazole20 mg once daily 40% ( 52 to 27) 40% ( 52 to 29)RPV/TVD US Prescribing Information, Gilead Sciences, Inc. July 22, 2011Do not copy or distribute Atripla does NOT have an indication for the treatment of naïve patients and there is NO Atripla promotion concerning treatment NAÏVE patients For internal Gilead use onlyEviplera does NOT have an indication for the treatment of experienced patients and there is NO Eviplera promotion concerning treatment experienced patients and until Italian AIC is grantedPresentation Name12
14Efficacy Outcomes, W24 ANRS 12 180 Primary endpoint : HIV RNA<50 cp/mL at W20 and W24, mITT (M=F, D/C=F)EFV N = 51RAL 400N = 51RAL 800PRIMARY ENDPOINTn% [95% CI]%[95% CI]Success3263[49-76]3976[65-88]4078[67-90]Failure1937[24-51]1224[12-35]1122[10-33]Virologic failure154AE leading to treatment discontinuation23DeathWithdrawal / Lost to Follow-upSecondary endpoint : HIV RNA<400 cp/mL at W20 and W24, mITT (M=F, D/C=F)EFVN = 51RAL 400RAL 800SECONDARY ENDPOINTn%[95% CI]Success3976[65-88]4180[69-91]4282[72-93]Failure1224[12-35]1020[9-31]918[7-28]Virologic failure82AE leading to treatment discontinuation3DeathWithdrawal / Lost to Follow-up
15Immunosuppressant agents CNI: cyclosporine, tacrolimus (CYP3A, Pgp)Antimetabolites: mycophenolate (UGT)Mamalian target-of-rapamycin (mTOR) inhibitors: sirolimus, everolimus (CYP3A, Pgp)Van Maarseveen EM, et al. AIDS Pat Care & STD 2012
16Antineoplastic agents Potential significance DrugMetabolismPotential significanceCyclophosphamide2B6 active3A4toxicIDV CPA CL by 1.5 in 40 patientsIfosfamide3A4 active2B6, 3A4toxicDocetaxel3A4RTV DOC AUC x50-fold in micePaclitaxel2C8>>3A4Mild interactions with NVPSevere mucositis/neutropenia with SQV/DLVVinca alkaloidsNeurotoxicity, myelosuppressionSevere neutropenia with vinblastine + LPV/rDoxorubicinDaunorubicinAKRNo interactions in 40 patients with IDVNo interactions in 19 patients with IDV/NFV/SQVEtoposide3A4>>2E1,1A2Mucositis, myelosuppression, transaminitisHigher incidence of severe mucositis with SQVIrinotecanCarboxylesterasesUGT, CYP3A4LPV/r IRI CL by 47% in 7 patients50% dose-reductionPersistent neutropenia in one patientEdmunds-Ogbuokiri et al. HIV Clinician 2009
17Actual/theoretical interaction Potential significance Recreational drugsDrugMetabolismActual/theoretical interactionPotential significanceEcstasy(X, MDMA)2D6>>1A2, 2B6, 3A4 2-3 fold with RTV or EFVFatal interactions reported. Hyponatremia, hypertermia, arrhytmias, seizures, rhabdomyolysisAmphetamines(speed, cristal)2D6Possible with RTVHypertension, hypertermia, arrhytmias, seizuresGHB(liquid ecstasy)Expired breath as CO2; first-pass metabolismLife-threatening case with SQV/rtvBradycardia, respiratory depression, seizuresLSD(acid, blotters)UnknownHallucinations, psychosisKetamine(special K, Kit-Kat)2B6>2C9, 3A4Possible with RTV or EFVRespiratory depression, loss of consciousness, hallucinationsCocainehydrolysis, hepatic cholinesterase >>CYP3A4Possible norcocaine with NVP or EFVHepatotoxicityPCP(angel dust)CYP3A4Hypertermia, seizures, rhabdomyolysisErectile disfunction(Sildenafil….)Hypotension, arrhytmiasAmyl nitrite(poppers)glutathione-organic nitrates reductaseHypotension with erectile disfunction agentsAntoniou et al. Ann Pharmacother 2002
