Case Report

Antiviral Treatment Failures After Transplantation of

Organs From Donors With Hepatitis C Infection: A Report
of 4 Cases
Julie M. Steinbrink, Shanti Narayanasamy, Cameron R. Wolfe, Eileen Maziarz, Jennifer Byrns, Jennifer J. Kiser,
and Susanna Naggie

The transplantation of organs from donors with hepatitis C virus (HCV) infection into uninfected re- Complete author and article
cipients has expanded the available organ donor pool. With the advancement of direct-acting antivirals information provided before
references.
(DAAs), high rates of cure among transplant recipients are possible. Although DAAs are highly
effective, treatment failure can occur following an appropriate 12-week course of a pan-genotypic Am J Kidney Dis.
regimen. Here we describe 4 kidney transplant recipients of organs from donors with HCV infection 82(3):368-372. Published
online February 4, 2023.
(3 with genotype 3, 1 genotype 1a) in whom first-line DAA treatment with either glecaprevir-
pibrentasvir or sofosbuvir-velpatasvir was unsuccessful, started 22-35 days after the day of trans- doi: 10.1053/
plantation. All ultimately achieved sustained virologic response with second- or third-line therapy. j.ajkd.2022.12.006
Post-treatment resistance-associated substitutions were tested and noted to be present in 2 cases.
Additionally, antiviral levels were assessed in 2 cases and found to be therapeutic in each. This article
explores possible reasons for treatment failure, including medication interactions, bariatric surgery, viral
dynamics, and drug resistance.

© 2023 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction daily replaced omeprazole 20 mg daily to avoid velpatasvir

Treatment of hepatitis C virus (HCV) infection now results
in high cure rates owing to the availability of direct-acting
antivirals (DAAs). Early studies suggesting safety and effi-
cacy of DAAs among transplant recipients have prompted
medical centers to transplant organs from donors with
HCV infection into uninfected recipients.1,2 While HCV
treatment guidelines are established for chronic HCV,
transplant recipients with acute infection remain a unique,
diverse, and understudied population. We present 4 cases
in which guideline-driven DAA therapy failed in recipients
of kidney transplants from HCV RNA+ donors. These cases
highlight the complexity of HCV-RNA+ transplantation,
potential predictors of failure, and approaches to salvage
therapy.
Case Report
The clinical characteristics of the 4 patients and their
clinical courses are depicted in Table 1 and Fig 1,
respectively. All patients were administered DAAs as part of
clinical care, and this work was ruled as institutional re-
view board exempt (Pro00112261).
Case 1
A 68-year-old female patient, who underwent deceased
donor kidney transplantation (DDKT) for end-stage renal
disease (ESRD) owing to polycystic kidney disease, was
treated initially with 12 weeks of sofosbuvir/velpatasvir
(400 mg/100 mg daily, respectively) starting on post-
transplant day (PTD) 28 for a pretreatment HCV RNA of
7,536,540 IU/mL, genotype 1a. Famotidine 20 mg twice
interaction with proton pump inhibitors (PPIs).3 At end of
therapy, HCV RNA was undetectable, though was subse-
quently quantifiable on PTD 136. Famotidine was stopped
and she then completed 12 weeks of sofosbuvir/velpa-
tasvir/voxilaprevir (400 mg/100 mg/100 mg daily). HCV
RNA became undetectable with sustained virologic
response at 12 weeks (SVR12). Resistance testing and drug
levels were not monitored.
Case 2
A 66-year-old male patient who underwent DDKT for ESRD
secondary to diabetes, with a history of biliopancreatic
diversion duodenal switch, was treated initially with 12
weeks of sofosbuvir/velpatasvir (400 mg/100 mg daily)
starting on PTD 28 for a pretreatment HCV RNA of 2,228
IU/mL, genotype 3. HCV RNA remained undetectable
through end of therapy but was subsequently quantifiable
on PTD 123. Resistance-associated substitution (RAS)
testing of the NS5A gene demonstrated S62T and Y93H
substitutions. (Resistance was only checked after DAA
exposure, and was not checked at baseline.) He subse-
quently completed 12 weeks of sofosbuvir/velpatasvir/
voxilaprevir (400 mg/100 mg/100 mg daily), and HCV
RNA was undetectable at end of therapy, but was again
subsequently quantifiable on PTD 250. He then completed
glecaprevir/pibrentasvir/sofosbuvir (300 mg/120 mg/
400 mg daily) + ribavirin 200 mg twice daily for 24 weeks
and ultimately achieved SVR12. There was concern that he
had inadequate gastric absorption; however, plasma levels
of sofosbuvir and the active form of sofosbuvir circulating in
plasma, GS-331007, were assessed under institutional

