Etravirine: a good option for concomitant use with chemotherapy for Hodgkin’s lymphoma

Abstract

The treatment of malignancies in HIV patients is challenged by the issue of drug–drug interactions between antiretroviral therapy and antineoplastic agents. While protease inhibitors have been shown to increase the incidence and severity of cancer therapy-related side effects, the impact of other antiretroviral agents on the tolerability and response to chemotherapy is less well documented. We report the successful use of an etravirine-based regimen in a patient treated with BEACOPP chemotherapy for advanced Hodgkin’s lymphoma. Etravirine constitutes a valuable option for concomitant use with chemotherapy due to its moderate inducing effect on drug metabolising enzymes.

Keywords

HIV AIDS antiretroviral therapy drug–drug interaction etravirine chemotherapy Hodgkin’s lymphoma

Introduction

The treatment of malignancies in HIV patients is challenged by the issue of drug–drug interactions (DDIs) between antiretroviral therapy (ART) and antineoplastic agents. Thus, despite proven evidence that patients treated concomitantly with cytostatic drugs and ART achieve better cancer survival rates, physicians tend to interrupt ART before initiating chemotherapy to avoid the detrimental effects of DDIs.¹ While protease inhibitors have been shown to increase the incidence and severity of cancer therapy-related side effects due to inhibition of drug metabolising enzymes,^2,3 the impact of other antiretroviral agents on the tolerability and response to chemotherapy protocols is less well documented. We report the successful use of an etravirine-based regimen in a patient concomitantly treated with BEACOPP chemotherapy for advanced Hodgkin’s lymphoma (HL).

Case presentation

A 46-year-old HIV-positive Caucasian man presented with a one-month history of persistent low-grade fever, night sweats and a progressive unilateral lymph node enlargement in the neck. The physical examination revealed a left-sided, non-tender cervical and supra-clavicular lymph node enlargement. The laboratory analyses were unremarkable with the exception of a mild anaemia (haemoglobin: 122 g/l). A fluordeoxyglucose-positron emission/computed tomography scan (FDG-PET/CT) detected an increased FDG uptake in all lymph node regions as well as in the spleen, liver, spine, proximal bones in the upper and lower extremities, and the skull base. A biopsy confirmed the diagnosis of HL. Given the advanced stage (IV B), it was decided to treat immediately with the intensive chemotherapy protocol BEACOPP escalated: bleomycin (10000 U/m²), etoposide (200 mg/m²), doxorubicin (35 mg/m²), cyclophosphamide (1250 mg/m²), vincristine (1.4 mg/m²), procarbazine (100 mg/m²) and prednisone (40 mg/m²).

Although HIV infection was well controlled under combined therapy with boosted darunavir, tenofovir and emtricitabine, ART was changed to a non-protease inhibitor-based regimen to limit the severity of chemotherapy-related toxicities due to DDIs. Raltegravir was favoured because of its low potential for DDIs. ART had to be intensified with etravirine due to the presence of the viral mutation M184V resulting in a less effective nucleoside reverse transcriptase inhibitor backbone. Two weeks after starting etravirine (200 mg BID) + raltegravir (400 mg BID) + emtricitabine (200 mg QD) + tenofovir (300 mg QD), the patient received six cycles (21-day cycles) of chemotherapy. The chemotherapy was administered at the full dosage without schedule interruption for the first four cycles. However, the dose of vincristine had to be halved in the last two cycles due to a mild polyneuropathy in the hands. The anaemia and thrombocytopaenia observed in the last cycle were corrected by blood transfusion. The HIV viral load remained well suppressed, whereas, as expected, the CD4 cell count dropped temporarily during the chemotherapy treatment (Table 1). The PET-CT scan one month after the end of treatment showed a complete remission. At present (i.e. eight months after chemotherapy completion), the patient has remained in good condition without clinical evidence of HL recurrence.

Table 1.

Haematological, immunological and virological responses before, during and after chemotherapy cycles.

Timeline	Total WBC count (×10⁹/l)	Haemoglobin count (g/l)	Thrombocyte count (×10⁹/l)	CD4 count (cells/mm³)	HIV viral load (copies/ml)
Baseline	12.9	141	351	912	<20
First cycle	14.8	99	435	191	<20
Second cycle	9.1	91	50	185	<20
Third cycle	14.3	106	291	91	<20
Fourth cycle	14.5	109	258	–	<20
Fifth cycle	15.8	95	144	–	<20
Sixth cycle	13.5	99	54	–	<20
Post treatment	9.1	133	252	292	<20

WBC: white blood cell.

The baseline parameters were measured three months prior to symptoms onset; the reported haematological parameters were measured two weeks after each chemotherapy cycle to reflect nadir values; the post-treatment parameters were measured six months after completion of the chemotherapy.

Discussion

There is a need to find safe ART options to use simultaneously with cancer therapy. The use of protease inhibitors is generally limited as they may inhibit the metabolism of co-administered cancer drugs and thereby increase their toxicity. Conversely, first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) (i.e. efavirenz, nevirapine) may induce metabolism and potentially reduce the efficacy of cancer drugs; nevertheless, no clinical interactions (decreased efficacy or increased toxicity of the antineoplastic agent) have been described in the literature for those NNRTIs. Although raltegravir has a low potential for DDIs, the presence of viral mutations limit its use as single active agent in a regimen. Etravirine, a second-generation NNRTI, constitutes a good option to intensify raltegravir-based regimens without compromising the efficacy of chemotherapy as illustrated in this case. Etravirine has been reported to be a weak inducer of cytochrome P450 (CYP) 3A and a weak inhibitor of P-glycoprotein.⁴ When considering the antineoplastic agents used in this patient, bleomycin and doxorubicin undergo mainly non-CYP-mediated metabolism and thus are unlikely to interact with etravirine. Procarbazine is activated by CYP2B6 which is not affected by etravirine. Etoposide is only partially metabolised by CYP3A4, thus limiting the effect of etravirine-mediated CYP3A induction. Cyclophosphamide is mainly activated by CYP2B6, while a minor proportion is inactivated to the neurotoxic chloroacetaldehyde metabolite by CYP3A4.⁵ Finally, vincristine is mainly metabolised by CYP3A5.⁶ Using human liver microsomes, CYP3A5 was shown to mediate approximately 80% of the CYP3A metabolism for individuals with high CYP3A5 expression (at least one CYP3A5*1 allele).⁷ Of interest, etravirine was shown to minimally induce CYP3A5 in vitro,⁸ whereas ritonavir has been shown to be a potent non-selective inhibitor of CYP3A5 and CYP3A4.⁹

The complete response to chemotherapy, the maintenance of HIV viral suppression and the absence of severe drug toxicities suggest that etravirine constitutes a valuable option for concomitant use with chemotherapy for HL due to its moderate inducing effect on drug metabolising enzymes.

Footnotes

Declaration of Conflicting Interests

The authors MK, FK and CM declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MS serves as a consultant for Merck Sharp & Dohme and Gilead Sciences. MB participated in advisory board from Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme and Janssen-Cilag AG. His institution has received unrestricted educational or grants from Gilead Sciences, Janssen and ViiV.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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