Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C

Abstract

Background and Aims

Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT.

Methods

Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8–12, and 20–24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine.

Results

All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT.

Conclusions

Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment.

Trial Registration

ClinicalTrials.gov NCT03118674.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10620-023-07859-8.

Introduction

Porphyria cutanea tarda (PCT) is caused by reduced activity of hepatic uroporphyrinogen decarboxylase (UROD), the fifth enzyme of the heme biosynthetic pathway [1]. It is usually an acquired disorder that occurs chiefly in middle-aged men who present with blisters or bullae and increased fragility of the skin, especially on the dorsa of the hands and forearms [2, 3]. Combinations of several acquired factors affect susceptibility for PCT in humans, including alcohol use, smoking, chronic hepatitis C [CHC], estrogens, iron in the liver, and HIV infection [2, 4]. Additional genetic factors, found in some patients, include heterozygous UROD mutations that decrease the activity of the enzyme, and mutations of the HFE gene that increase iron absorption from the GI tract and contribute to hepatic iron overload [2, 5]. Patients with chronic renal failure are particularly prone to the development of PCT, due to iron overload and failure of urinary excretion of uroporphyrin and its poor removal by dialysis [6]. In the absence of end-stage renal disease, PCT responds readily to repeated therapeutic phlebotomies to reduce hepatic iron or to low-dose [hydroxy]chloroquine, which mobilizes porphyrins that have accumulated in hepatocytes and enhances their urinary excretion [7, 8].

CHC is an important susceptibility factor found in ~ 70% of PCT patients in the U.S [2]. Past treatments for CHC with agents such as interferon and ribavirin were lengthy, caused significant side effects, and often lacked efficacy. Therefore, in patients with PCT and CHC, it was generally recommended to treat and relieve the significant symptoms of PCT first, and attempt treatment of CHC later [9]. However, the recent availability of direct-acting antiviral (DAA) drug combinations for the treatment of CHC, has made the treatment of CHC highly successful with few side effects [10]. Scattered case reports and small series have reported that DAA treatment alone has been effective for treatment of both PCT and CHC; however, in these reports, the duration of follow-up has been brief and biochemical confirmation of PCT remission has often been scant or nil [11–17]. In this investigator-initiated pilot study, we assessed primary treatment of PCT with ledipasvir/sofosbuvir [Harvoni, Gilead Sciences] in patients with CHC in terms of efficacy, safety, and time to remission of PCT. Some results were presented at the annual meeting of the American College of Gastroenterology, October 2022, Charlotte, NC [18].

Methods and Patients

Trial Design and Oversight

We conducted a single-arm trial at two clinical centers [Atrium Wake Forest Baptist Health and University of Texas Medical Branch] in the United States to assess whether Harvoni alone is an effective therapy of active PCT in patients with CHC. The protocol was approved by the local institutional review boards at these centers and all patients provided written informed consent. An independent data and safety monitoring board, appointed by the National Institute of Diabetes and Digestive and Kidney Diseases, provided external oversight. All authors had access to the study data and reviewed and approved the final manuscript.

Patients and Interventions

Adults ≥ 18 years were included if they had a confirmed diagnosis of PCT with consistent symptoms and signs, urinary total porphyrins > 500mcg/g creatinine, and RNA positive chronic hepatitis C genotype 1, 4, 5, or 6, for which genotypes ledipasvir/sofosbuvir alone is an approved and effective therapy. [All enrolled subjects were infected with HCV genotype 1]. Patients were excluded if they had HIV infection, ongoing active alcohol abuse, any ongoing injection drug use, or a history of clinically significant liver dysfunction.

Study drug [Harvoni, combination tablet of ledipasvir (90 mg) + sofosbuvir (400 mg)] was provided by Gilead Pharmaceuticals and shipped to both study sites. Patients were prescribed one tablet of Harvoni for oral administration once daily for 8, 12, or 24 weeks per standard prescribing guidelines, according to their stage of disease [19].

Study visits were monthly for the first year and quarterly for the second year of the study. Assessments at study visits included skin assessments and physical exams, laboratory tests (safety labs, porphyrin measurements, HCV RNA, etc.), adverse events, and medication compliance reviews. Adherence was assessed by pill counts of remaining study drug at the times of return visits during active drug therapy, generally for the first 8–12 weeks. All subjects who completed the prescribed treatments took ≥ 80% of the expected numbers of pills.

