L

1
Limportanza delle interazioni farmacologiche
nella gestione dellHIV/AIDS, delle comorbosità e
della co-infezione HCV

• Stefano Bonora
• Università di Torino
• 12 Aprile 2013

2
Premessa

• Un farmaco introdotto nellorganismo (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
  leffetto desiderato.

3
Premessa

• Le interazioni possono avere differenti
  meccanismi (non solo inibizione o induzione del
  metabolismo).
• Le interazioni possono alterare la quantità di
  farmaco disponibile nellorganismo con potenziale
  impatto su efficacia e tossicità.
• Leffetto di un farmaco interagente nel tempo è
  diverso in funzione del meccanismo di interazione.

4
OUTLINE

• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs

5
OUTLINE

• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs

6
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!
7
Drug Interactions will be greater as patients age
gt 50 years
Marzolini C et al J Antimicrob Chemother
2011662107
8
Failure to Recognise Drug Interactions

• HIV drugs amongst the most therapeutically risky
• - 20-40 patients on ARVs at risk of clinically
  significant interactions
• PIs gt NNRTIs gtgt MVC/RAL gt 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 2007271379, Evans-Jones et al. CID
2010501419, de Maat et al. Ann Pharmacother
200236410-15 Mok et al. Am J Health Sys Pharm
20086555, Seden et al. Int J STD AIDS 2012 (in
press) Seden et al (unpublished)
9
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 dellintegrasi
  vs. NNRTI o IP).

10
OUTLINE

• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs

11
Drug Interaction Data for RPV (Rilpivirina)
Change in RPV exposure (AUC) Change in other drugs exposure (AUC)
TDF1 23
LPV/r2 52 (CYP inhibition)
DRVRTV3 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
Omeprazole13 -40 (pH increase)
Sildenafil14
Crauwels H, et al. ACTHIV 2011 Denver. Colorado.
TPOI-4
12
Rilpivirine Drug InteractionRationale 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) Cmax AUC
Famotidine 40 mg single dose taken 2 hours before rilpivirine ? 85(? 88 to ? 81) ? 76(? 80 to ? 72)
Omeprazole 20 mg once daily ? 40(? 52 to ? 27) ? 40(? 52 to ? 29)
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
13
Tuberculosis
Protease inhibitors
NNRTIs
Entry / Integrase inhibitors
Fonte http//www.hiv-druginteractions.org/
14
Efficacy Outcomes, W24
ANRS 12 180
Primary endpoint HIV RNAlt50 cp/mL at W20 and
W24, mITT (MF, D/CF)
EFVN 51 EFVN 51 EFVN 51 RAL 400 N 51 RAL 400 N 51 RAL 400 N 51 RAL 800 N 51 RAL 800 N 51 RAL 800 N 51
PRIMARY ENDPOINT n 95 CI 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 RNAlt400 cp/mL at W20
and W24, mITT (MF, D/CF)
EFV N 51 EFV N 51 EFV N 51 RAL 400 N 51 RAL 400 N 51 RAL 400 N 51 RAL 800 N 51 RAL 800 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
15
Immunosuppressant 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
16
Antineoplastic agents
Drug Metabolism Potential significance
Cyclophosphamide 2B6 ? active 3A4?toxic IDV ? CPA CL by 1.5 in 40 patients
Ifosfamide 3A4? active 2B6, 3A4?toxic
Docetaxel 3A4 RTV ? DOC AUC x50-fold in mice
Paclitaxel 2C8gtgt3A4 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 3A4gtgt2E1,1A2 Mucositis, myelosuppression, transaminitis Higher incidence of severe mucositis with SQV
Irinotecan Carboxylesterases UGT, CYP3A4 LPV/r ? IRI CL by 47 in 7 patients 50 dose-reduction Persistent neutropenia in one patient
Edmunds-Ogbuokiri et al. HIV Clinician 2009
17
Recreational drugs
Drug Metabolism Actual/theoretical interaction Potential significance
Ecstasy (X, MDMA) 2D6gtgt1A2, 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/rtv Bradycardia, respiratory depression, seizures
LSD (acid, blotters) Unknown Possible ? with RTV Hallucinations, psychosis
Ketamine (special K, Kit-Kat) 2B6gt2C9, 3A4 Possible ? with RTV or EFV Respiratory depression, loss of consciousness, hallucinations
Cocaine hydrolysis, hepatic cholinesterase gtgtCYP3A4 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 Hepatotoxicity Hypotension with erectile disfunction agents
Antoniou et al. Ann Pharmacother 2002
18
(No Transcript)
19
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
20
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
21
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 dellepatite.
• Affiancare queste nuove terapie a combinazioni
  farmacologiche anti-HIV con scarse interazioni
  aumenta la probabilità dellesito positivo di
  questo percorso, come ci dicono gli studi clinici
  sui farmaci anti-HIV di nuove classi (es. INI).

22
OUTLINE

• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Manegement of DDIs

23
(No Transcript)
24
Statins and HAART management of drug-drug
interactions
Nachega JB et al AIDS 2012
25
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).

26
Corticosteroids

• Case report of Cushings syndrome and adrenal
  suppression in a patient on ATV/r and
  dexamethasone 0.1 eye drops1
• Cushings syndrome reported with the use of intra
  articular triamcinolone injections in patients on
  boosted PIs24
• Several cases of Cushings syndrome with inhaled
  fluticasone and ritonavir7

CHECK EVERY KIND OF MEDICATION Check every route
of administration
1.Molloy A, et al. AIDS. 20112513379. 2. Dort
K, et al. AIDS Res Ther. 2009610. 3. Danaher
PJ, et al. Orthopedics 200932450. 4.Ramanathan
R, et al. Clin Infect Dis. 200847e979. 5. Gray
D, et al. S Afr Med J. 20101002967. 6. Frankel
JK, Packer CD. Ann Pharmacother. 2011458234.
7. Foisy MM, et al. HIV Medicine 2008938996.
27

• 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.

