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Effective Treatment of Chronic Hepatitis C Virus Infection With Ledipasvir/Sofosbuvir in 2 Teenagers With HIV Coinfection: A Brief Report

Pokorska-Śpiewak, Maria MD, PhD*,†; Dobrzeniecka, Anna MD; Ołdakowska, Agnieszka MD, PhD*,†; Marczyńska, Magdalena MD, PhD*,†

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The Pediatric Infectious Disease Journal: December 2021 - Volume 40 - Issue 12 - p 1087-1089
doi: 10.1097/INF.0000000000003264
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Abstract

Recent clinical trials have shown that a fixed-dose combination of ledipasvir/sofosbuvir (LDV/SOF) is highly effective, safe and well tolerated in children age 3 years and older with chronic hepatitis C (CHC).1–3 On this basis, the US Food and Drug Administration and the European Medicines Agency approved the use of LDV/SOF for the treatment of hepatitis C virus (HCV) infection in adolescents (12–17 years of age) in 2017 and in children between 3 and 11 years of age in 2020. However, no data on the efficacy, safety or tolerability of LDV/SOF in specific groups of patients, such as in children and adolescents with HIV coinfections, are available. Thus, the aim of this brief report was to present the effects of LDV/SOF treatment in 2 teenagers with HIV/HCV coinfection.

MATERIALS AND METHODS

Between July 2019 and December 2020, 37 pediatric patients were included in the real-life therapeutic program “Treatment of Polish Adolescents with CHC Using Direct Acting Antivirals (POLAC PROJECT)” launched in our tertiary healthcare department for HCV-infected children from all Polish regions. The program is available courtesy of the donation of LDV/SOF by the pharmaceutical company. In this project, we included children of age 12–18 years with CHC (detectable HCV RNA for at least 6 months) infected with HCV genotype 1 or 4, irrespective of the stage of liver fibrosis or previous antiviral treatment. The duration of LDV/SOF treatment was established according to the recommendations of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN): patients received 12 weeks of therapy unless they were infected with HCV genotype 1 and had a history of previous ineffective interferon-based treatment and presented with cirrhosis.4 All patients in this study were prospectively followed every 4 weeks during the treatment and at the end of the therapy. The efficacy of the treatment was assessed based on whether the patients achieved a sustained virologic response 12 weeks after the end of treatment (SVR12). Biochemical and serological tests were performed using commercially available laboratory kits, and nucleic acid tests (for hepatitis B virus [HBV] DNA, HCV RNA and HIV RNA) was performed using real-time polymerase chain reaction (RT-PCR method; Abbott m2000 RealTime System; Abbott Laboratories, IL, with the following lower limits of detection: HBV DNA of 10 IU/mL, HCV RNA of 12 IU/mL and HIV RNA of 20 copies/mL). Written informed consent was collected from all the patients and/or their parents/guardians before their inclusion in the study.

RESULTS

Among the patients included in the project, 2 boys, of age 15 and 16 years, had HIV/HCV coinfections. Their infections with HIV and HCV genotype 4 were the result of vertical transmission, and they received effective antiretroviral therapy (ART), resulting in undetectable HIV viral loads for at least the previous 5 years (Table 1). Before starting anti-HCV treatment, the possibility of drug interactions between ART and LDV/SOF were excluded using the online HEP Drug Interactions Checker provided by the University of Liverpool (www.hep-druginteractions.org). Patient 1 had a history of previous ineffective treatment with interferon and ribavirin. The median liver stiffness measurement (LSM) obtained with transient elastography before the initiation of treatment was 14 kPa, which corresponded to a METAVIR F4 score (liver cirrhosis). His Child-Pugh class was A. He had no evidence of present or previous HBV infection. Patient 2 had no significant fibrosis on transient elastography (a METAVIR F0-1 score), but he had evidence of previous HBV infection (detectable anti-HBc total antibodies with negative HBsAg and undetectable HBV DNA).

Table 1. - Clinical and Laboratory Characteristics of 2 Patients With HIV/HCV Coinfection
Feature Patient 1 Patient 2
Sex Male Male
Age at start of the treatment 16 years 10 months 15 years 10 months
HCV genotype 4 4
Mode of HCV/HIV coinfection Vertical Vertical
BMI (kg/m2) 25.7 18.4
BMI z-score 1.55 −0.64
Previous anti-HCV treatment Yes (interferon plus ribavirin) No
ART TAF/FTC/RAL TAF/FTC/RPV
HBsAg/anti-HBc total Negative/negative Negative/positive
HBV DNA PCR (IU/mL) NA Undetectable
CD4+ T-lymphocyte count (cells/µL) 755 822
ALT (IU/mL)
 Start of LDV/SOF 52 32
 4 weeks 22 27
 8 weeks 39 22
 12 weeks 63 23
 Posttreatment week 12 27 21
HCV viral load (IU/mL)
 Start of LDV/SOF 4.89 × 105 7.06 × 105
 4 weeks <12 Undetectable
 12 weeks Undetectable Undetectable
 Posttreatment week 12 Undetectable Undetectable
HIV viral load (copies/mL)
 Start of LDV/SOF Undetectable Undetectable
 4 weeks Undetectable Undetectable
 12 weeks Undetectable Undetectable
LSM (median; kPa/METAVIR)
 Start of LDV/SOF 14/F4 4.8/F0–F1
 Posttreatment week 12 33.6/F4 NA
ALT indicates alanine aminotransferase; ART, antiretroviral therapy; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; FTC, emtricitabine; LDV/SOF, ledipasvir/sofosbuvir; LSM, liver stiffness measurement; NA, not applicable; PCR, polymerase chain reaction; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide.

