STANFORD MULTIDISCIPLINARY SEMINARS

Sustained Virological Response After 4 Weeks of Telaprevir,Peginterferon, and Ribavirin in an Asian Patient with Genotype 1Chronic Hepatitis C and IL28B Genotype CC

Natalie Brulotte • Hejin Hahn • Maximilian Lee

Received: 26 September 2013 / Accepted: 27 September 2013

� Springer Science+Business Media New York 2013

Case Presentation and Evolution

A 66-year-old ethnic Chinese man was evaluated for

chronic fatigue.

He was diagnosed 2 years ago in Burma with chronic hep-

atitis C (HCV), genotype 1b and viral load = 3,502,804 IU/

ml. He was otherwise healthy; his only medication was a daily

multivitamin. Physical examination revealed a pleasant man,

weight = 55 kg and height = 167.5 cm, body mass index

(BMI) = 23.2. His sclerae were anicteric, and his abdomen

was soft, non-tender, non-distended, and without hepato-

splenomegaly. Two small tattoos were noted on the dorsum of

his hands.

Additional laboratory data was significant for a platelet

count of 115 K/cmm, aspartate aminotransferase (AST) = 148

U/l, alanine aminotransferase (ALT) = 94 U/l, alkaline phos-

phatase = 175 U/l, and international normalized ratio

(INR) = 1.0. His interleukin 28B (IL28B) genotype was CC.

His hepatitis A IgG antibody was positive, but his hepatitis B

surface antigen was negative, as were tests for autoimmune and

metabolic liver diseases.

Given his thrombocytopenia, an abdominal computerized

tomography (CT) was obtained to evaluate for possible cir-

rhosis, but this was reported as normal liver morphology.

Liver biopsy was then performed, which showed mild portal,

interface, and lobular inflammation (Batts–Ludwig grade 2;

METAVIR activity grade 1) (Fig. 1) and mild fibrosis

(Batts–Ludwig stage 2; METAVIR stage 2) (Fig. 2). He

subsequently started triple therapy with pegylated interferon

alfa-2a 180 lg once/week, ribavirin 600 mg qAM/400 mg

qPM, and telaprevir 750 mg t.i.d., with a projected sustained

virological response (SVR) rate of 79 % after 6 months of

therapy. One week into treatment, there was a significantly

decreased platelet count of 89 K/cmm, but a normal white

blood cell count and hemoglobin (Hgb) level = 17.1 g/

dl. The next day, the patient complained of anorexia, inter-

mittent fevers, chills, and nausea with significant epigastric

and periumbilical abdominal pain that occasionally radiated

to the back. An emergency department evaluation did not

support the diagnosis of pancreatitis; therefore, HCV treat-

ment was resumed the following day with instructions to use

a proton pump inhibitor, an anti-emetic, and a protein sup-

plement to boost nutrition. The patient had missed a total of 3

doses of ribavirin and 4 doses of telaprevir at this point. Due

to recurrent symptoms, an upper GI endoscopy was per-

formed at the end-of-treatment week 3, which was reported

as showing chronic gastritis.

Over the course of treatment, the patient developed

interferon-related gastrointestinal and psychiatric side

effects, including insomnia and worsening mood swings.

Increased creatinine and Hgb, likely reflecting intravascu-

lar volume depletion, were noted, which, in combination

with anorexia related to gastrointestinal upset and abdom-

inal pain, was attributed to the development of mild renal

failure with an end-of-treatment week 4 creatinine con-

centration = 1.59. The patient was advised to discontinue

treatment due to intolerance related to multiple symptoms

and side effects. End-of-treatment week 4, labs revealed a

detectable viral load of 12 IU/mL; however, post-treatment

liver function tests were normal and HCV viral loads at 1,

2, 3, 6, and 10 months were undetectable, which indicated

that the patient had achieved an SVR (Table 1).

N. Brulotte � M. Lee (&)

Digestive Disease Institute, Virginia Mason Medical Center,

1100 9th Ave., Seattle, WA 98101, USA

e-mail: maxlee@gmail.com

H. Hahn

Department of Pathology and Laboratory Medicine, Virginia

Mason Medical Center, 1100 9th Ave., Seattle, WA 98101, USA

123

Dig Dis Sci

DOI 10.1007/s10620-013-2903-7

Discussion

Standard-of-care treatment for genotype 1 chronic hepatitis

C is triple therapy with pegylated interferon, ribavirin, and

a direct-acting antiviral or protease inhibitor, such as

telaprevir or boceprevir, for 6–12 months [1]. This patient

only completed 4 weeks of triple therapy with pegylated

interferon alfa 2a, ribavirin, and telaprevir. His treatment

was discontinued early, due to intolerance and gastroin-

testinal and psychiatric adverse effects. Although his end-

of-treatment week 4 viral load was just above the detection

threshold (12 IU/ml), his viral loads became and remained

undetectable up to 10 months post-treatment.

