Reactivation of chronic hepatitis B during treatment with tenofovir disoproxil fumarate: drug interactions or low adherence?

Abstract

We describe a case of a 61-year-old man with chronic hepatitis B, hepatitis B e antibody (HBeAb) positive, treated with tenofovir disoproxil fumarate (TDF), who developed virological and biochemical viremic reactivation with an increase in transaminase plasma levels. The patient's history revealed that he had discontinued TDF about 5 days before admission and, from December 2013, had been taking venlafaxine, paroxetine and zolpidem for some episodes of depression. Clinical evaluation and laboratory findings excluded the presence of systemic diseases that might have been able to explain the drug inefficacy, while pharmacological evaluation suggested a possible drug-drug interaction. In order to assess the possible occurrence of resistance, mutational analysis of hepatitis B virus (HBV) was performed and excluded the presence of resistance for TDF. TDF was prescribed, and venlafaxine, paroxetine and zolpidem were discontinued. The follow-up at 3, 6 and 12 months documented a good response to TDF with a time-related decrease of HBV-DNA and alanine aminotransferase.

Background

Antiviral therapy for chronic hepatitis B (CHB) has modified the clinical evolution of the disease with an improvement in terms of morbidity, mortality and quality of life. To date, entecavir and tenofovir disoproxil fumarate (TDF) represent the first choice for the treatment of hepatitis B virus (HBV) infection, having demonstrated high efficacy and good tolerability.¹

Other studies in 1597 patients with CHB (mean age 47 years, 75% hepatitis B e antigen (HBeAg) negative, 26% with cirrhosis) demonstrated that a 3–4-year course of TDF achieved virological-response rates ranging from 92% to 100% without the development of resistance.^{2 3}

We report an unusual case of viral reactivation in a patient with HBV treated with tenofovir. To date, no papers of viral reactivation during tenofovir therapy have been published.

Case presentation

A 61-year-old man was referred to our facility for evaluation of CHB infection. Medical history revealed that about 22 years earlier (1991), a CHB (HBeAg positive) infection was diagnosed and on September 2003, treatment with interferon was started (HBV-DNA 10 000 000 IU/mL; normal range <20 IU/mL).

About 10 years later (March 2013), the patient presented to us and laboratory analysis revealed high HBV-DNA levels (757 000 IU/mL) with HBeAg negative. TDF, (245 mg/day) was prescribed, resulting in complete virological suppression in about 6 months (HBV-DNA not detected).

On November 2013, the patient's psychiatric consultant had diagnosed mood depression with insomnia and a treatment with venlafaxine (150 mg/day), paroxetine (20 mg/day) and zolpidem (10 mg/day) was started, with an improvement of symptoms in about 1 month. On January 2014, at the time of the present admission, the patient mentioned that he had stopped taking TDF 5 days prior because he had ran out of medication and its prescription had expired. No other drugs were taken by the patient at the time of presentation except for the above described psychotropic medications.

Investigations

Microbiological and biochemical evaluation revealed an increase in liver enzymes and serum HBV-DNA (605 000 IU/mL; table 1), and excluded an HIV infection. Clinical evaluation and laboratory findings excluded the presence of systemic diseases that might have been able to explain the drug inefficacy, while pharmacological evaluation postulated a possible drug-drug interaction (DDI) (Drug Interaction Probability Scale (DIPS) score 3). In order to assess the occurrence of resistance to TDF, mutational analysis of HBV (search of variants of the Pol gene) was performed on a blood sample, showing the presence of a single mutation (rtM204I) known for adefovir but not for TDF.

Table 1.

