Overview on Opportunistic Infections of the Central Nervous System

Transcription

1 Second HIV Infection and the Central Nervous System: Developed and Resource-Limited Settings Venice, Italy April 14 16, 2007 Overview on Opportunistic Infections of the Central Nervous System Adriana Ammassari INMI L. Spallanzani IRCCS Rome, Italy

2 The extraordinary effect of HAART Time period Mortality rates Total years (age standardized) Potential years of life lost years Life expectancy Exact age 20 years % surviving from 20 to 44 y Lima VD. AIDS 2007

3 Survival estimates by ART period: Danish HIV Cohort study From age 25 years, the median survival was: General population: 51.1 years (95%CI ) HIV+: 19.9 yrs (95%CI ) HIV period: 32.5 yrs (95%CI ) HIV+ no HCV co-infection period: 38.9 yrs (95%CI ) Lohse N. Ann Intern Med 2007

4 Good news in AIDS-associated CNS-OIs Epidemiology: A declining incidence of CNS-D in the era of HAART has been described Clinical/radiological manifestations: CNS-D generally occur at advanced stages of immune suppression and individually show some characteristic clinical-radiological findings Diagnosis: Minimally invasive approaches by using innovative diagnostic techniques are widely used Outcome and treatment : Survival of patients with CNS-OIs significantly increased with HAART

5 Good news in epidemiology A declining incidence of CNS-D in the era of HAART has been described

6 Incidence of CNS-D according to calendar year: EuroSIDA Cohort st phase 2 nd phase 10 Non CNS-D CNS-D 1 0, d Arminio Monforte A, Ann Neurol 2004

7 Positive effect of anti- Toxoplasma prophylaxis on TE 120 TE PML PCNSL other Ammassari A,JAIDS 1998

8 Declining incidence of OIs according to time on HAART 0-3 months 4-6 months 7-12 months months months d Arminio Monforte A, Arch Intern Med 2005

9 Increasing prevalence of HIV-D after introduction of HAART Proportion (%) of cases CD4/mmc HIVD OTHER CD4 HIVD Dore G, AIDS 1999

10 Good news in epidemiology A declining incidence of CNS-D in the era of HAART has been described, however

11 Incidence of individual CNS-D according to calendar year: EuroSIDA cohort 10 Toxo ADC Crypto PML PBL FBL 1 0,1 0, Annual decrease in incidence: ADC 45% (95% CI 40-49%) vs CNS-OIs 37% (95% CI 34-41%) p<0.01 d Arminio Monforte, Ann Neurol 2004

12 HIV D PML Cryptococcosis Toxoplasmosis CNS lymphoma Incidence rates of CNS-D : MACS cohort Sacktor N, Neurology 2001

13 Proportion of major CNS-D among total observed cases in the pre- and HAART period % TE PML PCNSL other Population: 239 cases Period: (Ammassari A, J AIDS 1998) 120 TE PML PCNSL other Population: 1440 cases Period: Jan 2000 Dec 2006 (IRINA Study) 100 % /2006

14 Good news in epidemiology A declining incidence of CNS-D in the era of HAART has been described, however 1. The reduction of HIV-D incidence seems more pronounced compared with that of CNS-OIs 2. PML does not show evidence of incidence decline over time 3. During the years of HAART, relative distribution of the major CNS-D among patients presenting with CNS disease seems fairly constant

15 Good news in clinical/radiological manifestations CNS-D generally occur at advanced stages of immune suppression and individually show some characteristic clinical-radiological findings

16 Characteristic clinical and radiological findings in major CNS-OIs CNS-OI Clinical Features CT scan/mri TE CD4 <100/mm 3 Fever, reduced alertness, headache, focal neurological deficits, seizure. Crypto. CD4 <100/mm 3 Fever, headache, alert; less common are visual changes, stiff neck, cranial nerve deficit, seizure; no focal neurological deficits. CMV CD4 <100/mm 3 Fever, lethargy, disorientation; headache, stiff neck, photophobia, cranial nerve deficit, seizure; no focal neurological deficits. PML CD4 <100/mm 3 some >200/mm 3 No fever; no headache; impaired speech, vision, motor function, cranial nerves. TBC CD4 <300/mm 3 Fever, reduced alertness, headache, meningismus, focal deficits Location: basal ganglia, gray-white junction Sites: usually multiple Enhancement: +++; usually ring lesions Edema/mass effect: usually not as great as lymphoma Usually normal or shows increased intracranial pressure Enhancement: - or meningeal enhancement Edema/mass effect: ventricular enlargement/obstructive hydrocephalus Location: periventricular, brainstem Sites: confluent Enhancement: variable Location: white matter, subcortical, multifocal Sites: variable Enhancement: negative No mass effect Intracerebral lesions in 50-70% Bartlett JG and Gallant JE. Medical Management of HIV Infection

