moderator: melissa badowski, pharm.d., bcps, aahivp · progression to cirrhosis or liver...

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.

©American College of Clinical Pharmacy 1

Self-Assessment Questions

Self-assessment questions are available online at www.accp.com/am


http://www.accp.com/am

2016 ACCP Annual Meeting

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



Conflict of Interest

• Participated on clinical advisory boards for Gilead Sciences and Janssen Therapeutics



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.



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



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


Presenter

Presentation Notes

* some studies suggest that ART may slow the progression of liver disease by preserving or restoring immune function and by reducing HIV-related immune activation and inflammation I have deferred only one patient Continued use of the modified regimen is necessary b/c of prolonged half life of some HCV drugs and potential risk of DDIs


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)



Helpful Drug Target Hints

‘’-previr” – NS3/NS4A protease inhibitors

“-asvir”- NS5A inhibitors

“-buvir”- NS5B polymerase inhibitors (nucleotides/non-nucleotides)

7©American College of Clinical Pharmacy 9

http://www.clipartpanda.com/categories/tip-20clipart

http://www.clipartpanda.com/categories/tip-20clipart


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.



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

9©American College of Clinical Pharmacy 11

Presenter

Presentation Notes

If RAVs for GT1a, need to add RBV and extend to 16 weeks If Q80K present in tx exp and cirrhosis, use other regimen. If failed simeprevir + PEG + RBV, cannot use PrOD and if using EBV/GZP, need to add RBV.


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



Presenter

Presentation Notes

DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin. ****in GT3 tx experienced cirrhotic patients, guidelines recommend using RBV with SOF/VEL, even though not in package insert. And if Y93 positive, add RBV.****


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


Presenter

Presentation Notes

SIM/SOF: In an intention-to-treat analysis, SVR rates were 76% (31/41) for simeprevir (SMV)/SOF, 94% (16/17) for SMV/SOF/ribavirin (RBV). Per protocol 31/35 (89%) 16/16 (100%). We had 4 virologic relapses, 3 were tx experienced, 3 had cirrhosis, none with RBV. ION-4: Overall, the SVR12 rate was 96% (321/335); 2 patients had on-treatment virologic failure judged to be a result of nonadherence, 10 had virologic relapse after discontinuing treatment, 1 died from endocarditis associated with injection drug use, and 1 was lost to follow-up. TURQUOISE: Of the 31 patients who received 12 weeks of PrOD and ribavirin, 29 (93.5%) achieved an SVR12, 1 relapsed, and 1 withdrew consent from study participation. Similarly, of the 32 subjects in the 24-week arm, 29 (90.6%) achieved an SVR12, 1 experienced viral breakthrough, and 2 had apparent HCV reinfection ALLY-2: However, among patients who received 8 weeks of combination therapy, only 76% of patients achieved an SVR. Factors associated with relapse in this patient group included high baseline HCV RNA level (>2 million IU/mL; 69%), concomitant use of a boosted darunavir-based antiretroviral regimen with 30 mg of daclatasvir (67%), and the presence of cirrhosis (60%).


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.


Presenter

Presentation Notes

HOWEVER, GECCO study published end of August 2016. GECCO study was German cohort looking at real world SOF/LDV for 8 weeks. 35 HIV-HCV-coinfected patients. 96.4% (27/28) in HIV-HCV coinfected patients. Only 28 were included in efficacy analysis - Cirrhosis was excluded. ITT was 91% (30/33)


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.


Presenter

Presentation Notes

SMV/SOF: 1 developed full body rash after starting new HTN medicine, another had N/V after 1 dose. Of course with RBV added, rash pruritis and fatigue were increased.


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]


Presenter

Presentation Notes

BCRP, breast cancer resistance protein; DAA, direct-acting antiviral; DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OATP, organic anion-transporting polypeptide; OBV, ombitasvir; PTV, paritaprevir; RAV, resistance-associated variants; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir; VEL, velpatasvir.


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↑


Presenter

Presentation Notes


• 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


Presenter

Presentation Notes

Drug interaction studies with antiretroviral drugs in HIV-uninfected volunteers suggested no substantial interactions with tenofovir, rilpivirine, or raltegravir; however, simeprevir concentrations were substantially decreased when dosed with efavirenz and substantially increased when dosed with ritonavir-boosted darunavir. Use with efavirenz, etravirine, cobicistat, or boosted HIV protease inhibitors is not recommended SMV: ETR no data but I wouldn’t risk it


• 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


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↑


Presenter

Presentation Notes

ION-4 excluded PIs and E/C because cobi trough levels are increased 4 fold. ARVs studied: RAL, RPV, EFV (with TDF/FTC) N=335 Avoid administering TDF with RTV boosted PIs and LDV because TDF levels exceeded those deemed renally safe. **If urgency of HCV and risk of switching ART are high and no safer alternative to LDV/SOF, then frequent urine monitoring q2-4 weeks is recommended for RTV boosted PIs. Healthy volunteer study showed E/C/F/TAF and LDV/SOF found TFV levels were only 20% of typical exposures seen with TDF


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.


