HIV PRN Focus Session—HIV in Special Populations Activity Number: 0217-0000-16-129-L01-P, 1.50 hours of CPE credit; Activity Type: A Knowledge-Based Activity
Monday, October 24, 2016 3:15 p.m. to 4:45 p.m. Plaza Room B
Moderator: Melissa Badowski, Pharm.D., BCPS, AAHIVP Clinical Assistant Professor, Section of Infectious Diseases Pharmacotherapy University of Illinois at Chicago, College of Pharmacy, Illinois Department of Corrections HIV Telemedicine, Chicago, Illinois
Agenda
3:15 PM Management of HIV/HCV Co-Infections Agnes, Cha, Pharm. D., BCACP, AAHIVP Associate Professor of Pharmacy Practice, LIU Pharmacy Clinical Pharmacy Educator, HIV Ambulatory Care, Brooklyn Hospital Center, Brooklyn, New York
3:45 PM Solid Organ Transplantation in the HIV Patient Jennifer Cocohoba, Pharm. D. Professor of Clinical Pharmacy, University of California San Francisco, San Francisco, California
4:15 PM Malignancy in the HIV Patient David L. DeRemer, Pharm. D., BCOP Clinical Associate Professor; PGY-2 Oncology Residency Program Director, University of Georgia, Athens, Georgia
Conflict of Interest Disclosures Melissa Badowski: Consultancies: (Gilead Sciences) Agnes Cha: no conflicts to disclose Jennifer Cocohoba: no conflicts to disclose David L. DeRemer: no conflicts to disclose
Learning Objectives 1. Evaluate complex drug-drug interactions between HIV antiretrovirals and HCV direct-acting antivirals.2. Explain the expected HCV virologic clinical outcomes with direct acting antivirals in HIV/HCV co-
infected patients.3. Discuss expected adverse drug reactions described with the direct-acting antivirals in HIV/HCV co-
infected patients.4. Outline unique solid-organ pre-transplant evaluations required in an HIV-infected patient.5. Assess critical drug-drug interactions between antiretrovirals and immunosuppressive therapy used in
organ transplantation.6. Compare and contrast the clinical outcomes in HIV-infected versus uninfected organ transplant
recipients.7. Summarize the incidence of AIDS and non-AIDS related cancer diagnoses in HIV-infected patients.8. Identify potential drug-drug interactions between chemotherapy regimens and antiretrovirals.9. Explain the expected clinical outcomes associated with HIV-infected cancer patients.
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Self-Assessment Questions
Self-assessment questions are available online at www.accp.com/am
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Management of HIV/HCV Coinfections
Agnes Cha, PharmD, AAHIVP, BCACPAssociate Professor/HIV Clinical Pharmacist
Long Island University/The Brooklyn Hospital CenterBrooklyn, NY
October 24, 2016
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Conflict of Interest
• Participated on clinical advisory boards for Gilead Sciences and Janssen Therapeutics
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Learning Objectives
• Explain the expected HCV virologic clinical outcomes with direct acting antivirals in HIV/HCV coinfected patients.
• Discuss expected adverse drug reactions described with the direct-acting antivirals in HIV/HCV coinfected patients.
• Evaluate complex drug-drug interactions between HIV antiretrovirals and HCV direct-acting antivirals.
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Abbreviations• 3TC, lamivudine• ABC, abacavir• ART, antiretroviral therapy• ARV, antiretroviral• ATV, atazanavir• COBI, cobicistat• DAA, direct acting antiviral • DCV, daclatasvir• DDI, drug–drug interaction • ddI, didanosine• DRV, darunavir• DSV, dasabuvir• DTG, dolutegravir• EBR, elvasvir• EFV, efavirenz
• EVG, elvitegravir• ETR, etravirine• GZR, grazoprevir• LDV, ledipasvir• PTV, paritaprevir• RAL, raltegravir• RBV, ribavirin• RPV, rilpivirine• RTV, ritonavir• SMV, simeprevir• SOF, sofosbuvir• TAF, tenofovir alafenamide• TDF, tenofovir disoproxil fumarate• TFV, tenofovir• VEL, velpatasvir
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HIV/HCV coinfection• HIV/HCV co-infected have 3-fold higher risk of
progression to cirrhosis or liver decompensation• ART may slow progression of liver disease
• ART recommended in all co-infected patients (AI)• In HIV treatment naïve patients with CD4 >500, may
consider deferring ART until HCV treatment is completed to avoid drug-drug interactions (CIII)
• If ART regimen is modified for HCV treatment, HIV RNA should be monitored within 4-8 weeks
• Modified ART regimen should be continued for at least 2 weeks after HCV treatment is completed
1. Graham, et al. CID 2001:33(4):562-569 2. DHHS Adult and Adolescent Guidelines 2016
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Direct Acting Antiviral (DAA) Regimens
• sofosbuvir (NS5B) + simeprevir (NS3/4A)• sofosbuvir/ledipasvir (NS5A)• paritaprevir (NS3/4A)/r/ombitasvir (NS5A) +
dasabuvir (NS5B) • “PrOD”
• sofosbuvir + daclatasvir (NS5A)• elbasvir (NS5A)/grazoprevir (NS3/4A)• sofosbuvir/velpatasvir (NS5A)
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Helpful Drug Target Hints
‘’-previr” – NS3/NS4A protease inhibitors
“-asvir”- NS5A inhibitors
“-buvir”- NS5B polymerase inhibitors (nucleotides/non-nucleotides)
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Treatment for HIV/HCV Coinfection
• 8-wk regimens are NOT recommended in HCV/HIV coinfection
• Otherwise, treatment and retreatment are the same as for HCV monoinfection
• After recognizing and managing drug interactions with ARVs
• Daclatasvir + sofosbuvir, with or without RBV is a recommended regimen when ART changes cannot be made to accommodate other HCV regimens
AASLD/IDSA. HCV guidance. July 2016.
