REVIEW URRENT C OPINION
Neuro OIs: developed and developing countries Edwina J. Wright a,b,c
Purpose of review To review recent studies that address the pathogenesis, diagnosis and treatment of HIV positive patients with cryptococcal and tuberculous meningitis and progressive multifocal leukoencephalopathy in resourcedifferent settings. Recent findings Central nervous system opportunistic infections remain globally prevalent in HIVþ populations. Several recent papers have highlighted the urgent need for rapid point of care tests in low-income settings for cryptococcal and tuberculous meningitis, better access to antifungal therapy for cryptococcal meningitis and better treatment strategies for tuberculous meningitis. In one recent study of 299 HIVþ patients with cryptococcal meningitis, amphotericin plus flucytosine was associated with less mortality and disability compared to amphotericin alone. In a study of patients with tuberculous meningitis in Indonesia, short-term, high dose rifampicin and moxifloxacin, designed to achieve higher levels of anti-TB drugs in the brain, saw significantly reduced patient mortality at 6 months. The timing of ART initiation in patients with central nervous system opportunistic infections remains challenging and a recent study reported that deferred vs early antiretroviral therapy was associated with better survival outcomes in patients diagnosed with cryptococcal meningitis. Recent studies have reported on predictors of immune reconstitution inflammatory syndrome for patients with central nervous system opportunistic infections, but require validation in resource-different settings. Summary Recent studies related to the diagnosis and treatment of central nervous system opportunistic infections in HIVþ populations show promising findings. Increased funding and research commitment are required to maintain this positive momentum and to achieve improved global outcomes for people who develop central nervous system opportunistic infections. Keywords central nervous system, cryptococcal meningitis, HIV, opportunistic infections, progressive multifocal leukoencephalopathy, tuberculous meningitis
INTRODUCTION Opportunistic infections in the central nervous system (CNS) remain a major global health issue for HIVþ people more than 30 years after HIV infection was first described. The reasons for this ongoing challenge include the following: first, advanced immunosuppression is the leading risk factor for CNS opportunistic infections and because 25% of individuals in low- and middle-income countries present late with CD4þ cell counts less than 100 cells/ml [1], CNS opportunistic infections remain prevalent in these settings; second, advances in the diagnosis, treatment and management of CNS opportunistic infections have been relatively modest over the past 3 decades and third, the ironic challenge posed by antiretroviral therapy (ART)-induced CNS immune reconstitution inflammatory syndrome (IRIS) [2] has compounded the
therapeutic difficulties faced by HIVþ patients with CNS opportunistic infections and their healthcare providers. This article will focus on recent advances in the pathogenesis, screening and management of three CNS opportunistic infections that have dominated the recent literature: cryptococcal and tuberculous meningitis and progressive multifocal leukoencephalopathy (PML).
a Department of Infectious Diseases, Alfred Health, bMonash University and cBurnet Institute, Melbourne, Victoria, Australia
Correspondence to Edwina J. Wright, MD, The Alfred, Commercial Road, Melbourne, VIC 3004, Australia. Tel: +61 3 9076 6078; e-mail: [email protected] Curr Opin HIV AIDS 2014, 9:539–544 DOI:10.1097/COH.0000000000000109
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KEY POINTS Diagnostic tests for cryptococcal meningitis and TBM that are suitable for resource-different settings are available.
(LFA) for determination of serum CRAG was recommended by the WHO in 2011 [8] because it has the benefits of lower costs, rapid results, no need for refrigeration compared with the CRAG latex agglutination assay or enzyme immunoassays. Recently Kabanda et al. [9 ] reported on results from two prospective cohorts of HIVþ patients with meningitis in Uganda where a new LFA CRAG assay that costs $2 per strip was tested on their cerebrospinal fluid (CSF). The authors found that the LFA assay’s sensitivity and specificity were high (both 100%) and that the pretreatment LFA CSF CRAG titers correlated with quantitative pre-treatment CSF cultures and 2- and 10-week mortality [9 ]. The authors suggested that CSF LFA titers more than 1000 could be used to predict mortality risk as patients with CSF titers more than 1 : 1280 vs. titers less than or equal to 1 : 640 at 2 weeks had a six-fold greater mortality [9 ]. As a corollary, a recent highly practical and useful study of HIVþ patients with cryptococcal meningitis in Tanzania found that readings of CSF pressure using intravenous giving sets were highly correlated with readings obtained by use of formal CSF manometers (r ¼ 0.96) [10]. In the same study, the authors showed that intensive intracranial pressure monitoring and repeated lumbar punctures were associated with lower mortality rates [10]. Recently, findings from the largest study, to date, of the determinants of mortality in HIVþ patients with cryptococcal meningitis were reported [11 ]. In this study, the authors combined the findings of nine trials conducted at five international sites over a period of 8 years to provide the power to determine predictors of mortality. The overall mortality rates were 17% at 2 weeks and 34% at 10 weeks. The authors reported that baseline altered mental status [odds ratio (OR) 3.1; 95% confidence interval (CI) 1.7–5.9], CSF fungal burden (OR, 1.4 per log10 colony-forming units/ml increase; 95% CI, 1.0–1.8) and rate of clearance of infection were associated with acute mortality (within the first 2 weeks of diagnosis) [11 ]. Factors associated with 10-week mortality included age more than 50 vs. less than 50 years (OR, 3.2; 95% CI 1.3–7.8) and use of amphotericin vs. fluconazole (OR 0.4; 95% CI 0.2–0.6). The authors’ conclusions referred to the need for greater capabilities to rapidly diagnose cryptococcal meningitis and for greater global availability of fungicidal (amphotericin-based) regimens [11 ]. This recommendation was paralleled by Loyse et al. [12] who provided a compelling review of the evidence for flucytosine’s use in combination with either amphotericin, or high-dose fluconazole in the treatment of cryptococcal meningitis. Here, the authors lament the fact that flucytosine is widely unavailable and unregistered across many Africa &
In patients with cryptococcal meningitis, amphotericin plus flucytosine is associated with significantly reduced mortality and disability compared with amphotericin alone. Both antifungal agents require greater scale up and a long acting formulation of flucytosine is urgently needed. Deferral of ART for 5 vs. 1 to 2 weeks after the diagnosis of cryptococcal meningitis in HIVþ patients was associated with significantly decreased mortality in a randomized, controlled trial. These findings are likely to shape future therapeutic guidelines on the management of cryptococcal meningitis. Mefloquine was found to have no efficacy in the treatment of PML. Development of antiviral agents with activity against PML is urgently needed. Increased funding and research commitment and a greater availability of better formulated drugs used to treat CNS opportunistic infections are required to achieve improved global outcomes for people who develop CNS opportunistic infections.