19Summary of Telaprevir – ARV interactions HIV drugEffect on ARV AUCEffect on TVR AUCCan be used?ReferenceEFV*-7%-18%YesVan Heeswijk et al. CROI 2011ETR-6%-16%Kakuda et al.HIV PK 2012RPV+79%-8%ATV/r+17%-20%DRV/r-40%-35%NoFPV/r-47%-32%LPV/r+6%-54%RAL+31%+7%Van Heeswijk et al. ICAAC 2011TDF+30%0%Van Heeswijk et al. ICAAC 2008*TVR dose 1125mg q8h
20Summary of Boceprevir – ARV interactions HIV drugEffect on ARV AUCEffect on BOC AUCCan be used?ReferenceTDF+5%+8%YesKassera et al.CROI 2011EFV+20%-19%NoETR-23%+10%Hammond et al. JAIDS 2013ATV/r-35%-5%Hulskotte et al. CID 2012LPV/r-34%DRV/r-44%-32%RAL+1%+7%*De Kanter et al.CID 2012?* vs. historical controls
21Epatite C e HIV: cenniPer una persona sieropositiva, che deve assumere una terapia per tutta la vita, prendersi cura del proprio fegato è una priorità.Il fegato è il principale organo deputato al metabolismo e alla detossificazione dai farmaci e, quindi, soggetto a danno da parte delle sostanze chimiche e farmacologiche da cui ci depura.Oggi esistono terapie che aumentano in modo sostanziale la possibilità di un successo terapeutico per la cura dell’epatite.Affiancare queste nuove terapie a combinazioni farmacologiche anti-HIV con scarse interazioni aumenta la probabilità dell’esito positivo di questo percorso, come ci dicono gli studi clinici sui farmaci anti-HIV di nuove classi (es.: INI).
22OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of informationManegement of DDIs
24Statins and HAART: management of drug-drug interactions Nachega JB et al AIDS 2012
25Cardiovascular drugs and HAART: scarce data Digoxin serum concentrations were increased by 86% with RTV coadministration due to inhibition of P- glycoprotein (NO DATA IN HIV+)Many antiarrhythmic medications are CYP450 3A4 substrates. The use of amiodarone, bepridil, flecainide, propafenone and quinidine are contraindicated with PI/r due to the potential risk of exacerbating cardiac arrhythmias (NO CLINICAL DATA).
26CHECK EVERY KIND OF MEDICATION Check every route of administration CorticosteroidsCase report of Cushing’s syndrome and adrenal suppression in a patient on ATV/r and dexamethasone 0.1% eye drops1Cushing’s syndrome reported with the use of intra articular triamcinolone injections in patients on boosted PIs2–4Several cases of Cushing’s syndrome with inhaled fluticasone and ritonavir7CHECK EVERY KIND OF MEDICATIONCheck every route of administration1.Molloy A, et al. AIDS. 2011;25:1337–9. 2. Dort K, et al. AIDS Res Ther. 2009;6: Danaher PJ, et al. Orthopedics2009;32: Ramanathan R, et al. Clin Infect Dis. 2008;47:e97–9. 5. Gray D, et al. S Afr Med J. 2010;100:296–7. 6. Frankel JK, & Packer CD. Ann Pharmacother. 2011;45:823– Foisy MM, et al. HIV Medicine 2008;9:389–96.
27Le interazioni farmacologiche esistono e bisogna conviverci. Il numero di possibili interazioni è altissimo, pertanto non è prevedibile avere dati certi di farmacocinetica per tutte le possibili interazioni.è importante per il clinico ma non è RISOLUTIVO.
28OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of informationInterpretation and management of DDIsHIV+ vs Healthy volunteersInterindividual variabilityClinical significanceNew mechanisms?
