expanding the pool of deceased donors: use of hepatitis c and …€¦ · hcv and opioids: a...

Expanding the Pool of Deceased Donors: Use of Hepatitis C and HIV Positive OrgansDAVID WOJCIECHOWSKI

Disclosures§I will discuss off label use of drugs

§Research support: Merck and Abbvie

Adults Listed for Kidney Transplant

SRTR Annual Data Report 2017

Three Year Outcomes for Those Listed in 2014

SRTR Annual Data Report 2017

Unadjusted Graft Survival in 56,587 Recipients of Deceased Donor Kidney Transplants by Length of Dialysis Treatment Before Transplant

Meier-Kriesche et al. Transplantation 2002;74:1377-1381.

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free

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0 12 24 36 48 60 72 84 96 108 120Months Post Transplant

24+ months12-24 months6-12 months

0-6 months

preemptive

Underutilized deceased donor populationsHEPATITIS C NAT POSITIVE

HCV and Opioids: A growing problem in the US

7

Estimated Number of New Hepatitis B and Hepatitis C Infections in the United States, by Year

Liang et al NEJM 2018; MMRW; Jan 1, 2016

Morbidity and Mortality Weekly Report

MMWR / January 1, 2016 / Vol. 64 / Nos. 50 & 51 1379US Department of Health and Human Services/Centers for Disease Control and Prevention

(e.g., fentanyl and tramadol), which nearly doubled from 1.0 per 100,000 to 1.8 per 100,000 (Figure 2). Heroin over-dose death rates increased by 26% from 2013 to 2014 and have more than tripled since 2010, from 1.0 per 100,000 in 2010 to 3.4 per 100,000 in 2014 (Figure 2). In 2014, the rate of drug overdose deaths involving natural and semisynthetic opioids (e.g., morphine, oxycodone, and hydrocodone), 3.8 per 100,000, was the highest among opioid overdose deaths, and increased 9% from 3.5 per 100,000 in 2013. The rate of drug overdose deaths involving methadone, a synthetic opioid classified separately from other synthetic opioids, was similar in 2013 and 2014.

Discussion

More persons died from drug overdoses in the United States in 2014 than during any previous year on record. From 2000 to 2014 nearly half a million persons in the United States have died from drug overdoses. In 2014, there were approximately one and a half times more drug overdose deaths in the United States than deaths from motor vehicle crashes (4). Opioids, primarily prescription pain relievers and heroin, are the main drugs associated with overdose deaths. In 2014, opioids were involved in 28,647 deaths, or 61% of all drug overdose deaths; the rate of opioid overdoses has tripled since 2000. The 2014 data demonstrate that the United States’ opioid overdose

epidemic includes two distinct but interrelated trends: a 15-year increase in overdose deaths involving prescription opioid pain relievers and a recent surge in illicit opioid overdose deaths, driven largely by heroin.

Natural and semisynthetic opioids, which include the most commonly prescribed opioid pain relievers, oxycodone and hydrocodone, continue to be involved in more overdose deaths than any other opioid type. Although this category of opioid drug overdose death had declined in 2012 compared with 2011, and had held steady in 2013, there was a 9% increase in 2014.

Drug overdose deaths involving heroin continued to climb sharply, with heroin overdoses more than tripling in 4 years. This increase mirrors large increases in heroin use across the country (5) and has been shown to be closely tied to opioid pain reliever misuse and dependence. Past misuse of prescription opioids is the strongest risk factor for heroin initiation and use, specifically among persons who report past-year dependence or abuse (5). The increased availability of heroin, combined with its relatively low price (compared with diverted prescrip-tion opioids) and high purity appear to be major drivers of the upward trend in heroin use and overdose (6).