Serum HCV RNA levels and other standard biochemical testing were performed at the Covance Central Laboratory [Indianapolis, IN] by Covance standard methods. Genetic testing for pathogenic mutations in the UROD gene, the gene affected in familial-type PCT [PCT type 2], was performed by Invitae Labs [San Francisco, CA] or Sema4 Lab [Stamford, CT]. Assays of plasma and urinary total porphyrins and HPLC separations were performed in the laboratory of Dr. Anderson at UTMB, Galveston, TX, by methods described in Egger et al. [20].

Endpoints

The primary endpoint was the resolution of active PCT, defined as the normalization of plasma porphyrins (less than 0.9 mcg/dL) by 7 months after the start of therapy. Secondary endpoints included the following: (1) time to resolution of active PCT, defined as no new PCT skin lesions; (2) complete biochemical remission of PCT, defined as a decrease of the sum of urinary uro- and hepta-carboxyl porphyrins to less than 100 mcg/g creatinine and a normal urine porphyrin HPLC pattern, defined as the total of highly carboxylated porphyrins (uro- and heptacarboxyl-porphyrins) being less than that of coproporphyrins, and the absence of a plasma fluorescence peak by fluorescence scanning; and (4) cure of CHC, defined as no detectable HCV RNA at EOT and persisting for at least 12 weeks after EOT. Safety endpoints included grade 3 or 4 toxicities and worsening PCT. In ad-hoc analyses, the following endpoints were also assessed: (1) ‘normalization’ of urinary porphyrin profile, defined as < 41% urinary uroporphyrin + heptacarboxyl porphyrin, 3 months or more after EOT; and (2) HCV cure defined as a sustained viral response (SVR).

Statistical Analysis

The primary study hypothesis is that the proportion of patients whose PCT resolves by 7 months will be non-inferior to the performance goal of 50%. This performance goal was based on previously published data that reported a median time to resolution at 7 months for PCT patients undergoing treatment with iron reduction by therapeutic phlebotomies or hydroxychloroquine [7]. The non-inferiority margin was set to 10%; a difference from the performance goal judged to be both clinically acceptable and well within the margin needed to assure that the performance of Harvoni is at established levels of benefit from conventional therapies. The original design’s sample size requirement was based on an exact test of a binomial proportion. Assuming that the study drug has a true success probability of 58%, 49 subjects would yield 80% power to reject the null hypothesis at a one-sided significance level of 0.05. Due to low accrual rates on December 31, 2020, enrollment but not follow-up was halted by the study sponsor. At that point, 15 patients had been enrolled. Analyses of the final trial population are descriptive and were conducted using SAS version 9.4 (SAS Institute, Cary, NC).

Results

Between September 2017 and May 2020, 23 patients were screened and 15 (65%) were eligible and enrolled. Of the 8 ineligible patients, 6 did not meet the “Urinary total porphyrin excretion > 500 mcg/g creatinine with HPLC pattern typical of PCT-predominance of 8- and 7-carboxyl porphyrins (> 50% of total)” inclusion criterion; one had already started ledipasvir/sofosbuvir treatment; and the last met the alcohol abuse exclusion criterion. Of the 15 patients enrolled, 13 (87%) initiated treatment and had > 3 months of follow-up.

Selected demographic and clinical features of the subjects studied are summarized in Table 1. 13 of the 15 enrolled subjects were men. The mean age was 58.9 years (range 51.8–70.1 year). 14 were White; one was Black. All were infected with HCV genotype 1. At baseline, serum HCV RNA ranged from 25,700 to 4,320,000 IU/mL. Two [subjects # 7 and #13] had previously been treated for HCV with interferon alpha + ribavirin without achieving SVR. 13/15 had elevations in serum ALT and 14/15 elevations in serum AST at baseline. Only one had mildly elevated serum total bilirubin, and she also had a decreased platelet count at baseline [112,000/uL, reference range 140,000–400,000/uL]. All had normal serum albumin levels, INR, blood hemoglobin, and WBC counts.

Table 1.

