Learning Objectives - IAS- · PDF fileNew York, NY: September 9, 2015 1. Slide 4 of 50...
Transcript of Learning Objectives - IAS- · PDF fileNew York, NY: September 9, 2015 1. Slide 4 of 50...
Lucas A. Hill, PharmDClinical Instructor
University of California San Diego Skaggs School of Pharmacy and
Pharmaceutical SciencesSan Diego, California
Drug-Drug Interactions Between
Antiretrovirals and the HCV Treatments in
HIV/HCV Coinfection Management
AU EDITED: 09/01/15
New York, NY: September 9, 2015
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Slide 2 of 50
Financial Relationships With Commercial Entities
Dr Hill has no relevant financial affiliations to
disclose. (Updated 09/01/15)
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Learning Objectives
After attending this presentation, participants will be
able to describe:
Available efficacy data for treatment of HCV in
HIV/HCV coinfected patients
Important drug interactions between HIV
antiretrovirals and HCV direct acting antivirals
Future therapies for the treatment of HCV in
HIV/HCV coinfection
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Potential issues in treating HIV/HCV co-infection with new HCV antivirals
HCV Therapy in
HCV/HIV
Efficacy
ProvidersAccess
D-D-I
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MD (evaluation, assessment, treatment planning)
Clinic Pharmacist (treatment planning, follow-up)
Health Educator, Drug and Alcohol Counselor (rehab, lifestyle changes)
Psychiatrist
Family, Friends
HIV-HCV Management Team
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Patient Case #1• 64 yo African American male
• HIV-HCV coinfected
• DM2 diagnosed 2006 last A1c 6.0
– Glipizide 10 mg bid + metformin 1g bid + insulin glargine 50u hs
• Seizure disorder dx 2007
– Levetiracetam 1000 mg bid
• HTN dx 1990s
– Hydrochlorothiazide 50 mg + quinapril bid + amlodipine
• Dyslipidemia
– Simvastatin 20 mg/day
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HIV History• Most recent VL and CD4 (6/15)
– HIV RNA not detected– CD4 769 cells/µL (33%)
• ARV History– Zidovudine, didanosine, zalcitabine during 1980s– Stavudine, nelfinavir, ritonavir during 1990s– Tenofovir, lamivudine, efavirenz 12/2003 – 5/2007– Tenofovir/emtricitabine/efavirenz (FDC) since 5/2007 to
present• HIV-1 viral load undetectable since 2003
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HCV History• Treatment history:
Failed peginterferon/ribavirin x 2 (relapsed after 42 wks)
• Genotype 1A
• HCV RNA (6/2015) – 7,700,000 IU/mL (6.89 log10 IU/mL)
• Liver biopsy (2013):– Cirrhosis
• CTP A
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HCV Genotype NS3/4A
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Audience Response Question• Based on the patient’s ARV regimen of
tenofovir/emtricitabine/efavirenz, which treatment regimen would allow the patient to remain on his current ARVs and start HCV treatment.
1. Paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin x 24 weeks
2. Sofosbuvir + daclatasvir + ribavirin x 24 weeks
3. Ledipasvir/sofosbuvir x 24 weeks
4. Sofosbuvir + simeprevir x 24 weeks
9%
30%
57%
4%
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Audience Response Question• Based on the patient’s ARV regimen of
tenofovir/emtricitabine/efavirenz, which treatment regimen would allow the patient to remain on his current ARVs and start HCV treatment.
1. Paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin x 24 weeks
2. Sofosbuvir + daclatasvir + ribavirin x 24 weeks
3. Ledipasvir/sofosbuvir x 24 weeks
4. Sofosbuvir + simeprevir x 24 weeks
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Efficacy in HIV/HCV co-infection
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PHOTON: SOF/RBV FOR HIV/HCV
• Cirrhosis permitted • Most ART allowed– CD4>500 not on ART– CD4>200 on ART
SOF/RBV (n=114)
SOF/RBV (n=68)
SOF/RBV (n=41)
GT1 TN
GT 2,3 TN
GT 2,3 TE
SOF/RBV (n=19)
SOF/RBV (n=55)
SOF/RBV (n=200)
GT 2,3 TE
GT 1,3,4 TN
GT 2 TN
12 36Weeks
PH
OTO
N-1
PH
OTO
N-2
Naggie S. EASL 2014. Molina J-M. IAS 2014.