The rate of drug overdose deaths involving synthetic opioids nearly doubled between 2013 and 2014. This category includes both prescription synthetic opioids (e.g., fentanyl

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FIGURE 1. Age-adjusted rate* of drug overdose deaths† and drug overdose deaths involving opioids§,¶ — United States, 2000–2014

Source: National Vital Statistics System, Mortality file.* Age-adjusted death rates were calculated by applying age-specific death rates

to the 2000 U.S. standard population age distribution. † Drug overdose deaths are identified using International Classification of

Diseases, Tenth Revision underlying cause-of-death codes X40–X44, X60–X64, X85, and Y10–Y14.

§ Drug overdose deaths involving opioids are drug overdose deaths with a multiple cause-of-death code of T40.0, T40.1, T40.2, T40.3, T40.4, or T40.6. Approximately one fifth of drug overdose deaths lack information on the specific drugs involved. Some of these deaths might involve opioids.

¶ Opioids include drugs such as morphine, oxycodone, hydrocodone, heroin, methadone, fentanyl, and tramadol.

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Drug overdose deaths involving opioidsNatural and semisynthetic opioidsSynthetic opioids excluding methadoneMethadone

Year

Heroin

FIGURE 2. Drug overdose deaths* involving opioids,†,§ by type of opioid¶ — United States, 2000–2014

Source: National Vital Statistics System, Mortality file.* Age-adjusted death rates were calculated by applying age-specific death rates

to the 2000 U.S. standard population age distribution.† Drug overdose deaths involving opioids are identified using International

Classification of Diseases, Tenth Revision underlying cause-of-death codes X40–X44, X60–X64, X85, and Y10–Y14 with a multiple cause code of T40.0, T40.1, T40.2, T40.3, T40.4, or T40.6.

§ Opioids include drugs such as morphine, oxycodone, hydrocodone, heroin, methadone, fentanyl, and tramadol.

¶ For each type of opioid, the multiple cause-of-death code was T40.1 for heroin, T40.2 for natural and semisynthetic opioids (e.g., oxycodone and hydrocodone), T40.3 for methadone, and T40.4 for synthetic opioids excluding methadone (e.g., fentanyl and tramadol). Deaths might involve more than one drug thus categories are not exclusive.

Characteristics of Opioid-Related Deaths

Mass. Dept. of Public Health, 2016 data

Texas Opioid Related Deaths

NIH National Institute on Drug Abuse; March 2019 report.

Rising Percentage of HCV+ Donors

Durand et al, Ann Intern Med 2018

High HCV+ Discard Rate

Reese PP, et al. N Engl J Med 373; 2015.

Progress of HCV Treatment

Baid-Agrawal at al. AJT 2014

Direct-Acting Antiviral Agents

High Cure Rates with Elbasvir/Grazoprevir in CKD Populations

THINKER: PENN ExperienceINCLUSION/EXCLUSION CRITERIA§RECIPIENT§Adults 40 – 65 years old§cPRA level < 97%§No evidence of liver injury§Patients with anticipated long wait times but on the wait list < 548 days§Extensive Informed Consent Process§ In-person educational sessions§ 2nd-stage discussion with patient

separated by 24 hours

DONOR

§KDPI < 85%

§Donor positivity for HCV on qualitative NAT

§Donor has HCV genotype 1

Reese, PP. Ann Intern Med. 2018

THINKER DemographicsN = 20 recipients

Median donor KDPI 46% (IQR: 33% - 54%)

Donor HCV RNA ranged from 1,332 -20,513,681 IU/mL (median, 290,760 IU/mL)

Elbasvir/Grazoprevir initiated on POD #3

19/20 kidney recipients had detectable HCV RNA at the first assessment (Post-Op D 2 -4)

◦ 1/20 had undetectable HCV RNA level D2 that increased to 288 IU/ml on D5


THINKER: Viral Loads Rapidly Become Undetectable


THINKER Results§100% detectable HCV VL post-transplant

§3 NS5A RAS- Elb/Grz 16 weeks + RBV

§100% cured

§25% DGF

§AEs:§ 25% transient increase in LFTs§ 1 developed de novo FSGS§ De novo DSA in 20%