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Genotype 1 Treatment RecommendationsGenotype SMV + SOF LDV/SOF PrOD DCV + SOF EBV/GZP SOF/VEL
1a; No cirrhosis
12 weeks 12 weeks 12 weeks + RBV
12 weeks 12 weeks if no RAVs*if RAVs: 16 weeks +RBV*
12 weeks
1a; Cirrhosis
(Alternative 24 weeks +/-RBV)
12 weeks*if Tx-exp: 12 weeks+ RBV or 24 weeks*
(Alternative 24 weeks +RBV)
(Alternative 24 weeks +/-RBV)
12 weeks if no RAVs*if RAVs: 16 weeks +RBV*
12 weeks
1b; No cirrhosis
12 weeks 12 weeks 12 weeks 12 weeks 12 weeks 12 weeks
1b; Cirrhosis
(Alternative 24 weeks+/-RBV)
12 weeks*if Tx-exp: 12 weeks+ RBV or 24 weeks*
12 weeks (Alternative 24 weeks+/-RBV)
12 weeks 12 weeks
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Genotypes 2-6 Treatment Recommendations
HCV Genotype Recommended or Alternative Treatment
2 Sofosbuvir/velpatasvir x 12 weeks (+RBV if SOF+RBV failed) Daclatasvir + sofosbuvir x 12 weeks (16-24 weeks if cirrhosis)
3 Daclatasvir + sofosbuvir x 12 weeks (24 weeks ±RBV if cirrhosis) Sofosbuvir/velpatasvir x 12 weeks (+RBV if tx-exp or cirrhosis)
4 Paritaprevir/ritonavir/ombitasvir + ribavirin x 12 weeks Sofosbuvir/velpatasvir x 12 weeks Elbasvir/grazoprevir x 12 weeks Ledipasvir/sofosbuvir x 12 weeks
5 or 6 Ledipasvir/sofosbuvir x 12 weeks Sofosbuvir/velpatasvir x 12 weeks
AASLD/IDSA. HCV guidance. July 2016.
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Clinical outcomes in Co-infectionRegimen(clinical trial)
N Design Overall SVR Mono-infection SVR
Simeprevir + sofosbuvir 58 Observational 76% and 94% (w/RBV)
83-97%
Ledipasvir/sofosbuvir(ION-4)
335 Single arm 96% 97%-99%
PrOD(TURQUOISE-1)
63 RCT: 12 vs 24 weeks
92% (94% vs 91%)
90-97%
Daclatasvir + sofosbuvir(ALLY-2)
203 RCT: 12 vs 8 weeks
97% (98% vs 76%)
76-100%
Elbasvir/grazoprevir(C-EDGE)
218 Single arm 96% 92-99%
Sofosbuvir/velpatasvir(ASTRAL-5)
106 Single arm 95% 98-99%
D DelBello, A Cha, et al. CID 2016;62(12):1497-504 S Naggie et al. NEJM 2015; 373:705-713JK Rockstroh et al. IAC 2016 DL Wyles et al. NEJM 2015;373(8):714-25JK Rockstroh et al. Lancet HIV 2015:Aug;2(8):e319-27 DL Wyles et al. EASL 2016
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Why are 8 weeks not recommended?• Lower SVR in
coinfected (ALLY-2) vs monoinfected(ION-3)
• Real world VA cohort had greater failure rates
• OR 0.54 (0.40-0.74)• Black veterans
• Failure can lead to NS5A resistance
DL Wyles et al. NEJM 2015;373(8):714-25L Backus et al. AASLD 2015.
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Adverse Drug ReactionsHCV regimen Most frequently reported ADE D/C
Simeprevir + sofosbuvir(real world data)
Rash (12%), pruritis (12%) 2
Ledipasvir/sofosbuvir (ION-4) Headache (25%), fatigue (21%), diarrhea (11%) 0
PrOD (TURQUOISE-1) Faituge (24%), nausea (21%), diarrhea (16%), headache (14%), insomnia (15%), pruritus (11%)
0
Daclatasvir + sofosbuvir(ALLY-2)
Fatigue (17%), nausea (13%), headache (11%) 0
Elbasvir/grazoprevir (C-EDGE) Fatigue (13%), headache (12%) 0
Sofosbuvir/velpatasvir(ASTRAL-5)
Fatigue (25%), headache (13%) 2
D DelBello, A Cha, et al. CID 2016;62(12):1497-504 S Naggie et al. NEJM 2015; 373:705-713JK Rockstroh et al. IAC 2016 DL Wyles et al. NEJM 2015;373(8):714-25JK Rockstroh et al. Lancet HIV 2015:Aug;2(8):e319-27 DL Wyles et al. EASL 2016.
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Potential for Drug–Drug Interactionssimeprevir
(SMV)sofosbuvir
(SOF)ledipasvir
(LDV)
paritaprevir/r/ ombitasvir/ dasabuvir
(PrOD)
daclatasvir(DCV)
elbasvir/ grazoprevir(EBR/GZR)
velpatasvir(VEL)
3A4 substrate --- ---
3A4 substrate & inhibitor; 2C8
substrate
3A4 substrate
3A4 substrate
3A4, 2B6, 2C8 substrate
P-gpinhibitor
P-gpsubstrate
P-gpsubstrate &
inhibitor
P-gpsubstrate
P-gpinhibitor
P-gpsubstrate &
inhibitor
P-gpsubstrate &
inhibitor
OATP1B1/3 inhibitor
BCRP substrate
BCRP substrate &
inhibitor
BCRP substrate;OATP1B1/3 substrate &
inhibitor;UGT1A1 inhibitor
OATP1B1, BCRP, and
OCT1 inhibitor
OATP1B1/3 substrate;
BCRP inhibitor
BCRP substrate &
Inhibitor;OATP1B
substrate &inhibitor
1. Simeprevir [package insert]. 2016. 2. Sofosbuvir [package insert]. 2015. 3. Ledipasvir/sofosbuvir [package insert]. 2016. 4. Paritaprevir/r/ombitasvir/dasabuvir [package insert]. 2015. 5. Elbasvir/grazoprevir [package insert]. 2016. 6. sofosbuvir/velpatasvir [package insert]
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Drug interactions between HIV and HCV treatment
SMV SOF LDV PrOD DCV EBR/GZR VEL
ATV/r No data No data LDV↑A↑ P↑ATV↑ DCV 30 E/G↑A↑ VEL↑A↑
DRV/r SMV↑ SOF↑ LDV↑ P↑↓D↓ DCV↑ E/G↑ ↔
LPV/r No data No data No data P↑ DCV↑ E/G↑ ↔
EFV SMV↓ ↔ LDV↓E↓ No PK data DCV 90 E/G↓E↓ VEL↓E↓
RPV ↔ ↔ ↔ ↔ No data ↔ ↔
ETR No data No data No data No data DCV 90 No data No data
RAL ↔ ↔ ↔ RAL↑ No data ↔R↑ ↔
EVG/COBI No data SOF↑C↑ LDV↑C↑ No data DCV 30 E/G↑C↑ VEL↑C↑
DTG No data No data ↔ P↓DTG↑ DTG↑ ↔D↑ ↔
TDF ↔ ↔ TDF↑ ↔ ↔ ↔T↑ ↔TDF↑
TAF No data SOF↑T↑ TAF↑ No data No data No data ↔TAF↑
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• Cannot be used with most ARVs• ARVs studied (N=58):
• Raltegravir (with NRTIs)• Rilpivirine (with NRTIs)
• AVOID use with CYP3A4 inducers or inhibitors• Not recommended to use simeprevir with:
• ARVs: Efavirenz, etravirine, cobicistat, or boosted HIV PIs• 3A4 (-): azoles, macrolides• 3A4 (+): anticonvulsants, rifamycins, St. John’s Wort