Selected baseline demographic and laboratory features of subjects studied and overall response to therapy

Subj #		1	2	3	4	5	6	7	8	9	10	11	12	13	14	15
Demographics
Age (year)		58.4	60.4	54.9	55.9	51.8	65.3	60.8	58.3	56.3	62.8	70.1	57.7	60.7	51.9	57.9
M/F		Male	Male	Female	Male	Male	Male	Male	Male	Male	Male	Male	Male	Male	Male	Male
Lab Values	Reference ranges
HCV RNA (IU/mL)	0.0	4320000	223000	2090000	908000	6320000	8290000	1380000	1350000	2760000	1560000	895000	25700	643000	279000	772000
ALT (U/L)	6–43	32	64	45	34	67	47	106	96	85	119	49	78	144	63	165
AST (U/L)	11–36	28	79	64	45	80	61	190	115	57	81	38	83	86	101	211
AP (U/L)	35–125	92	100	106	68	79	62	146	91	121	152	106	85	16	93	102
TBR (umol/L)	3–21	9	9	3	5	7	5	21	12	7	26	7	9	14	3	9
Albumin (g/dL)	3.3- 4.9 g/dL	3.9	4.4	4.1	4.6	4.5	4.1	3.4	3.9	4.6	3.7	4.9	4.1	3.7	4.0	3.9
INR	0.8–1.2	1	1	1	1	1	1	1.1	1.2	1	1.1	0.9	1	1.1	1	1
Hgb (g/dL)	12–16	14.7	16.2	13.7	15.5	16.3	13.4	14.5	15.1	16.8	14.9	15.4	17.8	16.4	14.5	16.6
WBC (#/uL)	3,800–10,800	6,460	7,240	9,590	10,470	7,470	6,870	8,810	9,400	5,910	8,060	8,840	6,390	6,160	7,080	6,290
Plat (#/uL)	140,000–400,000	203,000	168,000	250,000	269,000	172,000	146,000	246,000	199,000	191,000	112,000	221,000	205,000	206,000	314,000	181,000
Fibrosis stage 0–1		2	2	2	2	3	2	ND	3	4	4	ND	1	4	0	3
EtOH use 0–7, F; 0–14/wk, M		Never	Never	Never	4 + /wk	2–3/wk	4 + /wk	2–3/wk	2–3/wk	4 + /wk	Never	4 + /wk	4 + /wk	4 + /wk	Never	4 + /wk
Tobacco use. None		Past Smoker	Current Smoker	Past Smoker	Current Smoker	Current Smoker	Past Smoker	Current Smoker	Current Smoker	Current Smoker	Current Smoker	Current Smoker	Current Smoker	Current Smoker	Current Smoker	Current Smoker
Wks of Rx/HCV Response to Rx		8/SVR	8/SVR	8/Unkn, lost to F/U	8/Unkn*	8/SVR	8/SVR	8/SVR	8/SVR	12/SVR	24/SVR	8/SVR	8/SVR	24/SVR	12/CVR; relapse; later SVR	12/Unkn#
PCT Remitted		Yes	Yes	Yes; then lost to F/U	Yes; later relapsed	Yes; then lost to F/U	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Unkn

ALT serum alanine aminotransferase, AP serum alkaline phosphatase, AST serum aspartate aminotransferase, CVR complete virological response, EtOH ethanol, F female, F/U follow-up, HCV hepatitis C virus, Hgb blood hemoglobin, concentration, INR international normalized ratio, M male, ND not done, PCT porphyria cutanea tarda, Plat platelet count, RNA ribonucleic acid, Rx antiviral therapy, SVR sustained virological response, TBR serum total bilirubin, Ukn unknown, WBC white blood cell count, wk week

*Compliant with medication, noncompliant with visits so CVR unknown; retreated elsewhere; ^#Subject took Harvoni for only 4 wks and did not return

As regards PCT risk factors besides chronic hepatitis C, 10/15 reported ongoing alcohol use and 12/15 were current smokers. The other three reported having smoked cigarettes in the past. All 15 had genetic testing for the UROD gene. Only subject #3 (Table 1) had a pathogenic UROD mutation, namely, c. 238G > T (p.A80S). Regrettably, this woman withdrew at month 2 by which time porphyrin levels had decreased substantially but before viral response could be assessed. She did not return for follow-up.

Of the 11 patients tested, HFE mutations were found in 8: 2 were compound heterozygous for both the C282Y and H63D mutations; 3 were heterozygous for C282Y; 3 were heterozygous for H63D; none had the S65C mutation.