CRYPTOCOCCAL MENINGITIS In sub-Saharan Africa, cryptococcal infection is a leading cause of meningitis in adults, and in a study in the HIV high prevalence city of Cape Town, it accounted for 63% of cases of meningitis [3]. Currently in South Africa, individuals with less than 100 CD4þ cells/ml who are commencing ART are not screened for, or prophylaxed against cryptococcal disease [4 ]. In a recent analysis it was shown that for individuals entering ART programs in South Africa with less than 100 CD4þ cells/ml, the most feasible and cost-effective strategy to prevent cryptococcal meningitis is to screen all individuals with a serum cryptococcal antigen (CRAG) test and to treat those with positive results using high dose fluconazole [4 ]. This study’s findings are similar to those reported recently from Vietnam [5], are important at a programmatic level and are relevant for other countries and cohorts with a high prevalence of CRAG positivity, including newly diagnosed HIVþ patients in the United Kingdom [6]. The need for rapid point of care tests (POCTs) for neurological infections in Africa was highlighted recently in a review by Yansouni et al. [7 ]. Here, the authors defined rapid tests as those that yield results during the clinic visit and that can be used in settings with little infrastructure, including electricity, or trained personnel [7 ]. The lateral flow assay &&
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and Asian countries and call for increased generic manufacturing and a slow-release formulation of flucytosine to be developed [12]. The recommendations for the wider availability of these two antifungal agents are highly apposite given the findings from a very important study conducted by Day et al. [13 ] in Vietnam. This open-label study enrolled 299 HIVþ patients with severe cryptococcal meningitis and randomized them to receive induction therapy with amphotericin alone for 4 weeks, or amphotericin plus flucytosine, or amphotericin plus fluconazole for 2 weeks [13 ]. Patients then received fluconazole consolidation therapy. Thirty percent of patients received, or were commenced on ART during the 6-month follow-up period. The study’s chief finding was that mortality at days 14 and 70 was reduced in patients receiving amphotericin plus flucytosine (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% CI, 0.30–1.08; unadjusted P ¼ 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39–0.97; unadjusted P ¼ 0.04) [13 ]. There was no difference in survival between those receiving amphotericin alone or in combination with fluconazole (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44–1.41; P ¼ 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45–1.11; P ¼ 0.13). Important secondary outcomes showed that amphotericin-B plus flucytosine was associated with less disability at 6 months and that rates of adverse events were similar across all three induction arms. The effect of ART upon survival was not presented in this analysis [13 ]. The challenge of providing appropriate antifungal therapy is matched by the challenge of determining when to start ART in patients with cryptococcal meningitis in terms of affording patients longevity and minimizing the risk of cryptococcal meningitis IRIS. Cryptococcal meningitis IRIS occurs in approximately 19% of patients with cryptococcal meningitis commencing ART [2]. In a large study undertaken in South Africa of HIVþ patients with cryptococcal meningitis, Chang et al. [14 ] reported that the risk of cryptococcal meningitis IRIS was increased in those patients who remained CSF culture positive at the time of ART commencement and in those had a poor CD4þ T-cell gain on ART. Other studies undertaken by this group on the pathogenesis of cryptococcal meningitis and for cryptococcal meningitis IRIS, provided original insights into the immunoregulatory role of Natural Killer cells and monocytes in cryptococcal meningitis [15], and that an increased trafficking of CD8þ T cells and cells of myeloid origin in the CSF prior to ART initiation [16 ] and lower cryptococcal mannoprotein-induced &&
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production of interferon gamma [17 ] were associated with a higher risk of cryptococcal meningitis IRIS. In a systematic review of studies designed to determine the optimal timing of ART in patients with cryptococcal meningitis, Njei et al. [18] pooled data from two eligible randomized controlled trials [19,20] and found that early vs. delayed ART (< or >4 weeks after starting antifungal therapy) was not associated with a survival benefit [Relative risk ¼ 1.40, 95% CI (0.42,4.68)] [18]. Subsequently, the Cryptococcal Optimal Antiretroviral Timing (COAT) study results have become available [21 ]. The COAT study enrolled 177 HIVþ patients with cryptococcal meningitis and randomized them to receive ART at 1 to 2 vs. 5 weeks following the diagnosis of cryptococcal meningitis. Patients were treated with amphotericin and fluconazole for 14 days then received 800 mg daily fluconazole consolidation therapy [21 ]. The findings of the COAT study showed that deferred vs. early ART is associated with significantly higher survival at week 26 [45% (40 of 88 patients) vs. 30% (27 of 89 patients); hazard ratio for death, 1.73; 95% CI, 1.06–2.82; P ¼ 0.03]. This difference in excess mortality was seen 2–5 weeks following the diagnosis of cryptococcal meningitis, after which no difference in mortality between the two ART treatment initiation strategies was seen. Importantly, the highest risk of death was seen in those patients initiating early ART with less than 5 vs. more than 5 white cells/ml in the CSF at the time of randomization [Harzard ratio 3.87 (95% CI 1.2–4.96)]. Boulware et al. [22] and Chang et al. [14 ] have reported this observation previously wherein individuals with minimal CSF inflammation and cryptococcal meningitis are at highest risk of cryptococcal meningitis IRIS. An excess of cryptococcal meningitis-related deaths was seen in the early treatment group of Boulware et al.’s [21 ] recent study and the authors could not confidently ascertain whether cryptococcal meningitis IRIS was the chief cause of the excess deaths in the early treatment group because the definition of cryptococcal meningitis IRIS requires initial improvement then decline. Hence, an ascertainment of whether patients’ early deterioration was progressive cryptococcal meningitis or cryptococcal meningitis IRIS could not be made. This study was stopped prematurely by its Data Safety and Monitoring Board because of the excess deaths in the early treatment arm and hence did not enroll enough patients to power the study as originally designed. However, the authors contend reasonably that this study’s chief finding is of important clinical significance and is generalizable to both high and
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low-income settings because the study was conducted rigorously using protocols and procedures that are available across resource-different settings [21 ]. &&