17 Good news in clinical/radiological manifestations CNS-D generally occur at advanced stages of immune suppression and individually show some characteristic clinical/radiological findings, however

18 CNS-D prevalence, CD4 count and plasma VL at diagnosis over time Numberof CNS-D per calendaryear CNS-OIs ADC CD4 cell counts/µl HIV-1 RNA log10 c/ml ?2001 > Changes in proportion CNS-OI / ADC p = Changes in CD4 cell counts p < Changes in HIV-1 RNA copy levels p = 0.11 d Arminio Monforte A, Ann Neurol 2004

19 Prevalence of individual CNS-D by CD4 cell count 35 % 30 CD4 > 200/mmc CD4 <= 200/mmc TE HIVE PML Crypto Other EUO PCNSL TB CMV NHL HSV Double CNS-D IRINA Study

20 Prevalence of CNS-D according with HIV-RNA values in 457 patients on HAART at diagnosis 30 % HIV-RNA < 50 cp/ml Other CNS-D (n=71): HIV-RNA >= 50 cp/ml Vascular disorder (16) Meningoencephalitis (9) Bacterial meningitis (8) Brain abscess (8) Neoplasm (7) Acute HIV infection (3) TE HIVE PML Crypto Other EUO PCNSL TB CMV NHL HSV Double CNS-D IRINA Study

21 Characteristics of 1440 patients by ART history General characteristics Naive (49.3%) Experienced not on HAART (17.7%) Experienced on HAART (33.0%) Previous AIDS 8.7% 48.9% 57.0% CD4 cell/ml, median (IQR) 46 Extremely (20-124) low CD4 48 cells (17-148) and 103 (34-237) Plasma HIV RNA log 10 cp/ml, median (IQR) 5.23 ( ) high HIV 5.09 RNA ( ) 3.44 ( ) CSF HIV RNA log 10 cp/ml, median (IQR) 4.28 ( ) 3.93 ( ) 2.18 ( ) Median of HAART exposure (months), IQR - 12 (1-37) 18 (3-40) Clinical characteristics Focal signs 53.8% 51.1% 53.2% Cognitive symptoms 62.4% 56.5% 54.3% Meningeal symptoms 13.9% 18.1% 12.7% Abnormal mental status 32.8% More severe neurological 30.0% 20.0% presentation Neuroradiological characteristics Contrast enhancement 43.8% 37.1% 42.5% Mass effect 33.1% 27.4% 30.1% Cerebral atrophy 30.3% 32.1% 37.0% White matter involvement Single Multifocal Diffuse Focal lesion Single Multiple 16.3% 28.6% 6.0% 1 st phase epidemic 11.8% 28.7% 8.0% 15.4% More frequent multiple 14.8% FBL 40.3% 33.8% 4.7% 30.5% 15.4% 19.4% 35.4% IRINA Study

22 Characteristics of 1440 patients by ART history General characteristics Naive (49.3%) Experienced not on HAART (17.7%) Experienced on HAART (33.0%) Higher CD4 cells and lower plasma/csf HIV Previous AIDS 8.7% 48.9% 57.0% CD4 cell/ml, median (IQR) 46 (20-124) 48 (17-148) 103 (34-237) Plasma HIV RNA log 10 cp/ml, median (IQR) 5.23 ( ) 5.09 ( ) 3.44 ( ) CSF HIV RNA log 10 cp/ml, median (IQR) 4.28 ( ) 3.93 ( ) 2.18 ( ) RNA Median of HAART exposure (months), IQR - 12 (1-37) 18 (3-40) Clinical characteristics Focal signs 53.8% 51.1% 53.2% Cognitive symptoms 62.4% 56.5% 54.3% Meningeal symptoms 13.9% 18.1% 12.7% Abnormal mental status 32.8% 30.0% 20.0% Neuroradiological characteristics 30-42% ME or CE Contrast enhancement 43.8% 37.1% 42.5% Mass effect 33.1% 27.4% 30.1% 37% atrophy Cerebral atrophy 30.3% 32.1% 37.0% White matter involvement Single Multifocal Diffuse Focal lesion Single Multiple 16.3% 28.6% 6.0% 15.4% 40.3% 11.8% 28.7% 8.0% 14.8% 33.8% 2 nd phase epidemic 4.7% 30.5% 15.4% 19.4% 35.4% IRINA Study