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7688
67
92 9485 89 91
83 86
0
20
40
60
80
100
GT1/4 GT2 TN GT3 TN GT2 TE GT3 TE
SVR
12
(%
)
PHO-1
PHO-2
Naggie S. EASL 2014. Molina J-M. IAS 2014.
PHOTON: SOF/RBV FOR HIV/HCV
PHOTON 2: 65% (11/17) GT1 cirrhosis; 78% (18/23) GT 3 TE, cirrhosis
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ION-4 – LDV/SOF
• Phase 3, multicenter, open-label study (NCT02073656)
• HCV GT 1 or 4 patients in US, Canada, and New Zealand
• Broad inclusion criteria
– HCV treatment-naïve or treatment-experienced
– 20% with compensated cirrhosis
– Platelets ≥50,000/mm3; hemoglobin ≥10 mg/dL, CrCl ≥60 mL/min
– HIV-1 positive, HIV RNA <50 copies/mL; CD4 cell count >100 cells/mm3
• ART regimens included emtricitabine and tenofovir disoproxil fumarate plus efavirenz, raltegravir, or rilpivirine
Wk 0 Wk 12 Wk 24
SVR12LDV/SOFN=335
Naggie S, Cooper C, Saag M, et al. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015; 373:705-713.
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Slide 16 of 50ION-4 Results: Demographics and Baseline Characteristics
LDV/SOF 12 weeksN=335
Mean age, y (range) 52 (26-72)
Male, n (%) 276 (82)
Black, n (%) 115 (34)
Hispanic or Latino, n (%) 56 (17)
Mean BMI, kg/m2 (range) 27 (18-66)
IL28B CC, n (%) 81 (24)
GT 1 327 (98)
HCV treatment experienced, n (%) 185 (55)
Cirrhosis, n (%) 67 (20)
Mean HCV RNA, log10 IU/mL ± SD 6.7 ± 0.6
Median CD4 cell count, cells/µL (range) 628 (106-2069)
HIV ARV Regimen
Efavirenz + FTC + TDF 160 (48)
Raltegravir + FTC + TDF 146 (44)
Rilpivirine + FTC + TDF 29 (9)
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96 95 97 96 94
0
20
40
60
80
100
Naïve vs ExperiencedOverall Cirrhosis Status
LDV/SOF 12 Weeks
ExperiencedNaïve No Cirrhosis Cirrhosis
321/335 142/150 179/185 63/67258/268
SV
R12 (
%)
Results: SVR12 by Prior TreatmentExperience and Cirrhosis Status
Overall
Error bars represent 95% confidence intervals.
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ION-4 Results: Renal FunctionEFV+FTC+TDF (n=160)
RAL+FTC+TDF (n=146)
RPV+FTC+TDF (n=29)
LDV/SOF +
60708090
100110120130140150
Cre
atin
ine
Cle
aran
ce(m
L/m
in),
mea
n
SD
WeekBL 1 2 4 6 8 10 12 FU-4
4 patients (1%) had change in creatinine ≥ 0.4 mg/dL
– 2 completed treatment with no ART change
– 1 had dose reduction of TDF, 1 discontinued TDF
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SVR12ABT450/r/267 + 333 + R
ABT450/r/267 + 333 + R
12 24Weeks
SVR12
N=31
N=32
• Stable ART
– ATV or RAL
– HIV RNA <40 copies/mL
– CD4 >200
Wyles. EASL 2014.
.
12 Week 24 Week
Male 94% 91%
Naïve 65% 69%
Null 16% 16%
1a 87% 91%
F4 19% 19%
CD4 633 625
TURQUOISE I: PrOD + RBV in HIV/HCV
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TURQUOISE I: PrOD + RBV in HIV/HCV
• In 12-week arm 1 patient withdrew consent• Two patients in 24-week arm were re-infected causing decrease to 90.6% at SVR12• Two virologic failures — both 1a cirrhotic null responders, both on raltegravir
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Slide 21 of 50Daclatasvir-ALLY-2
■ Primary endpoint: SVR12 in treatment-naive patients with GT 1 treated for 12 weeks
■ Standard DCV dose is 60 mg– Dose-adjusted for concomitant ARV therapy: 30 mg with ritonavir-boosted PIs, 90 mg with
NNRTIs except RPV* HCV RNA <LLOQ (TD or TND) at posttreatment Week 12, assessed using the Roche HCV COBAS TaqMan Test v2.0 (LLOQ 25 IU/mL).
