limportanza delle interazioni farmacologiche nella gestione dellhiv/aids, delle comorbosità e della...
TRANSCRIPT
L’importanza delle interazioni farmacologiche
nella gestione dell’HIV/AIDS, delle comorbosità e della co-
infezione HCV
Stefano Bonora
Università di Torino12 Aprile 2013
Un 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.
Premessa
Premessa
Le 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.
OUTLINE
• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs
OUTLINE
• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs
Considerations 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!
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Drug Interactions will be greater as patients age
Marzolini C et al J Antimicrob Chemother 2011;66:2107
Failure to Recognise Drug Interactions
• HIV drugs amongst the most therapeutically risky- 20-40% patients on ARVs at risk of clinically significant interactions
• PIs > NNRTIs >> MVC/RAL > NRTIs- PIs associated with 5-fold prevalence risk of significant DDIs compared to raltegravir, and 10-fold risk compared to NRTIs
• Physicians 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;36:410-15 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)
Il 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).
Quindi
OUTLINE
• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs
Drug Interaction Data for RPV (Rilpivirina)
Crauwels H, et al. ACTHIV 2011; Denver. Colorado. #TPOI-4
Rilpivirine Drug Interaction:Rationale for Contraindication & Spacing
Parameter
Mean % Change (90% CI)Cmax AUC
Famotidine40 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)
• H2 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 exposures
• PPIs are contraindicated with RPV due to significant 40% reduction in RPV exposure
• Antacids should be given ≥ 2h before or ≥ 4h after RPV
RPV/TVD US Prescribing Information, Gilead Sciences, Inc. July 22, 2011
Do 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 only
Eviplera 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 granted
Tuberculosis
Protease inhibitors
NNRTIs
Entry / Integrase inhibitors
Fonte: http://www.hiv-druginteractions.org/
ANRS 12 180ANRS 12 180 Efficacy Outcomes, W24
Primary endpoint : HIV RNA<50 cp/mL at W20 and W24, mITT (M=F, D/C=F)
EFV
N = 51
RAL 400
N = 51
RAL 800
N = 51
PRIMARY ENDPOINT n % [95% CI] n % [95% CI] n % [95% CI]
Success 32 63 [49-76] 39 76 [65-88] 40 78 [67-90]
Failure 19 37 [24-51] 12 24 [12-35] 11 22 [10-33]
Virologic failure 15 12 4
AE leading to treatment discontinuation 2 0 3
Death 2 0 2
Withdrawal / Lost to Follow-up 0 0 2
Secondary endpoint : HIV RNA<400 cp/mL at W20 and W24, mITT (M=F, D/C=F)
EFV
N = 51
RAL 400
N = 51
RAL 800
N = 51
SECONDARY ENDPOINT n % [95% CI] n % [95% CI] n % [95% CI]
Success 39 76 [65-88] 41 80 [69-91] 42 82 [72-93]
Failure 12 24 [12-35] 10 20 [9-31] 9 18 [7-28]
Virologic failure 8 10 2
AE leading to treatment discontinuation 2 0 3
Death 2 0 2
Withdrawal / Lost to Follow-up 0 0 2
Immunosuppressant agents
CNI: cyclosporine, tacrolimus (CYP3A, Pgp)Antimetabolites: mycophenolate (UGT)Mamalian target-of-rapamycin (mTOR) inhibitors: sirolimus, everolimus (CYP3A, Pgp)
Glucocorticoids Calcineurin inhibitors
(CNI)
Antimetabolites mTOR inhibitors
NRTIs - 0 0 -
NNRTIs [GCs] [CNI] 0 [mTOR]
Protease inhibitors [GCs] [CNI] 0 [mTOR]
Integrase inhibitors - 0 - 0