Laboratory findings

Blood	March 2013	January 2014	March 2014	January 2015
Cholesterol (nr 110–220 mg/dL)	210	211	216	216
Cholesterol HDL (nr 35–65 mg/dL)	54	53	54	54
Glucose (nr 70–100 mg/dL)	85	84	84	85
γ-glutamyl transpeptidase (nr 0–73 UI/L)	33	666	65	35
Aspartate aminotransferase (nr 3–46 UI/L)	29	575	46	30
Alanine aminotransferase (nr 3–46 UI/L)	35	961	48	39
HBV DNA (nr <20 IU/mL)	<200	605 000	<20	<20
Serum albumin (nr 38–47 g/dL)	41	42		42
Serum creatinine (nr 0.7–1.2 mg/dL)	0.8	0.8	0.8	0.8
CKD-epi (nr >60 mL/min)	88	92	93	93
Alkaline phosphatase (nr 115–359 IU/L)	270	272	271	272
Phosphate (nr 35–104 IU/L)	98	202		99
Phosphorus (nr 2.7–4.5 mg/dL)	3.3	3.2	3.2	3.2
Calcium (nr 8.5–10.5 mg/dl)	9.4	9.6	9.7	9.6
Potassium (nr 3.6–5 mEq/L)	4.4	4.3	4.3	4.4
Sodium (nr 135–145 mEq/L)	142	141	141	141
25-Hydroxyvitamin D (nr 20–100 ng/mL)	32	30	30	31
1,25-Dihydroxyvitamin D (nr 25–66 ng/mL)	39	41	40	40

CKD-epi: chronic kidney disease epidemiology Collaboration; HBC, hepatitis B virus; HDL, high-density lipoprotein; nr, normal range.

Treatment

TDF (245 mg/day) was prescribed and, in agreement with the specialist in psychiatry, paroxetine and zolpidem were discontinued, while venlafaxine dosage was initially reduced to 75 mg/day and then discontinued, with a rapid decrease in serum HBV-DNA levels and liver enzymes.

Outcome and follow-up

Follow-up performed 6 and 12 months later documented a good response to TDF, with a time-related decrease of serum HBV-DNA and liver transaminases levels (table 1).

Discussion

Tenofovir is a potent and selective inhibitor of HBV-DNA polymerase/reverse transcriptase (pol/RT) in vitro,⁴ approved for the treatment of CHB in patients 12 years of age and older.

Two international multicentre randomised double-blind phase 3 studies evaluating 641 patients for the effects of once-daily TDF versus once-daily adefovir dipivoxil (ADV) for 1 year, showed that TDF was more effective than ADV in viral suppression and for improving histological inflammation.⁵

Moreover, extending treatment with TDF is associated with increasing HBV-DNA suppression and higher HBeAg seroconversion rates.⁶

In our case, a man with a CHB infection and treated with tenofovir developed a new viral reactivation. Three relevant points must be considered to explain this reactivation:

1. Development of resistance,

2. Low adherence to drug treatment; in fact, tenofovir was discontinued 5 days before the observation,

3. DDI reducing the plasma levels of tenofovir.

Regarding the first point, a recent paper reported that no evidence of resistance to TDF has been observed through year 6 (288 weeks) of treatment in patients with CHB,^7–9 since the mutation rtA181 V/T confers cross-resistance to lamivudine and ADV, and reduces the sensitivity to tenofovir.^{10 11}

In our patient, the genomic mutation pattern of HBV revealed the presence of a single mutation (rtM204I), previously described for adefovir.¹² The administration of tenofovir induced a rapid normalisation of HBV-DNA and liver enzymes levels, suggesting that this mutation does not induce the development of resistance to tenofovir. Therefore, we ruled out this point.

Considering the second point, TDF, an oral prodrug of tenofovir, exhibits long plasma (17 h) and intracellular (≥60 h) half-lives;¹³ it is eliminated unchanged in the urine by a combination of glomerular filtration and proximal tubular secretion,¹⁴ therefore, in a patient without kidney dysfunction, tenofovir is totally excreted from the body in about 7 days. Our patient, with normal renal function, discontinued tenofovir only 5 days before admission, therefore, the time was not sufficient to induce a clinical inefficacy.