§Median 12 month SCr 1.1 mg/dL

§THINKER 12 month eGFR was better than KDPI matched HCV negative recipients § Median 72.8 mL/min vs 67.2 mL/min

THINKER transplanted N = 20

Median days to transplant

57 (12 – 91)

Median KDPI 45 (33-54)


EXPANDER: JHU Experience§Grazoprevir/Elbasvir +/- Sofosbuvir given on call to the OR

§Inclusion§ ≥50 years old§ On RRT or GFR < 15 ml/min for ≥ 90 days§ Negative for HCV (NAT and Ab)§ No living donor available§ No prior transplant

§ Exclusion§ HIV, Hep B, Cirrhosis, history of liver disease such as NASH

Durand CM, et al. Ann Intern Med 168: 2018.

EXPANDER Population


EXPANDER HCV Characteristics


MGH HCV NAT+ to HCV-ProtocolPILOT TRIAL

MGH PILOT STUDY

§Funded by Merck to Provide 10 HCV NAT positive kidneys to HCV-negative recipients

§Targeting recipients most likely to benefit: Long wait time remaining (3-6yrs)

§Test feasibility of preemptive therapy (starting before transplant, on call to the OR) to block viral transmission in this NAT D(+)/R(-) combination

MGH PILOT STUDY

§Donor Inclusion§Detectable HCV RNA, with HCV genotype 1 or 4 infection– rapid

genotyping occurs prior to Transplant§KDPI score ≤ 0.65

§Donor Exclusion§HIV or HBV§ Significant liver disease or signs of liver decompensation

MGH PILOT STUDY§Recipient Inclusion Criteria§Age 40 – 70§Meets all MGH criteria for liver and

kidney transplantation§No available living donor§On dialysis or eGFR < 15§Blood type A: ≤ 2 years accrued

wait-time§Blood type B and O: ≤ 3 years accrued

wait-time

§Recipient Exclusion Criteria§History of FSGS§Blood types AB§BMI > 35§Known liver disease§Pregnant/nursing

HCV+ to HCV- Kidney Transplantation

ELB/GRZ x 12w

- HCV (-) ESRD ptsPt education + Informed ConsentAdded to HCV+ waitlist

Transplant from HCV(+) donor with genotype 1 or 4 infection Cure: test viral load 12

weeks post treatment

F/U: 1 year

Process for Identifying Candidates

Sise ME, et al. Artif Organs 2019

Education SessionEducation Session

Sise ME, et al. Artif Organs 2019

Baseline characteristics of overall consented cohort and transplanted patients

Manuscript submitted

Viral Kinetics

All patients achieved SVR12

Serum Creatinine Post-Transplant

Mean Cr 1.28 mg/dL

§Glecaprevir/Pibrentasvir (G/P) now FDA approved§Hepatically metabolized§Treats all major genotypes (GT1-6)

§MYTHIC Trial: MGH is the lead site in an 8 center trial of G/P to prevent HCV infection after HCV+ à HCV- kidney transplantation§Will transplant 30 HCV RNA+ kidneys§Antibody positive NAT- donors will also be included with reactive

G/P should seroconversion occur

Pangenotypic Efficacy: Glecaprevir/Pibrentasvir

MYTHIC Study Design

MYTHIC TRIAL: Management of recipients of HCV Ab+ NAT- kidneys

Day 0 Transplant

If at any time post transplant HCV RNA is detected, patient begins treatment with G/P

Week 1 Week 4 Week 8 Week 12 Week 24

Patient followed with serial HCV RNA levels and deemed negative if all are negative by 6 months post-transplant

Are We Ready for Prime Time?§More data/experience§How many more? What thresholds?

§Insurer/institutional buy-in§DAAs “on the shelf”

§Pangenotypic agents§Glecaprevir/pibrentasvir§ Sofosbuvir/velpatasvir

§Registry framework§Clear reporting of outcomes, monitoring for rare AEs

§More data on costs

What are the Barriers to Widespread Adoption?