CCR5-antagonists - - - -
Fusion inhibitors - - - -
Van Maarseveen EM, et al. AIDS Pat Care & STD 2012
Antineoplastic agents
Edmunds-Ogbuokiri et al. HIV Clinician 2009
Drug Metabolism Potential significance
Cyclophosphamide 2B6 active3A4toxic
IDV CPA CL by 1.5 in 40 patients
Ifosfamide 3A4 active2B6, 3A4toxic
Docetaxel 3A4 RTV DOC AUC x50-fold in mice
Paclitaxel 2C8>>3A4 Mild interactions with NVPSevere mucositis/neutropenia with SQV/DLV
Vinca alkaloids 3A4 Neurotoxicity, myelosuppressionSevere neutropenia with vinblastine + LPV/r
DoxorubicinDaunorubicin
AKR No interactions in 40 patients with IDVNo interactions in 19 patients with IDV/NFV/SQV
Etoposide 3A4>>2E1,1A2 Mucositis, myelosuppression, transaminitisHigher incidence of severe mucositis with SQV
Irinotecan CarboxylesterasesUGT, CYP3A4
LPV/r IRI CL by 47% in 7 patients50% dose-reductionPersistent neutropenia in one patient
Recreational drugs
Drug Metabolism Actual/theoretical interaction
Potential significance
Ecstasy (X, MDMA)
2D6>>1A2, 2B6, 3A4
2-3 fold with RTV or EFV
Fatal interactions reported. Hyponatremia, hypertermia, arrhytmias, seizures, rhabdomyolysis
Amphetamines (speed, cristal)
2D6 Possible with RTV Hypertension, hypertermia, arrhytmias, seizures
GHB (liquid ecstasy)
Expired breath as CO2; first-pass
metabolism
Possible with RTV Life-threatening case with SQV/rtvBradycardia, respiratory depression, seizures
LSD (acid, blotters)
Unknown Possible with RTV Hallucinations, psychosis
Ketamine (special K, Kit-Kat)
2B6>2C9, 3A4 Possible with RTV or EFV
Respiratory depression, loss of consciousness, hallucinations
Cocaine hydrolysis, hepatic cholinesterase
>>CYP3A4
Possible norcocaine with NVP or EFV
Hepatotoxicity
PCP(angel dust)
CYP3A4 Possible with RTV Hypertermia, seizures, rhabdomyolysis
Erectile disfunction(Sildenafil….)
CYP3A4 Possible with RTV Hypotension, arrhytmias
Amyl nitrite(poppers)
glutathione-organic nitrates reductase
HepatotoxicityHypotension with erectile disfunction agents
Antoniou et al. Ann Pharmacother 2002
Summary of Telaprevir – ARV interactions
HIV drug Effect on ARV AUC
Effect on TVR AUC
Can be used? Reference
EFV* -7% -18% Yes Van Heeswijk et al. CROI 2011
ETR -6% -16% Yes Kakuda et al.HIV PK 2012
RPV +79% -8% Yes Kakuda et al.HIV PK 2012
ATV/r +17% -20% Yes Van Heeswijk et al. CROI 2011
DRV/r -40% -35% No Van Heeswijk et al. CROI 2011
FPV/r -47% -32% No Van Heeswijk et al. CROI 2011
LPV/r +6% -54% No Van Heeswijk et al. CROI 2011
RAL +31% +7% Yes Van Heeswijk et al. ICAAC 2011
TDF +30% 0% Yes Van Heeswijk et al. ICAAC 2008
*TVR dose 1125mg q8h
HIV drug Effect on ARV AUC
Effect on BOC AUC
Can be used? Reference
TDF +5% +8% Yes Kassera et al. CROI 2011
EFV +20% -19% No Kassera et al. CROI 2011
ETR -23% +10% Yes Hammond et al. JAIDS 2013
ATV/r -35% -5% No Hulskotte et al. CID 2012
LPV/r -34% -34% No Hulskotte et al. CID 2012
DRV/r -44% -32% No Hulskotte et al. CID 2012
RAL +1% +7%* Yes De Kanter et al.CID 2012
* vs. historical controls
Summary of Boceprevir – ARV interactions
?
?
?
?
Epatite C e HIV: cenni
Per 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).
OUTLINE
• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Manegement of DDIs
Nachega JB et al AIDS 2012
Statins and HAART: management of drug-drug interactions
Cardiovascular 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).