29PK differences (versus healthy volunteers) DrugHIV-infectedHIV/HCV co-infected*ATV↓ (Reyataz SPC)↑ (Regazzi et al. Ther Drug Monit 2011)ATV/r↓ (Reyataz SPC)↔ (Di Biagio et al. J Infect Chemother 2012)↔ (Regazzi et al. Ther Drug Monit 2011)DRV/r↑ (Prezista SPC)↔† (Sekar et al. Clin Pharmacokinet 2010)↑ RTV † (Sekar et al. Clin Pharmacokinet 2010)↔ (Sekar et al. 11th EACS 2011)↔ cirrhosis vs. historical controls (Curran et al. 13th WCPHT 2012)LPV/r↔ (Kaletra SPC)↔ (Barreiro et al. J Infect Dis 2007)↑ (Peng et al. J Clin Pharmacol 2006)↑ RTV (Peng et al. J Clin Pharmacol 2006)↔ (Canta et al. JAC 2005)↔ but ↑ V/F (Molto et al. Clin Pharmacokinet 2007)↑ RTV, ↓ CL/F V/F (Molto et al. Clin Pharmacokinet 2007)↔ (Seminari et al. JAC 2005)↓ (Dominguez et al. JAC 2010)EFV↓ (Mukonzo et al. Clin Pharmcokinet 2011) (Ugandan study)↓ (Dupont review report 1998)(↔ Caucasian; ↓ Black)↔ (Katsounas et al. Eur J Med Res 2007)↔ (Pereira et al. BJCP 2008)↑ cirrhosis versus no cirrhosis (Barreiro et al. J Infect Dis 2007)↑ (Dominguez et al. JAC 2010)RAL↓ (Arab-Alameddine et al. AAC 2012 )↔ (composite analysis, Merck)↑ cirrhosis versus no cirrhosis (Hemandez-Novoa et al. 19th CROI 2012)↔ Ұ (Iwamoto et al. AAC 2009)*Compared to HIV mono-infected; †Healthy individuals with & without mild/moderate hepatic impairmentҰHealthy individuals with and without moderate hepatic impairment
30Physiological changes (versus healthy volunteers) * Decreased albumin associated more with cirrhosis and significant liver damage† Significantly lower than HIV or HCV mono-infected patients1Mehta SH, et al. AIDS Res Human Retrovir 2006;22:14–21; 2Graham SM, et al. AIDS Res Human Retrovir 2007;23:1197–1200 3Nagao Y & Sata M. Virology Journal 2010;7:375; 4Monga HK, et al. Clin Infect Dis 2001;33:240–7 ; 5Boffito M, et al. Drug Metab Dispos 2002;30:859–60; 6Ozeki T, et al. Br J Exp Path 1988;69:589–95 7Welage LS, et al. Clin Infect Dis 1995;21:1431–38; 8Nam YJ, et al. Korean J Hepatol 2004;10:216–22
31DHHS Guidelines ( ):Rifabutin 150 mg (half dose) every other day or three times a week is recommended
3210 patients with HIV infection and active tuberculosis Lopinavir-ritonavir at, twice daily + rifabutin at 150 mg thrice weekly: 9 of 10 had low rifabutin Cmax valuesvalues for the area under the plasma concentration–time curve of rifabutinwere as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistanceOne of the 10 patients experienced relapse with acquired rifamycin resistance.
33One concentration does not fit all patients!! Time% InhibiitionIC50
34Pravastatin and DRV/RTV PatientPravastatin AUC Ratio (+DRV:-DRV)15.5326.7834.6943.8051.060.8570.5781.1692.16101.31112.43120.9213141.49Mean, CIMean, 1.81; 90% CI, 1.23, 2.66Range0.57, 6.78Sekar VJ, et al. Pharmacology Workshop Abstract 55.
35Statistical vs. Clinical Significance A statistically significant effect may not be clinically relevantA clinically relevant PK interaction would require a dose modification/warning/contra-indicationA consistent 10% decrease in AUC in 10 subjects is statistically significant (p<0.01), but not clinically relevant.Adapted from D Back
36Therapeutic window Narrow therapeutic window Wide therapeutic windowAdverse eventsAdverse eventsDrug concentrationDrug concentrationTherapeutic failureTherapeutic failureAdapted from D Back
37Ci sono scenari clinici dove il valore aggiunto di QD e STR rispetto a schemi più complessi (BID o QD multipill) può essere controbilanciato da altri fattori?Farmaci concomitanti (QD o BID)?Tollerabilità a lungo termine?
