95% CI - Nadir Onlus

L’importanza delle interazioni
farmacologiche nella gestione
dell’HIV/AIDS, delle comorbosità e
della co-infezione HCV
Stefano Bonora
Università di Torino
12 Aprile 2013
Premessa
 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
 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 comorbidities supports an earlier
‘older’ age designation in HIV
patients, ie 55 vs 65 years!
Drug Interactions will be greater as
patients age
A
<<5050
years
years
50
B
< 50 years
< 50
years
?50 years
> 50 years
60
?50 years
>50 years
***
50
patients (%)
(%)
patients
patients (%)(%)
Patients
40
30
20
40
***
30
***
20
***
10
10
**
*** ***
**
*
0
0
1
2
3
4
5
6
7
>8
***
***
***
0
numberof
of co-medications
Number
co-medications
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)
Quindi
 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).
OUTLINE
• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs
Drug 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)
«
Maraviroc
«
«
Raltegravir
«
«
Ketoconazole4,5
+ 49% (CYP inhibition)
- 24%
Acetaminophen6
«
«
Rifampicin4
-80% (CYP induction)
«
Rifabutin7
-46% (CYP induction)
«
Ethinylestradiol8 or norethindrone8
«
«
Atorvastatin9
«
«
Famotidine10
« (if separated by 4 hrs)
¯-16%
Methadone11, 12
«
«, «
Chlorzoxazone4
«
«
-40% (pH increase)
«
Omeprazole13
Sildenafil14
Crauwels H, et al. ACTHIV 2011; Denver. Colorado. #TPOI-4
«
Rilpivirine Drug Interaction:
Rationale for Contraindication & Spacing
• 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
Parameter
Mean % Change (90% CI)
Famotidine
40 mg single dose taken 2 hours
before rilpivirine
Omeprazole
20 mg once daily
Cmax
AUC
 85%
( 88 to  81)
 76%
( 80 to  72)
 40%
( 52 to  27)
 40%
( 52 to  29)
RPV/TVD US Prescribing Information, Gilead Sciences, Inc. July 22, 2011
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
Do not copy or distribute
Tuberculosis
Protease inhibitors
NNRTIs
Entry / Integrase inhibitors
Fonte: http://www.hiv-druginteractions.org/
ANRS 12 180
Efficacy Outcomes, W24
Primary endpoint : HIV RNA<50 cp/mL at W20 and W24, mITT (M=F, D/C=F)
PRIMARY ENDPOINT
n
EFV
RAL 400
RAL 800
N = 51
N = 51
N = 51
% [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)
SECONDARY ENDPOINT
Success
Failure
Virologic failure
AE leading to treatment discontinuation
Death
Withdrawal / Lost to Follow-up
EFV
RAL 400
RAL 800
N = 51
N = 51
N = 51
n
%
[95% CI]
n
%
[95% CI]
n
%
[95% CI]
39
12
8
2
2
0
76
24
[65-88]
[12-35]
41
10
10
0
0
0
80
20
[69-91]
[9-31]
42
9
2
3
2
2
82
18
[72-93]
[7-28]
Immunosuppressant agents
Glucocorticoids
Calcineurin
inhibitors
(CNI)
Antimetabolites
mTOR
inhibitors
-
0
0
-
NNRTIs
[GCs] 
[CNI]
0
[mTOR]
Protease inhibitors
[GCs] 
[CNI] 
0
[mTOR] 
Integrase inhibitors
-
0
-
0
CCR5-antagonists
-
-
-
-
Fusion inhibitors
-
-
-
-
NRTIs
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
Antineoplastic agents
Drug
Metabolism
Cyclophosphamide
2B6  active
3A4toxic
Ifosfamide
3A4 active
2B6, 3A4toxic
Docetaxel
3A4
Paclitaxel
2C8>>3A4
Potential significance
IDV  CPA CL by 1.5 in 40 patients
RTV  DOC AUC x50-fold in mice
Mild interactions with NVP
Severe mucositis/neutropenia with SQV/DLV
Vinca alkaloids
3A4
Neurotoxicity, myelosuppression
Severe neutropenia with vinblastine + LPV/r
Doxorubicin
Daunorubicin
AKR
No interactions in 40 patients with IDV
No interactions in 19 patients with IDV/NFV/SQV
Etoposide
3A4>>2E1,1A2
Irinotecan
Carboxylesterases
UGT, CYP3A4
Mucositis, myelosuppression, transaminitis
Higher incidence of severe mucositis with SQV
LPV/r  IRI CL by 47% in 7 patients
50% dose-reduction
Persistent neutropenia in one patient
Edmunds-Ogbuokiri et al. HIV Clinician 2009
Recreational drugs
Drug
Ecstasy
(X, MDMA)
Amphetamines
Metabolism
Actual/theoretical
interaction
Potential significance
 2-3 fold with RTV or
EFV
Fatal interactions reported. Hyponatremia,
hypertermia, arrhytmias, seizures, rhabdomyolysis
2D6
Possible  with RTV
Hypertension, hypertermia, arrhytmias, seizures
Expired breath as
CO2; first-pass
metabolism
Possible  with RTV
Life-threatening case with SQV/rtv
Bradycardia, respiratory depression, seizures
Unknown
Possible  with RTV
Hallucinations, psychosis
2B6>2C9, 3A4
Possible  with RTV or
EFV
Respiratory depression, loss of consciousness,
hallucinations
hydrolysis, hepatic
cholinesterase
>>CYP3A4
Possible  norcocaine
with NVP or EFV
Hepatotoxicity
2D6>>1A2, 2B6,
3A4
(speed, cristal)
GHB
(liquid ecstasy)
LSD
(acid, blotters)
Ketamine
(special K, Kit-Kat)
Cocaine
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
Hepatotoxicity
Hypotension 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
Summary of Boceprevir – ARV interactions
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
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
Statins and HAART: management of drug-drug interactions
Nachega JB et al AIDS 2012
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
CHECK EVERY KIND OF MEDICATION
Check every route of administration
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.
 Le interazioni farmacologiche
bisogna conviverci.
esistono
e
 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/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
ҰHealthy
to HIV mono-infected; †Healthy individuals with & without mild/moderate hepatic impairment
individuals with and without moderate hepatic impairment
Physiological changes (versus healthy volunteers)
HIV-infected
Parameter
HCV-infected
HIV/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
lower than HIV or HCV mono-infected patients
† Significantly
1Mehta
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
5
; Boffito 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.
Concentration
One concentration does not fit all patients!!
Time
% Inhibiition