• SOF regimens should never be used with TPV
Simeprevir + Sofosbuvir DDIs
1. AASLD/IDSA. HCV guidance. July 2016. 2. Simeprevir [package insert].
SMV
ATV/r No data
DRV/r SMV↑
LPV/r No data
EFV SMV↓
RPV ↔
ETR No data
RAL ↔
EVG/COBI No data
DTG No data
TDF ↔
TAF No data
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• Can be used with most ARVs• ARVs studied in ION-4 (N=335):
• Raltegravir (with TDF/FTC)• Rilpivirine (with TDF/FTC)• Efavirenz (with TDF/FTC)
• AVOID use with TDF if RTV or COBI boosted regimens
• TAF may be an alternative to TDF• TFV levels only 20% of typical exposures seen with TDF
• If high urgency for HCV treatment AND high risk of switching ART AND no safer alternative to LDV/SOF
• Frequent urinalysis monitoring q2-4 weeks
• SOF regimens should never be used with TPV
Ledipasvir/sofosbuvir DDIs with ART
AASLD/IDSA. HCV guidance. July 2016.
LDV
ATV/r LDV↑A↑
DRV/r LDV↑
LPV/r No data
EFV LDV↓E↓
RPV ↔
ETR No data
RAL ↔
EVG/COBI LDV↑C↑
DTG ↔
TDF TDF↑
TAF TAF↑
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LDV/SOF and Acid-Suppressing Agents• LDV solubility decreases with increasing pH
• Findings suggest greater decrease in LDV exposure when coadministered with acid suppressor in HCV/HIV infection vs HCV monoinfection
• In real-world HCV-TARGET database of pts receiving LDV/SOF, PPI use associated with higher failure rate
• Real-world TRIO Network analysis demonstrated no effect of PPI use on SVR rate with LDV/SOF except for BID PPI use in univariate analysis
• LDV/SOF package insert: Proton pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously under fasted conditions
1. LDV/SOF [package insert]. 2. Terrault N, et al. AASLD 2015. Abstract 94. 3. Afdhal N, et al. EASL 2016. Abstract LBP519. 4. German P, et al. AASLD 2015. Abstract 1133.
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PTV/r/OBV + DSV “PrOD” DDIs• Cannot be used with most ARVs
• ARVs studied in TURQUOISE-1 (N=63):• Raltegravir• Atazanavir *must administer same time as PrOD
and hold RTV*
• AVOID use with:• ARVs: darunavir, lopinavir, tipranavir, all
NNRTIs, cobi• Others: 3A4 inhibitors (clarithromycin), 2C8
inhibitors (gemfibrozil), inducers (anticonvulsants, rifamycins) 3A4 substrates (simvastatin, lovastatin), ethinyl estradiol
• Should not be used in patients who are not on ART
1. AASLD/IDSA. HCV guidance. July 2016. 2. Paritaprevir/ritonavir/ombitasvir/dasabuvir [package insert].
PrOD
ATV/r P↑ATV↑
DRV/r P↑↓D↓
LPV/r P↑
EFV No PK data
RPV ↔
ETR No data
RAL RAL↑
EVG/COBI No data
DTG P↓DTG↑
TDF ↔
TAF No data
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Daclatasvir + Sofosbuvir DDIs• Can be used with most ARVs
• ARVs studied in ALLY-2 (N=203):• PIs: atazanavir/r, darunavir/r, lopinavir/r• NNRTIs: efavirenz, rilpivirine, nevirapine• INSTIs: raltegravir, dolutegravir
• DCV + SOF recommended in HCV/HIV coinfection by AASLD when ART regimen changes cannot be made to accommodate other DAAs
• REMEMBER dose adjustments:• Decrease to 30mg when used with atazanavir/r
• No data with cobicistat• Increase to 90mg when used with efavirenz,
etravirine, nevirapine
1. Wyles DL, et al. N Engl J Med. 2015;373:714-725. 2. AASLD/IDSA. HCV guidance. July 2016.
DCV
ATV/r DCV 30
DRV/r DCV↑
LPV/r DCV↑
EFV DCV 90
RPV No data
ETR DCV 90
RAL No data
EVG/COBI DCV 30
DTG DTG↑
TDF ↔
TAF No data
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Elbasvir/grazoprevir DDIs• Cannot be used with most ARVs
• ARVs studied in C-EDGE COINFECTION (N=218):
• raltegravir• rilpivirine• dolutegravir
• AVOID use with:• All boosted regimens
• Increased grazoprevir exposure -> hepatotoxicity potential
• Inducers (EFV, ETR, NVP)• EFV reduced exposure of EBV/GZR 50%/80%
1. Rockstroh JK, et al. Lancet HIV. 2015;2:e319-e327 2. AASLD/IDSA. HCV guidance. July 2016.
EBR/GZR
ATV/r E/G↑A↑
DRV/r E/G↑
LPV/r E/G↑
EFV E/G↓E↓
RPV ↔
ETR No data
RAL ↔R↑
EVG/COBI E/G↑C↑
DTG ↔D↑
TDF ↔T↑
TAF No data
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• Can be used with most ARVs• ARVs studied in ASTRAL-5 (N=106):
• PIs: atazanavir/r, darunavir/r, lopinavir/r • NNRTI: rilpivirine• INSTIs: raltegravir, elvitegravir/cobi
• AVOID use with:• Efavirenz, etravirine, or nevirapine• TDF in patients with CrCl <60 ml/min
• If CrCl >60, TDF with boosted regimens did not lead to toxicity
• Renal monitoring recommended• TAF may be an alternative
Sofosbuvir/velpatasvir DDIs
AASLD/IDSA. HCV guidance. July 2016.
