Neurologic Opportunistic Processes in AIDS David B.Clifford, M.D.
Support Funding: NIH: NINDS, NIAID, NIMH Consulting: Biogen, Elan, Genzyme, Genentech, Millennium, Pfizer, Roche, Schering Plough Research support: Ortho Biotech, Pfizer, Neurogesx, Saviant, Bavarian Nordic, Schering Plough, Tibotec
HIV-Associated Neurologic Problems Secondary neurologic problems Cryptococcal meningitis Toxoplasmosis PML Tuberculosis Hepatitis C Primary CNS lymphoma Syphilis Cytomegalovirus encephalitis and radiculomyelitis Complications of therapy
HAART Helps Probable dementia Toxoplasmosis Progressive multifocal leukoencephalopathy Probable or possible dementia Cryptococcal meningitis CNS lymphoma Incidence rates (per 1,000 person-years) 20 18 16 14 12 10 8 6 4 2 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Calendar Year MACS Sacktor, personal comm 2007
Penetration of HAART
Evolution of Complications of HIV
Mortality of AIDS Defining Complications CROI 2007, Abstract 80, Mocroft et al Data derived from 15 HIV cohort studies including >30K subjects
Early Mortality in Developing Nations As HAART introduced, reports still emphasize distressing early mortality in treated population CNS OI disease appears to be a major contributor to this early mortality Research probing this phenomenon, likely to be regionally specific, may be important
Common Issues Diagnosis Rapid, cost effective, with available technology Optimal treatment HAART associated issues When to start IRIS
Overview PML Cryptococcal meningitis Toxoplasma encephalitis
Progressive Multifocal Leukoencephalopathy Acquired demyelinating CNS disease JC virus is etiologic agent ~5% of untreated HIV deaths Disease exclusively in immunocompromised Remains problem in HAART era, and in other populations Worldwide distribution
Signs and symptoms dependent on lesion location Motor sx Seizures (20%) Behavioral signs Progressive over weeks to a few months Generally have dominant clinical focus that progresses and is consistent with MR lesion visualized Clinical Aspects of PML
PML in the HAART Era Change in prognosis Immune reconstitution inflammatory response (IRIS) Change in diagnostic test accuracy
PML Survival in HAART Era Kaplan-Meier survival estimate with 95%CI (n=168 PML-related deaths in 372 patients with 465 PY follow up) 0.25.5.75 1 0 26 52 78 104 130 156 182 208 234 260 weeks 1-year cumulative proportion surviving: 0.56 (95%CI 0.50-0.61) 36.1 PML-related deaths/100 PY DeLuca, et al, 12 th CROI
PML in the HAART Era Change in prognosis Immune reconstitution inflammatory syndrome (IRIS) Change in diagnostic test accuracy
PML IRIS HIV associated PML with cognitive presentation Brisk increase of CD4 117 to 300 and drop in HIV VL Clinical state continued to progress Biopsy performed Vendrely, et al Acta Neuropathol (2005) 109:449455
IRIS Biopsy Severe inflammatory and demyelinating lesions Infiltration by macrophages and T Lymphocytes No JC detected Vendrely, et al Acta Neuropathol (2005) 109:449-455 H&E - CD8 immunostain Showing CD8+ infiltration
PML in the HAART Era Change in prognosis Immune reconstitution inflammatory response (IRIS) Change in diagnostic test accuracy
CSF PCR Performance Marzocchetti et al, J. Clin Microbiol, 2005
Patient Characteristics Marzocchetti et al, J. Clin Microbiol, 2005
Therapeutic Approaches Cytosine arabinoside Modification of BBB + Rx Interferon-,?interferon- Topoisomerase inhibitors Topotecan, Camptothecan Cidofovir IL-2 Gene therapy (?agnoprotein) Adoptive transfer therapy for VP1 CTL Chlorpromazine or other cell entry inhibitors Apoptosis inhibitor
Enfuvirtide enhanced HAART for PML Gasnault, et al, CROI 2007, Poster 379 Survival probabilty 0.2 0.4 0.6 0.8 1.0 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months n=27 n=20 n=18 n=13 n=10 ANRS 125 Trial. Kaplan-Meier estimate : Six-month cumulative probabilty of survival : 0.77 (CI = 0.63 to 0.95). Six patients died before M6.
P24 JCV SEB PHA 100% % patients with positive response 80% 60% 40% 20% 4% 23% 32% 47% 0% Baseline W6 M3 M6 ANRS 125 Trial. Anti-JCV CD4 T cell proliferative assay : Significant increase in the number of patients with a positive anti-jcv proliferative response at M3 (p=0.03) and M6 (p=0.008) compared with Baseline.