TUBERCULOUS MENINGITIS Tuberculous meningitis (TBM), as reviewed by Brancusi et al. [23], occurs in approximately 10% of all cases of tuberculosis (TB), is likelier to occur in the setting of HIV co-infection where TBM mortality rates exceed 65% [23]. A rapid POCT for TBM has remained highly elusive. In a recent review of studies evaluating POCT for neurological infections, none of three POCT being evaluated for the rapid diagnosis of TB evaluated their use in CSF samples [7 ]. However, a recent prospective study undertaken in South Africa of 235 patients with a meningeal illness, 87% of whom were HIVþ, evaluated the utility of the Xpert MTB/RIF for the diagnosis of TBM [24]. In this study, the authors categorized 204 evaluable patients as having definite (n ¼ 59), probable (n ¼ 64), or non-TBM (n ¼ 81). The Xpert MTB/RIF was compared with a composite clinical and laboratory score for its diagnostic accuracy. The overall sensitivity and specificity of the Xpert MTB/RIF for TBM were 62% (95%CI 48–75%) and 95% (95%CI 87–99%), respectively [24]. Compared to CSF microscopy, the sensitivity of the Xpert MTB/RIF was significantly better (62 vs. 12%, P ¼ 0.001) and was also higher compared with the clinical score (62 vs. 30%; P ¼ 0.001). Notably, the sensitivity of the Xpert MTB/RIF was 80% when a centrifuged sample was used, presumably by increasing the concentration of TB pathogens. The authors called for further studies to validate the use of Xpert MTB/RIF for the diagnosis of TBM in both HIV endemic and nonendemic settings [24]. Treatment of TBM with a short course of higher dose rifampicin and moxifloxacin was evaluated in an important study undertaken in Indonesia [25 ]. In this study, 60 patients with severe TBM (6/60 were HIVþ) were randomized to receive standard dose oral rifampicin or high-dose intravenous rifampicin with 400 mg, or 800 mg moxifloxacin or ethambutol. All patients received isoniazid, pyrazinamide and adjunctive dexamethasone. After 14 days, patients were then switched back to the standard TBM treatment regimen. The authors reported that the use of higher dose rifampicin and moxifloxacin resulted in high plasma and CSF levels of these agents and was not associated with increased toxicity [25 ]. The use of intravenous rifampicin was associated with significantly reduced mortality at 6 months (35 vs. 65%), which was not explained, &&
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by patients’ TBM disease severity, or HIV status [25 ]. This study should propel larger studies to be undertaken to evaluate the benefits and feasibility of intensifying CNS penetration of antituberculous medications in patients with TBM, particularly those co-infected with HIV and living in low-income settings. In HIVþ patients, the risk factors associated with and the incidence of TBM IRIS have not been fully elucidated. In a recent prospective, observational study of 34 HIVþ patients with TBM in a Cape Town hospital, Marais et al. [26 ] reported that TBM IRIS occurred in 47% (16/34) of patients, all of whom initiated ART 2 weeks following commencement of antituberculous treatment and corticosteroids. Factors associated with TBM IRIS were a higher neutrophil CSF count and having a positive vs. a negative CSF culture for Mycobacterium tuberculosis whereupon the relative risk of developing TBM IRIS was 9.3 (95% CI 1.4–62.2%) if patients’ CSF culture was positive [26 ]. The current recommendations for ART initiation in patients with TB per se are to commence ART within 2 weeks following commencement of TB treatment for those patients with less than 50 CD4þ cells/ml, but otherwise to defer ART for 8–12 weeks in patients with more than 50 CD4þ cells/ml [27]. The optimal timing of ART for patients with TBM, especially those with less than 50 CD4þ cells/ml, is less clear, but early ART initiation is not associated with improved survival [28] in patients with TBM, carries a higher risk of toxicity [28] and high rates of IRIS were reported in this study [26 ]. &&
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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY PML is a demyelinating disease of the CNS and is caused by the JC DNA polyomavirus [29]. PML is a relatively rare disease that occurs in immunosuppressed populations and occurs in 4–7% of HIVþ patients, typically in those with less than 200 CD4þ cells/ml. Recently, PML has received widespread clinical and research attention because of its increased incidence in patients receiving immunomodulatory agents for the treatment of multiple sclerosis and inflammatory bowel disease [29]. The diagnosis of PML is been challenging across all settings including high-income settings because there is no single clinical, or diagnostic marker for PML; hence, its diagnosis requires clinical, radiological, laboratory, histopathological analyses [30]. Recently, Berger et al. [30] provided a very useful algorithm to assist in the diagnosis of patients with PML, although the recommendation for MRI brain scanning, as an integral part of their Volume 9 Number 6 November 2014
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algorithm, precludes its direct applicability to lowincome and middle-income settings [30]; nonetheless, CT brain scans would be available in some settings. Recently, Schneider-Hohendorf et al. [31 ] proposed that L-selectin (CD62L) levels on peripheral blood mononuclear cells (PBMCs) of HIVþ patients may be used as a marker of future risk for PML. They have adopted this approach previously for screening patients with multiple sclerosis receiving natalizumab who may be at future risk of PML [32]. In their current study, CD62L levels on patients’ cryopreserved PBMCs were lower than 25% in those HIVþ patients who had previously diagnosed PML compared with those HIVþ patients who had not [31 ]. The study’s authors appropriately recommend that a prospective validation study is required to assess the utility of developing an assay to evaluate levels of CD62L on PBMCs [31 ]. The first-line treatment of PML in HIV infection is ART and its use is associated with stabilization or clinical improvement in a reasonable proportion of patients [29]. However, in patients who are HIV negative, or in those HIVþ patients on ART who are fully virologically suppressed and develop PML, there are few therapeutic options available [29]. Recently, Clifford et al. [33 ] reported on the sobering findings of the efficacy of mefloquine in the treatment of PML in both HIV-negative and HIVþ patients. They found that mefloquine plus standard of care vs. standard of care alone was not associated with a decrease in CSF JC viral levels, or with clinical improvement. The study was closed prematurely because a pre-planned interim analysis determined that the likelihood of finding a difference between the study’s treatment arms was very low [33 ]. Finally, more than 16% of HIVþ patients develop PML IRIS upon commencing ART [2]. PML IRIS carries a high risk of morbidity and mortality and its pathogenesis remains largely undescribed. In a recent cross-sectional, retrospective study Martin-Blondel et al. [34] examined the histopathological findings from the brains of five HIVþ patients with PML IRIS and four HIVþ patients with PML but without IRIS. They found that the brains of patients with PML IRIS had high numbers of cytotoxic CD8þ T-cells. The authors speculate that although this avid CD8þ T-cell response may be highly efficient in targeting and clearing JCV-infected oligodendrocytes, it comes at the expense of increased CNS inflammation and damage [34]. The current treatment of PML IRIS in HIVþ patients, based upon expert opinion, is to cautiously administer corticosteroids [35,36]. This approach is likely to stand until further studies &
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that elucidate better treatment modalities both for PML and PML IRIS are available.