In all four subjects recruited at Wake Forest [subjects 12–15], we performed liver Fibroscans at baseline and at 1 and 2 years after. In 8/11 subjects enrolled at UTMB, we performed liver FibroMeter studies at baseline. The results were Metavir F1 in 2, F2 in 5, F3 in 3, and F4 in 2. Supplemental Table 1 shows summary results over time of liver Fibroscans in the four subjects followed at Wake Forest. Unfortunately, we were able to obtain longer-term follow-up results on only two of the four subjects; one who had no increase in stiffness at baseline showed stable results, whereas the other showed a sizable decrease after cure of HCV.

HCV Treatment Response

Two subjects (umbers 3 and 15 in Table 1) were lost to follow-up prior to 3-months so only their initial treatment responses are known. Of the 13 patients with sufficient follow-up, 11 experienced cure of HCV, whereas two, both of whom continued to drink alcohol and smoke cigarettes, had measurable serum HCV RNA 12 weeks or more after EOT. One of these two (subject 14 in Table 1), experienced a complete virological response while on treatment but later experienced a virological relapse with low recurrent levels of HCV RNA more than 12 weeks after EOT. Later treatment with sofosbuvir/velpatasvir (Epclusa®) led to an SVR and decreased porphyrins in this patient. He has remained cured of HCV and in clinical remission of PCT for 3 years. The other who failed initial treatment reported that he was adherent to treatment, but he did not return for study visits or follow-up until 3 years later, at which time HCV infection and active PCT were still present. He then chose to be retreated elsewhere closer to home.

PCT Treatment Response

All patients, including the two who were lost to follow-up or failed CHC treatment, exhibited substantial decreases in plasma and urine total porphyrin levels [− 74 ± 19% and − 63 ± 27% (mean ± SD)], respectively, and skin lesions improved during treatment.

Figure 1 shows the time courses of plasma total porphyrins, and Fig. 2 shows the time courses of urinary total porphyrins. Note that both showed prompt decreases, with the latter nearly normal by month 5. There was greater variability in plasma porphyrin levels over time, but with significant decreases occurring by month 7 in all subjects.

Fig. 1.

Time Course of Plasma Total Porphyrins (mcg/dL). Spaghetti plot of individual subjects (stratified by duration of treatment) with median values at each time point shown in red. The dashed blue line shows upper limit of reference range (0.9 mcg/dL)

Fig. 2.

Urinary Total Porphyrins (mcg/g creatinine). Spaghetti plot of individual subjects (stratified by duration of treatment) with median values at each time point shown in red. The dashed blue line shows upper limit of reference range (225 mcg/g creatinine)

Another measure of improvement in hepatic UROD activity as PCT is being treated is a decrease in the proportion of urinary porphyrins that are highly carboxylated [8 (uro)- and 7-(hepta) carboxyl porphyrins] and a gradual increase in the percentage of the total that is 4-carboxyl (copro) porphyrin. Results of the percent 8- and 7-carboxyl urinary porphyrins for all subjects are shown in Fig. 3, and the percent 4-[tetra] carboxyl porphyrin in Fig. 4. Time courses of plasma and urinary total porphyrins are shown in Supplemental Figs. 1 and 2, and percentages of urinary 8 + 7-carboxyl porphyrins and of 4-carboxyl porphyrins for each subject are shown in Supplemental Figs. 3 and 4.

Fig. 3.

Urinary Percent Uro- + Heptacarboxyl-Porphyrins. Spaghetti plot of individual subjects (stratified by duration of treatment) with median values at each time point shown in red. The dashed blue line shows upper limit of reference range (40% of total)

Fig. 4.

Urinary Percent Coproporphyrin. Spaghetti plot of individual subjects (stratified by duration of treatment) with median values at each time point shown in red. The dashed blue line shows lower limit of reference range (60% of total)

As anticipated, levels of serum ALT and AST fell promptly during Harvoni treatment (Fig. 5). The one patient who showed ongoing increases above the upper bound of the reference range was the one who failed to show a complete virological response to Harvoni. The time course of serum alkaline phosphatase levels is shown in Suppl Fig. 5.

Fig. 5.