VEL
ATV/r VEL↑A↑
DRV/r ↔
LPV/r ↔
EFV VEL↓E↓
RPV ↔
ETR No data
RAL ↔
EVG/COBI VEL↑C↑
DTG ↔
TDF ↔TDF↑
TAF ↔TAF↑
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Renal Function With SOF/VEL + TDF• No clinically relevant change in CrCl when SOF/VEL coadministered with TDF-
containing ART regimens
Med
ian
Cre
atin
ine
Cle
aran
ce
(mL/
min
)
Median CLcr,mL/min
103 98 97 95 100 10096 85 89 92 92 9380 86 81 81 82 87
Wyles D, et al. EASL 2016. Abstract PS104. Slide credit: clinicaloptions.com
140
120
100
80
60
Nonboosted TDF Boosted TDF Non-TDF–containing regimen
BL 1 2 4 6 8 10 12 FU-4 FU-12Wks
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What about SOF/VEL and acid suppressing agents?
• SOF/VEL package insert:• Coadministration with PPIs is not recommended
• If it is considered medically necessary, SOF/VEL should be administered with food and taken 4 hours before omeprazole 20 mg
• H2RAs simultaneously administered with or separate by 12 hours
• Not to exceed equivalent of famotidine 40mg BID• Antacids separate by 4 hours
Sofosbuvir/velpatasvir [package insert].
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http://www.hep-druginteractions.org/
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Other considerations in HIV/HCV coinfection
• Switching ART in virologically suppressed patients• Review ART history for intolerance or virologic failure and resistance
results• If prior resistance uncertain, consider switch only if new regimen likely to
maintain suppression of resistant virus
• Increase monitoring first 3 months after changes in ART• HBV coinfection• Failed NS3/4 or NS5A inhibitor therapy
• Defer treatment if possible• Resistance testing • Use SOF based treatment x 24 weeks PLUS RBV• If available, triple or quadruple DAA regimens should be considered
DHHS Guidelines. August 2016.©American College of Clinical Pharmacy 28
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Patient case• 60 year old male with PMH of HIV, HCV, PAD s/p stents,
HTN, HLD, BPH, COPD• Treated with PEG, ribavirin and telaprevir in 2012 but
discontinued d/t adverse effects • HIV well controlled on efavirenz + tenofovir + ABC/3TC• Other medications: atorvastatin 40, aspirin 81,
clopidogrel 75, lisinopril 40, nifedipine XL 60, metoprolol 100 BID, omeprazole 40, fishoils, tamsulosin, tiotropium
• Baseline labs:• HCV Genotype: 1b HCV RNA: 3,430,700 IU/mL Hgb: 15.8• F4 Child-Pugh Score A ALT: 151 U/L AST: 141U/L SCr 0.8
• What HCV regimens are options for treatment?
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Conclusions• Identify drug-drug interactions prior to choosing HCV
DAA regimen• All DAA regimens are unique
• Treatment in HIV/HCV coinfection is the SAME as HCV monoinfection
• Recommend against 8 week treatment• Adverse drug reactions are tolerable with minimal
discontinuations • Switching ART may be preferred
• If cannot change ART regimen, daclatasvir + sofosvuvir is recommended
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References• Graham, et al. CID 2001:33(4):562-569• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in
HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed August 8, 2016
• AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed August 8, 2016
• Simeprevir [package insert]. 2016. • Sofosbuvir [package insert]. 2015. • Ledipasvir/sofosbuvir [package insert]. 2016. • Paritaprevir/r/ombitasvir/dasabuvir [package insert]. 2015. • Elbasvir/grazoprevir [package insert]. 2016. • sofosbuvir/velpatasvir [package insert]• Martinello M, et al. CROI 2016. Abstract 451.• Garrison K, et al. International Workshop Clin Pharm HIV/Hep Therapy 2015. Abstract 71. • Custodio J, et al. IDWeek 2015. Abstract 727. • Terrault N, et al. AASLD 2015. Abstract 94. • Afdhal N, et al. EASL 2016. Abstract LBP519. • German P, et al. AASLD 2015• D DelBello, A Cha, et al. CID 2016;62(12):1497-504 • S Naggie et al. NEJM 2015; 373:705-713• JK Rockstroh et al. IAC 2016 • DL Wyles et al. NEJM 2015;373(8):714-25• JK Rockstroh et al. Lancet HIV 2015:Aug;2(8):e319-27 • DL Wyles et al. EASL 2016
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Solid organ transplantation in the HIV+ patient
Jennifer Cocohoba, PharmD, BCPS, AAHIVPUniversity of California San Francisco School of Pharmacy
10/24/2016
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Conflict of Interests
• I have no conflicts of interest to declare with regards to this presentation
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Learning Objectives
• Compare and contrast the clinical outcomes in HIV-infected versus uninfected organ transplant recipients.
• Outline unique solid-organ pre-transplant evaluations required in an HIV-infected patient.
• Assess critical drug-drug interactions between antiretrovirals and immunosuppressive therapy used in organ transplantation.