CONCLUSION Recent studies related to the diagnosis and treatment of CNS opportunistic infections in HIVþ populations are promising for the field. The LFA for the detection of cryptococcal antigen in the CSF of patients with cryptococcal meningitis and use of the Xpert MTB/RIF PCR test on CSF samples of patients with TBM are suitable for use in resourcedifferent settings and enhance the diagnostic acuity for these illnesses. For cryptococcal meningitis, recent studies have increased the understanding of the clinical and laboratory predictors of both mortality and IRIS. Importantly, the superiority of amphotericin plus flucytosine vs. amphotericin alone means that increased efforts to globalize access to these agents must be made. In the COAT study, deferred vs. early ART initiation in patients with cryptococcal meningitis was associated with decreased mortality at week 26 and this randomized controlled study’s findings are likely to inform future therapeutic guidelines on cryptococcal meningitis management in the HIV setting. TBM carries a high risk of mortality, but encouragingly a recent study showed that enhanced CNS penetration of initial MTB therapy reduced mortality and disability. Urgent future studies are required to explore this exciting new strategy. Findings that levels of expression of L-selectin on PBMCs may be used to identify immunocompromised patients at increased risk of PML require validation in future studies and the recent study finding that mefloquine is not efficacious against PML should spur the field to seek new effective PML treatment modalities. Increased funding and research commitment and a greater availability of better formulated drugs used to treat CNS opportunistic infections are required to maintain the current positive research momentum and to achieve improved global outcomes for people who develop CNS opportunistic infections. Acknowledgements None. Conflicts of interest Dr Wright receives funding from a research grant from NIH, a Career Development Fellowship from the National Health and Medical Research Council of Australia, research funding from the Victorian Department of Health and unrestricted research funds from Gilead, Abbott, Janssen Cilag and Boehringer Ingelheim.
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Dr Wright has received funding that has been used for research purposes only from ViiV, Merck, Gilead, and Abbott for consultancy work, payment for lectures from ViiV and payment for developing educational resources for ViiV and Gilead. Gilead Sciences has donated study drug for a PrEP demonstration Project led by Dr Wright.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. WHO, UNAIDS and UNICEF (2013), Global update on HIV treatment. Results, impact and opportunities (Geneva: WHO, UNAIDS and UNICEF). 2. Muller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10:251– 261. 3. Jarvis JN, Meintjes G, Williams A, et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. BMC Infect Dis 2010; 10:67. 4. Jarvis JN, Harrison TS, Lawn SD, et al. Cost effectiveness of cryptococcal && antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa. PLoS One 2013; 8:e69288. An important study that estimates the most cost-effective strategy for prevention of cryptococcal meningitis. 5. Smith RM, Nguyen TA, Ha HT, et al. Prevalence of cryptococcal antigenemia and cost-effectiveness of a cryptococcal antigen screening program– Vietnam. PLoS One 2013; 8:e62213. 6. Patel S, Shin GY, Wijewardana I, et al. The prevalence of cryptococcal antigenemia in newly diagnosed HIV patients in a Southwest London cohort. J Infect 2013; 66:75–79. 7. Yansouni CP, Bottieau E, Lutumba P, et al. Rapid diagnostic tests for && neurological infections in central Africa. Lancet Infect Dis 2013; 13:546– 558. A very informative, comprehensive review that provides an update on available POCTs for several common neurological infections in Africa. 8. WHO. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. Geneva: World Health Organization; 2011. 9. Kabanda T, Siedner MJ, Klausner JD, et al. Point-of-care diagnosis and & prognostication of cryptococcal meningitis with the cryptococcal antigen lateral flow assay on cerebrospinal fluid. Clin Infect Dis 2014; 58:113–116. This study provides data on the efficacy and feasibility of the POCT LFA to determine cryptococcal antigen positivity in CSF. 10. Meda J, Kalluvya S, Downs JA, et al. Cryptococcal meningitis management in Tanzania with strict schedule of serial lumber punctures using intravenous tubing sets: an operational research study. J Acquir Immune Defic Syndr 2014; 66:e31–e36. 11. Jarvis JN, Bicanic T, Loyse A, et al. Determinants of mortality in a combined && cohort of 501 patients with HIV-associated cryptococcal meningitis: implications for improving outcomes. Clin Infect Dis 2014; 58:736–745. This large study showed that mental status, fungal burden, rate of pathogen clearance and age are all determinants of survival in HIVþ patients with cryptococcal meningitis. 12. Loyse A, Dromer F, Day J, et al. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J Antimicrob Chemother 2013; 68:2435–2444. 13. Day JN, Chau TT, Lalloo DG. Combination antifungal therapy for cryptococcal && meningitis. N Engl J Med 2013; 368:2522–2523. A critical study that will shape treatment guidelines for the treatment of cryptococcal meningitis whereupon amphotericin and flucytosine vs. amphotericin alone afford significantly lower rates of mortality in patients with cryptococcal meningitis. 14. Chang CC, Dorasamy AA, Gosnell BI, et al. Clinical and mycological pre&& dictors of cryptococcosis-associated immune reconstitution inflammatory syndrome. AIDS 2013; 27:2089–2099. An important study that showed that CSF cryptococcal culture positivity at the time of ART initiation and poor CD4þ gains on ART were associated with an increased risk of cryptococcal IRIS. 15. Naranbhai V, Chang CC, Durgiah R, et al. Compartmentalization of innate immune responses in the central nervous system during cryptococcal meningitis/HIV coinfection. AIDS 2014; 28:657–666.