Several factors may have contributed to the unexpected

success of this patient’s shortened treatment, including

consideration for his HCV and IL28B genotypes. Genotype

1B patients are more likely to achieve a rapid virological

response, which is significantly associated with achieving

an SVR [2]. This patient also had a very favorable IL28B

genotype, which predicts response to interferon-based

therapies—IL28B genotype CC is significantly associated

with an increased response to interferon-based therapy. The

other IL28B genotypes, CT and TT, are associated with

impaired response to triple therapy, to the point that Clark

et al. [3] suggested that the IL28B genotype is the most

vital predictor of treatment response. The CC genotype is

more frequently detected in Asians [ subjects of Indo-

European ancestry [ subjects of African ancestry. In the

US, the SVR in African-Americans was 36 % higher in

patients with genotype CC than in those with TT. SVR in

African American CC, CT, and TT patients were 53, 19,

and 17 %, respectively. Similarly, in Caucasian patients,

the SVR in CC patients was 48 % higher than in their CT

counterparts. SVR in CC, CT, and TT patients were 82, 42,

and 20 %, respectively. In African Americans and Cauca-

sians, this equates to a success rate 2–3 times higher in CC

patients versus CT and TT patients [4]. This information

suggests that the IL28B genotype CC, although of varying

frequency according to ancestry, confers a similar response

to treatment.

Clark et al. [3] further proposed that IL28B might

optimize current treatment durations (between 6 and

12 months), including potentially reducing the length of

treatment for patients with IL28B genotype CC. In the

PROVE2 study, the efficacy of 12 weeks of peginterferon,

ribavirin, and telaprevir were studied in Caucasian patients

with HCV genotype 1, who were treatment-naı̈ve and non-

cirrhotic; and 100 % of patients with IL28B genotype CC

achieved SVR. This was more successful than those with

genotype CT and TT, who achieved SVR of 44 and 20 %,

respectively. The SVR rate for CC in this group was also

better than patients who received standard-of-care, mean-

ing 12 weeks of triple therapy utilizing telaprevir followed

by 24 weeks of peginterferon and ribavirin (SVR = 94 %)

[5], suggesting that there are certain patients with IL28B

genotype CC who will achieve an SVR with shorter

treatment durations. BMI also affect treatment outcomes

[2]; as this patient’s BMI was borderline low, it is possible

that his lack of adiposity may have enhanced the effect of

his HCV treatment. Conversely, cirrhosis can adversely

affect treatment outcomes. Although this patient had

thrombocytopenia, the diagnosis of cirrhosis was not sup-

ported by imaging or by biopsy. Thus, this patient had an

increased possibility of achieving SVR after a short dura-

tion treatment [1]. Moreover, the patient was treated with

telaprevir, which is a more potent alternative to its coun-

terpart boceprevir with overall full treatment duration

SVR = 89 and 76 %, respectively [1]. Furthermore, given

the 4-week lead-in for triple therapy with boceprevir, the

Fig. 1 Liver biopsy: mild portal, interface, and lobular inflammation

(Batts–Ludwig grade 2; METAVIR activity grade 1) on H&E stain at

9100 magnification

Fig. 2 Liver biopsy: mild fibrosis (Batts–Ludwig stage 2; METAVIR

stage 2) on trichrome stain at 940 magnification

Dig Dis Sci

123

patient would have stopped therapy prior to starting the

direct-acting antiviral drug [1]. Therefore, the use of tela-

previr may have further increased the probability of

attaining SVR after a 4 week course of therapy.

The patient’s viral load was barely detectable at 12 IU/

ml at week 4. Some may question the accuracy of the test

result; however, this can be explained, as liver cells have a

longer life span than that of a virion. HCV ribonucleic acid

(RNA) is measure of the number of affected cells, not the

number of active virions [6]. Therefore, one should expect

that, if cell death occurs over an extended period of time,

the HCV RNA would continue to decrease after treatment

end. Thus, it is not surprising that subsequent testing

showed undetectable virus.

Key Messages

• SVR was achieved after a 4-week course of triple

therapy.

• Predisposing factors underlying treatment success

include the use of the more potent direct-acting

antiviral drug, favorable HCV and IL28B genotypes,

the absence of cirrhosis, and a low BMI.

• The success of achieving SVR with ultra-short course

therapy will likely increase as more powerful therapies

emerge.

References

1. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment

of genotype 1 chronic hepatitis C virus infection: 2011 practice

guideline by the American Association for the Study of Liver

Diseases. Hepatology. 2011;54:1433–1444.

2. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, manage-

ment, and treatment of hepatitis C: an update. Hepatology.

2009;49:1335–1374.

3. Clark PJ, Thompson AJ, McHutchison JG. IL28B genomic-based

treatment paradigms for patients with chronic hepatitis C infection:

the future of personalized HCV therapies. Am J Gastroenterol.

2011;106:38–45.

4. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B

predicts hepatitis C treatment-induced viral clearance. Nature.

2009;461:399–401.

5. Bronowicki JP, Hezode C, Bengtsson L, et al. 100% SVR in IL28B

CC patients treated with 12 weeks of telaprevir, peginterferon and

ribavirin in the PROVE2 trial. J Hepatol. 2012;56:S430–S431.

6. Guedj J, Perelson AS. Second-phase hepatitis C virus RNA decline

during telaprevir-based therapy increases with drug effectiveness:

implications for treatment duration. Hepatology. 2011;53:

1801–1808.

Table 1 Liver function tests and hepatitis C viral load by treatment time points

Pre-

treatment

EOT

week 2

EOT

week 4

Post-treatment

(1 months)

Post-treatment

(2 months)

Post-treatment

(3 months)

Post-treatment

(6 months)

Post-treatment

(10 months)

Total bilirubin

(0.2–1.2 mg/dl)

0.6 1.2 1.4 0.6

AST (10–40 U/l) 110 49 43 19

ALT (10–55 U/l) 64 26 16 \6

Alkaline

phosphatase

(40–150 U/l)

128 162 132 146

HCV viral load

(\12 IU/ml)

3,502,804 12 \12 \12 \12 \12 \12

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