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Liver transplant in HIV
HIV+ patients in study • 1 year survival = 85% • 3 year survival = 66%• Reinfection with HCV =
94% • Factors: HBV,
undetectable HIV VL
SURVIVAL (U.S. SRTR)
• 1 year survival = 88%
• 3 year survival = 78%
• Reinfection with HCV = 95%
• Systematic review and meta-analysis• Pooled cohorts (random effects analysis)• Synthetic cohort of case data
• 15 cohort studies and 49 case series published through 2010
• Cohort data = 686 patients• Case series = 216 patients (10 lost)
• Median f/u = 19 months
Cooper, et. al. AIDS 2011, 25:777–786
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Kidney transplant in HIV
HIV+ patients in study • 1 year survival = 94.6% • 3 year survival = 88.2%• 3 year graft survival = 73.7%• Rejection at 1 years = 31%• No progression of HIV
disease
SURVIVAL (U.S. SRTR)
• 1 year survival = 96.2%
• 3 year survival = 90.6%
• 3 year graft survival = 82.8%
• Rejection at 1 years= 12.3%
• Multicenter prospective study (n=150)
• CD4 > 200, undetectable VL, on ART
• F/U: 1.7 years (IQR 0.7 – 3.0)
• Rejection: immunosuppression, memory and T cell response. Allosensitization, cross reactivity
Stock PG, et al. N Engl J Med. 2010;363:2004–14
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Heart transplant in HIV
SURVIVAL (U.S. SRTR)
• 1 year survival = 84%
• Predisposing factors to heart transplant in HIV
• Heart transplants in HIV+ persons• Pre-HAART = 11 patients, Modern era of ART = ~12 reported worldwide• 3 recorded cases of people who acquired HIV post-transplant
• Demographics (modern ART era, n=12)• Age > 50, on ART, CD4 > 200 cells/mm• 13/15 survived with normal graft function at end of follow up period• Rejection reported in 11/15; 2 deaths• No progression to AIDS but more severe hospitalizations
Aguero, et. al. Am J of Transplantation 2016; 16: 21–28
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Lung transplant in HIV
SURVIVAL (Thabut et al.)
• 1 year survival = 80%
• Case1 • 45 yo HIV/HBV+ M, CD4= 891, TDF/3TC/EFV, and CF (age 9)• Bilateral lung transplant, 9 months bronch stenosis/stent, 2 years post-op
• Case series patient #1• 40 yo F, CD4 > 1000 on AZT/3TC/EFV with PAH (NYHA III)• Bilateral lung transplant with complicated course
• Case series patient #2• 65 yo M, HCV+, CD4 = 302 on TDF/FTC/ATV with idiopathic pulm fibrosis
Bilateral lung transplant, rejection, granulationtissue/stent, pseudomonas
• Case series patient #3• 60 yo M, CD4 = 407 on ABC/3TC/ATV/RTV with idiopathic pulm fibrosis • Hx Hodgkin’s Lymphoma• Single R lung transplant: acute rejection but excellent status at 2 years
Weill et. al. J Heart Lung Transpl 2015; 34: 1-15 Kern, et. al. Annals Am Thoracic Society 2014; 11: 882-889Thabut et. al. JAMA. 2010;304(1):53-60
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HOPE for solid organ transplant in HIV
• National Organ Transplant Act (1980s)
• HIV Organ Policy Equity Act (November 2013)
• First HIV+/HIV+ transplants (March 2016)
192 kidneys247 livers
4-5 deaths/year 356 deaths/year
Richterman, et. al. Am J Transplantation 2015; 15: 2105–2116
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2016 ACCP Annual Meeting
A new era: HIV+ to HIV+ transplant
• Considerations for HIV+ donor screening
• Benefits• HIV+ donors and recipients• HIV(-) individuals
• Questions• Living donors
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2016 ACCP Annual Meeting
Pre-transplant evaluation for HIV+ patients
• Center criteria
• HIV-specific pre-transplant assessments• CD4: typically >200 cells/mm3 for kidney heart and lung, >100 cells/mm3 for liver, • HIV-1 viral load within the 16 weeks prior to transplant on stable ART• Active opportunistic infections (PCP, MAC, Toxo, etc.) & neoplasms• Outcomes better if BMI > 21 kg/m2 and healthy kidney in HIV/HCV+ • Assess HIV regimen for potential drug-drug interactions• Assess other medicines for potential drug-drug interactions
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2016 ACCP Annual Meeting
Managing the medications
• Great strides in solid organ transplant with HIV+ persons
• Rapidly evolving antiretroviral therapy (ART) regimens• Simpler• Better adverse effect profiles
• Balancing immunosuppression with effective ART• 1st regimen/new start – may be able to avoid/moderate drug interactions• Versus treatment experienced – may need to manage drug interactions
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ImmunosuppressantsClass Examples Metabolism Interaction ?
T-cell depletingantibodies
Alemtuzumab, muromonab-CD3, ATG
Phagocytosis
Calcineurin inhibitors Cyclosporine, tacrolimus Hepatic, CYP3A4 Antimetabolites Azathioprine,
mycophenolateHepatic, GST orhydrolysis/glucuronidation
Mammalian target of rapamaycin inhibitors
Sirolimus, everolimus Hepatic, CYP3A4
Corticosteroids Prednisone, prednisolone Hepatic, 11β-hydroxysteroiddehydrogenases, CYP3A4
Anti-CD28 Belatacept (amino acids)
Proteosome inhibitors Bortezomib Hepatic, CYP2C19, CYP3A4
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Case 1
• 50 yo M contracted HCV and HIV in 80’s due to IVDU, now pending liver transplant
• What HIV specific assessments to perform?
• How to manage HIV?
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2016 ACCP Annual Meeting
Case 1: Pre-transplant evaluation for HIV+ patients
• Center criteria
• HIV-specific pre-transplant assessments• CD4: 400 cells/mm3• No history of opportunistic infections or neoplasms• SCr = 1.0; BMI = 24 • HIV-1 viral load: not undetectable, treatment naïve, start therapy• Other medicines: Not on any other medications
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DHHS guidelines for treatment naïve
• Dolutegravir plus…• Abacavir/lamivudine• Tenofovir disoproxil
fumarate/emtricitabine• Tenofovir alafenamide/emtricitabine
• Raltegravir…• Tenofovir disoproxil
fumarate/emtricitabine• Tenofovir alafenamide/emtricitabine
• Elvitegravir/cobicistat plus…• Tenofovir disoproxil
fumarate/emtricitabine• Tenofovir alafenamide/emtricitabine
• Darunavir/ritonavir plus…• Tenofovir disoproxil
fumarate/emtricitabine• Tenofovir alafenamide/emtricitabine
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Recognizing ART interaction potentialClass Examples Effects
Protease inhibitors Atazanavir, darunavir, ritonavir
Inhibit CYP3A4 –↑ immunosuppressant levels
Non-nucleoside RT inhibitors
Efavirenz, etravirine, nevirapine, (rilpivirine*)
Mixed, often induce CYP3A4 –↓ immunosuppressants
Integrase inhibitors and PK enhancer
Elvitegravir/cobicistat(raltegravir, dolutegravir)
Cobicistat only - Inhibit CYP3A4 –↑ immunosuppressant levels
Nucleoside RT inhibitors Tenofovir, lamivudine, emtricitabine, abacavir
None
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Integrase inhibitors and immunosuppressants
• Minimal drug-drug interactions• Raltegravir: Case reports with cyclosporine, tacrolimus, sirolimus, mycophenolate --
- all ok at standard doses• Dolutegravir: no data, unlikely to interact• Treatment naïve patients – regimen of choice!