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16. Chang CC, Omarjee S, Lim A, et al. Chemokine levels and chemokine receptor expression in the blood and the cerebrospinal fluid of HIV-infected patients with cryptococcal meningitis and cryptococcosis-associated immune reconstitution inflammatory syndrome. J Infect Dis 2013; 208:1604–1612. This study contributes to the understanding of the pathogenesis of cryptococcal meningitis IRIS. 17. Chang CC, Lim A, Omarjee S, et al. Cryptococcosis-IRIS is associated with && lower cryptococcus-specific IFN-gamma responses before antiretroviral therapy but not higher T-cell responses during therapy. J Infect Dis 2013; 208:898–906. This study contributes to the understanding of the pathogenesis of cryptococcal meningitis IRIS. 18. Njei B, Kongnyuy EJ, Kumar S, et al. Optimal timing for antiretroviral therapy initiation in patients with HIV infection and concurrent cryptococcal meningitis. Cochrane Database Syst Rev 2013; 2:CD009012. 19. Makadzange AT, Ndhlovu CE, Takarinda K, et al. 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Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis 2010; 202:962– 970. 23. Brancusi F, Farrar J, Heemskerk D. Tuberculous meningitis in adults: a review of a decade of developments focusing on prognostic factors for outcome. Future Microbiol 2012; 7:1101–1116. 24. Patel VB, Theron G, Lenders L, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study. PLoS Med 2013; 10:e1001536. 25. Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen containing rifampicin && and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013; 13:27–35. This important proof of principle study showed that achieving high levels of plasma and CSF rifampicin and moxifloxacin using short-term high doses of these two drugs was associated with a significantly reduced mortality at 6 months in 60 patients, 10% of whom were HIVþ. 26. Marais S, Meintjes G, Pepper DJ, et al. Frequency, severity, and prediction of && tuberculous meningitis immune reconstitution inflammatory syndrome. Clin Infect Dis 2013; 56:450–460. This study contributes to further understanding of TB IRIS. 27. Guidelines for prevention and treatment of opportunistic infections in HIVinfected adults and adolescents. [Internet] [cited 1 August 2014]. Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. 28. Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)–associated tuberculous meningitis. Clin Infect Dis 2011; 52:1374–1383. 29. Brew BJ, Davies NW, Cinque P, et al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 2010; 6:667–679. 30. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013; 80:1430–1438. 31. Schneider-Hohendorf T, Philipp K, Husstedt IW, et al. Specific loss of cellular & L-selectin on CD4þ T cells is associated with progressive multifocal leukoencephalopathy development during HIV infection. AIDS 2014; 28:793–795. This article suggests a new biomarker for HIV. patients who may be at risk of PML. 32. Schwab N, Schneider-Hohendorf T, Posevitz V, et al. L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology 2013; 81:865–871. 33. Clifford DB, Nath A, Cinque P, et al. A study of mefloquine treatment for && progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol 2013; 19:351–358. This article reports the disappointing finding that the antimalarial drug mefloquine was not efficacious in HIVþ and HIV-negative patients with PML. 34. Martin-Blondel G, Bauer J, Cuvinciuc V, et al. In situ evidence of JC virus control by CD8þ T cells in PML-IRIS during HIV infection. Neurology 2013; 81:964–970. 35. Johnson T, Nath A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci 2010; 1184:106–120. 36. Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009; 72:1458– 1464. &&
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Neuro OIs: developed and developing countries Edwina J. Wright a,b,c
Purpose of review To review recent studies that address the pathogenesis, diagnosis and treatment of HIV positive patients with cryptococcal and tuberculous meningitis and progressive multifocal leukoencephalopathy in resourcedifferent settings. Recent findings Central nervous system opportunistic infections remain globally prevalent in HIVþ populations. Several recent papers have highlighted the urgent need for rapid point of care tests in low-income settings for cryptococcal and tuberculous meningitis, better access to antifungal therapy for cryptococcal meningitis and better treatment strategies for tuberculous meningitis. In one recent study of 299 HIVþ patients with cryptococcal meningitis, amphotericin plus flucytosine was associated with less mortality and disability compared to amphotericin alone. In a study of patients with tuberculous meningitis in Indonesia, short-term, high dose rifampicin and moxifloxacin, designed to achieve higher levels of anti-TB drugs in the brain, saw significantly reduced patient mortality at 6 months. The timing of ART initiation in patients with central nervous system opportunistic infections remains challenging and a recent study reported that deferred vs early antiretroviral therapy was associated with better survival outcomes in patients diagnosed with cryptococcal meningitis. Recent studies have reported on predictors of immune reconstitution inflammatory syndrome for patients with central nervous system opportunistic infections, but require validation in resource-different settings. Summary Recent studies related to the diagnosis and treatment of central nervous system opportunistic infections in HIVþ populations show promising findings. Increased funding and research commitment are required to maintain this positive momentum and to achieve improved global outcomes for people who develop central nervous system opportunistic infections. Keywords central nervous system, cryptococcal meningitis, HIV, opportunistic infections, progressive multifocal leukoencephalopathy, tuberculous meningitis
INTRODUCTION Opportunistic infections in the central nervous system (CNS) remain a major global health issue for HIVþ people more than 30 years after HIV infection was first described. The reasons for this ongoing challenge include the following: first, advanced immunosuppression is the leading risk factor for CNS opportunistic infections and because 25% of individuals in low- and middle-income countries present late with CD4þ cell counts less than 100 cells/ml [1], CNS opportunistic infections remain prevalent in these settings; second, advances in the diagnosis, treatment and management of CNS opportunistic infections have been relatively modest over the past 3 decades and third, the ironic challenge posed by antiretroviral therapy (ART)-induced CNS immune reconstitution inflammatory syndrome (IRIS) [2] has compounded the
therapeutic difficulties faced by HIVþ patients with CNS opportunistic infections and their healthcare providers. This article will focus on recent advances in the pathogenesis, screening and management of three CNS opportunistic infections that have dominated the recent literature: cryptococcal and tuberculous meningitis and progressive multifocal leukoencephalopathy (PML).
a Department of Infectious Diseases, Alfred Health, bMonash University and cBurnet Institute, Melbourne, Victoria, Australia
Correspondence to Edwina J. Wright, MD, The Alfred, Commercial Road, Melbourne, VIC 3004, Australia. Tel: +61 3 9076 6078; e-mail: [email protected] Curr Opin HIV AIDS 2014, 9:539–544 DOI:10.1097/COH.0000000000000109
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KEY POINTS Diagnostic tests for cryptococcal meningitis and TBM that are suitable for resource-different settings are available.