38(MK-###) (PN###) "CONFIDENTIAL - LIMITED ACCESS", Interim Deck-Expires when CSR Deck is Available 3/27/2017 2:54 AMProportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over TimeNon-Completer = Failure Approach8682817975697667281278279280277282Raltegravir 400 mg bid.Efavirenz 600 mg qHS.1224487296120144168192216240Weeks20406080100Percent of Patients withHIV RNA Levels <50 Copies/mLNumber of Contributing Patients71%61%White Template MASTER ppt38
39Yearly Efficacy Analyses (MK-###) (PN###) "CONFIDENTIAL - LIMITED ACCESS", Interim Deck-Expires when CSR Deck is Available3/27/2017 2:54 AMYearly Efficacy AnalysesStudy Week% (n/N) of Patients with vRNA <50 copies/mLChange (cells/mm3) from BL CD4 CountRAL (N=281)EFV (N=282)RAL – EFV (95% CI)4886.1 (241/280)81.9 (230/281)4.2 (-1.9, 10.3)*18916326 (4, 47)9681.1 (228/281)78.7 (222/282)2.4 (-4.3, 9.0)*24022515 (-12, 43)15675.4 (212/281)68.8 (194/282)6.6 (-0.8, 14.0)*33129536 (3, 68)19276.2 (214/281)67.0 (189/282)9.0 (1.6, 16.4)*°36130160 (24, 95)71.0 (198/279)61.3 (171/279)9.5 (1.7, 17.3)*°37431262 (22, 102)* P-value for non-inferiority <0.001.° Met criteria for superiority.n/N, number of pts with vRNA <50 c/mL over Number of evaluable pts at each time point. Non-Completer=Failure (NC=F): Pts who discontinued for any reason were considered as failures thereafter.¶ Observed Failure (OF): Pts who discontinued for lack of efficacy were considered as virologic failures thereafter, & BL CD4 values were carried forward. Difference calculated as RAL minus EFV (95% CI). A positive value favors RAL over EFV. The treatment difference & 95% CIs were weighted proportionally by the size of screening HIV RNA stratum (> or ≤50,000 c/mL). Difference calculated as RAL minus EFV (95% CI). A positive value favors RAL over EFV. The 95% CIs were calculated based on a t-distribution.§ RAL would be considered non-inferior to EFV if the lower bound of the 95% CI for the difference in response rates was above -12%, & superior to EFV if the entire 95% CI was >0.* P-value for non-inferiority <0.001.° Met criteria for superiority.White Template MASTER ppt39
40Sensitivity Analyses of Virologic Efficacy at Week 240 (MK-###) (PN###) "CONFIDENTIAL - LIMITED ACCESS", Interim Deck-Expires when CSR Deck is Available3/27/2017 2:54 AMSensitivity Analyses of Virologic Efficacy at Week 240Different Approachesto Handling Missing DataResponse by Treatment GroupTreatment EffectResponder/Evaluable†Difference Estimates‡RALGroupEFVDifference(95% CI)p-Value for Non-inferiority*Superiority Concluded*Prespecified as Primary AnalysisNon-Completer=Failure198/279 (71.0)171/279 (61.3)9.5(1.7, 17.3)<0.001YesPrespecified as Secondary Analyses Treatment-Related D/C=Failure198/236 (83.9)171/239 (71.5)12.4(4.9, 19.8)Observed Failure198/222 (89.2)171/212 (80.7)8.6(1.9, 15.5)† Number of evaluable patients in each treatment group according to the specified approach to handling missing data.‡ The 95% CIs and p-values for treatment differences were calculated using weights proportional to the size of each stratum (screening vRNA level >50,000 copies/mL or≤50,000 copies/mL).