§DAAs§Cure rates are not 100%§Proteinuria

§Cost

§Incomplete understanding of HCV reservoirs

§PHS IRD Label

§Quality

§Provider biases will sign on

Outstanding Questions

1. Should this be considered “standard of care”?2. What are other centers doing?

3. What about the use of HCV NAT positive donors for other organs?

Underutilized deceased donor populationsHIV POSITIVE

HIV Positive NIH Multisite StudyProspective trial150 kidney transplants in HIV+◦ CD4 > 200, VL < 50

Median age: 4669% African American80% maleCause of disease◦ 25% hypertension◦ 24% HIVAN◦ 9% diabetes

Stock PG/Roland M et al NEJM 2010.

HIV Positive NIH Multisite Study

Patient survival1 yr: 95%3 yr: 91%4 yr: 89%

Stock PG/Roland M et al NEJM 2010,Roland M et al. AIDS 2016

Graft survival1 yr: 90%3 yr: 74%4 yr: 70%

Between those aged >65 and all recipients

Worse if treated for rejection

US HIV+ Transplant Volumes

HIV+ Kidney Tx>40x increase in 14 years

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HIV Referral and Waitlist Issues

• Less frequently on the transplant list (17% vs 62%, p<0.001)

• Received fewer transplants (4.5% vs 38%, p <0.001)

South Africa Experience

Muller et al, NEJM 2010: 362: 2336-7

National Organ Transplant Act, 1984/88

42 U.S.C. 274(b) Sect 372(b):

“requires the OPTN to adopt and use standards for preventing the acquisition of organs from individuals known to be infected with HIV.”

• 2000-2008• 2 national registries (NIS,

HIVRN)• Excluded those with

missing data and medical contraindication

• 500-600 donors per year

HIV Organ Policy Equity (HOPE) Act signed: November 21, 2013

HIV+ Recipient Inclusion Criteria

§No active opportunistic infections

§Kidney CD4 > 200 cells within 16 weeks

§HIV RNA suppression for at least 26 weeks

§Liver CD4 > 100 cells within 16 weeks

§Anticipated effective and tolerable treatment

HIV+ Donor Inclusion Criteria

§Brain death or cardiac death

§No active opportunistic infections or cancer

§Any HIV VL or CD4 count is allowed but study team must describe effective post-transplant antiretroviral regimen for the recipient

§HCV RNA+ donors for HCV RNA+ recipients

March 2016, First HIV-to-HIV liver and kidney transplant in

the US

Transplant Centers

Outcomes§Primary outcome: all cause graft loss

§Secondary outcomes:§Graft function§ Incidence and severity of graft rejection – kidney protocol

biopsies§HIV virologic control§Detection of new drug resistance or viral strains

§ Incidence of infections§Donor derived AIDS-related infections

Outcomes - HIV renal diseases

§HIV associated nephropathy§HIV associated immune complex disease§Non-collapsing FSGS

§Thrombotic microangiopathy§ApoL1 protein variants in donors and recipients

Outcomes – clinical complications

§Post-transplant infections – validated definitions§Surgical and vascular complications§Viral associated malignancies (HCV, HBV, HPV, EBV)

Mechanistic Studies

§ Incidence of HIV-superinfection in blood

§ Incidence of HIV-superinfection in tissue by laser capture microdissection

§ Changes in HIV latent reservoir

HOPE Transplants (as of 07/09/2019)

LIVER (including SLK)KIDNEY

HIV D-/R+N = 39

HIV D+/R+N = 46HIV false positive D/R+

N = 34

Received transplantN = 119

HIV D-/R+N = 12

HIV D+/R+N = 22

HIV false positive D/R+N = 9

Received transplantN = 43

HOPE Donors (as of 07/09/19)

True Positive N = 41False Positive N = 25

False Positive Donors

Durand CM, et al. AJT 2018.

Thank You!QUESTIONS???

expanding the pool of deceased donors: use of hepatitis c and …€¦ · hcv and opioids: a...

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