PICO 4: What is the most appropriate type (routine or targeted) and frequency of monitoring to assess treatment response of patients on initial treatment regimens for Cryptococcal meningitis in resource limited settings?

1
PICO 4 What is the most appropriate type
(routine or targeted) and frequency of monitoring
to assess treatment response of patients on
initial treatment regimens for Cryptococcal
meningitis in resource limited settings?
2
PICO 4 framework

• What is the most appropriate type (routine or
  targeted) and frequency of monitoring to asses
  treatment response of patients on initial
  treatment regimens for Cryptococcal meningitis in
  resource limited settings?

P I C O
Adult and pediatric HIV-infected patients on initial treatment for symptomatic cryptococcal meningitis or non-meningeal cryptococcal disease Clinical monitoring Clinical monitoring Lumbar puncture - CRAG - CSF culture - Quantitative cultures - Quantitative cell counts Routine protocol driven lumbar at two weeks Symptom driven lumbar puncture in patients with persistent symptoms Treatment failure (sensitivity and specificity) Mortality
3
Searches
Search PubMed Strategy Result
4 Search ((1) AND 2) AND 3. Limits Publication date from 1980/1/1 to 2011/09/15 1049
3 (randomized controlled trialpt OR controlled clinical trialpt OR randomizedtw OR randomisedtw OR randomtw OR placebotw OR drug therapysh OR randomlytw OR trialtw OR RCTtw OR cohorttw OR cross sectionaltw OR cross-sectionaltw OR case controltw OR non-randomtw or nonrandomtw OR observationaltw OR odds ratiotw OR hazard ratiotw OR risk ratiotw OR rate ratiotw OR confidence intervaltw OR prospectivetw OR experimenttw) NOT (animalsmh NOT humansmh) 3464436
2 HIV InfectionsMeSH OR HIVMeSH OR hivtw OR hiv-1tw OR hiv-2tw OR hiv1tw OR hiv2tw OR hiv infecttw OR human immunodeficiency virustw OR human immunedeficiency virustw OR human immuno-deficiency virustw OR human immune-deficiency virustw OR ((human immun) AND (deficiency virustw)) OR acquired immunodeficiency syndrometw OR acquired immunedeficiency syndrometw OR acquired immuno-deficiency syndrometw OR acquired immune-deficiency syndrometw OR ((acquired immun) AND (deficiency syndrometw)) OR "sexually transmitted diseases, viral"MESHNoExp) 276647
1 Search Cryptococc meningitis (cryptococcaceaeAll Fields OR cryptococcaceesAll Fields OR cryptococcaemiaAll Fields OR cryptococcalAll Fields OR cryptococcalesAll Fields OR cryptococccosisAll Fields OR cryptococcemiaAll Fields OR cryptococcenAll Fields OR cryptococciAll Fields OR cryptococciaAll Fields OR cryptococcicAll Fields OR cryptococcicaAll Fields OR cryptococcidaeAll Fields OR cryptococcidalAll Fields OR cryptococcinAll Fields OR cryptococciqueAll Fields OR cryptococcisAll Fields OR cryptococcoAll Fields OR cryptococcoalAll Fields OR cryptococcocalAll Fields OR cryptococcoceaeAll Fields OR cryptococcociAll Fields OR cryptococcocidalAll Fields OR cryptococcocisAll Fields OR cryptococcocusAll Fields OR cryptococcoisisAll Fields OR cryptococcolAll Fields OR cryptococcomAll Fields ORAND ("therapy"Subheading OR "therapy"All Fields OR "treatment"All Fields OR "therapeutics"MeSH Terms OR "therapeutics"All Fields) AND monitoringAll Fields) AND "spinal puncture"MeSH Terms OR ("spinal"All Fields AND "puncture"All Fields) OR "spinal puncture"All Fields OR ("lumbar"All Fields AND "puncture"All Fields) OR "lumbar puncture"All Fields) AND "spinal puncture"MeSH Terms OR ("spinal"All Fields AND "puncture"All Fields) OR "spinal puncture"All Fields OR ("lumbar"All Fields AND "puncture"All Fields) OR "lumbar puncture"All Fields) AND AND ("antigens"MeSH Terms OR "antigens"All Fields OR "antigen"All Fields 17428

