We welcome the publication of the British HIV Association (BHIVA) and British Infection Association (BIA) opportunistic infection guidelines in the September issue , but wish to comment on three recommendations for management of cryptococcal meningitis in HIV infection (CM).
In contrast to the Infectious Diseases Society of America (IDSA) and recent World Health Organization (WHO) guidelines on induction treatment of CM [2, 3] which recommend conventional amphotericin B deoxycholate (AmBd) at 0.7–1 mg/kg/day with flucytosine (5FC) based on robust phase II and phase III randomized controlled trial (RCT) data, the UK panel recommends liposomal amphotericin B (4 mg/kg/day) in place of AmBd based on a shorter time to cerebrospinal fluid (CSF) sterilization in a very small RCT (n = 28) comparing AmBd at 0.7 mg/kg/d with AmBisome at 4 mg/kg/day . A subsequent larger RCT comparing AmBd at 0.7 mg/kg/day with AmBisome at 3 or 6 mg/kg/day found no difference in efficacy, but reduced nephrotoxicity with AmBisome . Neither trial included 5FC as a second drug.
Without question, liposomal products are less nephrotoxic. However, the severity of AmBd nephrotoxicity depends on pre-existing risk factors (e.g. underlying disease, baseline renal function and concomitant nephrotoxic drugs), the cumulative dose of AmBd, and the adequacy of fluid and electrolyte replacement. The retrospective study cited , reporting a high incidence of renal impairment, included few HIV-infected patients and mainly patients with haematological malignancy with abnormal baseline creatinine (concomitant nephrotoxic therapy not reported), for whom we entirely agree that liposomal products are appropriate.
We and others [7, 8] have previously demonstrated manageable and reversible renal impairment in cohorts of HIV-infected patients managed with AmBd at 0.7–1 mg/kg/day with careful prehydration and electrolyte monitoring and supplementation, without a requirement for renal replacement therapy.
In this era of financial austerity, we do not believe that the 75-fold cost differential (based on a 14-day course for a 70-kg adult at NHS list price including VAT) between AmBd at 1 mg/kg/day (£4.66/50 mg vial, 2 vials/day × 14 = £130.37) and AmBisome at 4 mg/kg/day (£116.03/50 mg vial, 6 vials/day × 14 = £9746.52) is justifiable for HIV-infected patients with normal baseline renal function and no other nephrotoxic drugs. Even use of AmBd in the first week, before switching to AmBisome, would incur a cost saving of £4808 per patient treated. Pharmacy departments can stock both preparations and support their safe prescribing by brand name.
As an oral alternative to AmBd, UK guidelines are again at odds with IDSA and WHO in recommending fluconazole at the low dose of 400 mg/day, combined with 5FC. Fluconazole is a fungistatic drug associated with worse outcomes when used in initial treatment of CM . Phase II trials have shown improved cryptococcal clearance and good tolerance using doses of fluconazole up to 1200 mg/day, without or including 5FC [10-12], a combination endorsed by WHO for areas where AmBd cannot be safely administered .
Lastly, in the management of raised intracranial pressure (ICP), we agree with recommendations regarding CSF manometry and repeat lumbar punctures, but, given the usual resolution, with appropriate management, of high ICP within the first weeks of induction therapy, would favour use of temporary lumbar drains over shunts in situations of high ICP unresponsive to daily lumbar punctures .
In light of these arguments, we would urge the panel to reconsider their recommendations for these aspects of management of patients with CM in the UK.