Development of gynecomastia following initiation of bictegravir/emtricitabine/tenofovir alafenamide

Introduction

Historically, the treatment of human immunodeficiency virus (HIV) involved the use of antiretrovirals (ARVs) associated with a number of clinically significant toxicities. Recent advancements have led to the development and approval of newer ARVs, such as integrase strand transfer inhibitor (INSTI)-based single-tablet regimens, considered to have a relatively low risk of toxicities while offering additional advantages of a decreased pill burden and convenient dosing schedules.

In February 2018, the US Food and Drug Administration (FDA) approved one of the newest INSTI-based single-tablet regimens, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), for use in adults living with HIV-1 who are ARV-naïve or as a replacement therapy for those who are virologically suppressed. ¹ Shortly thereafter, BIC/FTC/TAF was recommended as a first-line option for ARV-naïve patients. ² At that time, phase III clinical trial data contained a limited number of patients. Therefore, rare, but serious, adverse effects were undetected until the post-marketing phase.

Similarly, clinically significant nephrotoxicity was not observed in the early clinical trials leading to the approval of tenofovir disoproxil fumarate, but was observed in multiple case reports after its approval. ³ Post-marketing monitoring has reported numerous cases of ARVs causing gynecomastia, although not INSTIs.^4,5 Because of this, post-marketing monitoring and reporting of potential adverse effects is an important aspect of the drug use process. Here, we present the case of a previously ARV-naïve patient who was initiated on BIC/FTC/TAF and shortly afterwards developed gynecomastia, a previously unreported toxicity associated with its use.

Case summary

A 44-year-old African-American male (weight 103.4 kg, body mass index 26.3 kg/m²) diagnosed with HIV after routine screening presented to our clinic for initiation of ARV therapy. At the time of presentation, he had no known past medical history and was not taking any prescription medications or over-the-counter products and denied any illicit drug use. He reported his last negative HIV screen was approximately six months earlier. Baseline CD4 cell count and HIV-1 viral load (VL) were 475 (25%) cells/mm³ and 69 copies/ml, respectively. The patient was initiated on BIC/FTC/TAF at this time and instructed to return to clinic for routine monitoring with follow-up in approximately six weeks.

At the follow-up visit six weeks after BIC/FTC/TAF initiation, he voiced no complaints, with a CD4 cell count of 708 (32%) cells/mm³, and HIV-1 VL now suppressed (<20 copies/ml). Approximately ten weeks later (four months after starting BIC/FTC/TAF), the patient presented once again for routine follow-up. He reported painless swelling of the left breast without discharge for roughly two months, for which he saw an outside provider. He was empirically prescribed an oral course of cephalexin for suspected cellulitis. This failed to improve his condition.

Further laboratory work-up revealed both hyperestrogenism (serum estradiol 61 pg/ml [normal range: 20–47 pg/ml]) and hyperprolactinemia (30.8 ng/ml [normal range: 2.6–13.1 ng/ml]). Serum concentrations of follicle stimulating hormone (3.1 mIU/ml), luteinizing hormone (4.7 mIU/ml), thyroid stimulating hormone (2.73 mIU/l), and total testosterone (550 ng/dl) were all within normal limits. Additionally, ultrasound imaging demonstrated increased heterogenous tissue in the left breast compared to the right consistent with gynecomastia, but no evidence of a mass. The patient’s ARV regimen was consequently changed to darunavir/cobicistat/FTC/TAF (DRV/COBI/FTC/TAF) to maintain him on a single-tablet regimen while avoiding the INSTI-class. His gynecomastia subsequently resolved over the course of ten weeks.

Discussion

Gynecomastia is a known toxicity of various medications, including some ARVs. Historically, the most commonly implicated ARVs associated with gynecomastia have been didanosine, efavirenz, and various protease inhibitors.^4,5 To the best of our knowledge, INSTI-associated gynecomastia has not been previously reported in the literature. In the publicly available official FDA review application of BIC/FTC/TAF, the safety of BIC/FTC/TAF was assessed among 1511 patients who received at least a single dose in phase II/III clinical trials. ⁶ There were no cases of gynecomastia noted in the report although a single case of gradually progressing abdominal distention simply described by the investigator as ‘typical HIV drug-related central lipohypertrophy’ ultimately led to discontinuation in one patient. However, we were able to identify two cases of gynecomastia reported with BIC/FTC/TAF use during the post-marketing phase in the FDA Adverse Event Reporting System database. ⁷

In the present case, we believe that the onset of gynecomastia relative to the initiation of BIC/FTC/TAF, combined with the absence of any other medications or medical conditions known to be associated with gynecomastia, suggests it was due to BIC/FTC/TAF. The likelihood of an association between BIC/FTC/TAF and gynecomastia in our case was deemed ‘probable’ using the Naranjo algorithm (Score 6). ⁸ Furthermore, resolution of gynecomastia while continuing FTC and TAF (DRV/COBI/FTC/TAF) supports the premise that gynecomastia was most likely a consequence of the BIC component of the regimen.

While the full mechanism behind ARV-induced gynecomastia is currently unknown, three possible mechanisms have been proposed: inhibition of the cytochrome P450 (CYP450) enzyme system, ⁹ direct activation of the estrogen receptor, ¹⁰ and immune reconstitution inflammatory syndrome (IRIS). ¹¹ However, BIC is not an inhibitor of the CYP450 enzyme system ¹ and it is unknown whether BIC directly modulates the estrogen receptor. Qazi et al. ¹¹ previously proposed that immune restoration may lead to gynecomastia due to increased interleukin-2 (IL-2) and IL-6 production. IL-2 was reported to increase human breast carcinoma cell proliferation in vitro ¹² and IL-6 was shown to increase the activity of aromatase (which converts testosterone to estradiol) in breast tissue. ¹³

In theory, the resulting increase in estradiol would further promote breast growth and also stimulate release of prolactin, which may explain why serum estradiol and prolactin were increased in our patient. Pending future studies, we believe that BIC/FTC/TAF-induced IRIS is the most likely mechanism causing gynecomastia in our case given the onset time and known association between IRIS and INSTI use. ¹⁴ Although most common among patients with CD4 cell count <200 cells/mm³ and HIV VLs >10,000 copies/ml, IRIS has been previously reported to occur in patients similar to ours with CD4 cell counts ≥350 cells/mm³ and/or HIV VLs <1000 copies/ml. ¹⁵ Under this theory, it is possible that our patient’s gynecomastia may have resolved during continued BIC-based therapy once IRIS had subsided but it was determined that a change in ARV therapy was warranted at the time.

Widespread use of INSTI-based regimens, coupled with the current recommendation of BIC/FTC/TAF as a first-line option for ARV-naïve patients, is likely to promote its increased clinical use. As this occurs, adverse effects like the one we describe above may become more common. Our case highlights the potential limitation of clinical trials to identify rare, but serious, adverse events that may go undetected prior to reaching the market. Based on our experiences reported here, we recommend clinicians monitor patients for potential development of gynecomastia following initiation of BIC/FTC/TAF and strongly encourage clinicians to report their own post-marketing experiences with this agent.