Neurological syndrome in an HIV-prevention trial participant randomized to daily tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) in Bondo, Kenya
The participant we describe here was a healthy 24-year-old woman (height 174 cm, weight 56 kg) with no history of drug allergy and alcohol use. Laboratory tests conducted during screening on July 17, 2009, found that she was negative for HIV, syphilis, and hepatitis B. Her hepatic enzymes and creatinine clearance were within normal limits.\nAfter about 8 weeks of taking TDF-FTC, this participant complained of mild paresthesiae, numbness, and a tingling sensation in her upper limbs that was associated with pain and cold. The symptoms did not affect her daily activities, physical examination was normal, and she had not taken any medications that are known to cause peripheral neuropathy upon interaction with TDF-FTC. After an additional 4 days, she developed a disabling weakness of her upper limbs and bilateral weakness of power grip of grade 3–4 and fine tremors in her hands at rest and with activity. Neurological examinations found normal orientation in time and place as was her pupillary light reaction and fundoscopy. Muscle tone, reflexes, and somatic sensations were also normal, but there was a mild deviation of the mouth and the tongue to the left, on protrusion.\nAfter trial closure, analysis of her plasma and intracellular drug levels at week 4 and 8 were consistent with moderate adherence to TDF-FTC., At week 10, TDF-FTC was temporarily withheld due to safety concerns and as per the study protocol. The participant was given oral Neurorubine® (Vitamins B1, B6, and B12; Mepha Ltd, Aesch, Switzerland) for 2 weeks. Within 2 weeks after stopping the study drug, she was free of all symptoms. At week 12, she was restarted on the study drug according to the protocol. However, 1 month after restarting the pill, the participant complained of other neurological symptoms of posture-dependent numbness of her upper limbs. The numbness occurred while bending down and resolved after assuming an upright posture. She did not experience the earlier disabling muscle weakness or tremors. Her neurological exam was normal, and she continued taking the study drug. Her drug levels at week 24 (analyzed on stored samples after study closure) were consistent with low adherence to TDF-FTC.\nAt week 25, the study team decided to withdraw the study drug until neurologic exploration was completed. At week 28, the participant reported having taken a traditional herbal medicine, orally as a single dose. The nature of the herbal medication could not be determined by the study team.\nAt week 29, the magnetic resonance imaging (MRI) of her brain and cervical spine was found to be normal. Blood tests (performed at that time) revealed her lactate dehydrogenase was elevated at 514 U/L (normal range: 230–460), but her aldolase and creatinine phosphokinase were normal. The neurologist – with extensive experience in the treatment of HIV-infected patients – who assessed the participant observed:\nThe clinical manifestation in this patient was not the usual peripheral neuropathy known in patients receiving TDF-FTC. A typical TDF-FTC-related neuropathy starts with feet and only later goes to upper extremities. The fact that the paresthesiae occurs when the patient bends forward (Lhermitte’s sign) suggests a possible lesion of the cervical spine, though MRI findings were normal.\nIn addition to the study drug, Neurorubine®, and the unknown herbal medication, the participant reported taking the following medications: 1) medroxyprogesterone acetate, from enrolment throughout the study period; 2) ibuprofen at week five for one day; 3) amoxicillin/clavulanic acid at week seven for 10 days; and 4) diclofenac at weeks 9 and 10 for 3 and 7 days respectively.\nOverall, for safety concern, the participant was managed as if she was assigned the TDF-FTC arm. The clinical team decided not to un-blind the participant’s study group allocation, because this would not influence clinical case management. The participant’s postural numbness gradually improved and was completely resolved by her week 36 visit. The participant finished study follow-up on September 28, 2010. Her symptoms did not reoccur after she discontinued the study pill.\nAfter trial closure, levels of vitamin B12 on her stored blood samples at weeks 4, 8, 12, and 16 all showed normal values: 625, 727, 744, and 791 ng/L respectively (normal range: 239–931 ng/L).