DCV 30/60/90 mg +SOF 400 mg QD
24
DCV 30/60/90 mg +SOF 400 mg QD
12
NaiveRandomize 2:1
Experienced
DCV 30/60/90 mg + SOF 400 mg QD
Week 0 8
N
101
50
52
SVR12*
Wyles D, Ruane P, Sulkowski M, et al. Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015;373:714-725.
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Slide 22 of 50Slide 22 of 50
Demographic and HCV Disease CharacteristicsDemographic and HCV Disease Characteristics
ParameterNaive
12 WeekN = 101
Experienced12 Week
N = 52
Naive8 WeekN = 50
Age, median years (range) 52 (24–71) 57 (43–66) 50 (28–75)
Male, n (%) 92 (91) 43 (83) 42 (84)
Race, n (%)
White 66 (65) 31 (60) 28 (56)
Black 30 (30) 20 (38) 19 (38)
Other 5 (5) 1 (2) 3 (6)
HCV GT, n (%)
1a 71 (70) 33 (63) 35 (70)
1b 12 (12) 11 (21) 6 (12)
2 11 (11) 2 (4) 6 (12)
3 6 (6) 4 (8) 3 (6)
4 1 (1) 2 (4) 0
HCV RNA, mean log10 IU/mL (SD) 6.50 (0.76) 6.52 (0.79) 6.40 (0.71)
Cirrhosis, n (%)* 9 (9) 15 (29) 5 (10)
*Cirrhosis status determined by liver biopsy (METAVIR >F3), Fibroscan (>14.6 kPa), or Fibrotest >0.74 with APRI >2.
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0
20
40
60
80
100
SVR
12
, %
12-WeekNaive
12-WeekExperienced
8-WeekNaive
GT 1 (N = 168)
ALLY-2: SVR12
12-WeekNaive
0
20
40
60
80
100
12-WeekExperienced
8-WeekNaive
All Patients (N = 203)
96 98 76 97 98 76
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96 100 100 100 10097 100 100 100 100
0
20
40
60
80
100
1a 1b 2 3 4
SVR
12
, %
HCV genotype
Naive Experienced
SVR12 by HCV Genotype: 12-Week Groups
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Efficacy Summary
• Treatment recommendations are the same for mono-infected patients and co-infected patients based on efficacy
–Not recommended to treat co-infected patient with 8 weeks of LDV/SOF
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Drug-Drug Interactions in HIV/HCV co-infection
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Slide 27 of 50SOF and -007 Pharmacokinetics with ARV
Kirby AASLD 2012
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ARV Pharmacokinetics
Kirby AASLD 2012
• Avoid SOF and LDV with tipranavir/ritonavir due to P-gp induction
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• EFV: ~35% reduction in LDV exposure
– LDV: no impact of EFV
• LDV: 40-98% increase in TFV AUC
– 90-150% increase in Ctau
LDV/SOF DDIs with antiretrovirals
German P. 15th Inter Clin Pharm HIV and HCV 2014.
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LDV/SOF and Tenofovir
AUC of tenofovir 3000-3300 ng.hr/mL
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Slide 31 of 50
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LDV/SOF and Tenofovir
German et al. CROI 2015.
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LDV/SOF and Tenofovir
German et al. CROI 2015.
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LDV/SOF and Tenofovir
German et al. CROI 2015.