368 AJKD Vol 82 | Iss 3 | September 2023

 Steinbrink et al

review board–approved protocol Pro00106012 while on

glecaprevir/pibrentasvir/sofosbuvir + ribavirin. Sofosbuvir

checked

checked
Y93H*
Y93Ha

A30K,
S62L,
S62T,
Never

Never
and GS-331007 levels were 351 ng/mL and 1,506 ng/mL,
RAS respectively, approximately 2-3 hours post dos-
e—consistent with adequate absorption.3
Thymoglobulin

Case 3
Induction

A 67-year-old male patient, who underwent DDKT for

ESRD owing to diabetes and a history of Roux-en-Y gastric
Yes

Yes

Yes

Yes
bypass, was treated initially with glecaprevir/pibrentasvir
(300 mg/120 mg daily) on PTD 22 for a pretreatment
duodenal switch

HCV RNA of >100 million IU/mL, genotype 3, while

Biliopancreatic

Laparoscopic
diversion w/

continuing omeprazole 40 mg daily. However, after initial

Roux-en Y
Bariatric
Surgery

reduction in HCV RNA, there was an increase on PTD 62

and glecaprevir/pibrentasvir was stopped. NS5a RAS
No

No

testing demonstrated A30K, S62L, and Y93H substitutions.

Omeprazole was discontinued, and he completed 24
Treatment stopped at 45 days, earlier than initially planned 84-day course, owing to treatment failure. All other DAA regimens were completed in full as planned.
Suppressor
H2 blocker

weeks of sofosbuvir/velpatasvir/voxilaprevir (400 mg/

inhibitor

100 mg/100 mg daily), with which he achieved SVR12.

Proton
pump
None

None
Acid

While on sofosbuvir/velpatasvir/voxilaprevir, sofosbuvir

and GS-331007 in plasma were below the limit of quan-
tification and 705 ng/mL, respectively, and velpatasvir in
Adherence

plasma was 40.8 ng/mL, 21 hours postdose. These con-

reported

centrations are consistent with historical data and are

100%

100%

100%

100%

Abbreviations: DAA, direct-acting antiviral; HCV, hepatitis C virus; POD, postoperative day; RAS, resistance-associated substitutions.
Self-

believed to be therapeutic.3
Day of DAA

Case 4
transplant
Initiation

A 44-year-old male patient who underwent DDKT for

POD 28

POD 22

POD 35
PD 28

ESRD owing to hypertension (same donor as in case 3) was

Post-

treated initially with 12 weeks of glecaprevir/pibrentasvir

(300 mg/120 mg daily) on PTD 35 for a pretreatment
2. Sofosbuvir-velpatasvir-voxilaprevir × 168

HCV RNA of 409,220 IU/mL, genotype 3. HCV viral load

3. Glecaprevir-pibrentasvir + sofosbuvir +
2. Sofosbuvir-velpatasvir-voxilaprevir × 84

2. Sofosbuvir-velpatasvir-voxilaprevir × 84

became undetectable by end of therapy and subsequently

1. Glecaprevir-pibrentasvir × 45 daysb

2. Sofosbuvir-velpatasvir-voxilaprevir +
1. Glecaprevir-pibrentasvir × 84 days

quantifiable on PTD 133. He completed a 24-week course

1. Sofosbuvir-velpatasvir × 84 days

1. Sofosbuvir-velpatasvir × 84 days
HCV Regimen for Treatment and

of sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/

100 mg daily) + ribavirin 600 mg daily, with which he
Table 1. Clinical Characteristics of HCV Kidney Transplant Cases

achieved SVR12. Resistance testing and drug levels were

not completed for this patient.
ribavirin × 168 days

ribavirin × 168 days

Discussion
Retreatment

Transplantation of organs from donors with HCV

RAS not checked at baseline, checked after treatment failure.

infection has greatly increased organ availability. Though

achieving suppressed virus during treatment but expe-
days

days

days

riencing viral recurrence post-treatment (ie, a relapse) is

uncommon,1,2,4 not all patients achieve HCV cure with
DAA (IU/mL)
HCV Prior to

100,000,000

initial therapy. Although it is difficult to determine the

55,533,881

1,248,636

(>8.0 log)

exact cause of treatment failure, there are baseline

409,220
(6.1 log)