* RAL would be considered non-inferior to EFV if the lower bound of the 95% CI for the difference in response rates was above -12%, and superior to EFV if the entire 95% CI was >0.Two post-hoc snapshot analyses with windows of +/- 6 weeks or +/- 12 weeks around the Week-240 visit were performed to test the robustness of the prespecified analyses:The 6-week window resulted in the additional exclusion of 8 patients falling outside of the window (6 came in too early and 2 came in too late) compared to the protocol-specified NC=F analysis which used the nominal visit data and yielded response rates of 66.2% (186/281) in the RAL group and 59.6% (168/282) in the EFV group with a ∆ (95% CI) = 6.6% (-1.4, 14.5). All 8 excluded patients were in the RAL group, with 7 having vRNA levels <50 copies/mL at their nominal Week-240 visit.Since more patients fell outside the 6-week window for the Week-240 visit compared to previous time points, an analysis using a +/- 12 weeks window (extending the window to the prior visit at Week 228) was untaken at Week 240 which yielded response rates of 70.8% (199/281) in the RAL group and 62.8% (177/282) in the EFV group with a ∆ (95% CI) = 8.1% (0.3, 15.8).† Number of evaluable patients in each treatment group according the specified approach to handling missing data.‡ The 95% CIs and p-values for treatment differences were calculated using weights proportional to the size of each stratum (screening vRNA level >50,000 copies/mL or ≤50,000 copies/mL).* RAL would be considered non-inferior to EFV if the lower bound of the 95% CI for the difference in response rates was above -12%, and superior to EFV if the entire 95% CI was >0.Two post-hoc snapshot analyses with windows of +/- 6 weeks or +/- 12 weeks around the Week-240 visit were performed to test the robustness of the prespecified analyses:The 6-week window resulted in the additional exclusion of 8 patients falling outside of the window (6 came in too early and 2 came in too late) compared to the protocol-specified NC=F analysis which used the nominal visit data and yielded response rates of 66.2% (186/281) in the RAL group and 59.6% (168/282) in the EFV group with a ∆ (95% CI) = 6.6% (-1.4, 14.5). All 8 excluded patients were in the RAL group, with 7 having vRNA levels <50 copies/mL at their nominal Week-240 visit.For a long-term time point, the chance of falling outside a given window increases relative to earlier time points. Therefore, as there were a greater number of patients falling outside the 6-week window for the Week-240 visit compared to previous time points, an analysis using a +/- 12 weeks window (extending the window to the prior visit at Week 228) was untaken at Week 240 which yielded response rates of 70.8% (199/281) in the RAL group and 62.8% (177/282) in the EFV group with a ∆ (95% CI) = 8.1% (0.3, 15.8) . White Template MASTER ppt40
41(MK-###) (PN###) "CONFIDENTIAL - LIMITED ACCESS", Interim Deck-Expires when CSR Deck is Available 3/27/2017 2:54 AMSubgroup AnalysesWhite Template MASTER ppt41
42Specific Drug-Related Clinical Adverse Experiences Occurring in ≥ 5% of Either Group RAL Group(N = 281)EFV Group(N = 282)n(%)Gastrointestinal Disorders57(20.3)81(28.7)Diarrhoea14( 5.0)27( 9.6)Flatulence10( 3.6)Nausea25( 8.9)29(10.3)General Disorders28(10.0)47(16.7)Fatigue12( 4.3)Nervous System Disorders51(18.1)140(49.6)Dizziness22( 7.8)99(35.1)Headache26( 9.3)40(14.2)Somnolence3( 1.1)21( 7.4)Psychiatric Disorders52(18.5)87(30.9)Abnormal Dreams19( 6.8)37(13.1)Insomnia( 7.5)23( 8.2)Nightmare8( 2.8)15( 5.3)Skin And Subcutaneous Tissue Disorders16( 5.7)63(22.3)Rash
43Patients who tolerated EFV, with less than 50 copies/ml HIV-RNA, were randomized into two groups: the RAL-first group started with RAL (400 mg twice daily) and EFV placebo, and the EFV- first group with EFV (600 mg once daily) and RAL placebo. After 2 weeks, both groups switched to the alternate regimen.Half of patients previously on a stable EFV preferred to switch to RAL, after double-blind exposure to RAL for 2 weeks. Substitution of EFV by RAL significantly impacted on lipid levels, stress, and anxiety scores.
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