50% Overlapping JCV VP1 - peptides % patients with positive response 40% 30% 20% 10% 17% 23% 27% 37% 0% Baseline W6 M3 M6 ANRS 125 Trial. Ex vivo IFN-gamma CD8 T cell ELISPOT : Trends to an increase in the number of patients with positive response at M3 (p=0.18) and M6 (0.16) compared with Baseline.
Trial in development International, multicenter, HIV associated PML HIV Rx: Randomized HAART vs Super- HAART Key Issues Addressed Rate of clearance for CSF JC DNA Incidence of IRIS and its implications Serotonin receptor antagonist therapy
Trial in development Requires developed world technology MR scan, PCR diagnosis, Aggressive HAART Will provide background for intervention trials Will contribute to characterization of immune breakdown allowing dx, and dx specific immune reconstitution Background for study of non-hiv associated PML including those with immune modulating rx
Overview PML Cryptococcal meningitis Toxoplasma encephalitis
Cryptococcal Meningitis Demographics Untreated AIDS ~10% develop CD4 < 100 cells/mm 3 Generally thought to be primary infection Common in Southeast Asia as well as other developing world sites Factor in early deaths with HAART
Cryptococcal Meningitis Clinical Features >75% present with subacute meningitis or meningoencephalitis Fever Malaise Headache Stiff neck in only 25% Nausea and vomiting in ~40%
Cryptococcal Meningitis Clinical Features Encephalopathy in about 30% at onset Lethargy, altered mentation, memory loss Focal abnormalities uncommon Cryptococcomas are rare in AIDS MR/CT generally show only meningeal enhancement Seizures in only about 10%
Crypto Meningitis Diagnosis - Blood Blood cultures positive in >70% Latex antigen positive in 98% with proven meningitis
Cryptomeningitis Diagnosis - CSF Latex agglutination test for polysaccharide antigen is sensitive and specific CSF may be otherwise normal! Mild pleocytosis (< 20 cells/mm 3) Protein normal Sugar normal or low Dx can be reliably made without costly technology
Lortholary, et al HAART Helps
Cryptococcal Meningitis Therapy Amphotericin B (0.7 mg/kg daily) for induction therapy with or without flucytosine (~3-6 weeks duration) Fluconazole 400 mg/d consolidation therapy (8 10 weeks) Fluconazole 200 mg/d maintenance therapy
Cryptococcal IRIS Inflammatory responses subsequent to therapy are often seen in course of HIV associated cryptococcal meningitis Optimal timing of HIV therapy likely to be critical Likely to be factor in early deaths with HAART therapy
Crypto Iris Retrospective review of 59 HAART treated patients with HIV-associated cryptococcal disease Criteria: Clinical improvement to crypto rx Recurrent symptoms or new inflammatory symptoms after delay Cultures negative CSF CrAg declining from baseline if available 18/59 (30.5%) developed IRIS as defined above Median time 30 days after HAART rx Shelburne SA, et al. Clin Infect Dis 2005.
IRIS of Cryptococcosis Patients who developed IRIS were more likely to be antiretroviral naïve have a higher CSF CrAg have a higher baseline HIV viral load have initiated ART within 30 days after cryptococcal diagnosis. No statistical difference in mortality between those who had IRIS compared with those who did not (18 m followup) Formal study to consider timing of rx may be needed although late occurrence suggests the choice may be difficult Shelburne SA, et al. Clin Infect Dis 2005.
Pending Cryptococcal Meningitis Clinical Trial Cost/Toxicity/Complexity make AmB therapy problematic in developing nations Fluconazole alone used in some cases, unclear the limitations of this approach, or best dose A5225 pending ACTG study to evaluate doses of 1200 2000 mg/day for primary therapy of Cryptococcal meningitis
Trial in Development: A5225 A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis Protocol Co-Chairs: J. Allen McCutchan, M.D. Robert Larsen, M.D., Umesh Lalloo, M.D. Beatriz Bustamante, M.D.
A5225 Phase 1 with fluconazole dose escalation including 1200, 1600 and 2000 mg/day Phase 2 comparison of amphotericin B based initiation with fluconazole at each of the above doses that is tolerated Endpoint quantitative CSF crypto cultures
Quantitative CSF Cryptococcal Culture Brouwer AE, et al. Lancet 2004.
Overview PML Cryptococcal meningitis Toxoplasma encephalitis
Toxoplasma Encephalitis
Signs/Sx of Toxoplasmosis Headache Fever Confusion Hemiparesis, other focal signs Posterior fossa syndrome Seizures ICP elevation
REGIONAL DIFFERENCES Worldwide prevalence 3-90% Highest in Western Europe Causes for differences Seroprevalence Related to dietary habits Prevalent use of sulfa drugs might make difference in toxo prevalence in humans
IMMUNE STATUS Seroprevalence important Seroprevalence is higher in HIV infected individuals Country HIV+ HIV- India 68% 30% Nigeria 39% 21% South Africa 34% 5%
Toxoplasma Strain Differences Toxoplasma virulence associated with strains Three strains share 98% genetic identity, yet are markedly different in virulence Geographic distribution of strains incompletely described but probably differs
Toxoplasma Strains Multiplex PCR assay developed to genotype CSF samples from HIV associated human toxoplasma encephalitis cases examined A majority had Type I strains in CSF despite this being a rare human pathogen Khan, Su, German, Storch, Clifford and Sibley. J. Clin. Microbiol 2005;43:5881.