(LFA) for determination of serum CRAG was recommended by the WHO in 2011 [8] because it has the benefits of lower costs, rapid results, no need for refrigeration compared with the CRAG latex agglutination assay or enzyme immunoassays. Recently Kabanda et al. [9 ] reported on results from two prospective cohorts of HIVþ patients with meningitis in Uganda where a new LFA CRAG assay that costs $2 per strip was tested on their cerebrospinal fluid (CSF). The authors found that the LFA assay’s sensitivity and specificity were high (both 100%) and that the pretreatment LFA CSF CRAG titers correlated with quantitative pre-treatment CSF cultures and 2- and 10-week mortality [9 ]. The authors suggested that CSF LFA titers more than 1000 could be used to predict mortality risk as patients with CSF titers more than 1 : 1280 vs. titers less than or equal to 1 : 640 at 2 weeks had a six-fold greater mortality [9 ]. As a corollary, a recent highly practical and useful study of HIVþ patients with cryptococcal meningitis in Tanzania found that readings of CSF pressure using intravenous giving sets were highly correlated with readings obtained by use of formal CSF manometers (r ¼ 0.96) [10]. In the same study, the authors showed that intensive intracranial pressure monitoring and repeated lumbar punctures were associated with lower mortality rates [10]. Recently, findings from the largest study, to date, of the determinants of mortality in HIVþ patients with cryptococcal meningitis were reported [11 ]. In this study, the authors combined the findings of nine trials conducted at five international sites over a period of 8 years to provide the power to determine predictors of mortality. The overall mortality rates were 17% at 2 weeks and 34% at 10 weeks. The authors reported that baseline altered mental status [odds ratio (OR) 3.1; 95% confidence interval (CI) 1.7–5.9], CSF fungal burden (OR, 1.4 per log10 colony-forming units/ml increase; 95% CI, 1.0–1.8) and rate of clearance of infection were associated with acute mortality (within the first 2 weeks of diagnosis) [11 ]. Factors associated with 10-week mortality included age more than 50 vs. less than 50 years (OR, 3.2; 95% CI 1.3–7.8) and use of amphotericin vs. fluconazole (OR 0.4; 95% CI 0.2–0.6). The authors’ conclusions referred to the need for greater capabilities to rapidly diagnose cryptococcal meningitis and for greater global availability of fungicidal (amphotericin-based) regimens [11 ]. This recommendation was paralleled by Loyse et al. [12] who provided a compelling review of the evidence for flucytosine’s use in combination with either amphotericin, or high-dose fluconazole in the treatment of cryptococcal meningitis. Here, the authors lament the fact that flucytosine is widely unavailable and unregistered across many Africa &
In patients with cryptococcal meningitis, amphotericin plus flucytosine is associated with significantly reduced mortality and disability compared with amphotericin alone. Both antifungal agents require greater scale up and a long acting formulation of flucytosine is urgently needed. Deferral of ART for 5 vs. 1 to 2 weeks after the diagnosis of cryptococcal meningitis in HIVþ patients was associated with significantly decreased mortality in a randomized, controlled trial. These findings are likely to shape future therapeutic guidelines on the management of cryptococcal meningitis. Mefloquine was found to have no efficacy in the treatment of PML. Development of antiviral agents with activity against PML is urgently needed. Increased funding and research commitment and a greater availability of better formulated drugs used to treat CNS opportunistic infections are required to achieve improved global outcomes for people who develop CNS opportunistic infections.
CRYPTOCOCCAL MENINGITIS In sub-Saharan Africa, cryptococcal infection is a leading cause of meningitis in adults, and in a study in the HIV high prevalence city of Cape Town, it accounted for 63% of cases of meningitis [3]. Currently in South Africa, individuals with less than 100 CD4þ cells/ml who are commencing ART are not screened for, or prophylaxed against cryptococcal disease [4 ]. In a recent analysis it was shown that for individuals entering ART programs in South Africa with less than 100 CD4þ cells/ml, the most feasible and cost-effective strategy to prevent cryptococcal meningitis is to screen all individuals with a serum cryptococcal antigen (CRAG) test and to treat those with positive results using high dose fluconazole [4 ]. This study’s findings are similar to those reported recently from Vietnam [5], are important at a programmatic level and are relevant for other countries and cohorts with a high prevalence of CRAG positivity, including newly diagnosed HIVþ patients in the United Kingdom [6]. The need for rapid point of care tests (POCTs) for neurological infections in Africa was highlighted recently in a review by Yansouni et al. [7 ]. Here, the authors defined rapid tests as those that yield results during the clinic visit and that can be used in settings with little infrastructure, including electricity, or trained personnel [7 ]. The lateral flow assay &&
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and Asian countries and call for increased generic manufacturing and a slow-release formulation of flucytosine to be developed [12]. The recommendations for the wider availability of these two antifungal agents are highly apposite given the findings from a very important study conducted by Day et al. [13 ] in Vietnam. This open-label study enrolled 299 HIVþ patients with severe cryptococcal meningitis and randomized them to receive induction therapy with amphotericin alone for 4 weeks, or amphotericin plus flucytosine, or amphotericin plus fluconazole for 2 weeks [13 ]. Patients then received fluconazole consolidation therapy. Thirty percent of patients received, or were commenced on ART during the 6-month follow-up period. The study’s chief finding was that mortality at days 14 and 70 was reduced in patients receiving amphotericin plus flucytosine (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% CI, 0.30–1.08; unadjusted P ¼ 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39–0.97; unadjusted P ¼ 0.04) [13 ]. There was no difference in survival between those receiving amphotericin alone or in combination with fluconazole (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44–1.41; P ¼ 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45–1.11; P ¼ 0.13). Important secondary outcomes showed that amphotericin-B plus flucytosine was associated with less disability at 6 months and that rates of adverse events were similar across all three induction arms. The effect of ART upon survival was not presented in this analysis [13 ]. The challenge of providing appropriate antifungal therapy is matched by the challenge of determining when to start ART in patients with cryptococcal meningitis in terms of affording patients longevity and minimizing the risk of cryptococcal meningitis IRIS. Cryptococcal meningitis IRIS occurs in approximately 19% of patients with cryptococcal meningitis commencing ART [2]. In a large study undertaken in South Africa of HIVþ patients with cryptococcal meningitis, Chang et al. [14 ] reported that the risk of cryptococcal meningitis IRIS was increased in those patients who remained CSF culture positive at the time of ART commencement and in those had a poor CD4þ T-cell gain on ART. Other studies undertaken by this group on the pathogenesis of cryptococcal meningitis and for cryptococcal meningitis IRIS, provided original insights into the immunoregulatory role of Natural Killer cells and monocytes in cryptococcal meningitis [15], and that an increased trafficking of CD8þ T cells and cells of myeloid origin in the CSF prior to ART initiation [16 ] and lower cryptococcal mannoprotein-induced &&
