BRIEF REPORT

Efficacy of Etravirine for Treatment tified, suggesting resistance to zidovudine, stavudine, didano- sine, zalcitabine, and lamivudine according to the French Na- of Acute HIV Meningoencephalitis tional Agency for AIDS Research algorithm [2]. In 1996, her CD4 cell count was 10 cells/mL. 1,3 1,3 4 Carine Couzigou, Sophie Seang, Laurence Morand-Joubert, In 1996, the patient’s treatment was changed to contain Anne-Marie Roque-Afonso,2,3 Le´lia Escaut,1,3 and Daniel Vittecoq1,3 boosted indinavir in addition to lamivudine and stavudine; her Services des 1Maladies Infectieuses et Tropicales and 2Virologie, Assistance Downloaded from https://academic.oup.com/cid/article/48/6/e62/287828 by guest on 24 September 2021 Publique–Hoˆpital de Paris (AP-HP), Hoˆpital Paul Brousse, Villejuif, 3Universite´ CD4 cell count increased to 700 cells/mL, and her plasma HIV 4 ! ! Paris-Sud, Orsay, and Service de Bacte´riologie-Virologie, Centre Hospitalo– load became undetectable ( 400 copies/mL or 2.6 log10 copies/ Universitaire de Saint-Antoine, AP-HP, Paris, France mL). Boosted indinavir was stopped in January 1999, and treat- ment was switched to nelfinavir because of nephrolithiasis. In We describe a patient with human immunodeficiency virus November 2000, the patient developed asthenia, fever, skin hy- (HIV) and hepatitis C virus coinfection who experienced peresthesia, loss of memory, and psychomotor slowing. The recurrent episodes of acute HIV meningoencephalitis. The results of viral, fungal, bacterial, and mycobacterial cultures of addition of etravirine to the therapeutic regimen completely CSF specimens were negative, as were the results of CSF tests resolved symptoms, and HIV was no longer detected in cer- for syphilis, PCR for herpes virus and JC virus, and tests for ebrospinal spinal fluid specimens. Etravirine has a satisfac- cryptococcal antigen. The results of serologic tests for Lyme tory safety profile and, in this case, was a durable alternative disease were negative. The patient’s symptoms were consistent therapy for HIV meningoencephalitis. with those of acute meningoencephalitis secondary to HIV in- fection. This diagnosis was supported by a high CSF HIV load

First-generation nonnucleoside reverse-transcriptase inhibitors (4.3 log10 copies/mL), contrasting with an undetectable plasma (NNRTIs) are effective for the treatment of acute HIV menin- HIV load (table 1). Viral drug resistance was determined ge- goencephalitis [1]. However, data on the efficacy of the next- notypically in CSF specimens. The profile of resistance was generation NNRTI etravirine for treatment of acute HIV me- similar to the profile detected in plasma in 1996, in addition ningoencephalitis are lacking. We describe a patient who to the L74V mutation. There were no mutations conferring experienced 3 episodes of acute HIV meningoencephalitis dur- resistance to protease inhibitors or NNRTIs. CSF HIV levels ing 7 years of follow-up, despite having received long-term, were undetectable after receipt of treatment with boosted lo- effective HAART. The addition of etravirine to the treatment pinavir, efavirenz, and abacavir, and the patient no longer ex- regimen completely resolved clinical symptoms. perienced symptoms. Case report. A 37-year-old woman who was coinfected The patient developed nightmares and depression in June with HIV (subtype B) and hepatitis C virus (HCV) and who 2002 while receiving treatment with boosted lopinavir, efavi- had a CD4 cell count of 120 cells/mL started taking an anti- renz, and abacavir that were probably associated with efavirenz HIV regimen in 1987. The patient had cirrhosis without severe (table 1). Nevirapine was then substituted for efavirenz. Ne- liver failure and had no history of syphilis. She was treated virapine treatment was quickly stopped because of severe acute with various combinations of nucleoside analogues (zidovu- hepatic cytolysis and was finally switched to tenofovir, in ad- dine, lamivudine, didanosine, and stavudine) until 1996. Viral dition to abacavir and boosted lopinavir. The patient was no drug resistance was detected genotypically in plasma specimens. longer symptomatic within 1 month. M184V and thymidine analogue reverse-transcriptase inhibitor However, 3 years later (May 2005), while receiving identical resistance mutations (M41L, L210W, and T215Y/C) were iden- treatment, the patient presented with symptoms consistent with a second episode of acute HIV meningoencephalitis: tremors,

Received 23 July 2008; accepted 29 October 2008; electronically published 4 February loss of memory, and asthenia. The plasma HIV load was un-