Toxoplasma Strains Type II Most commonly cause toxoplasmosis Type III Rarely assoc with dx Type I : Rarer but pathologic
Biological Basis for Virulence Genetic mapping of virulence locates gene on parasite chromosome VIIa Strain specificity ROP18, serinethreonine kinase secreted into host cell on invasion Rhoptry Taylor, Barragan, et al Science 2006;314:1776.
Biological Basis of Virulence Strain specific modulation of host cell transcription, by ROP16 Injected by rhoptries into host cell Ultimately affects signal transducer and activator of transcripton (STAT) pathway Nature 2007; 445:324
Toxo impt in SE Asia Chiang Mai Khuanchai Supparatpinyo Helen Ling/Siwaporn Chankrachang
Rationale for study TE is most common OI causing focal brain lesions in HIV/AIDS patients TE is treatable with oral medications, yet fatal when treatment not provided Early diagnosis remains challenging Therapy in developed countries not uniformly available in developing countries Alternate therapy with trimethoprimsulfamethoxazole being used widely, considered for national standards in some developing sites
Randomized Trial of Trimethoprim-Sulfamethoxazole vs. Pyrimethamine-Sulfadiazine for Therapy of Toxoplasma Encephalitis in HIV/AIDS Patients Concept sheet in preparation Conceived as a joint ACTG/NARC project Team Forming David Clifford Jens Mielke (Zimbabwe) Scott Evans (SDAC) Farida Amod (Durban) Helen Ling (Chiang Mai) Christina Marra (Seattle)
Pilot study available as model Anecdotal experience and case reports Pilot study: Torre et al (Italian Collaborative Study Group), Antimicrob Agents and Chemoth 1998; 1346-9. Randomized pilot study Suggests T-S may be reasonable alternative to P-S, but lacked power to demonstrate noninferiority
Efficacy Torre et al, AAC 1998:1346.
Radiologic Response Torre et al, AAC 1998:1346.
Adverse Effects Profile Torre et al, AAC 1998:1346
Randomized Trial of Trimethoprim-Sulfamethoxazole vs. Pyrimethamine-Sulfadiazine for Therapy of Toxoplasma Encephalitis in HIV/AIDS Patients Non-inferiority trial planned Will require ~250-300 subjects for adequate power Strong interest exists in the international ACTG system for performance of this study Drug acquisition has been obstacle to achieving trial development
Situation Hypothesis that the more available therapy is noninferior seems reasonable Trial necessary as basis of policy development Study would undergird development of optimal diagnosis of focal brain lesions in developing world sites
Concept Non inferiority trial randomizing 1:1 between pyrimethamine-sulfadiazine (P-S) and Trimethoprim-Sulfamethoxazole (T-S) Primary outcome: clinical response, CT response Secondary outcomes: AE/Toxicity, rate of improvement, CSF PCR specificity/sensitivity for TE, immune reconstitution, cost
TE Clinical Trial Approved for development by NARC EAC Drug supply is challenging problem Cost of drugs for trial >$1million, not possible with NARC or ACTG alone Buying drugs from Indian would reduce cost but then trial would be hard to fund Seeking Gates Foundation support for purchase of drugs at present
HIV Associated OI Continue to Deserve Study to Improve Dx and Rx PML Cryptococcal meningitis Toxoplasma encephalitis Tuberculosis Malaria Hepatitis C Syphilis Cytomegalovirus
Thanks to NINDS/NIMH
Tuberculosis
Neurosyphilis and HIV Concurrent syphilis and HIV exposure not rare Course to neurosyphilis may be accelerated in HIV Treatment may be more difficult (ACTG 145) Care to consider syphilis, and treat aggressively with close followup important
ACTG 145 Marra et al. Clinical Infect Dx 2000; 30:540 Ceftriaxone(2 g IV daily) vs Pen G (4 MU IV q4h) for neurosyphilis Ten day treatment regimen, N=30 DX: RPR 1:16, reactive serum treponemal tests, either reactive CSF VDRL or active CSF No difference in change of CSF parameters Serum RPR declined more frequently in ceftriaxone treated IV ceftriaxone may be alternative to IV PCN G
Conclusion Opportunistic conditions remain important considerations in HIV When these conditions occur, HIV should also be considered Treatment for OI can be rewarding, and successful Opportunities remain to learn more about relatively rare conditions in the setting of HIV