Presenter

Presentation Notes

Coinfected patients have 30% less LDV exposure than mono, don’t know why. *Won’t go into all the drug interactions like amiodarone and rosuvastatin, but since PPIs are so commonly used did want to mention this. (no effect in multivariate analysis) * Personally, avoid use whenever possible. Only time have used was in a patient with h/o GI bleed and on dual antiplatelets b/c of significant CAD. And lowered dose from 40 to 20mg.


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


Presenter

Presentation Notes

Phase II study of PrOD + RBV in HCV/HIV coinfection included pts with ATV- or RAL-based ART only[1] What about darunavir? **in healthy volunteer studies, DRV troughs were decreased 48% QD and 43% BID, but in TURQUOISE I- part 1b QD was only decreased 35% and BID only 25% decreased so likely can use DRV but small Ns***Paritaprevir AUC increased 30% and 41% - clinical significance is not clear and should not be used with DRV/r. Healthy volunteers, EFV/TDF/FTC resulted in clinically significant GI and neurologic ADEs, with increased ALT levels. With RPV, RPV levels are substantially increased with risk of QT prolongation


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


Presenter

Presentation Notes

90mg with EFV based on modeling. 120mg was studied and was excessive. 20mg was studied with ATV/r which was excessive and got 30mg dose from modeling/simulation. ALLY-2 used 30mg in DRV/r and LPV/r and failures from DRV/r. The PK of DRV and LPV are not substantially affected by DCV. Gandhi, 2015 Dose adjustments need to be kept in mind when used with other inhibitors and inducers as well. For example, rifamycins and AEDs are contraindicated.


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



• 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


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↑


Presenter

Presentation Notes

(with TDF/FTC or ABC/3TC) **Different than ledipasvir!!! When volunteers took sofosbuvir/velpatasvir with efavirenz/TDF/FTC, velpatasvir exposure fell about 50% and efavirenz was excluded from phase 3 studies. Etravirine expected to have similar impact Taking sofosbuvir/velpatasvir with TDF-containing regimens resulted in 20% to 81% higher tenofovir exposure, but sofosbuvir/velpatasvir did not affect concentrations of TAF


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


Presenter

Presentation Notes

ART, antiretroviral therapy; BL, baseline; CrCl, creatinine clearance; HCV, hepatitis C virus; SOF, sofosbuvir; TDF, tenofovir disoproxil fumarate; VEL, velpatasvir.

http://www.clinicaloptions.com/oncology


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].


Presenter

Presentation Notes

LDV, ledipasvir; SOF, sofosbuvir; VEL, velpatasvir. **different than LDV of course. IF must use PPI, take 4hrs before omeprazole 20 whereas LDV is SIMULTANEOUSLY**


http://www.hep-druginteractions.org/


Presenter

Presentation Notes

Ribavirin – should not be used with ddI b/c potential for mitochondrial toxicity (increased ADE of ddI), steatosis, pancreatitis, lactic acidosis. Should not be used with AZT b/c of increase risk anemia


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

Presenter

Presentation Notes

Within-class switches usually maintain virologic suppression if no resistance to drugs in that class


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?


Presenter

Presentation Notes

He was hospitalized with severe anemia and required blood transfusions SMV/SOF? – No b/c h/o NS3/4A use LDV/SOF? – Yes, if you reduce omeprazole to 20mg or switch to H2RA. However would opt for 24 weeks instead of 12+RBV PrOD? – No b/c patient is on EFV DAC/SOF? – Yes, if you increase DAC to 90mg. But alt option b/c 24 weeks ELB/GZP? – Don’t need to worry about NS5A resistance b/c he’s GT1b, but No b/c patient is on EFV SOF/VEL? – Would also need to reduce omeprazole to 20mg and separate by 4 hours, but No b/c patient is on EFV Treated with LDV/SOF for 24 weeks. However, IF switched from EFV to RPV, could use SOF/VEL x 12 weeks or ELB/GZP x 12 weeks


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



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


http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf

http://www.hcvguidelines.org/


Solid organ transplantation in the HIV+ patient

Jennifer Cocohoba, PharmD, BCPS, AAHIVPUniversity of California San Francisco School of Pharmacy

10/24/2016



Conflict of Interests

• I have no conflicts of interest to declare with regards to this presentation



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.