Corticosteroids
• Case report of Cushing’s syndrome and adrenal suppression in a patient on ATV/r and dexamethasone 0.1% eye drops1
• Cushing’s syndrome reported with the use of intra articular triamcinolone injections in patients on boosted PIs2–4
• Several cases of Cushing’s syndrome with inhaled fluticasone and ritonavir7
1.Molloy A, et al. AIDS. 2011;25:1337–9. 2. Dort K, et al. AIDS Res Ther. 2009;6:10. 3. Danaher PJ, et al. Orthopedics 2009;32:450. 4.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;45:823–4. 7. Foisy MM, et al. HIV Medicine 2008;9:389–96.
CHECK EVERY KIND OF MEDICATIONCheck every route of administration
Le 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.
http://www.hiv-druginteractions.org è importante per il clinico ma non è RISOLUTIVO.
OUTLINE
• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs• HIV+ vs Healthy volunteers
• Interindividual variability
• Clinical significance
• New mechanisms?
PK differences (versus healthy volunteers)
Drug HIV-infected HIV/HCVco-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
Physiological changes (versus healthy volunteers)
Parameter HIV-infected HCV-infectedHIV/HCV
co-infected
Albumin ↓1,2 ↓*3 ↓†4
α1-acid glycoprotein ↑5 ↑6 ↑
Gastric pH ↑7 ↑8 ↑
Cytochrome P450 ↓ ↓ ↓
Cytokines ↑ ↑ ↑
Parameter HIV-infected HCV-infectedHIV/HCV
co-infected
Albumin ↓1,2 ↓*3 ↓†4
α1-acid glycoprotein ↑5 ↑6 ↑
Gastric pH ↑7 ↑8 ↑
Cytochrome P450 ↓ ↓ ↓
Cytokines ↑ ↑ ↑
* Decreased albumin associated more with cirrhosis and significant liver damage† Significantly lower than HIV or HCV mono-infected patients
1Mehta SH, et al. AIDS Res Human Retrovir 2006;22:14–21; 2Graham SM, et al. AIDS Res Human Retrovir 2007;23:1197–12003Nagao 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
DHHS Guidelines (2002 -2008):
Rifabutin 150 mg (half dose) every other day or three times a week is recommended
10 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 values
values 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 resistance
One of the 10 patients experienced relapse with acquired rifamycin resistance.
One concentration does not fit all patients!!
Co
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Time
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Inh
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IC50 IC50 IC50IC50
Pravastatin and DRV/RTVPatient Pravastatin AUC Ratio (+DRV:-DRV)
1 5.53
2 6.78
3 4.69
4 3.80
5 1.0
6 0.85
7 0.57
8 1.16
9 2.16
10 1.31
11 2.43
12 0.92
13 1.16
14 1.49
Mean, CI Mean, 1.81; 90% CI, 1.23, 2.66
Range 0.57, 6.78Sekar VJ, et al. Pharmacology Workshop. 2007. Abstract 55.
Statistical vs. Clinical Significance
• A statistically significant effect may not be clinically relevant
• A clinically relevant PK interaction would require a dose modification/warning/contra-indication
A consistent 10% decrease in AUC in 10 subjects is statistically significant (p<0.01), but not clinically relevant.
Adapted from D Back
Therapeutic windowD
rug
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Dru
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Narrow therapeutic window
Wide therapeutic window
Adverse eventsAdverse events
Therapeutic failureTherapeutic failure
Adapted from D Back
Ci 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?
Proportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over Time
Non-Completer = Failure Approach
86
82
81
79
75
69
76
67
281 278 279 280 281 281 277 280 281 281 277 279
282 282 282 281 282 282 281 281 282 282 282 279
Raltegravir 400 mg bid.
Efavirenz 600 mg qHS.
