Bevacizumab in HIV-positive patients: concerns about safety and potential for therapeutic use

Abstract

Human immunodeficiency virus (HIV) patients have more aggressive presentation of colorectal cancer (CRC) and less favourable outcome. Bevacizumab is an antiangiogenic agent that has emerged as a major drug for metastatic CRC. However, few data are available on the safety of bevacizumab in HIV patients. In the light of a case study, we briefly draw intention on how angiogenesis inhibitors could interact with antiviral tri-therapy.

Keywords:

• AIDS
• Bevacizumab
• Targeted therapies
• Toxicity

Introduction

Highly active antiretroviral therapies have considerably changed the outcome of patients with human immunodeficiency virus (HIV) infection.¹ Consequently, colorectal carcinoma (CRC) is becoming a major cause of death in patients with a long history of HIV. They have more aggressive presentation of CRC and less favourable outcome.^2,3 An increasing number of HIV patients will be susceptible to receive both antiviral tri-therapy and antiangiogenic bevacizumab, which has emerged as a major drug for metastatic CRC. However, few data are available on the safety of bevacizumab in HIV patients. In the light of a case study, we briefly draw intention on how angiogenesis inhibitors could interact with antiviral tri-therapy.

Case report

A 49-year-old male presented with a diagnosis of well-differentiated lieberkühnian colorectal adenocarcinoma with histologically confirmed peritoneal carcinomatosis. He had a previous history of HIV infection since 1986 and is currently being treated with Kivexa® (abacavir and lamivudine) and nevirapine as fourth line antiviral therapy. The patient had no other past-medical history. The CD4 count was 600/mm³ and the viral load was undetectable. A combination of chemotherapy with concurrent use bevacizumab was decided, oxaliplatin (85 mg/m²) with folinic acid (200 mg/m²/day) and 5-fluorouracile (bolus 400 mg/m² then infusion 600 mg/m² for two consecutive days). Bevacizumab was given at 10 mg/kg, every 2 weeks. After three cycles, the patient presented an acute substernal chest pain without other symptoms. The rest electrocardiogram revealed a transient ST-segment elevation. A coronary angiography revealed a coronary vasospasm without high-grade coronary stenoses. The treatment included the use of a calcium channel blocker (diltiazem) and a statin. The pain decreased rapidly and no ST-segment elevation was observed on the control electrocardiogram. The next six cycles of chemotherapy were delivered with electrocardiographic monitoring without further complications. The HIV infection was maintained under control during the chemotherapy period (CD4 count and viral load). No opportunistic infection was reported. Thereafter, the patient received heated intraperitoneal chemotherapy (HIPC) without perioperative complication. At the time of last follow-up, he remained disease-free.

Discussion

Bevacizumab exerts its antiangiogenic activity by binding to the VEGF, thus preventing its ability to interact with its receptor. This leads deprivation in nutrients, and normalization of the vascular window for alleviating hypoxia-related resistance to chemotherapy.⁴ On the other hand, the toxicity of bevacizumab includes non-cardiovascular (proteinuria, haemorrhage, impaired wound healing, gastrointestinal perforation, etc.) and cardiovascular events including hypertension and arterial thromboembolic events (transient ischemic attacks, strokes, angina, and myocardial infarction). The pathophysiology underlying the increased risk of thromboembolism in patients treated with inhibitors of angiogenesis remains unresolved.⁵ The main hypothesis is that perturbation of tumour-associated endothelial cells can switch the endothelium from a naturally anticoagulant surface to a pro-thrombotic surface. The VEGF pathway has been reported to protect and regulate endothelial cell function via pathways that inhibit inflammation. VEGF-induced nitric oxide production by endothelial cells has been proposed to block antiplatelet activity and leukocyte adhesion.⁶ Endothelial cell dysfunction may then expose pro-thrombotic phospholipids and underlying stroma.⁷ A large meta-analysis showed that the incidence of all grade venous thromboembolisms was 19% in the case of CRC when treated with bevacizumab.⁸ Severe bleedings have been also reported in patients with renal cell carcinoma. Although these data support much caution when delivering bevacizumab with concurrent drugs that might affect its safety profile, no strong interaction has been reported for bevacizumab, which is metabolized and eliminated via the reticuloendothelial system.

An overview of the metabolism of abacavir, lamividine, and nevirapine suggests that the risk for drug interaction with bevacizumab is low. Since nevirapine is an inductor of CYP3A and CYP2B6 enzymatic systems, other antiangiogenic agents such as tyrosine kinase inhibitors could be potentially affected. Still, there is increasing evidence that patients with AIDS would be more sensitive to chemotherapy-related side effects than healthy patients. Randomized trials suggested that dose reduction chemotherapy could be considered for patients with poor immune function (CD4 count<200/mm³).⁹ Hoffman et al. have demonstrated that patients with CD4<200 had markedly increased morbidity while receiving chemoradiation for anal carcinoma.¹⁰ Literature is much scarcer when focussing on targeted anticancer agents in patients with HIV infection and their concurrent use with antiretroviral therapy.

Baraboutis et al. have reported their clinical experience of an HIV-infected patient receiving bevacizumab for a metastatic hepatocellular carcinoma without side effect.¹¹ Another case suggests that a controlled HIV infection should not preclude the use of the standard therapy, including targeted therapies, in patients with a good performance status.¹² In our patient, the cardiac event was probably related to 5-fluorouracile, since coronary spasms have been widely described with this agent. However, it was demonstrated that the prevalence of subclinical functional and structural cardiac abnormalities was increased in patients receiving antiretroviral therapy.¹³ Bevacizumab could have favoured this cardiac event by worsening subjacent coronary obstructive disease.

Given its activity, bevacizumab has emerged as an important drug for the treatment of patients with poor prognosis malignancies. The National Cancer Institute has recently conducted a phase II study that aimed at assessing the safety and effectiveness of bevacizumab for treating AIDS-associated Kaposi's sarcoma. Seventeen HIV-infected patients were enrolled, 40 of them had received highly active antiretroviral therapy for at least 6 months. Patients received bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. Overall response rate was 31% (95% CI, 11–58·7%). Over 202 cycles, toxicity was easily manageable with grade 3–4 adverse events including hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2).¹⁴ Our case and data from literature suggest that people with well-controlled HIV infection, good physical status, and a non-AIDS-associated malignancy could be managed in essentially the same way like HIV-negative patients when bevacizumab is used. Further investigations are however encouraged for better dissecting the safety profile of bevacizumab, particularly in patients whose associated morbidities may potentially increase their susceptibility to severe side effects.¹⁵

No conflict of interest relative to this work.