28
OUTLINE

• Epidemiology
• New antiretrovirals/drugs combination
• Sources of information
• Interpretation and management of DDIs
• HIV vs Healthy volunteers
• Interindividual variability
• Clinical significance
• New mechanisms?

29
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) ? ? (Iwamoto et al. AAC 2009)
Compared to HIV mono-infected Healthy
individuals with without mild/moderate hepatic
impairment ?Healthy individuals with and without
moderate hepatic impairment
30
Physiological changes (versus healthy volunteers)
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
2006221421 2Graham SM, et al. AIDS Res Human
Retrovir 200723119712003Nagao Y Sata M.
Virology Journal 20107375 4Monga HK, et al.
Clin Infect Dis 2001332407 5Boffito M, et
al. Drug Metab Dispos 20023085960 6Ozeki T,
et al. Br J Exp Path 19886958995 7Welage LS,
et al. Clin Infect Dis 199521143138 8Nam YJ,
et al. Korean J Hepatol 20041021622
31
(No Transcript)
32

• 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
  concentrationtime 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.

33
One concentration does not fit all patients!!
34
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 0.57, 6.78
Sekar VJ, et al. Pharmacology Workshop. 2007.
Abstract 55.
35
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-indicat
  ion

A consistent 10 decrease in AUC in 10 subjects
is statistically significant (plt0.01), but not
clinically relevant.
Adapted from D Back
36
Therapeutic window
Narrow therapeutic window
Wide therapeutic window
Adverse events
Adverse events
Drug concentration
Drug concentration
?
?
Therapeutic failure
Therapeutic failure
Adapted from D Back
37

• 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?

38
Proportion () of Patients Achieving HIV RNA lt50
copies/mL (95 CI) Over Time
Non-Completer Failure Approach
39
Yearly Efficacy Analyses
Study Week (n/N) of Patients with vRNA lt50 copies/mL (n/N) of Patients with vRNA lt50 copies/mL (n/N) of Patients with vRNA lt50 copies/mL Change (cells/mm3) from BL CD4 Count Change (cells/mm3) from BL CD4 Count Change (cells/mm3) from BL CD4 Count
Study Week RAL (N281) EFV (N282) RAL EFV (95 CI) RAL (N281) EFV (N282) 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 lt0.001. Met criteria for superiority. P-value for non-inferiority lt0.001. Met criteria for superiority. P-value for non-inferiority lt0.001. Met criteria for superiority. P-value for non-inferiority lt0.001. Met criteria for superiority. P-value for non-inferiority lt0.001. Met criteria for superiority. P-value for non-inferiority lt0.001. Met criteria for superiority. P-value for non-inferiority lt0.001. Met criteria for superiority.
40
Sensitivity Analyses of Virologic Efficacy at
Week 240
    Different Approaches to Handling Missing Data Response by Treatment Group Response by Treatment Group Treatment Effect Treatment Effect Treatment Effect Treatment Effect
    Different Approaches to Handling Missing Data Responder/Evaluable Responder/Evaluable Difference Estimates Difference Estimates Difference Estimates Difference Estimates
    Different Approaches to Handling Missing Data RAL Group EFV Group Difference (95 CI) p-Value for Non-inferiority p-Value for Non-inferiority Superiority Concluded
Prespecified as Primary Analysis Prespecified as Primary Analysis Prespecified as Primary Analysis Prespecified as Primary Analysis Prespecified as Primary Analysis Prespecified as Primary Analysis Prespecified as Primary Analysis
Non-CompleterFailure 198/279 (71.0) 171/279 (61.3) 9.5 (1.7, 17.3) lt0.001 Yes Yes
Prespecified as Secondary Analyses  Prespecified as Secondary Analyses  Prespecified as Secondary Analyses  Prespecified as Secondary Analyses  Prespecified as Secondary Analyses  Prespecified as Secondary Analyses  Prespecified as Secondary Analyses 
Treatment-Related D/CFailure 198/236 (83.9) 171/239 (71.5) 12.4 (4.9, 19.8) lt0.001 Yes Yes
Observed Failure 198/222 (89.2) 171/212 (80.7) 8.6 (1.9, 15.5) lt0.001 Yes 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 gt50,000 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 gt0. 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 NCF 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 lt50 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 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 gt50,000 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 gt0. 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 NCF 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 lt50 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 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 gt50,000 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 gt0. 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 NCF 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 lt50 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 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 gt50,000 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 gt0. 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 NCF 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 lt50 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 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 gt50,000 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 gt0. 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 NCF 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 lt50 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 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 gt50,000 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 gt0. 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 NCF 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 lt50 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 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 gt50,000 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 gt0. 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 NCF 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 lt50 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).
41
Subgroup Analyses
42
Specific Drug-Related Clinical Adverse
Experiences Occurring in 5 of Either Group
RAL Group (N 281) RAL Group (N 281) EFV Group (N 282) 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)
43
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.
44
Altri esempi
Studio STaR (Glasgow, Cohen O425) Spring 2 e
Single (Glasgow, Eron P204) Sailing (Atlanta,
Croi 2013, Pozniak 179 LB)
45
Grazie al contributo di MSD Italia