Previously, the WHO reported that poor adherence to therapy is a complex challenge for physicians treating patients with chronic diseases and, in clinical practice, adherence rates average 50%, falling most dramatically after the first 6 months of treatment.¹⁵ In the treatment of HBV, a suboptimal adherence to therapy has been described. In particular, Chotiyaputta et al,¹⁶ using pharmacy refill records, reported a good adherence in 55.3% of patients. Giang et al,¹⁷ using structured questionnaires in 80 patients, documented a good adherence in 66%, and a suboptimal adherence in 33.8%. Moreover, these authors reported that 43% of patients skipped medications, and in 10% the reason was that they had run out of medications.

Similarly, Sogni et al,¹⁸ in a cross-sectional study performed in 190 patients treated with anti-HBV analogues for at least 3 months, reported that 61% of patients were totally adherent, 32% moderately adherent and 7% of patients were non-adherent to the treatment, and suggested that adherence seems to be an independent factor associated with virological suppression.

In the present case, the patient came to our facility for clinical evaluation, and also because he had run out of the drug, and the prescription had expired. Therefore we cannot exclude the fact that he stopped taking the drug for several days before the admission, with a decrease in clinical efficacy.

Unfortunately, we did not perform therapeutic drug monitoring of TDF, therefore we do not know its levels at the time of admission.

Finally, HBV is a DNA virus that cannot be eradicated completely from the organism by treatment, only its replication can be suppressed to low levels. Since nucleos(t)ide analogues significantly reduce the risk of HBV reactivation, this risk increases with the degree of induced immunosuppression, particularly during treatment with corticosteroids or with biological drugs.¹⁹ It has also been reported that HBV/HIV co-infection is associated with an increased frequency of HBV reactivation.²⁰

In the present case, our patient did not take any of these drugs, while microbiological assay excluded an HIV infection, therefore we can exclude this mechanism.

Tenofovir is not a substrate of cytochrome P 450 and its renal elimination as unchanged drug is via two pathways, the major elimination is freely, by glomerular filtration (due to its low-protein binding), and the remaining 20–30% of tenofovir is actively transported into renal proximal tubule cells by organic anion transporters (hOAT1 human renal organic anion transporters, and to a lesser extent, OAT3) in the basolateral membrane.^21–23 Subsequently, it is secreted to the tubular lumen by the apical membrane transporters MDRP4 and MDRP2 (multidrug resistance proteins).²⁴ It has recently been reported that tenofovir is a safe and well-tolerated drug in patients with comorbidities as well as in patients with a decreased glomerular filtration rate.^{25 26} Previously, we reported that DDIs may be able to induce clinical inefficacy,²⁷ and some studies have reported that paroxetine and venlafaxine are able to induce the development of DDIs through the inhibition of cytochrome P450^28–31 or through the stimulation of efflux protein expression (eg, P-glycoprotein and breast cancer resistance protein),³² respectively.

Even if several drugs interact with hOATs and MDRPs, causing excessive entry or reduced outflow of tenofovir, favouring intracellular accumulation and increasing renal toxicity,^33–36 to date, no studies have been published concerning the effects of paroxetine or venlafaxine on these transporters. However, the discontinuation of these drugs induced a decrease of both HBV-DNA and liver enzymes, therefore using the DIPS we can only postulate that DDI could be possibly involved in the reduced efficacy of tenofovir.

In fact, the administration of psychotropic drugs induced an increase of HBV-DNA levels, while their discontinuation induced a virological suppression. However, we did not know the early serum HBV-DNA levels, from before the administration of psychotropic drugs, and the virological suppression was recorded after the administration of tenofovir.

Therefore, since we are not able to rule out this point, we cannot exclude the fact that a DDI in a patient with low adherence to drug administration may lead to HBV reactivation.

The reporting of this case is meant to arouse the interest of the scientific community on the issue of drug adherence as well as drug interactions, in order to increase drug surveillance.

Learning points.

• To date, tenofovir represents an efficacious treatment in patients with hepatitis B virus, and papers related to inefficacy or development of resistances have so far not been published.

• Viral reactivation can occur during tenofovir treatment and, after the exclusion of resistance, low adherence or drug interaction should be considered.

• Drug surveillance must be performed by each physician in order to reduce the risk of low adherence and drug interactions.