23 Immune reconstitution inflammatory syndrome (IRIS) Wide variety of systemic infections: mycobacteria, cryptococcus neoformans, CMV, PML Occurrence after the start of HAART Atypical clinical-radiological pictures

24 Good news in clinical/radiological manifestations CNS-D generally occur at advanced stages of immune suppression and individually show some characteristic clinical-radiological findings, however 1. In recent years CNS-D can occur at higher CD4 cell count and also in virologically suppressed patients 2. These neurological events include vascular events, non HIV-associated infections and neoplasms, acute retroviral syndrome 3. In ART naïve patients clinical-radiological characteristics are similar to those of the pre-haart era. In HAARTtreated patients no typical pattern can be identified. 4. IRIS has been described with a variety of etiological agents and determines a paradoxical clinical evolution

25 Good news in diagnosis Minimally invasive approaches by using innovative diagnostic techniques are widely used

26 Brain biopsy in AIDS-related FBLs of the pre-haart period Diagnoses/Cases Sens Morb Mort (%) (%) (%) Levy, / Chappell, / Zimmer, / Bise, / Alesch, / Luzzati, / Antinori, / Gildenberg, /

27 Outcome after biopsy in 158 patients in the pre-haart period Definitive diagnosis 138 (87%) Disorder sensible to change in therapy 125 (78%) Patients able to start a new treatment after biopsy 88 (56%) Patients with improvement or stable disease 46 (29%) Antinori A, Neurology 2000

28 High diagnostic value of combined 201 Tl-SPECT and CSF EBV-DNA for PCNSL diagnosis SPECT and/or EBV-DNA: Sens 100%; Spec 88.9%; PPV 86.7%; NPV 100% Antinori A, J Clin Oncol, 1999

29 Diagnostic accuracy of CSF PCR for the diagnosis of some CNS-D Sensitivity (%) Specificity (%) JCV CMV Toxoplasma gondii M. Tuberculosis EBV Skiest D, CID 2002 Portegies P, Eur J Neurol. 2004

30 Diagnostic algorithm for FBL with mass effect FBL with mass effect Anti-Toxoplasma therapy CSF EBV-DNA (when feasible) 201 Tl-SPECT EBV+/SPECT+ EBV-/SPECT- EBV+/SPECT- EBV+/SPECT- CSF PCR for: Toxo, Mtb, HSV, CMV, JCV PCNSL Tx pos neg failure Biopsy Improvement at 2 weeks Specific Tx Continuing of anti-toxo Tx

31 Diagnostic algorithm for FBL without mass effect FBL without mass effect Specific Tx pos CSF PCR for: JCV, CMV, HSV, VZV pos RMN compatible with PML, CMV, HSV neg Repetition of CSF PCR (JCV-DNA) at 7 days neg RMN not compatible with PML, CMV, HSV Cognitive impairment HIV-RNA plasma/lcr <10 No cognitive impairment No HAART Specific Tx HIV-D NDE

32 Good news in diagnosis Minimally invasive approaches by using innovative diagnostic techniques are widely used, however

33 Reduced diagnostic value of 201 Tl-SPECT for PCNSL diagnosis in recent calendar years Giancola L, AIDS Res Hum Retrovir 2004

34 Reduced diagnostic value of EBV- DNA in CSF for PCNSL diagnosis in recent calendar years Prevalence Sens. Spec. PPV % n.a. 79% 26% % 97% 98% 90% % 97% 98% 67% Lack of standardization for nucleic acid amplification protocols, and differences between laboratories Reduction in overall PCNSL prevalence lowers PPV 1 Ivers LC, Clin Infect Dis Cinque P, Clin Infect Dis 2004

35 Reduced diagnostic value of JCV- DNA for PML diagnosis in the HAART era Positive detection rate Pre-HAART era 89.5% vs HAART era 57.5%; p=0.014 Marzocchetti A. J Clin Microbiol 2005