• (PICO 4)
• Databases (01 Jan 1980 15 Sept 2011)
• PubMed
• No language limits
• Conference Abstracts (CROI, IAS, Crypto meeting)

Total of records 1049
Records excluded 1035
Full-text articles obtained 14
4
What do key Guidelines say?
IDSA 2010 "the 2-week LP culture result is a test for determining fungicidal success of induction therapy."
CDC 2009 Consolidation treatment initiated after at least a 2-week period of successful induction therapy, defined as substantial clinical improvement and a negative CSF culture after repeat lumbar puncture"
MSF 2006 "If the initial opening pressure was normal, perform a follow up LP at 1 and 2 weeks or if any worsening of headache, visual, or hearing problems"
South Africa 2007 No specific recommendation
European Mycoses Group 2008 "Repeated sampling of CSF is required to assess the therapeutic response, because clinical symptoms may not correlate with control of disease"
Jackson review 2010 "Some experts suggest a follow up LP after 2 weeks, and prolongation of the induction phase if the CSF culture is not sterile".
5
Summary
2 week LP quantitative cultures 2 week LP quantitative cultures 2 week LP quantitative cultures 2 week LP quantitative cultures
Brouwer 2004 RCT n 64 Baseline log CFU associated with death
Pitisuttihum 2001 Non-RCT n106 Higher total Crypto counts (gt900x103/ml) associated wit early and later mortality. Delayed CSF yeast clearence associated with later mortality (RR 3.6 95 CI 1.9-6.4) and relapse (RR3.9 95 CI 1.4-10.8)
Robinson 1999 Non-RCT n 236 Strong association between CSF culture status at day 14 and outcome at 10 weeks
Bicanic 2009 Observational n 262 Greater EFA associated with 2 and 10 weeks mortality independent of other prognostic factors. Non-survivors at 2 weeks EFA -0.17 log cfu/day vs -0.40 for survivors

6
Summary
2 week LP CSF or serum CrAg 2 week LP CSF or serum CrAg 2 week LP CSF or serum CrAg 2 week LP CSF or serum CrAg
Antinori 2005 Retrospective cohort n 66 8 (12) had increase in CSF CRAG and 5 (8). All but 2 had persistent ve cultures and died
Lu 2005 Retrospective cohort n 29 (HIV -ve) CSF CRAG persistence even with culture negative.
Powderly 1994 Prospective cohort in RCT n 281 Relapse was associated with CSF CRAG rise (43 vs. 5 in responders plt0.001). No relationship with serum CRAG
Aberg 2000 Retrospective cohort n 136 No association between change in serum CRAG and treatment response
7
In vitro susceptibility testing

• Dannaoui 2006 Primary resistance to first line
  antifungal drugs is uncommon and susceptibility
  testing is not relevant as it is not predictive
  of the clinical outcome at 2 weeks (N 74 only
  15 on Flu monotherapy).
• Murine models (Larsen 2005, Lortholary 1999)
  support not only the concept of in vivo and in
  vitro dose-response correspondence, but also that
  fungal burden influence the in vivo efficacy of
  Flu, a static agent.

