Peripheral oedema and high arterial blood flow as a complication of antiretroviral therapy

We describe here three patients with severe lower extremity oedema associated with high blood flow of the common femoral arteries. Oedema developed over several months after the initiation of antiretroviral therapy, and regressed slowly upon treatment discontinuation, and in association with a normalization of the arterial blood flow. The common factor for the three patients included the use of stavudine. This syndrome appears as a novel drug adverse event with an unclear pathogenesis.

In 1997 a 45-year-old woman initiated a regimen combining zidovudine and lamivudine. As a result of anaemia, zidovudine was replaced by stavudine. Within weeks of the substitution she developed oedema of the lower extremities, which extended to the inguinal area over 5 months. A computed tomography (CT) scan of the abdomen, a transthoracic echocardiography, and an electromyogram were all normal. Thyroid tests, serum albumin level, and the plasma glucose concentration were normal and no proteinuria was detected. The blood lactate level was not measured. A duplex scan showed a sevenfold increase in blood flow in the common femoral arteries. Stavudine was replaced by zidovudine and the oedema resolved over a few weeks. As a result of anaemia attributed to zidovudine, stavudine was re-started. Within few weeks the leg oedema recurred, and oedema of the face and upper extremities was noted. Stavudine was again discontinued, leading to a slow resolution.

A 42-year-old man had been on antiretroviral therapy for 3 years, which consisted of stavudine, lamivudine and indinavir during the first year; indinavir was switched to saquinavir and ritonavir during the second year. Ritonavir was switched to nelfinavir for the next 8 months. Two months after initiating nelfinavir, the patient developed oedema of lower extremities and a fourfold increase in blood flow in the common femoral arteries. Oedema gradually extended to the inguinal area. A duplex scan performed 8 months later identified a worsening common femoral artery blood flow to a sixfold increase. A CT scan of the abdomen and a transthoracic echocardiography were normal. An electromyogram showed a sensorimotor polyneuropathy without impairment of the sympathetic nervous system. In order to test the sympathetic axon reflex in the lower limbs, the venoarteriolar response was measured upon lowering of the leg at 90° from the supine position. A reduced skin blood flow measured by laser Doppler was observed, demonstrating an adequate venoarteriolar response and the absence of neuropathy. Thyroid and glucose values were normal, a reduced albumin level at 30 g/l with no proteinuria was observed. The discontinuation of treatment was accompanied by a diminution of oedema over 4 months. A regimen containing abacavir, nelfinavir and saquinavir was restarted for one month without a recurrence of oedema.

A 44-year-old woman initiated treatment, including zidovudine, lamivudine and nelfinavir. Treatment was modified after 2 months to stavudine, lamivudine and efavirenz. Painful oedema of the lower extremities developed over 8 months, and at this time the patient developed severe hyperlactatemia (9.09 mmol/ml) and acidosis (pH 7.25). The abdomen CT scan was normal, and thyroid tests were normal. A duplex scan of the legs identified a fourfold increase in blood flow in the common femoral arteries. The flow in the brachial arteries was also increased. The sympathetic axon reflex in the lower limbs and venoarteriolar response were intact. Treatment was discontinued, and arterial flow became normal within 6 weeks. The patient presented with a rapid (over 6 weeks) development of severe lipodystrophy (profound loss of facial and limb fat, buffalo hump, and abdominal fat accumulation). Two months after the discontinuation of therapy, antiretroviral therapy was re-started, including lopinavir, saquinavir and efavirenz. An improvement of the fat redistribution syndrome was noted over the following months.

WhPWhereas oedema has been associated with the use of antiretroviral therapy (Table 1), in particular with the use of lopinavir [^1,2] and ritonavir [³], the syndrome described in this paper appears to be distinct by the less inflammatory nature of the oedema, the slower development and resolution of oedema, and the lack of association with protease inhibitors. The common denominator of all three patients was use of stavudine, elevated arterial blood od flow, improvement when the drug was stopped, and for one patient, recurrence upon re-challenge.

Table 1

The differential diagnosis of elevated arterial blood flow includes hyperthyroidism, diabetes mellitus, inflammatory states and polyneuropathy with reduced resistance or loss of the veno-arteriolar reflex. Impairment of the sympathetic nervous system was excluded in two patients. Severe hyperlactatemia and rapidly progressing lipodystrophy was associated with oedema in the third patient. Drug toxicity constitutes a common complication of antiretroviral therapy [⁴]. In this report we wish to draw attention to a new syndrome, and to the potential importance of evaluating the arterial blood flow in a prospective fashion, in particular in individuals presenting with metabolic toxicity associated with antiretroviral treatment.