Time Course of Serum ALT (U/L) during and after Treatment with Ledipasvir/Sofosbuvir. Spaghetti plot of individual subjects (stratified by duration of treatment) with median values at each time point shown in red. (The dashed blue line shows the upper limit of the reference range, 43 U/L)

The persistence of active PCT (with elevated porphyrins and skin lesions) was observed in one subject who did not experience a complete virological response to ledipasvir/sofosbuvir. We did not observe worsening of PCT, as has sometimes occurred with earlier interferon-based CHC treatment regimens [9].

Brief clinical vignettes of some of the subjects studied are presented in the Supplemental Material.

Discussion

The main finding of this work is that ledipasvir/sofosbuvir [Harvoni] alone is highly effective both for treatment and cure of CHC and of active PCT. Specifically, we observed cure of HCV in 11 of 13 subjects whom we treated for the full recommended duration of treatment, based upon the stage of liver disease, in accordance with current prescribing information for ledipasvir/sofosbuvir [19]. Although we formally studied only ledipasvir/sofosbuvir, based upon the mechanisms of action of this combination and other DAAs for HCV, we anticipate that other DAAs will achieve similarly high rates of cure of CHC and remission of PCT. Indeed, our one patient who achieved a complete virological response during treatment with ledipasvir/sofosbuvir but who then experienced a relapse of HCV infection was eventually cured of HCV infection by 12 additional weeks of therapy with sofosbuvir 400 mg/velpatasvir 100 mg [Epclusa, Gilead Sciences].

All subjects who completed the prescribed treatment with ledipasvir/sofosbuvir also experienced clinical remission of PCT, with cessation of development of new blisters or bullae and with gradual healing of active PCT skin lesions. This held true even among those who continued to consume alcohol and to use tobacco, despite advice to the contrary. It also held true equally in subjects with elevated serum ferritin levels at baseline, suggesting some degree of iron loading, another recognized risk factor for PCT [8]. Thus, it is clear that the currently available, highly active DAA’s such as Harvoni or Epclusa can cure HCV and can lead to long-term remission of PCT, even despite continued exposures to other major known risk factors for PCT, such as iron overload, alcohol use, and smoking. We cannot comment upon the other major risk factor, namely, the use of estrogens, because none of our study subjects was using estrogens [4].

Our results confirm and extend those recently reported by others [10–16]. It has been found consistently, across different countries and regions and with persons of different races and ethnicities, that Harvoni, Epclusa, or other DAA’s cure both CHC and lead to clinical remission of PCT. Furthermore, we followed our subjects for at least 1 year after clinical remission of PCT, and we obtained more follow-up plasma and urines than most prior investigators, thus increasing the level of confidence in our findings.

Nevertheless, it is true that some of our subjects continued to show an abnormal PCT-like pattern of urinary porphyrins, with increased percentages of uro- and heptacarboxyl-porphyrins, even after the cure of HCV and clinical remission of PCT. We continue to follow all our subjects, insofar as possible [some no longer return, despite our urging], in order to see whether their clinical remissions will be permanent or only temporary. It is well known that PCT is subject to relapses, especially among persons with hemochromatosis who are likely over time to re-accumulate hepatic iron [21] and/or among those who continue or resume use of excess alcohol and tobacco [2].

In a previous PCT treatment study, we found that the median time to achieve a normal plasma porphyrin level for patients treated with phlebotomy or low-dose hydroxychloroquine was 6.9 and 6.1 months, respectively [7]. Time to achieving a normal plasma porphyrin in this study was evaluable in 9 patients who were sufficiently compliant with repeated study visits and was a median of 6.5 months (range 3.0–7.1 months). Therefore, remission of PCT as defined by lowering plasma porphyrins to normal occurred as rapidly with DAA treatment as in previous patients who received either of the two established treatments for this disease. These observations do not support considering either of these time-honored treatments for PCT + HCV before proceeding with DAA treatment, which is effective for both conditions.

Moreover, all of the 12 patients who achieved SVR with ledipasvir/sofosbuvir in this study experienced clearing of skin manifestations of PCT and lowering of porphyrin levels and have not required subsequent treatment of PCT with phlebotomy or low-dose hydroxychloroquine. Complete resolution of porphyrin abnormalities after treatment of PCT is gradual, presumably because time is required for the removal of the marked excess of accumulated porphyrins found in the liver in this disease. Also, other PCT susceptibility factors may persist, such as alcohol use or smoking, and some patients have more advanced chronic liver disease than others [2]. How much these individual features contribute to the rapidity of biochemical improvement with any type of PCT treatment remains rather ill-defined.