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Slide 35 of 50Tenofovir alafenamide (TAF)Novel Prodrug of Tenofovir
Tenofovir (TFV)
Tenofovir disoproxil fumarate (TDF)
Tenofovir alafenamide (TAF)
GI Tract Blood Lymphoid Cell
TFV
TDF TFV
TAF TFV
TFV-MP = tenofovir monophosphateTFV-DP = tenofovir diphosphateCatA = Cathepsin A
TFV
TFV-MP
TFV-DP
esterase
CatAAMPK
AMPK
Modified from CROI 2015 - Sax et al. Abstract 143LB
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LDV/SOF and TAF
LDV Mean (%CV)
LDV/SOF + E/C/F/TAF
n=30LDV/SOF
n=30GMR
(90% CI)
AUC ng.h/mL 22,900 (35.7) 12,700 (36.3) 1.79 (1.63, 1.96)
Cmax ng/mL 1140 (32.1) 684 (32.3) 1.65 (1.53, 1.78)
Ctau ng/mL 896 (37.7) 459 (40.3) 1.93 (1.74, 2.15)
Garrison et al. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2015
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LDV/SOF and TAF
LDV Mean (%CV)
LDV/SOF + DTG+FTC/TDF
n=29LDV/SOF
n=30GMR
(90% CI)
AUC ng.h/mL 8940 (35.1) 10,300 (37.4) 0.89 (0.84, 0.95)
Cmax ng/mL 523 (33.9) 626 (33.6) 0.85 (0.81, 0.90)
Ctau ng/mL 316 (39.2) 365 (41.2) 0.89 (0.84, 0.95)
Garrison et al. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2015
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LDV/SOF and TAF
Garrison et al. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2015
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LDV/SOF and TAF
Garrison et al. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2015
TFV Mean (%CV)
LDV/SOF + DTG+FTC/TDF
n=29DTG+FTC/TDF
n=30GMR
(90% CI)
AUC ng.h/mL 4900 (24.1) 3020 (26.6) 1.65 (1.59, 1.71)
Cmax ng/mL 495 (24.0) 310 (24.4) 1.61 (1.51, 1.72)
Ctau ng/mL 117 (23.2) 55.7 (28.7) 2.15 (2.05, 2.26)
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LDV/SOF and TAF
Conclusions• Safe to administer E/C/F/TAF with LDV/SOF – increases in COBI and EVG levels not considered
clinically significant• Monitor for TFV toxicity when using DTG-FTC/TDF with LDV/SOF
Garrison et al. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2015
LDV/SOF + E/C/F/TAF
n=30E/C/F/TAF
n=30GMR
(90% CI)
TFV Mean(%CV)
AUC ng.h/mL 397 (15.9) 315 (18.7) 1.27 (1.23, 1.31)
Cmax ng/mL 20.7 (16.1) 17.8 (20.4) 1.17 (1.12, 1.22)
Ctau ng/mL 15.5 (16.6) 11.7 (20.0) 1.33 (1.28, 1.38)
TAF Mean (%CV)
AUClast, ng.h/mL 195 (29.2) 239 (45.9) 0.86 (0.78, 0.95)
Ctaung/mL 148 (48.2) 166 (50.8) 0.90 (0.73, 1.11)
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PrOD D-D-I: RAL, RPV, EFV, DTG• Healthy volunteer study
– Studied with RAL, TDF/FTC, RPV 25mg, EFV
• EFV arm discontinued prematurely
• RPV exposure similar to 75mg (QTc 10s)
• Study with PrOD + DTG or ABC/3TC– No significant changes in ABC/3TC or DTG levels– Reduction in paritaprevir levels by 34% with DTG and 27% by
ABC/3TC• Not studied with FDC DTG/ABC/3TC
• Do not use PrOD for patients not on ARV regimenKatri A. ICAAC 2014.,
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• Healthy volunteer study of 3D regimen with:– ATV/r 300/100mg QAM or QPM
• rit omitted if given in AM with 3D regimen– DRV/r 800/100mg QAM or QPM or 600/100mg BID
• rit omitted if given in AM with 3D regimen– LPV/r 800/200mg QPM or 400/100mg BID
• DRV Cmin 43-48% lower– DRV/r BID with 3D comparable exposure to DRV/r QD– DRV/r QD and BID being evaluated in TURQUOISE I
• Dasabuvir Cmin 46% lower with DRV BID (AUC27%)
PrOD DDIs: LPV, ATV, DRV
Katri A. ICAAC 2014.
HIV PI LEVELS ABT-450 LEVELS
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Daclatasvir drug interactions: Unique role in Co-infection?