2009. detectable, but the CSF HIV load was now 4.6 log10 copies/mL Reprints or correspondence: Dr. Carine Couzigou, Service des Maladies Infectieuses et (table 1). A recurrence of acute HIV meningoencephalitis was Tropicales, AP-HP, Hoˆpital Paul Brousse, 12 Ave. Paul Vaillant Couturier, 94804 Villejuif, France ([email protected]). diagnosed by exclusion of other causes of acute meningoen- Clinical Infectious Diseases 2009;48:e62–5 cephalitis and by MRI of the brain. Brain MRI revealed diffuse 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2009/4806-00E2$15.00 cerebral atrophy and diffuse bilateral and symmetrical increase DOI: 10.1086/597109 in T2-weighted signal in the periventricular matter of the fron- e62 • CID 2009:48 (15 March) • BRIEF REPORT Table 1. Description of the 3 episodes of acute HIV meningoencephalitis that occurred during 2000–2007.

Date Characteristic November 2000 June 2002 May 2005 January 2006 March 2007 May 2007 August 2007 Diagnosis First episode of Depression related Second episode of Depression related Third episode of Third episode of Resolution HIV encephalitis to EFV HIV encephalitis to EFV HIV encephalitis HIV encephalitis of symptoms Associated antiretroviral therapy 3TC, d4T, NFV ABC, EFV, LPV/r ABC, TDF, LPV/r ABC, TDF, EFV, LPV/r ABC, TDF, LPV/r, SQV ABC, TDF, LPV/r, SQV ABC, TDF, LPV/r, SQV, ETR ! ! ! ! ! ! ! Plasma HIV RNA level, log10 copies/mL 1.7 1.7 1.7 1.7 1.6 1.6 1.6 CD4+ cell count, cells/mL 1010 1140 700 650 1010 1350 1240 CSF analysis Cells/mL 74 0 15 0 3 13 1 Lymphocyte percentage 100 … 100 … … 100 … Protein level, g/La 1.06 0.3 0.6 0.39 0.38 0.38 0.32 ! ! ! ! HIV RNA level, log10 copies/mL 4.3 2.6 4.6 1.6 1.6 1.9 1.6 Genotypeb L74V, M184V, M41L, … L74V, M184V, M41L, …… … … L210W, T215Y/C L210W, T215Y Time to symptom resolution after 3 Weeks 1 Month 3 Weeks 1 Month … 2 Weeks after starting Persistence of symptom intervention (change in antiretroviral ETR treatment resolution 17 months therapy) later

NOTE. ABC, abacavir; d4T, stavudine; EFV, efavirenz; ETR, etravirine; LPV/r, boosted lopinavir; NFV, nelfinavir; SQV, saquinavir; TDF, tenofovir; 3TC, lamivudine. a There was no hypoglycorachia.