36 Characteristics of 89 Encephalopathy of Unknown Origin (EUO) HIV transmission route: IVDU MSM Heterosexual 54.1% 9.4% 18.8% Previous AIDS 40.0% CD4 cell/ml, median (IQR) CD /mmc (64-340) Plasma HIV-1 RNA log 10 cp/ml, median (IQR) 4.29 ( ) CSF HIV-1 RNA log 10 cp/ml, median (IQR) 3.04 ( ) Naïve Experienced not on HAART Experienced on HAART 28.6% 47.1% 24.3% Clinical characteristics Focal signs 54.1 Cognitive symptoms 41.2 Meningeal symptoms - Abnormal mental status 11.8 Neuroradiological characteristics Contrast enhancement 25.9 Mass effect - Cerebral atrophy 20.0 White matter involvement Single 10.6 Multifocal 50.6% Diffuse 10.6 Focal lesion Single Multiple IDU 54.1% AIDS 40% ART exp 71.4% IRINA Study

37 Good news in diagnosis Minimally invasive approaches by using innovative diagnostic techniques are widely used, however 1. Tests used for minimally invasive PCNSL diagnosis might have a reduced diagnostic capacity as disease prevalence declines 2. The diagnostic capacity for PML of CSF JCV- DNA PCR depends on the technique, but seems to decline in the HAART era 3. Encephalopathies of Unknown Origin have been observed in recent years

38 Good news in outcome and treatment Survival of patients with CNS-OIs significantly increased with HAART

39 Reduced risk of mortality in the HAART era for CNS-OIs: French Hospital Database on HIV Grabar S. CROI 2007 Abst.#525

40 Positive effect of HAART on survival in patients with PML De Luca A, AIDS 2000

41 Good news in outcome and treatment Survival of patients with CNS-OIs significantly increased with HAART, however

42 CNS-OIs are leading cause of death in the HAART era: EuroSIDA Cohort Mocroft A. CROI 2007 Abst.#80

43 Survival curves of 1081 patients by individual CNS-D P al log-rank< year survival probability EUO 85% HIVE 81% TE 78% Other 76% Crypto 74% TB 67% PML 49% PCNSL+NHL 15% IRINA Study

44 Survival curves according to HAART during follow up 1-year survival probability naive starting HAART during follow up 89% experienced not on HAART at diagnosis and re-starting HAART during follow-up 85% experienced on HAART at diagnosis and on HAART during follow up 77% never on HAART during follow-up 38% P al log-rank< IRINA Study

45 Factors that should be considered when defining time of start of HAART Extent of positive impact of HAART on 6- months survival Availability of effective therapy for some CNS-OIs Overlapping drug toxicities Risk of IRIS Willingness and ability of patients to adhere to their regimens Risk of PK drug-drug interactions

46 Timing of HAART in ART-naive Patients ART-naïve Effective Tx for CNS-OI? NO YES Start HAART as soon as possible Start HAART after 2 weeks of Tx for CNS-OI IDSA Guidelines for treatment of opportunistic infections. CID 2006.

47 Timing of HAART in ART-treated Patients on ART Does CNS-OI occurred within 12 weeks after initiating HAART? Start Tx for CNS-OI and continue HAART YES NO Plasma HIV-RNA <50 c/ml YES NO Start Tx for CNS-OI and continue/modify HAART Start Tx for CNS- OI and optimize HAART (resistance test) IDSA Guidelines for treatment of opportunistic infections. CID 2006.

48 Good news in treatment and outcome Survival of patients with CNS-OIs significantly increased with HAART, however 1. Probability of surviving at one year is still low 2. HAART during follow-up strongly reduces mortality 3. Best timing of start of HAART still needs to be defined

49 Conclusion Further research on a wide range of issues related to CNS-OIs is absolutely needed to improve differential diagnosis, clinicaltherapeutical management, patient s quality of life and survival.

50 INMI L. Spallanzani Rome, Italy A Antinori ML Giancola P Lorenzini MP Trotta A Ammassari V Tozzi C Bibbolino E Busi Rizzi V Schininà Italian Register Investigative NeuroAIDS (IRINA study) HSR Milan, Italy P Cinque A Lazzarin Catholic University Rome, Italy A De Luca A Cingolani