• Elvitegravir (used with cobicistat)• Likely to ↑↑ immunosuppressants, but no case reports or studies• Consider starting with lower dose or longer interval• Monitor levels
©American College of Clinical Pharmacy 48
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Protease inhibitors and immunosuppressants
• Tacrolimus• Case reports: ↑ ↑ ↑ with lopinavir/ritonavir, amprenavir, nelfinavir,
fosamprenavir/ritonavir, darunavir/ritonavir• Begin with VERY small doses ~0.05/day• May need to ↑ interval (e.g. 0.5mg/week) to achieve doses
• Cyclosporine• Case reports: ↑ with indinavir/ritonavir, lopinavir/ritonavir, ritonavir• Recommended reduction of 5-20% to maintain optimal levels
©American College of Clinical Pharmacy 49
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PIs and immunosuppressantsReference HIV Drug Immunosuppressant Outcome
Frassetto (2007) Any protease inhibitor
Cyclosporine 4-5 fold lower CSA dose PLUS 50% increase in dosing interval as compared to NNRTI. Ritonavir required even further dose reduction and increased interval!
Vogel (2004) Lopinavir/ritonavirIndinavir/ritonavir
Cyclosporine 80-95% dose reduction required for CSA. In case reports 0.5 mg- 1.0mg weekly
Jain (2003) Schonder (2003)
Protease inhibitors Tacrolimus Minimum suggested tacrolimus dose reduction =50%
Barau (2009) Fosamprenavir/ ritonavir
Tacrolimus Dose at 0.5mg every 4 days
Barau (2009) Fosamprenavir/ ritonavir
Sirolimus Dose at 1 mg weekly
Meretz (2009) Darunavir/ ritonavir Tacrolimus Dosed at 0.5 mg weekly
Tsaperas (2011) Atazanavir Tacrolimus Dosed at 1.5 mg twice daily
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NNRTIs and immunosuppressants
• Tacrolimus• Case reports: no change or ↓ with efavirenz, nevirapine• No data: etravirine, rilpivirine• Rilpivirine not inducer or inhibitor of CYP, therefore unlikely to cause interactions• May need to increase tacrolimus dose
• Cyclosporine• Case reports: ↓ with efavirenz (no data for nevirapine, etravirine, rilpivirine)• May need to increase cyclosporine dose
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NNRTIs and immunosuppressantsReference HIV Drug Immunosuppressant Outcome
Frassetto (2007) Efavirenz Cyclosporine Not much dose adjustment needed
Nevirapine Cyclosporine Not much dose adjustment needed
Stock (2003) Nevirapine Cyclosporine Not much dose adjustment needed
Frassetto (2007) Efavirenz Cyclosporine Increased (small) CSA dose required
Teicher (2007) Efavirenz Tacrolimus Increased (small) tacrolimus required
©American College of Clinical Pharmacy 52
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Case 2• 50 yo female ESRD
• HIV, uncontrolled HTN, regular crack use• Hoping for kidney transplant
• HIV• Tx previously but doesn’t recall regimens• Initially tenofovir/emtricitabine/efavirenz• Switched to abacavir/lamivudine,
efavirenz• Not suppressed• Genotype = K103N, M184V, M41L• Switched to abacavir/lamivudine,
darunavir/ritonavir, dolutegravir
Question from team,
“Can we just put her on abacavir/lamivudine/dolutegravir?”
©American College of Clinical Pharmacy 53
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A reminder: manage the medicines
• Divalent cations (calcium, iron)
• Proton pump inhibitors
• Voriconazole
• Atazanavir +/- ritonavir
• Dolutegravir
• Rilpivirine
• Darunavir +/- ritonavir
• Efavirenz
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Summary• Exciting era for solid organ transplant in HIV+ patients
• Survival similar to those without HIV -- learning more as more transplants are performed• May be higher rates of rejection
• Most ART – immunosuppressant interactions can be managed• ↓ doses of common immunosuppressants with protease inhibitors• doses of common immunosuppressants with NNRTIs• Monitor, monitor, monitor
• Pharmacist plays an important role in supporting appropriate pharmacotherapy for maintaining immmunosuppression, reducing risk of drug interactions, and maintaining control of HIV virus
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Malignancy in the HIV PatientDavid DeRemer, Pharm.D. BCOP FCCP
Clinical Associate Professor
Outpatient Hematological Malignancies/BMT Specialist
University of Georgia College of Pharmacy
Georgia Cancer Center
October 24, 2016
©American College of Clinical Pharmacy 56
2016 ACCP Annual Meeting
Conflict of Interests
• Merck Speaker’s Bureau
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Learning Objectives
• Summarize the incidence of AIDS and non-AIDS related cancer diagnoses in HIV-infected patients
• Identify potential drug-drug interactions between chemotherapy regimens and antiretrovirals
• Explain the expected clinical outcomes associated with HIV-infected cancer patients.