b There was no resistance to protease inhibitors and nonnucleoside reverse-transcriptase inhibitors according to the French National Agency for Research on AIDS consensus statements on antiretroviral drug resistance [2]. Downloaded from https://academic.oup.com/cid/article/48/6/e62/287828 by guest on 24 September 2021 September 24 on guest by https://academic.oup.com/cid/article/48/6/e62/287828 from Downloaded tal and parieto-occipital regions. There was no mass effect or HCV infection in our patient, migrate across the blood-CSF enhancement after administration of gadolinium. The antiret- barrier. In advanced stages of HIV infection, the presence of roviral genotype in the CSF was identical to that reported in HIV in the CSF is more likely to have derived from another 2000. Efavirenz was reintroduced and, in association with source, presumably the CNS itself [3]. HIV infection in the boosted lopinavir, tenofovir, and abacavir, led to a prompt res- CSF is sustained within the CNS by latently infected resting olution of clinical symptoms. Efavirenz was stopped 6 months CD4 cells carrying replication-competent HIV and cells that later because of a recurrence of nightmares and depression. At have a longer life-span and that, thus, do not require a continual this time (January 2006), the CSF findings were normal (table renewal from blood. Under these circumstances, in the early 1). Treatment with enfuvirtide was started in June 2006, but it stages of infection, systemic treatment also reduces trafficking was rapidly stopped because of a difficulty in performing the of infected cells into the CSF, so that the CSF responses to injections; this treatment was switched to saquinavir hard-gel therapy may not necessarily require blood-brain–penetrating capsule. drugs for effective viral reduction. In the advanced stages of Downloaded from https://academic.oup.com/cid/article/48/6/e62/287828 by guest on 24 September 2021 A third episode of HIV meningoencephalitis was clinically infection, highly blood-brain–penetrating drugs are needed, suspected in March 2007 on the basis of a recurrence of tremors, particularly for management of HIV-associated neurological loss of memory, and asthenia, even though the CSF HIV load disease [4]. Nevertheless, these arguments are under debate in was undetectable (table 1). However, 2 months later, this di- clinical practice, and HIV in the CSF in our patient may have agnosis was supported by low HIV replication in the CSF and originated from both blood and the CNS [5]. the exclusion of other causes of acute meningoencephalitis (ta- In addition to the L74V mutation, the main viral isolate in ble 1, May 2007). Etravirine (200 mg twice per day) was in- the CSF specimens obtained in 2000 and 2005 had an identical troduced in June 2007. Clinical symptoms resolved completely mutation pattern to that isolated in 1996. The L74V mutation within 2 weeks. The CSF HIV load was undetectable 2 months may have arisen in association with poor distribution of di- later (August 2007) (table 1). As of January 2009, the patient danosine in the CNS [5, 6]. Thus, the poorer penetration of was still free of symptoms. antiretroviral drugs into the CNS may have allowed continued The patient reported that she had adhered to therapy out- HIV replication in the CNS, as indicated by higher CSF HIV lined over the course of the entire follow-up period and did loads. not use drugs—particularly drugs such as heroin or cocaine HIV replication in the CSF can lead to the subsequent onset that may have stimulated immune responses. Also, she did not of neuropsychologic impairment in HIV-infected patients; thus, experience liver failure or hypoalbuminemia, and her Child controlling HIV replication in the CSF is an important goal in Pugh remained class A. preventing neurocognitive decline [4]. This highlights the nec- Discussion. We describe a patient with chronic HIV infec- essary use of adequate antivirals to attain complete control of tion who experienced 3 episodes of acute HIV meningoen- HIV replication in the CSF and plasma. In the event of treat- cephalitis while receiving long-term effective HAART (for 7 ment failure, investigation of the CSF compartment for poten- years), although HIV was undetectable in plasma specimens tial resistance may prove to be useful. obtained during each episode in the follow-up period. Efavirenz First-generation NNRTIs are effective for treatment of acute was successfully used to treat the first 2 episodes but was HIV meningoencephalitis [1]. However, there are limitations stopped because of its adverse effects. Nevirapine use was lim- to treatment with efavirenz and nevirapine: there is a low level ited because of acute hepatic cytolysis. Etravirine treatment of genetic resistance to first-generation NNRTIs, and virologic completely resolved the symptoms within 2 weeks, with no failure associated with a regimen that contains efavirenz or recurrence 17 months later, and decreased the CSF HIV load nevirapine may result in point mutations in the reverse-tran- to undetectable levels. scriptase gene, leading to the development of high-level cross- During each episode, HIV was detectable in CSF specimens resistance to this nonnucleoside antivirals class. Furthermore, and was associated with lymphocytic pleocytosis, despite this adverse events, such as depression (for efavirenz) and severe being controlled in the plasma for 7 years. What was the origin hepatic cytolysis (for nevirapine), which were probably en- of HIV in the CSF in our patient? hanced by the patient’s chronic HCV coinfection, may limit Two major origins of HIV in the CSF have been reported the use of first-generation NNRTIs. (a blood-derived origin and a CNS-derived origin), depending Etravirine is effective in treatment-experienced patients in- on the stage of HIV infection [3]. In the early stages of HIV fected with HIV-1 [7, 8] with resistance to first-generation infection, HIV in the CSF is more likely to occur secondary to NNRTIs if there are !3 baseline mutations conferring NNRTI transitory infection by cells (mostly CD4 cells) moving into the resistance [9, 10]. Our report suggests that etravirine was ef- CSF space from the blood. HIV-replicating CD4 cells, which fective for treatment of acute HIV meningoencephalitis. This emerge in blood after an immune activation, such as through is interesting, because 99.9% of etravirine is bound to plasma e64 • CID 2009:48 (15 March) • BRIEF REPORT proteins (primarily to albumin), leaving only 0.1% available to Acknowledgments cross an intact blood-brain barrier. Potential conflicts of interest. All authors: no conflicts. Our findings nonetheless raise several questions. First, if HIV is derived only from blood, adding a fifth antiretroviral to the References regimen may have simply further suppressed a persistently low 1. von Giesen HJ, Ko¨ller H, Theisen A, Arendt G. Therapeutic effects of level of HIV replication in the blood, leading to reductions in nonnucleoside reverse transcriptase inhibitors on the central nervous immune activation and in migration of activated lymphocytes system in HIV-1-infected patients. J Acquir Immune Defic Syndr 2002; 29:363–7. into the CSF. Thus, the control of HIV in the CNS may have 2. HIV French Resistance. HIV-1 genotypic drug resistance interpreta- been attributable to the addition of the fifth antiretroviral drug tion’s algorithms. July 2007. Available at: http://www.hivfrench rather than specifically due to etravirine. resistance.org. Accessed 1 February 2009. 3. Price RW. The two faces of cerebrospinal fluid (CSF) HIV infection? Second, the neuroeffectiveness of etravirine in our patient Trends Microbiol 2000; 8:387–90.

