An HIV-infected 32-year-old male presented to Mulago National Referral Hospital, Uganda with a 2-week history of headache with fevers and a 1-day history of confusion ( Figure 1). He had been on ART (zidovudine, lamivudine, efavirenz) and co-trimoxazole prophylaxis for 5 years. 5 months prior, he was diagnosed with pulmonary TB by positive sputum Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA). He had completed 2 months of induction TB therapy (rifampicin, isoniazid, ethambutol, pyrazinamide) and was 3 months into continuation phase (rifampicin, isoniazid). He endorsed poor adherence to both ART and anti-tuberculous medications.
On examination, the patient was febrile (38.6 C). His blood pressure was 112/71 mmHg, pulse 94 beats/minute, respiratory rate 48, and oxygen saturation 98%. He was wasted, dehydrated, and had overt rigors. His Glasgow Coma Scale was 14/15 with nuchal rigidity and positive Kernig's sign. Cranial nerves were intact. He had normal tone and power in all limbs. A clinical diagnosis of HIV-associated meningitis was suspected and he was recruited into the 'Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis' study (registration: ISRCTN42218549). Whilst awaiting further investigations, he received empiric therapy of ceftriaxone 2 g twice daily for possible bacterial meningitis.
A finger stick cryptococcal antigen lateral flow assay (CrAg LFA) (IMMY, Norman, Oklahoma, USA) was negative. Liver and renal function tests were normal. Cerebrospinal fluid (CSF) opening pressure was elevated to 33 cm CSF (normal <20 cm CSF), CSF white cells 590 /microl, protein 419 mg/dl (normal range 15-45 mg/dl), CSF lactate 9.5 mmol/L (normal range <2.5 mmol/l). CSF glucose was unavailable. Mycobacterium tuberculosis in CSF was confirmed on Xpert MTB/RIF Ultra; there was no evidence of rifampicin resistance. On day 2, he was initiated on dexamethasone at 0.4 mg/kg/day and induction TB-medications were re-commenced (rifampicin, isoniazid, ethambutol, pyrazinamide) for TBM. The IV ceftriaxone was stopped, his ART was continued. He continued to spike high-grade fevers (39.6 C.) with tachycardia (pulse 118 beats/min). A peripheral blood smear showed P. falciparum parasites (1+ trophozoites), despite a negative malaria histidine rich protein-2 (PfHPR2)-based rapid diagnostic test (Malaria Plasmodium falciparum Rapid Test Cassette, Vaxpert, Florida, USA). Given his ongoing neurological symptoms, which could be compatible with cerebral malaria, the decision was made to treat for severe malaria. Drug-drug interactions (DDIs) between rifampicin and artemisinin compounds, and rifampicin and quinine are recognized ( Table 1); a decision was made to treat with IV artesunate as the most efficacious anti-malarial for severe malaria . He received three doses of IV artesunate (3 mg/kg), after which a repeat peripheral blood smear showed no malaria parasites. He then completed 3 days of oral artemether/lumefantrine. His fevers subsided on day 6. He was discharged on day 8; medication adherence counselling was provided for the patient and his guardian and outpatient follow-up was arranged for the following week.