Although normalization of plasma and urine total porphyrin levels was achieved in 6 of the 12 patients (50%) with an SVR who also showed a normal proportion of highly carboxylated urinary porphyrins [uro- and heptacarboxyl-porphyrins < 40% of total porphyrins at a median of 240 days (range 100–615 days) after the start of treatment], modest abnormalities persisted at last follow-up in the remaining subjects (Fig. S3). It seems likely that, absent HCV reinfection, longer follow-up will reveal further gradual improvements in the remaining minor porphyrin elevations. Our observations suggest strongly that successful DAA treatment can be depended upon to achieve clinical remission of PCT associated with CHC, although attainment of complete biochemical remission of PCT may require longer follow-up and/or may not be achieved in all patients.

The pathogenesis of PCT involves increased oxidative stress in hepatocytes, leading to increased oxidation of uro- and hepta-carboxyl porphyrinogens, to their corresponding porphyrins and/or to uroporphomethene, which are not substrates, but rather inhibitors of UROD [8, 22–24]. All of the recognized risk factors for PCT, namely, HCV, iron, alcohol, smoking, and estrogens, increase oxidative stress in hepatocytes and lead to an increased propensity for formation of inhibitory oxidation products from the porphyrinogens, which are the physiologic substrates of UROD.

Strengths of this study include the careful and ongoing assessments of both clinical and laboratory features of a well-characterized cohort of subjects with both CHC and PCT.

Limitations include the fact that we were not able to recruit as many subjects as we had originally planned and hoped to enroll [original target n = 49]. This was likely due to at least two main factors: 1–the sponsor of the study, Gilead Sciences, closed the study to enrollment on Dec 31, 2020; and 2—the number of subjects presenting or referred to us with both active PCT and CHC decreased considerably in the years 2019 and 2020. We speculate that the latter was due to the Covid-19 pandemic and to the many and varied adverse effects that the pandemic had upon clinical research and recruitment, but also to the fact that, during those years [and still continuing], physicians increased successful treatment of such patients with DAAs alone, leading to far fewer referrals to us than in earlier years.

In conclusion, Harvoni, and likely other DAAs, are effective treatment for HCV in the presence of PCT and can lead to remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. The presence of active PCT does not adversely influence the efficacy of DAAs to cure HCV.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

ALT

Serum alanine aminotransferase

AP

Serum alkaline phosphatase

AST

Serum aspartate aminotransferase

CHC

Chronic hepatitis C

CT

Computed tomography

CVR

Complete virological response

DAA

Direct-acting antiviral drugs

EOT

End-of-treatment

HCV

Hepatitis C virus

HFE

The gene mutated in classical, HLA-linked hereditary hemochromatosis

HIV

Human immunodeficiency virus

INR

International normalized ratio

LiRADS

Liver reporting and data system

PCT

Porphyria cutanea tarda

PT

Prothrombin time

RUQ

Right upper quadrant

SVR

Sustained virological response

UROD

Uroporphyrinogen decarboxylase

WBC

White blood cell

Declarations

Conflict of interest

In the past 3 years, Dr. Bonkovsky has received funding for clinical research studies, awarded to Atrium Wake Forest Baptist Health, from Alnylam Pharmaceuticals, Disc Medicine, Calliditas SA, Gilead Sciences, and Mitsubishi-Tanabe, NA. He has served as a consultant to Alnylam, Disc Medicine, Mitsubishi-Tanabe, and Recordati Rare Chemicals. Dr. Rudnick has served as a consultant to Alnylam Pharmaceuticals; Christopher D. Ma, Jessica Overbey, Kelly Wang, Denise Faust, Csilla Hallberg, and Karli Hedstrom report no potential conflicts; Dr. Naik has served as a consultant to Alnylam Pharmaceuticals, Disc Medicine, Mitsubishi Tanabe, and Recordati Rare Diseases; Dr. Moghe has served as a consultant to Alnylam Pharmaceuticals; Dr. Anderson has received funding for clinical studies, awarded to UTMB, from Mitsubishi-Tanabe, NA and Disc Medicine. He has served as a consultant to and on advisory boards for Alnylam Pharmaceuticals, Mitsubishi-Tanabe, NA, and Recordati Rare Chemicals; the fees for this work have gone to UTMB.