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People Living with HIV/AIDS (PLWHA)
Grulich AE et al. Lancet 2007 Jul 7;370(9581):59-67Schneider E et al. MMWR Recomm Rep. 2008 Dec 5;57(RR-10):1-12Deeken JF et al. Clin Infect Dis 2012 55(9):1228-35
AIDS- Defining Cancers (ADCs) Risk* Non-AIDS Defining Cancers (NADCs) Risk*
Kaposi sarcoma 3640 Anal 33.4-42.9
Hodgkins Lymphoma 14.7-31.7
Liver 7-7.7
Non-Hodgkins Lymphoma• Primary CNS• Burkitt’s• Diffuse large B-cell• Plasmablastic• Primary effusion
77 Skin• SCC/BC• Melanoma
3.21.1-2.6
Head and Neck 1-4.1
Lung 2.2-6.6
Leukemia 2.2-2.5
Cervical 6 Renal 1.8-2.2
*- Cancer risk (Standardized Incidence Ratio)
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ADCs – Incidence
Shiels MS et al. J Natl Cancer Inst. 2011;103(9):753-762
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NADCs- Incidence
Shiels MS et al. J Natl Cancer Inst. 2011;103(9):753-762
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NADCs• Pre-HAART era 8-38% (all HIV malignancies) -> ↑ 50-58% • Risk factors
• Advancing age (HR 1.99 per 10 years; P<0.001)• Caucasian (HR 1.56; P=0.02) • Length of HIV infection
• CD4+ T-cell counts < 200 cells/m3
• Smoking• Oncogenic viruses
Rubinstein PG et al. AIDS 2014 Feb 20;28(4):453-65 Reekie J et al. Cancer 2010 Nov 15; 116(22):5306-15
Shiels MS et al. J Natl Cancer Inst. 2011;103(9):753-762
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Global Burden of Virus Inducing Cancers
HPV
Hepatitis B
Hepatitis C
EBV
Other- Human T-cell lymphotrophic virus, Kaposi Sarcoma Herpesvirus (KSHV), Merkel cell polyomavirus (MCPV)
• 2012: 14 million new cases of cancer 15.4% attributable to carcinogenic infections
Plummer M et al. Lancet Glob Health 2016 Jul 25 [epub ahead of print]Parkin DM Int J Cancer 2006 Jun 15; 118 (12):3030-44
ADCs Virus NADCs VirusKaposi sarcoma KSHV 100% Anogenital carcinoma HPV 100%
Hodgkins lymphoma EBV 30-50%
Hepatocellular carcinoma HBV >90%
Non-Hodgkins Lymphoma• Primary CNS• Burkitt’s• Diffuse large B-cell• Plasmablastic• Primary effusion
EBV 80%EBV 20-90%EBV 10-20%
EBV 80%KSHV (+/-EBV)
Skin• Merkel cell carcinoma
MCPV >90%
Head and neck carcinoma 20-30%
Invasive cervical carcinoma HPV 100% ** Percentages represent attributable fraction
©American College of Clinical Pharmacy 63
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Link of cART and Developing Cancer ?
NEGATIVE
POSITIVE
Reekie J et al. Cancer 2010;116:5306-5315Guiguet M et al. Lancet Oncol 2009 Dec; 10(12):1152-9Crum-Cianflone NF et al. J Acquir Immune Defic Syndro. 2009 51:305-309
Chao C et al. AIDS 2012;26:2223-2231Varadarajan J et al. Proc Natl Acad Sci USA 2013;110:14747-14752Powles T et al. J Clin Oncol 2009;27:884-890
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Opportunities for Lifestyle Modifications• Smoking
• PLWHA > 50% compared to 18% of US general population
• ↑ risk of lungs, esophageal, genitourinary, head & neck, cervix
• ↑5x mortality in PLWHA
• Alcohol• PLWHA 2x consumption than general population• ↑ risk of oral, esophageal, hepatocellular
carcinoma Niaura R et al. Clin Infect Dis 2000 Sep;31(3):808-12Thun MJ et al. N Engl J Med 1997 Dec 11;337(24):1705-14Rubinstein PG et al. AIDS 2014 Feb 20;28(4):453-65
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Recent FDA Drug Approvals
0
2
4
6
8
10
12
14
2010 2011 2012 2013 2014 2015 2016
HIVCancer
*www.fda.gov Accessed August 1, 2016*August 2016
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Common Adverse Events – cART and Chemotherapy Adverse Event Chemotherapeutic agent or class HIV agent or class
Myelosuppression Alkylating agents, anthracyclines, antimetabolites, camptothecans, etoposide, taxanes, vinca alkaloids
Zidovidine
Neuropathies (motor/peripheral) Taxanes, vinca alkaloids, oxalipatin, bortezomib
Didanosine, stavudine
Nephrotoxicity Platinum alkylating agents –cisplatin, carboplatin
Tenofovir, indinavir
Nausea/vomiting Alkylating agents, anthracyclines,many others
Protease inhibitors, didanosine, zidovudine,
Hepatotoxicity Doxorubicin, dacarbazine Protease inhibitors, NRTIs, NNRTIs
Cardiotoxicity Anthracyclines, tyrosine kinase inhibitors (TKIs)
Atazanavir, saquinavir, ritonavir + lopinavir
Diarrhea Irinotecan, flurouracil Nelfinavir, lopinavirRubinstein PG et al. AIDS 2014 Feb 20;28(4):453-65Deekin JF et al. Clin Inf Dis 2012;55(9):1228-35
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Interactions – Chemotherapy and cARTEnzyme HAART inhibitor HAART inducer Chemotherapy
CYP3A4 Delavirdine, ritonavir, amprenavir, ataznavir, idinavir, lopinavir, nelfinavir, saquinavir
Nevirapine, efavirenz Cyclophosphamide, etoposide,paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine
CYP2C9 Efavirenz, ritonavir Cyclophosphamide
CYP2C19 Efavirenz, amprenavir Cyclophosphamide, ifosfamide
CYP2D6 Ritonavir Tamoxifen
CYP2B6 Efavirenz, nelfanivir, ritonavir Nevirapine Cyclophosphamide, ifosfamide
CYP2E1 Ritonavir Etoposide, dacarbazine
UG1A1 Atazanavir Irinotecan
Rubinstein PG et al. AIDS 2014 Feb 20;28(4):453-65Deekin JF et al. Clin Inf Dis 2012;55(9):1228-35
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Explosion of Oral Oncolytics
……AND MANY MORE ARE COMING !!!!!