Both patients qualified for 12 weeks of therapy with a fixed daily dose of LDV/SOF (90/400 mg) according to the current recommendations of ESPGHAN.4 After the first 4 weeks of treatment, the HCV viral load had decreased to detectable but below the lower limit of quantification in patient 1 and was undetectable in patient 2 (Table 1). At the end of the treatment, as well as 12 weeks later, HCV RNA was undetectable in both patients, which confirmed that both patients achieved SVR12 and that the HCV infections had been eliminated. Although patient 1 had compensated cirrhosis at the beginning of the therapy, HCV was successfully eliminated. His median LSM 12 weeks after the treatment was 33.6 kPa (METAVIR F4). Patient 2 was monitored due to evidence of past HBV infection (positive anti-HBc antibodies). No reactivation of HBV was observed during or after LDV/SOF treatment. In both patients, the HIV viral load remained undetectable at the end of LDV/SOF treatment and 12 weeks after the end of treatment. During the first 2 weeks of therapy, patient 1 complained of a mild headache, which responded well to ibuprofen. No other adverse events, including severe effects, were reported during LDV/SOF treatment.

DISCUSSION

The management and treatment of children with HIV/HCV coinfection is challenging.5 There is evidence that chronic HCV infection in the presence of HIV coinfection may be associated with a higher risk of progressive liver disease than HCV infection alone.6,7 At the end of adolescence, more than 25% of patients with HIV/HCV coinfection due to vertical transmission present with advanced liver disease.8 However, it has been shown that their response to peg-interferon and ribavirin therapy is poor, particularly in children infected with HCV genotypes 1 and 4.7 Thus, children with HIV/HCV coinfections should receive rapid access to early treatment based on novel direct-acting antivirals (DAAs).7,8

According to a recent systematic review and meta-analysis performed by Indolfi et al, children and adolescents with CHC can be safely treated with DAAs, and the efficacy is similar to that in adult patients.3 However, data on the efficacy, safety and tolerability of LDV/SOF in pediatric patients come mainly from a limited number of clinical trials that did not include specific groups of patients, such as children with HIV/HCV coinfection.1,2,8 To our knowledge, this is the first report on the use of LDV/SOF in teenagers with HIV/HCV coinfection. Two adolescents with HIV/HCV coinfection were effectively treated with glecaprevir/pibrentasvir in the DORA Study.9 In our report, we demonstrated that 12 weeks of treatment with a fixed-dose combination of LDV/SOF (90/400 mg) was effective, safe and well tolerated in teenagers coinfected with HIV. Both patients achieved SVR12. The therapy did not influence the efficacy of ART; HIV RNA remained undetectable at weeks 4 and 12 of anti-HCV therapy. Treatment was well tolerated, and the only temporary complaint was a mild headache in patient 1. According to the meta-analysis performed by Indolfi et al, headache was the most common (19.9%) side effect in children and adolescents treated with DAAs.3 No interactions between LDV/SOF and ART were observed, although both patients received tenofovir alafenamide (TAF)-based ART. As it has been shown that LDV/SOF coadministered with tenofovir disoproxil fumarate leads to higher tenofovir exposure, especially with a boosted protease inhibitor, and data on the interactions between LDV/SOF and TAF are lacking, our data on the safety of the coadministration of TAF and SOF/LDV are particularly important.10

According to the ESPGHAN recommendations, our patients were treated for 12 weeks. Recent data suggest that a shortened 8-week regimen of LDV/SOF is safe and effective with 100% of treatment-naive children without cirrhosis infected with HCV genotype 4 achieving SVR12.11 However, there is insufficient evidence to support the shortening of the treatment regimen in pediatric patients with HCV/HIV coinfection or cirrhosis.

One of our patients had detectable anti-HBc antibodies, which indicated previous HBV infection. DAA treatment in individuals with HCV/HBV coinfection may lead to a life-threatening reactivation of the HBV infection.12 Based on the results of the study performed recently on a large cohort of adults with HCV/HBV coinfection, the risk of HBV reactivation in HBsAg-negative/anti-HBc-positive patients was only 0.16%.12 To avoid HBV reactivation in such patients, those scheduled for DAA treatment should be tested for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc. In patients with serologic evidence of a previous or current HBV infection, the clinical and laboratory signs of a hepatitis flare or HBV reactivation should be monitored during HCV treatment and posttreatment follow-up. If clinically indicated, appropriate treatment for HBV infection should be started.

Our report is limited to only 2 patients. However, considering the low prevalence of pediatric patients with HIV/HCV coinfection, most clinicians take care of too few such patients to develop adequate experience directly.5 Our experience with successful treatment of these 2 teenagers with HIV/HCV coinfection with 12 weeks of LDV/SOF may encourage other clinicians to use LDV/SOF for similar patients—and report their results in the literature to expand evidence for guiding management of this patient population. Further research with larger groups of patients is needed to confirm our observations.

REFERENCES

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10. Solas C, Bregigeon S, Faucher-Zaegel O, et al. Ledipasvir and tenofovir drug interaction in human immunodeficiency virus-hepatitis C virus coinfected patients: Impact on tenofovir trough concentrations and renal safety. Br J Clin Pharmacol. 2018;84:404–409.
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Keywords:

coinfection; direct acting antiviral; hepatitis C; HIV; ledipasvir/sofosbuvir

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