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production of interferon gamma [17 ] were associated with a higher risk of cryptococcal meningitis IRIS. In a systematic review of studies designed to determine the optimal timing of ART in patients with cryptococcal meningitis, Njei et al. [18] pooled data from two eligible randomized controlled trials [19,20] and found that early vs. delayed ART (< or >4 weeks after starting antifungal therapy) was not associated with a survival benefit [Relative risk ¼ 1.40, 95% CI (0.42,4.68)] [18]. Subsequently, the Cryptococcal Optimal Antiretroviral Timing (COAT) study results have become available [21 ]. The COAT study enrolled 177 HIVþ patients with cryptococcal meningitis and randomized them to receive ART at 1 to 2 vs. 5 weeks following the diagnosis of cryptococcal meningitis. Patients were treated with amphotericin and fluconazole for 14 days then received 800 mg daily fluconazole consolidation therapy [21 ]. The findings of the COAT study showed that deferred vs. early ART is associated with significantly higher survival at week 26 [45% (40 of 88 patients) vs. 30% (27 of 89 patients); hazard ratio for death, 1.73; 95% CI, 1.06–2.82; P ¼ 0.03]. This difference in excess mortality was seen 2–5 weeks following the diagnosis of cryptococcal meningitis, after which no difference in mortality between the two ART treatment initiation strategies was seen. Importantly, the highest risk of death was seen in those patients initiating early ART with less than 5 vs. more than 5 white cells/ml in the CSF at the time of randomization [Harzard ratio 3.87 (95% CI 1.2–4.96)]. Boulware et al. [22] and Chang et al. [14 ] have reported this observation previously wherein individuals with minimal CSF inflammation and cryptococcal meningitis are at highest risk of cryptococcal meningitis IRIS. An excess of cryptococcal meningitis-related deaths was seen in the early treatment group of Boulware et al.’s [21 ] recent study and the authors could not confidently ascertain whether cryptococcal meningitis IRIS was the chief cause of the excess deaths in the early treatment group because the definition of cryptococcal meningitis IRIS requires initial improvement then decline. Hence, an ascertainment of whether patients’ early deterioration was progressive cryptococcal meningitis or cryptococcal meningitis IRIS could not be made. This study was stopped prematurely by its Data Safety and Monitoring Board because of the excess deaths in the early treatment arm and hence did not enroll enough patients to power the study as originally designed. However, the authors contend reasonably that this study’s chief finding is of important clinical significance and is generalizable to both high and
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low-income settings because the study was conducted rigorously using protocols and procedures that are available across resource-different settings [21 ]. &&
TUBERCULOUS MENINGITIS Tuberculous meningitis (TBM), as reviewed by Brancusi et al. [23], occurs in approximately 10% of all cases of tuberculosis (TB), is likelier to occur in the setting of HIV co-infection where TBM mortality rates exceed 65% [23]. A rapid POCT for TBM has remained highly elusive. In a recent review of studies evaluating POCT for neurological infections, none of three POCT being evaluated for the rapid diagnosis of TB evaluated their use in CSF samples [7 ]. However, a recent prospective study undertaken in South Africa of 235 patients with a meningeal illness, 87% of whom were HIVþ, evaluated the utility of the Xpert MTB/RIF for the diagnosis of TBM [24]. In this study, the authors categorized 204 evaluable patients as having definite (n ¼ 59), probable (n ¼ 64), or non-TBM (n ¼ 81). The Xpert MTB/RIF was compared with a composite clinical and laboratory score for its diagnostic accuracy. The overall sensitivity and specificity of the Xpert MTB/RIF for TBM were 62% (95%CI 48–75%) and 95% (95%CI 87–99%), respectively [24]. Compared to CSF microscopy, the sensitivity of the Xpert MTB/RIF was significantly better (62 vs. 12%, P ¼ 0.001) and was also higher compared with the clinical score (62 vs. 30%; P ¼ 0.001). Notably, the sensitivity of the Xpert MTB/RIF was 80% when a centrifuged sample was used, presumably by increasing the concentration of TB pathogens. The authors called for further studies to validate the use of Xpert MTB/RIF for the diagnosis of TBM in both HIV endemic and nonendemic settings [24]. Treatment of TBM with a short course of higher dose rifampicin and moxifloxacin was evaluated in an important study undertaken in Indonesia [25 ]. In this study, 60 patients with severe TBM (6/60 were HIVþ) were randomized to receive standard dose oral rifampicin or high-dose intravenous rifampicin with 400 mg, or 800 mg moxifloxacin or ethambutol. All patients received isoniazid, pyrazinamide and adjunctive dexamethasone. After 14 days, patients were then switched back to the standard TBM treatment regimen. The authors reported that the use of higher dose rifampicin and moxifloxacin resulted in high plasma and CSF levels of these agents and was not associated with increased toxicity [25 ]. The use of intravenous rifampicin was associated with significantly reduced mortality at 6 months (35 vs. 65%), which was not explained, &&
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by patients’ TBM disease severity, or HIV status [25 ]. This study should propel larger studies to be undertaken to evaluate the benefits and feasibility of intensifying CNS penetration of antituberculous medications in patients with TBM, particularly those co-infected with HIV and living in low-income settings. In HIVþ patients, the risk factors associated with and the incidence of TBM IRIS have not been fully elucidated. In a recent prospective, observational study of 34 HIVþ patients with TBM in a Cape Town hospital, Marais et al. [26 ] reported that TBM IRIS occurred in 47% (16/34) of patients, all of whom initiated ART 2 weeks following commencement of antituberculous treatment and corticosteroids. Factors associated with TBM IRIS were a higher neutrophil CSF count and having a positive vs. a negative CSF culture for Mycobacterium tuberculosis whereupon the relative risk of developing TBM IRIS was 9.3 (95% CI 1.4–62.2%) if patients’ CSF culture was positive [26 ]. The current recommendations for ART initiation in patients with TB per se are to commence ART within 2 weeks following commencement of TB treatment for those patients with less than 50 CD4þ cells/ml, but otherwise to defer ART for 8–12 weeks in patients with more than 50 CD4þ cells/ml [27]. The optimal timing of ART for patients with TBM, especially those with less than 50 CD4þ cells/ml, is less clear, but early ART initiation is not associated with improved survival [28] in patients with TBM, carries a higher risk of toxicity [28] and high rates of IRIS were reported in this study [26 ]. &&