 
  
  
 

  












 

 
















IC50 IC50 IC50 IC50
Pravastatin and DRV/RTV
Patient
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
Sekar VJ, et al. Pharmacology Workshop. 2007. Abstract 55.
0.57, 6.78
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 window
Narrow therapeutic window
Wide therapeutic window
Adverse events
  

      

Therapeutic failure
Drug concentration
Drug concentration
Adverse events
  

     
Therapeutic 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
Percent of Patients with
HIV RNA Levels <50 Copies/mL
100
86
81
75
76
69
67
71%
80
82
79
60
61%
40
20
0
0 12 24
48
72
96
120
144
168
192
216
240
Weeks
Number of Contributing Patients
Raltegravir 400 mg bid. 281 278 279
280
281
281
277
280
281
281
277
279
Efavirenz 600 mg qHS. 282 282 282
281
282
282
281
281
282
282
282
279
Yearly Efficacy Analyses
% (n/N) of Patients with vRNA <50 copies/mL
Study
Week
Change (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‡
RAL
Group
EFV
Group
Difference
(95% CI)
198/279
(71.0)
171/279
(61.3)
9.5
(1.7, 17.3)
<0.001
Yes
p-Value for
Superiority
Non-inferiority* Concluded*
Prespecified as Primary Analysis
Non-Completer=Failure
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 Failure
198/222
(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
HIV RNA
< 50 Copies/mL (%)
HIV RNA
< 400 Copies/mL (%)
CD4 Cell Counts
(cells/mm 3)
Total
Baseline Plasma HIV RNA (copies/mL)
 50,000 copies/mL
> 50,000 copies/mL
Baseline Plasma HIV RNA (copies/mL)
 100,000 copies/mL
> 100,000 copies/mL
Screening Plasma HIV RNA (copies/mL)
 50,000 copies/mL
> 50,000 copies/mL
3
Baseline CD4 Cell Counts (cells/mm )
 50 cells/mm 3
> 50 and  200 cells/mm 3
> 200 cells/mm 3
-50 -25 0
25 50 -50
-25
0
25 -100 -50 0 50 100 150
Difference (95% CI)
Difference (95% CI)
Difference (95% CI)
favors EFV favors RAL
favors EFV
favors RAL favors EFV favors RAL
mk518p21CSRSubgroupsw k240 June 7, 2012
Specific Drug-Related Clinical Adverse
Experiences Occurring in ≥ 5% of Either Group
Gastrointestinal Disorders
Diarrhoea
Flatulence
Nausea
General Disorders
Fatigue
Nervous System Disorders
Dizziness
Headache
Somnolence
Psychiatric Disorders
Abnormal Dreams
Insomnia
Nightmare
Skin And Subcutaneous Tissue Disorders
Rash
RAL Group
(N = 281)
n
(%)
57
(20.3)
14
( 5.0)
10
( 3.6)
25
( 8.9)
28
(10.0)
12
( 4.3)
51
(18.1)
22
( 7.8)
26
( 9.3)
3
( 1.1)
52
(18.5)
19
( 6.8)
21
( 7.5)
8
( 2.8)
16
( 5.7)
3
( 1.1)
EFV Group
(N = 282)
n
(%)
81
(28.7)
27
( 9.6)
14
( 5.0)
29
(10.3)
47
(16.7)
25
( 8.9)
140
(49.6)
99
(35.1)
40
(14.2)
21
( 7.4)
87
(30.9)
37
(13.1)
23
( 8.2)
15
( 5.3)
63
(22.3)
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.
Altri esempi
Studio STaR (Glasgow, Cohen O425)
Spring 2 e Single (Glasgow, Eron P204)
Sailing (Atlanta, Croi 2013, Pozniak 179 LB)
Grazie al contributo di MSD Italia