(5.6 log)
(7.7 log)

characteristics that have been identified as predictors of

poor response, even in the DAA era, including high
pretreatment HCV RNA, concomitant drug-drug in-
Genotype

teractions, bariatric surgery, HCV genotype, and pres-

ence of RAS. In the peritransplant setting there are likely
others, including timing of DAA initiation and induction
1a

immunosuppression. In the cases described here, the

Case

patients had various combinations of these negative

predictors.
1

b
a

AJKD Vol 82 | Iss 3 | September 2023 369

 Steinbrink et al

Commenced
HCV RNA 7,536,540 IU/mL HCV RNA undetectable SOF/VEL/VOX
Genotype 1a 12 weeks
Commenced EOT HCV RNA 115,000 IU/mL EOT
Transplant SVR12
SOF/VEL 12 weeks HCV RNA undetectable Famotidine ceased HCV RNA undetectable

CASE 1
Day 0 Day 5 Day 28 Day 79 Day 112 Day 136 Day 154 Day 238 Day 322

HCV RNA 2,228 IU/mL HCV RNA <15 IU/mL Commenced HCV RNA 22,784
Genotype 3 HCV RNA undetectable detectable SOF/VEL/VOX IU/mL
12 weeks
HCV RNA Commenced
Commenced EOT EOT GLE/PIB/SOF/RBV EOT
581,840 SVR12
Transplant SOF/VEL 12 weeks HCV RNA undetectable HCV RNA undetectable 24 weeks HCV RNA undetectable
IU/mL

CASE 2
Day 0 Day 5 Day 28 Day 67 Day 112 Day 123 Day 138 Day 148 Day 232 Day 250 Day 272 Day 440 Day 524

HCV RNA 144,273 IU/mL HCV RNA

Genotype 3 41,600,000 IU/mL
HCV RNA Commenced
>100 million IU/mL HCV RNA GLE/PIB EOT
SOF/VEL/VOX 24 weeks
Transplant Commenced 13,100,867 IU/mL ceased HCV RNA undetectable SVR12
Omeprazole ceased HCV RNA undetectable
GLE/PIB 12 weeks

CASE 3
Day 0 Day 5 Day 22 Day 55 Day 62 Day 67 Day 108 Day 162 Day 276 Day 360

HCV RNA 52,438 IU/mL

HCV RNA 409,220 IU/mL HCV RNA undetectable Commenced SOF/VEL/VOX/RBV
Genotype 3 24 weeks SVR12
EOT HCV RNA HCV RNA HCV RNA EOT HCV RNA
Commenced undetectable
Transplant undetectable 233 IU/mL undetectable
GLE/PIB 12 weeks

CASE 4
Day 0 Day 5 Day 35 Day 59 Day 119 Day 133 Day 143 Day 163 Day 311 Day 395

DAYS FOLLOWING TRANSPLANTATION

Figure 1. Clinical course timeline of all described kidney transplant cases, including time relative to transplant and initial and sub-
sequent antiviral regimen(s), through final sustained virologic response 12 weeks post treatment. Abbreviations: EOT, end of treat-
ment; GLE, glecaprevir; HCV RNA, hepatitis C viral load; PIB, pibrentasvir; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained
virologic response 12 weeks post treatment; VEL, velpatasvir; VOX, voxilaprevir.