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PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY PML is a demyelinating disease of the CNS and is caused by the JC DNA polyomavirus [29]. PML is a relatively rare disease that occurs in immunosuppressed populations and occurs in 4–7% of HIVþ patients, typically in those with less than 200 CD4þ cells/ml. Recently, PML has received widespread clinical and research attention because of its increased incidence in patients receiving immunomodulatory agents for the treatment of multiple sclerosis and inflammatory bowel disease [29]. The diagnosis of PML is been challenging across all settings including high-income settings because there is no single clinical, or diagnostic marker for PML; hence, its diagnosis requires clinical, radiological, laboratory, histopathological analyses [30]. Recently, Berger et al. [30] provided a very useful algorithm to assist in the diagnosis of patients with PML, although the recommendation for MRI brain scanning, as an integral part of their Volume 9 Number 6 November 2014
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algorithm, precludes its direct applicability to lowincome and middle-income settings [30]; nonetheless, CT brain scans would be available in some settings. Recently, Schneider-Hohendorf et al. [31 ] proposed that L-selectin (CD62L) levels on peripheral blood mononuclear cells (PBMCs) of HIVþ patients may be used as a marker of future risk for PML. They have adopted this approach previously for screening patients with multiple sclerosis receiving natalizumab who may be at future risk of PML [32]. In their current study, CD62L levels on patients’ cryopreserved PBMCs were lower than 25% in those HIVþ patients who had previously diagnosed PML compared with those HIVþ patients who had not [31 ]. The study’s authors appropriately recommend that a prospective validation study is required to assess the utility of developing an assay to evaluate levels of CD62L on PBMCs [31 ]. The first-line treatment of PML in HIV infection is ART and its use is associated with stabilization or clinical improvement in a reasonable proportion of patients [29]. However, in patients who are HIV negative, or in those HIVþ patients on ART who are fully virologically suppressed and develop PML, there are few therapeutic options available [29]. Recently, Clifford et al. [33 ] reported on the sobering findings of the efficacy of mefloquine in the treatment of PML in both HIV-negative and HIVþ patients. They found that mefloquine plus standard of care vs. standard of care alone was not associated with a decrease in CSF JC viral levels, or with clinical improvement. The study was closed prematurely because a pre-planned interim analysis determined that the likelihood of finding a difference between the study’s treatment arms was very low [33 ]. Finally, more than 16% of HIVþ patients develop PML IRIS upon commencing ART [2]. PML IRIS carries a high risk of morbidity and mortality and its pathogenesis remains largely undescribed. In a recent cross-sectional, retrospective study Martin-Blondel et al. [34] examined the histopathological findings from the brains of five HIVþ patients with PML IRIS and four HIVþ patients with PML but without IRIS. They found that the brains of patients with PML IRIS had high numbers of cytotoxic CD8þ T-cells. The authors speculate that although this avid CD8þ T-cell response may be highly efficient in targeting and clearing JCV-infected oligodendrocytes, it comes at the expense of increased CNS inflammation and damage [34]. The current treatment of PML IRIS in HIVþ patients, based upon expert opinion, is to cautiously administer corticosteroids [35,36]. This approach is likely to stand until further studies &
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CONCLUSION Recent studies related to the diagnosis and treatment of CNS opportunistic infections in HIVþ populations are promising for the field. The LFA for the detection of cryptococcal antigen in the CSF of patients with cryptococcal meningitis and use of the Xpert MTB/RIF PCR test on CSF samples of patients with TBM are suitable for use in resourcedifferent settings and enhance the diagnostic acuity for these illnesses. For cryptococcal meningitis, recent studies have increased the understanding of the clinical and laboratory predictors of both mortality and IRIS. Importantly, the superiority of amphotericin plus flucytosine vs. amphotericin alone means that increased efforts to globalize access to these agents must be made. In the COAT study, deferred vs. early ART initiation in patients with cryptococcal meningitis was associated with decreased mortality at week 26 and this randomized controlled study’s findings are likely to inform future therapeutic guidelines on cryptococcal meningitis management in the HIV setting. TBM carries a high risk of mortality, but encouragingly a recent study showed that enhanced CNS penetration of initial MTB therapy reduced mortality and disability. Urgent future studies are required to explore this exciting new strategy. Findings that levels of expression of L-selectin on PBMCs may be used to identify immunocompromised patients at increased risk of PML require validation in future studies and the recent study finding that mefloquine is not efficacious against PML should spur the field to seek new effective PML treatment modalities. Increased funding and research commitment and a greater availability of better formulated drugs used to treat CNS opportunistic infections are required to maintain the current positive research momentum and to achieve improved global outcomes for people who develop CNS opportunistic infections. Acknowledgements None. Conflicts of interest Dr Wright receives funding from a research grant from NIH, a Career Development Fellowship from the National Health and Medical Research Council of Australia, research funding from the Victorian Department of Health and unrestricted research funds from Gilead, Abbott, Janssen Cilag and Boehringer Ingelheim.
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Dr Wright has received funding that has been used for research purposes only from ViiV, Merck, Gilead, and Abbott for consultancy work, payment for lectures from ViiV and payment for developing educational resources for ViiV and Gilead. Gilead Sciences has donated study drug for a PrEP demonstration Project led by Dr Wright.
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Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis 2010; 202:962– 970. 23. Brancusi F, Farrar J, Heemskerk D. Tuberculous meningitis in adults: a review of a decade of developments focusing on prognostic factors for outcome. Future Microbiol 2012; 7:1101–1116. 24. Patel VB, Theron G, Lenders L, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study. PLoS Med 2013; 10:e1001536. 25. Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen containing rifampicin && and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013; 13:27–35. 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Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 2010; 6:667–679. 30. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013; 80:1430–1438. 31. Schneider-Hohendorf T, Philipp K, Husstedt IW, et al. Specific loss of cellular & L-selectin on CD4þ T cells is associated with progressive multifocal leukoencephalopathy development during HIV infection. AIDS 2014; 28:793–795. This article suggests a new biomarker for HIV. patients who may be at risk of PML. 32. Schwab N, Schneider-Hohendorf T, Posevitz V, et al. L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology 2013; 81:865–871. 33. Clifford DB, Nath A, Cinque P, et al. A study of mefloquine treatment for && progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol 2013; 19:351–358. 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