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%


• 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


Presenter

Presentation Notes

Hepatitis associated liver disease still high cause of death in people living with HIV+ Both of these 1-year survival rates (16% in HIV and 17% in European Centers) are slightly lower than that reported in the Scientific Registry of Transplant Recipients in the United States of America between 2003 and 2005 (12% mortality at year 1) individuals positive for HBV were 8.28 (95% CI 2.26– 30.33) times more likely to survive when compared to undetectable HIV viral load at the time of transplantation were 2.89 (95% CI 1.41–5.91) times more likely to survive HCV negative predictor of survival in unadjusted model [0.23 (95% CI 0.07–0.79)] but not when adjusted for by other key predictors of patient survival [0.54 (95% CI 0.17–1.80


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


• 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


Presenter

Presentation Notes

Renal disease on the rise in people living with HIV due to HIVAN and other HIV associated kidney dysfunction, and increasing comorbidities such as diabetes and HTN Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected recipients. N Engl J Med. 2010;363:2004–14. Year = 2003-2009; 19 centers HIV Vl < 50 or < 75 by bDNA in the 16 weeks prior to transplant Previous Ois acceptable except for those without treatment PML, CNS lymphoma, visceral KS, etc. Deceased and living kidney donors Immune suppresion was used including glucocorticoids, cyclosporine, tac, sirolimus, IL2 and ATG permitted No ART restriction PCP px, fluconazole, CMV px (depending on donor recipient status), MAC px PRN HBV and HCV required bx with no cirrhosis (> stage 2 fibrosis). HBV needed undetectable HBSag and HCV could elect IFN tx Eval frequently monthly, then 2-3 months year 2/3, q 6 months year 4/5 Allograft biopsies were performed for clinical indications, and rejection was defined according to the Banff classification, required biopsy confirmation. Most reviewed by central pathologist. Graft survival = patient needing dialysis or death. U.S. Scientific Registry of Transplant Recipients Aggressive acute rejection within 6 months after transplantation suggests an inherently enhanced response to donor antigens Summary: A prospective, nonrandomized trial of kidney transplantation in 150 HIV-infected patients. The patient survival of HIV-infected recipients in this study was similar to that observed in HIV-uninfected recipients older than 65 years of age during the same time period. Rejection rates were higher in HIV-infected kidney recipients than what is observed in non-infected patients. However, the higher observed rejection rates did not have a significant impact on overall short-term graft survival


Heart transplant in HIV



• 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


Presenter

Presentation Notes

Kendall CE, Wong J, Taljaard M, et al. A cross-sectional, population-based study measuring comorbidity among people living with HIV in Ontario. BMC Public Health 2014; 14: 161.� Patients with HIV infection have a significantly higher risk of cardiovascular disease (CVD) than non-HIV-infected patients and the prevalence of heart failure is reportedly 3%, that is, twofold higher than in the non- HIV-infected cohort. However, the prevalence of end-stage heart failure (ESHF) in HIV-infected patients is unknown. cART seems to have caused a shift from dilated cardiomyopathy with severely reduced ejection fraction to mildly reduced left ventricular function Approximately 20 people will need a LVAD or transplant anually (Uriel N, Nahumi N, Colombo PC, et al. Advanced heart failure in patients infected with human immunodeficiency virus: Is there equal access to care? J Heart Lung Transplant 2014; 33:924–930)


Lung transplant in HIV

SURVIVAL (Thabut et al.)


• 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


Presenter

Presentation Notes

HIV = independent risk for COPD, asthma, lung cancer, interstitial lung disease, and PAH (0.5% in subgroups) International Society of Heart Lung Transplant (2014) consensus statement: For patients infected with human immunodeficiency virus (HIV), a lung transplant can be considered in patients with controlled disease with undetectable HIV-RNA, and compliant on combined anti-retroviral therapy. The most suitable candidates should have no current acquired immunodeficiency syndrome–defining illness. Lung transplantation in HIV-positive candidates should be performed in centers with expertise in the care of HIV-positive patients 1 published report of HIV/HBV for CF – survived at 2 years post transplant Case series patient #1 = = grade 3 graft dysfunction, recurrent grade A2 rejection 1st year, RSV at 15 months, brochiolitis obliterans, limited functional status at 4 years but surviving. Case series patient #2 = stents remain patent and the patient is free of bronchiolitis obliterans syndrome 3 years post-transplant