Adequate drug absorption is imperative to treatment drug levels from their initial therapy. Unfortunately, there
success. All included patients reported 100% DAA adher- are no commercially available assays for DAA therapeutic
ence, confirmed biweekly with Transplant Pharmacy. Acid drug monitoring.
suppressants are commonly used post-transplant; however, Timing of DAAs may also impact virologic response in
PPIs have a severe interaction with velpatasvir, reducing this unique setting. All described patients started DAAs
area under the curve (AUC) concentrations by 26%-55% within 1 month post-transplant, while other centers
owing to decreased solubility at increased gastric pH.3 initiate DAAs pre-emptively within 1 week post-trans-
Histamine-blocking antacids (eg, famotidine) have a plant.1,2,4 The delayed DAA initiation may result in higher
moderate interaction with velpatasvir, decreasing AUC levels of pretreatment HCV RNA, which, although less
concentrations by approximately 15%.3 The interaction predictive of treatment outcomes with newer DAAs, has
with acid suppressants and glecaprevir/pibrentasvir is less been a predictor of treatment response with early DAA
clear. PPIs can decrease glecaprevir AUC by 29% and therapies. All the cases described in this report had high
maximum serum concentration by 22%, but evidence of initial HCV RNA levels (ranging from 409,000 to >100
treatment failure in clinical practice is lacking.5,6 million IU/mL). This is in contrast to other HCV transplant
There are little data on the effect of bariatric surgery on studies, such as the MYTHIC trial, where treatment was
DAA absorption. Available literature describes decreased started within the first week post-transplant, and median
systemic drug levels of some DAAs.7 This impact on drug peak HCV RNA was approximately only 2,000 IU/mL.4
levels may be attributable to distorted anatomy (such as Several barriers to a pre-emptive approach exist,
malabsorption owing to decreased gastric volume or sur- including administration/absorption for patients unable to
gical intestinal alteration impacting the digestive process) take medications by mouth (particularly with thoracic
leading to increased incidence of failure.7-11 The type of transplant), higher incidence of drug-drug interactions
surgery may impact the degree of absorption and should early in the postoperative period, and financial burden of
be considered before initiating treatment. In our study, 2 drug cost and securing medications while hospitalized.
patients had a history of bariatric surgery, with both Induction immunosuppression is an additional potential
restrictive and absorptive elements. Although both patients contributing factor to treatment failure. At our institution,
had drug levels in their final (curative) courses of therapy induction immunosuppression for kidney transplantation
consistent with adequate drug exposure, we do not have typically consists of solumedrol. Thymoglobulin is used