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Selected TKIs in Non-Small Cell Lung Cancer (NSCLC) TKI Target Effect on CYP450 /transporters cART Avoid or Monitor
Afatinib EGFR P-gp: substrate and inhibitorCYP450: no effect
Cobicistat, darunavir, ritonavir, saquinavir
Alectinib ALK, RET CYP3A4 (minor) None
Ceritinib ALK, IGF-1R, ROS1 P-gp: substrateCYP3A4 (strong); 2C9 (moderate)
Atazanavir, cobicistat, darunavir, indinavir, nelfinavir, ritonavir, saquinavir
Crizotinib ALK, c-MET P-gp: substrate and inhibitorCYP3A4 (moderate), OCT1, OCT2
Same as above
Erlotinib EGFR CYP3A4 (major substrate), 1A2 (minor), UGT1A1 (inhibitor)
Same as above
Gefitinib EGFR CYP3A4 (major substrate), 2D6 (major substrate), 2C19 (weak inhibitor), 2D6 (weak inhibitor)
Tipranavir
Osimertinib EGFR P-gp:substrateCYP3A4 (minor substrate)
Atazanavir, indinavir, lopinavir, nelfinavir, ritonavir
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Case Presentation Patient ST is 58 year Caucasian male who recently presents with dyspnea and cough. Dx – Stage IIIA (T2,N1,MO) NSCLC adenocarcinoma
Pertinent pathology: positive exon 21 (L858R) mutation
PMH: HIV diagnosed in 2013 Current medications: darunavir 800 mg/cobicistat 150 mg 1 tab Qday + emtricitabine 200 mg/tenofovir 300 mg 1 tab Qday
• Carboplatin AUC 6• Paclitaxel 225 mg/m2 IV • Repeat every 21 days
Treatment A
• Erlotinib 150 PO daily Treatment B
THOUGHTS/QUESTIONS ?
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Guidance for Concurrent cART and Chemotherapy • Establish an ongoing partnership between HIV and oncology teams
• Initial therapy selection, changes in therapeutic plans• Dose modifications guidance is lacking
• Avoid overlapping toxicities • Newer generational agents with less drug interactions
• Dolutegravir, raltegravir, maraviroc
• Emphasize adherence • Prevent financial toxicity
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AIDS Malignancy Consortium Trial AMC 061• Phase I, n=19 enrolled into 2 arms• Arm 1- NNRTI based therapy + sunitinib 50 mg/day x 4 weeks followed by
2-week treatment break (6-week cycles)• Arm 2- Ritonavir PI- based therapy + escalated sunitinib 25 mg/day in
12.5 mg/day increments to a 50 mg/day
Study Design
• HIV+ with solid or hematological malignancy • CD4+ ≥ 50 cells/µL and stable HAART for a least 4 weeks• PI-based or NNRTI based regimen ≥ 3 drugs
Patient Population
• NNRTI patients tolerated sunitinib 50 mg/day • Ritonavir-based therapy recommended dose of sunitinib – 37.5 mg/day• No significant effect on CD4+ cell count or HIV viral load was observed Outcomes
Rudek MA et al. Cancer 2014 Apr 15;120(8):1194-202
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Analysis of Cancer Mortality in US HIV Patients • HIV/AIDS Cancer Match (HACM) data
• 14 population-based HIV and US cancer registries • Six HACM sites (CO, CN, GA, MI, NJ, and TX)
• Study population• n=1,816,461 (cancer); 6459 HIV/AIDS• HIV-infection – DLBCL (26%), lung (16.4%), anal (10.3%)
• Results• HIV-infected less likely to receive 1st course cancer tx (68.8% vs. 74.6%; P <0.01)• More advanced at dx (32.2% vs. 17%; P<0.01)
Coghill AE et al. J Clin Oncol 2015 33;2376-2383
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Analysis of Cancer Mortality in US HIV Patients
Malignancy HR 95% CI
Colorectal 1.49 1.21-1.84
Pancreas 1.71 1.35-2.18
Larynx 1.62 1.06-2.47
Lung 1.28 1.17-1.39
Melanoma 1.72 1.09-2.70
Breast 2.61 2.06-3.31
Prostate 1.57 1.02-2.41
Increased cancer-specific mortality (after adjustment for patient characteristics)
Coghill AE et al. J Clin Oncol 2015 33;2376-2383
** No increases in mortality noted for DLBCL, Hodgkin lymphoma, and anal cancer
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Historical Questions in HIV+ B-Cell Lymphoma
• Should be lower the doses of chemotherapy to reduce immunosuppression and risk of opportunistic infections?
• Continue cART during chemotherapy?• Optimal regimen? • Should we use rituximab due to increased risk of infection?
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DLBCL/Burkitt Lymphoma TreatmentSC-EPOCH-RR x 2 cycles
CT/FDG-PET
SC-EPOCH-RR x 1 SC-EPOCH-RR x 2-4
Resume cART
CR PR
No cARTEPOCH: etoposide, vincristine, doxorubicin, cyclophosphamideRR: rituximab days 1&5
Dunleavy K and Wilson WH. Blood 2012 Apr 5;199(14):3245-55
5-year follow up: PFS 84%, OS 68%
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National Comprehensive Cancer Network (NCCN) -2016• Regimens – No category 1 recommendation
• Rituximab containing, if CD4 <50 benefit of rituximab less clear• Intrathecal (IT) chemotherapy
• cART• AZT + non-boosted ritonavir should not be given -> myelosuppression• Consider changing to non-PI based or CYP3A4 neutral regimen
• Supportive care• Required- myeloid growth factor support, prophylaxis -> PCP, MAC (if CD4
<100), fungal • Strongly consider- HSV/VZV prophylaxis
National Comprehensive Cancer Network. Non-Hodgkin’s Lymphoma (Version 3.20146. https://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf Accessed August 10, 2016.
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Lung Cancer in HIV Patients• Onset 25-30 years earlier and lower exposure to cigarette smoking• Pathology – adenocarcinoma; advanced stage – III/IV• Chemotherapy +/- radiation
• GICAT study (n=68), improved OS (7 months vs. 3.8 months; p=0.01) in post-HAART era
• Molecularly targeted therapy• EGFR- Japanese study in HIV patients 29% of patients harbored mutation• ALK/KRAS/ROS-1 no data exists
Winstone TA et al. Chest. 2013;143:305-314Mok TS et al. N Engl J Med. 2009;361:947-957Bearz A et al. Eur Rev Med Pharmacol Sci 2014;18(4):500-8
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Immunotherapy in HIV Patients
Under Investigation in HIV patients
ClinicalTrials.gov IdentifierNCT02028403
PD-L1 Inhibitor in HIV+ patients receiving cART
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Summary • Increases in NADCs continues to be observed
• Active cancer prevention • Novel treatment strategies are warranted
• Drug interactions are probable but manageable• Interdisciplinary communication is essential
• Despite treatment advances PLWHA in general have ↑ cancer-specific mortality
©American College of Clinical Pharmacy 81
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