• Substrate of Pgp and CYP3A4
– Moderate Pgp inhibitor
• ATV/r- DCV 20mg: AUCt: 0.70, C24: 1.21
– 30mg (est): AUCt: 1.05, C24: 1.83
• EFV- DCV 120mg: AUCt: 1.37, C24: 0.83
– 90mg (est): AUCt: 1.03, C24: 0.62
• TDF- DCV 60mg: AUCt: 01.10, C24: 1.17Bifano M. CROI 2012.
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Audience Response Question• Based on the patient’s ARV regimen of
tenofovir/emtricitabine/efavirenz, which treatment regimen would allow the patient to remain on his current ARVs and start HCV treatment.
1. Paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin x 24 weeks
2. Sofosbuvir + daclatasvir + ribavirin x 24 weeks
3. Ledipasvir/sofosbuvir x 24 weeks
4. Sofosbuvir + simeprevir x 24 weeks
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Which DAA regimen with which HAART regimenSOF/RBV SOF/SMV SOF/LDV SOF/DCV PrOD/RBV
TDF
ABC, 3TC, FTC
DRV/RTVCaution only if with TDF
ATV/RTVCaution only if with TDF
Use 30mg dose
EFVCaution when using with TDF
Use 90mg dose
ETR No data Use 90mg dose No data
RPV
RAL
EVG/COBI/TDF/FTC
Can consider with TAF No data No data
DTG No data No data
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Investigational Therapies
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C-EDGE• All patients treated with Grazoprevir (PI)/Elbasvir (NS5A)
fixed dose combination for 12 weeks
• Co-infected, genotype 1, 4, and 6 treatment naïve patients with and without cirrhosis
• Naïve to ART with CD4 > 500 cells/mm3 and HIV RNA < 50k copies/mL or on stable ART with undetectable viral load and CD4 >200
• ART allowed was tenofovir or abacavir + emtricitabine or lamivudine + rilpivirine, raltegravir, or dolutegravir
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Demographics
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C-EDGE results
• Well tolerated, most common side effects were headache, nausea, and fatigue
• Anticipate will not be able to use with efavirenz- or ritonavir-boosted protease inhibitors
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Regimen Switching in the Setting of Viral Suppression Prior to Starting Hep
C Treatment• Cardinal principle of regimen switching
– Maintain viral suppression without jeopardizing future options
• Virologic failure with emergence of new resistance mutations
– Increases need for more complex, difficult-to-follow, or expensive regimens
DHHS. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 1, 2014.
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 1, 2014;1-285. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
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Slide 51 of 50Principles for Successful Regimen Switching
• Review ART history
– Virologic suppression, resistance test results, and past adverse events
– If resistance data are unavailable, resistance may often be inferred by treatment history
– Consult with an HIV specialist for patients with a history of resistance >1 drug classes
• During first 3 months after a regimen switch
– More intensive monitoring of tolerability, viral suppression, adherence, and laboratory changes is recommended
DHHS. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 1, 2014.
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 1, 2014;1-285. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
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Monitoring After Switching Regimens• Evaluate more closely for several months after a treatment switch
– 1 to 2 weeks post switch: a clinic visit or phone call
– 4 to 8 weeks post switch: viral load test (rebound viremia)
• Goal of the intensive monitoring
– Assess medication tolerance
– Conduct targeted laboratory testing within 3 months after the regimen switch (ie, pre-existing laboratory abnormalities or potential concerns with the new regimen)
• Absent any specific complaints, laboratory abnormalities, or evidence of viral rebound at this 3-month visit, clinical and laboratory monitoring of the patient may resume on a regularly scheduled basis
DHHS. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 1, 2014.
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 1, 2014;1-285. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
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Slide 53 of 50
Summary
• Efficacy in HIV/HCV co-infection patients treated with DAAs appears to mimic efficacy seen in mono-infected patients
• Drug interactions and management have become easier in HCV treatment but still exist
• Remains “unique” population due to frequent complex drug regimens and co-morbid conditions
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IAS–USA
An IAS–USA State-Of-The-Art Clinical Conference on the
Management of Hepatitis C
Virus in the New Era: Small
Molecules Bring Big Changes
September 9, 2015—New York, NY
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New York, NY: September 9, 2015 18