Severe myositis on commencement of efavirenz, abacavir and lamivudine, in the absence of lactic acidosis or classical abacavir hypersensitivity

Abstract

Myositis in HIV may be due to HIV itself, or to opportunistic infection, malignancy or drug treatment. Severe myositis or rhabdomyolysis have never been reported with the commonly used nucleoside reverse transcriptase inhibitor abacavir, although creatine phosphokinase may rise modestly, particularly if abacavir hypersensitivity occurs. We report an unusual case of abacavir use associated with a thousand-fold rise in creatine phosphokinase in the absence of features of hypersensitivity. The case was also notable firstly in that there was an absence of the HLA-B5701 allele, the most common human leucocyte antigen (HLA) allele associated with hypersensitivity, and, secondly, as the case occurred in an African patient, African people not being prone to abacavir hypersensitivity.

BACKGROUND

This is the first case of a massive rise in creatinine phosphokinase (CPK) after treatment with the commonly used drug for HIV infection, abacavir. Hospitalisation resulted. Acute renal failure may follow acute rises in CPK, thus rendering the reaction significant. Hypersensitivity, which may cause mild rises in CPK, seemed not to be the cause, based on clinical presentation and genetic data, or, if present, was extremely atypical.

CASE PRESENTATION

An African male in his thirties was diagnosed with asymptomatic HIV in October 2004. His CD4 count was 69 cells/μl and HIV viral load 53 000 copies/l. Prophylactic co-trimoxazole was prescribed. Antiretroviral treatment (ART) was commenced later, in January 2005, with abacavir 300 mg twice daily, lamivudine 150 mg twice daily and efavirenz 600 mg at night.

Five weeks into treatment he presented to the outpatient clinic complaining of malaise, nausea, considerable myalgia, irritated skin and impotence. Physical examination was normal with, in particular, no fever, rash or oral ulceration. A full blood count, urea and electrolytes, cytomegalovirus (CMV) PCR and serum cryptococcal antigen were normal. CD4 count repeated at this time had fallen slightly to 58 cells/μl, while HIV viral load had become fully suppressed. Alanine transaminase was initially normal. The CPK, first taken a few days later, was markedly elevated at 36 390 U/l (normal range: 45–195 U/l) (fig 1). Serum bicarbonate was normal. Urine was of normal colour and dipstick testing for haemoglobin was negative. ART was immediately stopped. Intravenous rehydration with normal saline 3 litres/day resulted in a rapid improvement in the CPK. A transient rise in liver transaminases occurred concurrently with the CPK rise (fig 2), but the full blood count and urea and electrolytes remained normal. He remained well and was discharged from hospital on day 4. Over a 6-week period his symptoms and biochemical disturbance resolved. Electromyography (EMG) 4 weeks after stopping ART was normal. Human leucocyte antigen (HLA)-B5701 typing, done in December 2005 when first made available, was negative. The patient remained well, without symptoms of myopathy, for 4 years after this episode, but refused further ART until 2008 when he accepted a regimen of ritonavir-boosted fosamprenavir, tenofovir and emtricitabine without ill effect.

Figure 1.

Variation of serum creatine phosphokinase with time elapsed since onset of antiretroviral treatment.

Figure 2.

Variation of serum alanine aminotransferase with time elapsed since onset of antiretroviral treatment.

INVESTIGATIONS

EMG was normal at 4 week follow-up; full blood counts and creatinine remained normal. HLA-B5701 was negative (see figs 1 and 2)

DIFFERENTIAL DIAGNOSIS

Potential causes of his raised CPK and myalgia, which have been previously reported in this context, are: myositis directly related to HIV infection itself, myositis due to HIV-associated malignancy, infective myositis, lactic acidosis, atypical immune reconstitution reaction, drug-related myositis without hypersensitivity and abacavir hypersensitivity.

TREATMENT

ART was immediately stopped. Intravenous rehydration with normal saline 3 litres/day resulted in a rapid improvement in the CPK

OUTCOME AND FOLLOW-UP

He remained well and was discharged from hospital on day 4. Over a 6-week period his symptoms and biochemical disturbance resolved. EMG 4 weeks after stopping ART was normal. The patient has remained well, without symptoms of myopathy, for 4 years after this episode but has refused further ART until recently. CD4 count 3 years after this episode was 90 cells/μl, and after 4 months of ART 110 cellsμl.

DISCUSSION

The patient we describe here developed severe symptomatic and biochemical myositis, which was temporally associated with commencement of abacavir, lamivudine and efavirenz. The patient had commenced co-trimoxazole 4 months prior to this. The myositis resolved quickly in response to intravenous fluid treatment and stopping ART. A CPK at the level described in our patient is indicative of rhabdomyolysis and often leads to renal failure.¹ Early intravenous fluid treatment may have aborted progression.

Potential causes of his raised CPK and myalgia, which have been previously reported in this context, are: myositis directly related to HIV infection² or associated malignancy,³ infective myositis,^4–7 lactic acidosis,⁸ atypical immune reconstitution reaction, drug-related myositis without hypersensitivity⁹ and abacavir hypersensitivity.¹⁰

Considering these, there was no clinical or serological evidence of infection, nor was antimicrobial treatement given. The patient has not subsequently developed malignancy. Our patient’s normal serum bicarbonate would make lactic acidosis as a cause of his myositis unlikely, although a serum lactate was not performed. There was no CD4 rise by the time of the reaction, making immune reconstitution an unlikely cause. Co-trimoxazole has been reported as causing rhabdomyolysis in one case report,¹¹ but our patient’s symptoms and elevated CPK resolved despite its continuation.

Given the temporal association with commencement of ART, it is most likely that our patient’s presentation was due to an adverse effect of ART. An inflammatory rhabdomyolysis has been reported in association with lamivudine in one patient.¹² Inclusion body myositis has also been described with ART, though particularly with zidovudine and didanosine¹³ To our knowledge, efavirenz and abacavir have not been reported to cause myositis in the absence of lactic acidosis and abacavir hypersensitivity, respectively. Abacavir hypersensitivity occurs in 7% of patients, but is more common with once-daily dosing (9%),¹⁴ whilst our patient was dosed twice daily. Myalgia with CPK rise has been reported in up to 6% of patients with hypersensitivity,¹⁰ but rises of the magnitude seen in our patient have not been reported. A CPK rise without myalgia has been associated with abacavir in the absence of hypersensitivity.⁹ HLA-B5701, the presence of which is known to be associated with an increased risk of hypersensitivity, was not detected in this patient.

In summary, significant myositis can occur with the combination of abacavir, lamivudine and efavirenz, and in the absence of lactic acidosis or classical abacavir hypersensitivity. Based on the published evidence and due to the occasional reports of mild CPK rises without hypersensitivity.⁹ we believe abacavir to have been the most likely cause.

LEARNING POINTS

• The nucleoside reverse transcriptase inhibitor abacavir, commonly used first line in HIV infection, may cause myositis.

• A high rise in CPK may occur and cause renal failure.

• CPK should be checked in all patients with non-specific complaints on HIV therapy.