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


Presenter

Presentation Notes

With worse outcomes on the waitlist, HIV-infected patients may actually be disproportionately affected by the organ shortage in the United States Organs from HIV+ donors being thrown away d/t Retrospective study of 6 clinics in Philadelphia, PA (2009-2014) assessing potential for HIV infected donors. Possibly 4-5 annually 356 donors, 192 kidneys, 247 livers nationally, this would approximate 356 potential HIVDD yielding 192 kidneys and 247 livers annually. Donor risk indices = quality of kidneys due to age of donors and comorbidities. Livers similar quality to HIV(-) donors, but high prevalence hepatitis C+. 3 years later after the congressional bill was signed into law by President Obama, the first HIV+ HIV+ liver and kidney transplants from a deceased HIV+ donor were performed by Dr. Dorry Segev at John Hopkins. South Africa has reported HIV+ kidney transplants, but this is 1st liver


A new era: HIV+ to HIV+ transplant

• Considerations for HIV+ donor screening

• Benefits• HIV+ donors and recipients• HIV(-) individuals

• Questions• Living donors


Presenter

Presentation Notes

Donor screening: same as others but a few more, risk of disease due to HIV alone, superinfection,


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


Presenter

Presentation Notes

Lower patient and graft survival was observed in patients with a BMI less than 21 kg/m2, and who needed a concomitant kidney transplant[15••], For liver transplantation, a CD4+ T-cell count of >100 cells/mm3presumed splenic sequestration due to portal hypertension level checked in the 16 weeks prior to transplant [19]. One exception to this is in liver transplant candidates who are not able to tolerate HAART because of drug-associated hepatotoxicity. In this case, HIV-infected patients can be considered for transplantation if viral suppression could be confidently predicted to occur post-transplantation with available antiretroviral therapies.


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


Presenter

Presentation Notes

Great strides, yet delicate, as rejection may be worse. Pharmacokinetic: “When a drug interrupts what the body does to another drug” Two drugs interrupt the other’s Absorption… Distribution… Metabolism… Elimination… Pharmacodynamic: “What the drugs do to the body” PD interaction often results in enhanced toxicity due to additive effects: * Morphine + benadryl = sleepiness PD interaction can result in antagonism of effects: * Beta blocker BP but antipsychotic BP


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


Presenter

Presentation Notes

Many different types: T-cell depleting antibodies (such as alemtuzumab, muromonab-CD3, antithymocyte globulin, the interleukin 2 receptor blocking antibodies calcineurin inhibitors (ciclosporin and tacrolimus) Antimetabolites (azathioprine and mycophenolate) glutathione S-transferase mTORi (sirolimus and everolimus) Corticosteroids Anti-CD28: belatacept Proteosome inhibitors: Bortezomib Others: leflunomide, FTY720, efalzumab Most centres start treatment with triple therapy of tacrolimus, mycophenolate and corticosteroids, reducing to mono- or double therapy. Worry about renal failure due to CNI


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?



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


Presenter

Presentation Notes

Lower patient and graft survival was observed in patients with a BMI less than 21 kg/m2, and who needed a concomitant kidney transplant[15••], For liver transplantation, a CD4+ T-cell count of >100 cells/mm3presumed splenic sequestration due to portal hypertension level checked in the 16 weeks prior to transplant [19]. One exception to this is in liver transplant candidates who are not able to tolerate HAART because of drug-associated hepatotoxicity. In this case, HIV-infected patients can be considered for transplantation if viral suppression could be confidently predicted to occur post-transplantation with available antiretroviral therapies.


DHHS guidelines for treatment naïve

• Dolutegravir plus…• Abacavir/lamivudine• Tenofovir disoproxil

fumarate/emtricitabine• Tenofovir alafenamide/emtricitabine

• Raltegravir…• Tenofovir disoproxil


• Elvitegravir/cobicistat plus…• Tenofovir disoproxil


• Darunavir/ritonavir plus…• Tenofovir disoproxil




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



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



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



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



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



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



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?”



A reminder: manage the medicines

• Divalent cations (calcium, iron)

• Proton pump inhibitors

• Voriconazole

• Atazanavir +/- ritonavir

• Dolutegravir

• Rilpivirine

• Darunavir +/- ritonavir

• Efavirenz



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



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



Conflict of Interests

• Merck Speaker’s Bureau



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.



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)



ADCs – Incidence

Shiels MS et al. J Natl Cancer Inst. 2011;103(9):753-762



NADCs- Incidence




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




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



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



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



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


http://www.fda.gov/


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



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



Explosion of Oral Oncolytics

……AND MANY MORE ARE COMING !!!!!



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



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 ?



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



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



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



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



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?



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%



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.



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



Immunotherapy in HIV Patients

Under Investigation in HIV patients

ClinicalTrials.gov IdentifierNCT02028403

PD-L1 Inhibitor in HIV+ patients receiving cART



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


moderator: melissa badowski, pharm.d., bcps, aahivp · progression to cirrhosis or liver...

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