0 12 24 48 72 96 120 144 168 192 216 240
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Number of Contributing Patients
71%
61%
Yearly Efficacy Analyses
Study Week
% (n/N) of Patients with vRNA <50 copies/mLChange (cells/mm3) from
BL CD4 Count
RAL (N=281)
EFV (N=282)
RAL – EFV (95% CI)
RAL (N=281)
EFV (N=282)
RAL – EFV (95% CI)
48 86.1 (241/280) 81.9 (230/281) 4.2 (-1.9, 10.3)* 189 163 26 (4, 47)
96 81.1 (228/281) 78.7 (222/282) 2.4 (-4.3, 9.0)* 240 225 15 (-12, 43)
156 75.4 (212/281) 68.8 (194/282) 6.6 (-0.8, 14.0)* 331 295 36 (3, 68)
192 76.2 (214/281) 67.0 (189/282) 9.0 (1.6, 16.4)*° 361 301 60 (24, 95)
240 71.0 (198/279) 61.3 (171/279) 9.5 (1.7, 17.3)*° 374 312 62 (22, 102)
* P-value for non-inferiority <0.001.
° Met criteria for superiority.
Sensitivity Analyses of Virologic Efficacy at Week 240
Different Approaches to Handling Missing Data
Response by Treatment Group
Treatment Effect
Responder/Evaluable† Difference Estimates‡
RALGroup
EFVGroup
Difference(95% CI)
p-Value for Non-inferiority*
Superiority Concluded*
Prespecified as Primary Analysis
Non-Completer=Failure198/279
(71.0)171/279
(61.3)9.5
(1.7, 17.3)<0.001 Yes
Prespecified as Secondary Analyses
Treatment-Related D/C=Failure
198/236 (83.9)
171/239 (71.5)
12.4(4.9, 19.8)
<0.001 Yes
Observed Failure198/222
(89.2)171/212
(80.7)8.6
(1.9, 15.5)<0.001 Yes
† 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:
1. 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.
2. 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).
Subgroup Analyses
Total
Baseline Plasma HIV RNA
50,000 copies/mL
> 50,000 copies/mL
Baseline Plasma HIV RNA
100,000 copies/mL
> 100,000 copies/mL
Screening Plasma HIV RNA
50,000 copies/mL
> 50,000 copies/mL
Baseline CD4 Cell Counts
50 cells/mm3
> 50 and 200 cells/mm3
> 200 cells/mm3
(cells/mm3)
(copies/mL)
(copies/mL)
(copies/mL)
-50 -25 0 25 50
Difference (95% CI)
HIV RNA < 50 Copies/mL (%)
favors EFV favors RAL
-50 -25 0 25
Difference (95% CI)
mk518p21CSRSubgroupsw k240 June 7, 2012
HIV RNA < 400 Copies/mL (%)
favors EFV favors RAL
-100 -50 0 50 100 150
Difference (95% CI)
CD4 Cell Counts
(cells/mm3)
favors EFV favors RAL
Specific Drug-Related Clinical Adverse Experiences Occurring in ≥ 5% of Either Group
RAL Group(N = 281)
EFV Group(N = 282)
n (%) n (%)
Gastrointestinal Disorders
57 (20.3) 81 (28.7)
Diarrhoea
14 ( 5.0) 27 ( 9.6)
Flatulence
10 ( 3.6) 14 ( 5.0)
Nausea
25 ( 8.9) 29 (10.3)
General Disorders 28 (10.0) 47 (16.7) Fatigue
12 ( 4.3) 25 ( 8.9)
Nervous System Disorders
51 (18.1) 140 (49.6)
Dizziness
22 ( 7.8) 99 (35.1)
Headache
26 ( 9.3) 40 (14.2)
Somnolence
3 ( 1.1) 21 ( 7.4)
Psychiatric Disorders
52 (18.5) 87 (30.9)
Abnormal Dreams
19 ( 6.8) 37 (13.1)
Insomnia
21 ( 7.5) 23 ( 8.2)
Nightmare
8 ( 2.8) 15 ( 5.3)
Skin And Subcutaneous Tissue Disorders
16 ( 5.7) 63 (22.3)
Rash
3 ( 1.1) 23 ( 8.2)
Patients 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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