may be due to increased permeability of the blood-brain barrier 4. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS Downloaded from https://academic.oup.com/cid/article/48/6/e62/287828 by guest on 24 September 2021 favored by HCV infection, thus leading to higher etravirine penetration-effectiveness rank for quantifying antiretroviral penetra- tion into the central nervous system. Arch Neurol 2008; 65:65–70. concentrations in the CNS than would occur in the general 5. McGee B, Smith N, Aweeka F. HIV pharmacology: barriers to the population. Thus, HCV that is thought to infect astrocytes, eradication of HIV from the CNS. HIV Clin Trials 2006; 7:142–53. macrophages, and microglial cells of HIV-HCV–coinfected pa- 6. Enting RH, Hoetelmans RM, Lange JM, et al. Antiretroviral drugs and the central nervous system. AIDS 1998; 12:1941–55. tients may have altered the blood-brain barrier [11]. The per- 7. Madruga JV, Cahn P, Grinsztejn B, et al.; DUET-1 study group. Efficacy meability of the blood-brain barrier in our patient may have and safety of TMC125 (etravirine) in treatment-experienced HIV-1- been estimated by determining etravirine concentrations in the infected patients in DUET-1: 24-week results from a randomised, dou- ble-blind, placebo-controlled trial. Lancet 2007; 370:29–38. CSF. However, CSF penetration may not necessarily be equiv- 8. Lazzarin A, Campbell T, Clotet B, et al.; DUET-2 study group. Efficacy alent to the parenchymal penetration of the antiretroviral drug. and safety of TMC125 (etravirine) in treatment-experienced HIV-1- Furthermore, drug levels in the CSF may have little or no infected patients in DUET-2: 24-week results from a randomised, dou- ble-blind, placebo-controlled trial. Lancet 2007; 370:39–48. relationship to drug levels in the brain extracellular fluid, and 9. Vingerhoets J, Buelens A, Peeters M, et al. Impact of baseline NNRTI the effect in CSF may be different from that in brain paren- mutations on the virological response to TMC125 in the phase III chyma, such as that described for efavirenz [12, 13]. clinical trials DUET-1 and DUET-2 [abstract 32]. In: Program and abstracts of the 16th International HIV Drug Resistance Workshop: Third, a reduction of drug-binding protein concentrations Basic Principles and Clinical Implications (Barbados, West Indies). in blood that is associated with cirrhosis may result in a larger Antivir Ther 2007; (Suppl 1):S34. unbound fraction of the drug in blood, resulting in higher 10. Scott C, Grover D, Nelson M. Is there a role for etravirine in patients with nonnucleoside reverse transcriptase inhibitor resistance? AIDS etravirine concentrations in the CSF. However, this is an un- 2008; 22:989–90. likely explanation for our finding, because the patient in our 11. Letendre S, Paulino AD, Rockenstein E, et al.; HIV Neurobehavioral Research Center Group. Pathogenesis of hepatitis C virus coinfection study did not have severe liver failure or hypoalbuminemia. in the brains of patients infected with HIV. J Infect Dis 2007; 196: Additional studies are necessary to determine whether the 361–70. neuroeffectiveness of etravirine pertains more to individuals 12. Antinori A, Perno CF, Giancola ML, et al. Efficacy of cerebrospinal fluid (CSF)–penetrating antiretroviral drugs against HIV in the neu- who are coinfected with HIV and HCV than to those who are rological compartment: different patterns of phenotypic resistance in infected with HIV alone. In conclusion, etravirine may provide CSF and plasma. Clin Infect Dis 2005; 41:1787–93. an alternative therapy for HIV meningoencephalitis in the event 13. Tashima KT, Caliendo AM, Ahmad M, et al. Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug of intolerance or resistance to first-generation NNRTIs in HIV- concentrations in HIV-1–infected patients receiving combination ther- HCV–coinfected patients. apy. J Infect Dis 1999; 180:862–4.

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