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Is there a role for maraviroc to treat HIV-associated central nervous system white matter disease?

Ball, Colin; Sudhanva, Malur; Jarosz, Jozef; Post, Frank A.; Hamlyn, Elizabeth

doi: 10.1097/QAD.0000000000000954
Correspondence
Free

King's College Hospital NHS Foundation Trust, London, UK.

Correspondence to Colin Ball, Department of Child Health, Kings College Hospital, London SE5 9RS, UK. Tel: +44 203 299 3478; e-mail: colin.ball@nhs.net

Received 16 October, 2015

Accepted 18 October, 2015

We describe the case of a boy born to African parents in the UK with vertically acquired HIV-1 infection. His mother was diagnosed with HIV infection just prior to delivery and was given intravenous zidovudine in labour. The infant received oral zidovudine post exposure prophylaxis for 6 weeks; HIV PCR at birth and 6 weeks were negative. He was never breastfed. HIV diagnosis was confirmed at 6 months of age following positive HIV-1 PCR. He had initial feeding problems and a urinary tract infection with normal renal ultrasound scan and started antiretroviral treatment at the age of 17 months, consisting of abacavir, lamivudine, zidovudine and nevirapine.

One week after starting treatment, he developed pyrexia, rash and elevated liver enzymes. An abacavir hypersensitivity reaction was suspected and all treatment was discontinued. After resolution of the symptoms, he started tenofovir and lopinavir/ritonavir and maintained a fully suppressed viral load until the age of 9 years when he developed recurrent abdominal pains, which were temporarily related to tenofovir ingestion. Abdominal examination and investigations were normal. Symptoms resolved upon tenofovir discontinuation. His HIV viral load rose to 1214 copies/ml. Two months later, he was admitted with collapse associated with dysarthria and right-sided weakness. His HIV viral load was 923 copies/ml and CD4+ cell count 1245 (43%) cells/μl.

An MRI scan revealed dramatic white matter hyperintensity but no evidence of focal abnormality (Fig. 1a). The weakness and dysarthria resolved within 24 h. Cerebrospinal fluid (CSF) investigation revealed an elevated protein (515 mg/l), 7 white blood cells (WBC), and oligoclonal bands. Bacterial cultures and CSF encephalitis PCR panel for John Cunningham virus DNA, BK virus DNA, enterovirus RNA, cytomegalovirus DNA, herpes simplex virus 1 and 2 DNA and varicella zoster virus DNA were all negative; Epstein–Barr virus DNA was detected at 99 copies/ml. Cranial Doppler and electroencephalogram were normal, and antibodies to HTLV-1 and 2, NMDA receptor, aquaporin-4, and beta-2 glycoprotein were all negative. Tenofovir/emtricitabine was added to his lopinavir/ritonavir, and he was empirically prescribed low dose aspirin.

Fig. 1

Fig. 1

His HIV viral load became undetectable and remained fully suppressed. Although generally well, he was often described as having a shuffling gait, despite repeatedly normal neurological assessments. He had mild learning difficulties and a supporting educational statement. Thirteen months after the episode of collapse, the MRI white matter changes were unaltered; repeat CSF showed protein 406 mg/l, 32 WBC and the oligoclonal bands persisted. CSF HIV viral load was 48 copies/ml, with a plasma HIV viral load of less than 40 copies/ml. Five months later, he developed effortless recurrent early morning vomiting and occasional dizzy spells. He was afebrile: there were no signs of raised intracranial pressure, and MRI brain was unchanged; the vomiting was thought to be central in origin and settled with daily ondansetron.

On the basis of reports suggesting that maraviroc might have beneficial effects on HIV-associated central nervous system (CNS) disease [1,2] we approached the manufacturer for compassionate use of this agent, which is unlicensed in children under 18 years of age. HIV-1 sequencing predicted CCR5 tropism, and maraviroc was added to his antiretroviral regimen. The vomiting and dizzy spells subsided and he was able to discontinue ondansetron 6 weeks later. One year later, he no longer required additional learning support at school, and low dose aspirin was discontinued. Repeat MRI of the brain after 13 months of maraviroc showed dramatic improvement of the white matter disease (Fig. 1b), and his CSF had normalized (protein 260 mg/l, WBC <5/cmm, CSF HIV RNA undetectable).

In summary, we describe the onset of extensive white matter disease in an HIV-positive child who was treated with protease inhibitor monotherapy. Intensification with tenofovir/emtricitabine suppressed plasma viraemia but did not improve the neuroradiological manifestations and CSF abnormalities, and did not prevent development of new CNS symptoms. However, the addition of maraviroc, provided on a named patient basis, was associated with a complete resolution of vomiting and dizziness, improvement in school performance and quality of life, significant regression in the white matter changes on MRI scan, and normalization of the CSF. This may well be due to the effect of therapeutic concentration of maraviroc in CSF [3]. The improvement seen in this case may have implications for other children and young people who are HIV positive and virologically suppressed, and yet who develop subclinical or overt manifestations of CNS disease that are not explained by other aetiologies. Further research is indicated into the poorly understood phenomenon of CSF viral escape and HIV-associated white matter disease in patients with undetectable plasma HIV viral load.

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Acknowledgements

Sally Hawkins, Daya Nayagam, Shema Doshi, Susanna Gilmour-White and Ming Lim contributed to the clinical management of this patient.

Authors contributions: C.B. was responsible for overall clinical management of the patient and wrote the first draft of this report. E.H., S.M. and F.P. advised on clinical and virological management, reviewed the related literature and contributed to subsequent drafts. J.J. reviewed neuroradiological images. All authors approved the final draft of this report.

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Conflicts of interest

There are no conflicts of interest.

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References

1. Melica G, Canestri A, Peytavin G, Lelievre JD, Bouvier-Alias M, Clavel C, et al. Maraviroc-containing regimen suppresses HIV replication in the cerebrospinal fluid of patients with neurological symptoms. AIDS 2010; 24:2130–2133.
2. Gates TM, Cysique LA, Chaganti J, Siefried KJ, Brew BJ. Maraviroc-enhanced CART improves cognition in virally suppressed HAND: a pilot study. Conference on Retroviruses and Opportunistic Infections. Seattle, Washington; 2015.
3. Yilmaz A, Watson V, Else L, Gisslen M. Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients. AIDS 2009; 23:2537–2540.
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