370 AJKD Vol 82 | Iss 3 | September 2023

Steinbrink et al
for higher-risk cases or delayed graft function. For context,
of 106 recipients of kidneys from donors with HCV
infection at our institution, 40 received thymoglobulin
induction; those with steroid induction alone did not
develop treatment failure and were not described in this
manuscript. However, the treatment failures in these 4
cases required thymoglobulin along with routine
maintenance immunosuppression with tacrolimus, myco-
phenolate, and prednisone. This high degree of immu-
nosuppression could theoretically impact viral clearance.
However, in the HCV-transplantation literature, thymo-
globulin induction has been used without evidence of
higher treatment failure.1,2,12
Of the cases in this report, 1 was genotype 1a (histor-
ically most prevalent in the United States), while the rest
were genotype 3.13 Genotype 3 is increasingly seen in
acute HCV, particularly with injection drug use, and thus
increasingly seen in organs from donors with HCV infec-
tion. Genotype 3 is associated with a higher incidence of
virologic failure, particularly when grouped with other
negative baseline predictors. Additionally, pretreatment
HCV resistance testing is not standard practice for all
regimens or patients. Although many transplant recipients
are DAA naı̈ve, often the donor treatment status is
unknown—prior DAA failure results in treatment-
emergent RASs the majority of the time.14 Two patients
described here were found to have a post-treatment relapse
Y93H mutation, which has been associated with decreased
SVR rates to sofosbuvir/velpatasvir in patients with geno-
type 3 infection (84% vs 97%).15 No patient had evidence
of liver dysfunction during relapse.
We acknowledge that this is a small number of cases,
with only 4 patients described. Additionally, postrelapse
RAS testing and drug levels were not systematically
checked and thus are not available for 2 of the 4 cases.
In summary, organs from donors with HCV infection
are a safe and viable option for organ transplantation, but
there are many factors to consider when a transplant
recipient experiences treatment failure. Transplant pro-
viders must be aware of potential barriers to cure and
attempt to optimize the initial treatment course, be vigilant
about monitoring for failure, and be alert to antiviral
salvage options.
Article Information
Authors’ Full Names and Academic Degrees: Julie M. Steinbrink,
MD, Shanti Narayanasamy, MBBS, Cameron R. Wolfe, MBBS,
Eileen Maziarz, MD, Jennifer Byrns, PharmD, Jennifer J. Kiser,
PharmD, PhD, and Susanna Naggie, MD.
Authors’ Affiliations: Division of Infectious Diseases, Duke
University School of Medicine, Durham, North Carolina (JMS, SN,
CRW, EM, SN); Department of Pharmacy, Duke University Medical
Center, Durham, North Carolina (JB); Department of
Pharmaceutical Sciences, University of Colorado Anschutz
Medical Campus, Aurora, Colorado (JJK); and Section of
Infectious Diseases, Durham Veterans Affairs Health Care System,
Durham, North Carolina (SN).
AJKD Vol 82 | Iss 3 | September 2023
Address for Correspondence: Julie Steinbrink, MD, #150 Hanes
House, Duke University Medical Center, 315 Trent Dr, Durham,
NC 27710. Email: julie.steinbrink@duke.edu
Support: Dr Steinbrink was funded by NIH/NIAID T32 grant
AI100851. The funders had no role in defining the content of the
manuscript.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
Patient Protections: The authors declare that they have obtained
written consent from each patient reported in this article for
publication of the information about him/her that appears within
this case report.
Peer Review: Received August 17, 2022. Evaluated by 2 external
peer reviewers, with direct editorial input from an Associate Editor
and a Deputy Editor. Accepted in revised form December 10, 2022.
References
1. Reese PP, Abt PL, Blumberg EA, et al. Twelve-month outcomes
after transplant of hepatitis C-infected kidneys into uninfected
recipients: a single-group trial. Ann Intern Med. 2018;169(5):
273-281.
2. Durand CM, Bowring MG, Brown DM, et al. Direct-acting
antiviral prophylaxis in kidney transplantation from hepatitis C
virus-infected donors to noninfected recipients: an open-label
nonrandomized trial. Ann Intern Med. 2018;168(8):533-540.
3. Epclusa (sofosbuvir and velpatasvir) [prescribing information].
Foster City, CA: Gilead Sciences Inc; Revised: April 2022.
Accessed December 2022.
4. Sise ME, Goldberg DS, Kort JJ, et al. Multicenter Study to
Transplant Hepatitis C-Infected Kidneys (MYTHIC): an open-
label study of combined glecaprevir and pibrentasvir to treat
recipients of transplanted kidneys from deceased donors with
hepatitis C virus infection. J Am Soc Nephrol. 2020;31(11):
2678-2687.
5. Mavyret (glecaprevir and pibrentasvir) [prescribing informa-
tion]. North Chicago, IL: AbbVie Inc; December 2021.
6. Flamm S, Reddy KR, Zadeikis N, et al. Efficacy and pharma-
cokinetics of glecaprevir and pibrentasvir with concurrent use
of acid-reducing agents in patients with chronic HCV infection.
Clin Gastroenterol Hepatol. 2019;17(3):527-535.e526.
7. Smolders EJ, Willemse SB, El-Sherif O, Khoo S, Burger DM.
The observed effect of gastric bypass surgery on direct-acting
antiviral treatment: a case report. Ann Hepatol. 2018;17(3):
525-529.
8. Tow CY, Reinus JF. Ineffective absorption? Failure of direct-
acting therapy for chronic hepatitis C in cirrhotic patients
with Roux-en-Y gastric bypass. J Investig Med High Impact
Case Rep. 2019;7:2324709619858127.
9. Asselah T, Kowdley KV, Zadeikis N, et al. Efficacy of glecap-
revir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C
virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin
Gastroenterol Hepatol. 2018;16(3):417-426.
10. Naganuma A, Sato K, Fukuchi T, et al. Successful prolonged
treatment of glecaprevir/pibrentasvir for chronic hepatitis C
patient with treatment failure after 8-week therapy: a case
report. Clin J Gastroenterol. 2019;12(6):592-597.
11. Hupa KL, Deterding K, Port K, et al. Stomach reduction or
gastric bypass as risk factor for treatment failure after DAA
therapy for hepatitis C? J Hepatol. 2018;68(4):851-853.
12. Molnar MZ, Nair S, Cseprekal O, et al. Transplantation of kid-
neys from hepatitis C-infected donors to hepatitis C-negative
371

recipients: single center experience. Am J Transplant.
2019;19(11):3046-3057.
13. Reau N, Sulkowski MS, Thomas E, et al. Epidemiology and
clinical characteristics of individuals with hepatitis C virus
infection in the United States, 2017-2019. Adv Ther.
2021;38(12):5777-5790.
372
Steinbrink et al
14. Wyles DL, Luetkemeyer AF. Understanding hepatitis C virus
drug resistance: clinical implications for current and future
regimens. Top Antivir Med. 2017;25(3):103-109.
15. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and vel-
patasvir for HCV genotype 2 and 3 infection. N Engl J Med.
2015;373(27):2608-2617.
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