8
Summary

• Quantitative cultures or EFA (CFU) are the most
  reliable way to assess mycological response
• CSF culture status after induction (2w) predicts
  outcome BUT not accessible in LRS
• Serum CrAg useful for diagnosis, but not
  monitoring
• Stability or rise in CSF CRAG predictive of
  treatment failure or relapse but not the converse
  ie. cannot be used as index of cure.
• No evidence for good corrrelation between in
  vitro drug susceptibility and clinical outcome

9
Recommendations to assess antifungal treatment
response (1)

• Assessment of treatment response relies on both
  clinical and mycological criteria.
• CSF culture conversion is the most reliable and
  objective gold standard measure of treatment
  response, but is not widely available in RLS, and
  results may take 1-2 weeks.
• India ink and serum CRAG titres are of limited
  value in monitoring response to antifungal
  therapy. A four fold rise in CSF CRAG titres has
  some correlation with initial treatment failure
  or relapse.
• Clinical response is an effective measure of
  global treatment response, but with limited
  sensitivity and specificity for fungal clearance.
  
• We recommend that all patients are monitored
  carefully for clinical response (resolution of
  fever, headache, signs of raised ICP) over the 2
  weeks of induction therapy, and for early signs
  of recurrence of symptoms or signs during
  consolidation and maintenance, especially if
  induction treatment was fluconazole monotherapy.

10
Recommendations to assess antifungal treatment
response (2)

• If evidence of a sustained clinical response, we
  do not recommend routine 2 week follow-up LP and
  measurement of opening pressure, and/or CSF
  fungal culture (if available) to assess the
  success of initial induction therapy, or to guide
  a switch to a consolidation regimen.
• If evidence of persistent or recurrent symptoms
  and signs at 2 weeks or during consolidation
  regimen
• We recommend a repeat LP and measurement of
  opening pressure, to help distinguish between
  raised ICP and treatment failure.
• In settings with additional access to fungal
  culture and drug susceptibility testing we
  recommend a repeat LP and measurement of opening
  pressure, with CSF culture (and fluconazole drug
  susceptibility testing if treated with
  fluconazole), to guide drug, dose and duration of
  induction and consolidation regimen. If culture
  positive - see PICOT 9 for recommendations on
  management.
• Pediatrics As for adults

11
Recommendations for monitoring raised ICP

• If initial LP opening pressure was normal (lt 20
  cm), and no symptoms of raised ICP and evidence
  of clinical response, we do not recommend routine
  follow-up LPs to monitor CSF pressure.
• The need for repeat therapeutic LPs to alleviate
  symptoms of raised intracranial pressure
  (headache, confusion, nausea and vomiting,
  altered level of consciousness, 6th cranial nerve
  palsy with diplopia and visual impairment,
  papillodema) should be dictated by persistence or
  recurrence of symptoms of raised intracranial
  pressure.
• Patients may require daily LPs.
• See PICOT x for management of raised ICP

12
Research Gaps

• What is value in continuing induction beyond 14
  days in patients who are still culture positive,
  and therefore monitoring CSF culture status at 2
  weeks?
• Is relationship between greater EFA and outcome
  linear, or is there a value of EFA above which
  one no longer confers additional benefit?
• How well does clinical symptomatology correlate
  with culture positivity. What is sensitivity and
  specificity of symptoms vs. culture.? ie what is
  added pick up of treatment failures with LP and
  CSF culture beyond clinical response?

13

• PICOT 8 What is optimal management of
  complications of raised intracranial pressure and
  cryptococcoma in Cryptococcal meningitis?

14
PICO 8 framework

• What is optimal management of complications of
  raised intracranial pressure and cryptococcoma in
  Cryptococcal meningitis?

P I C O
Adult and pediatric HIV-infected and HIV-uninfected patients undergoing intial or subsequent therapy for symptomatic cryptococcal meningitis Protocol-driven CSF reduction Adjunct ICP reduction (lumbar drain, VP shunt Steroid therapy Mannitol therapy Antifungal treatment intensification Symptomatic CSF reduction Mortality Decreased ICP Neurological deficit Serious adverse events
15
Searches
Search PubMed Strategy Result
4 Search((1) AND 2) AND 3. Limits Publication date from 1980/1/1 to 2011/09/15 768
3 (randomized controlled trialpt OR controlled clinical trialpt OR randomizedtw OR randomisedtw OR randomtw OR placebotw OR drug therapysh OR randomlytw OR trialtw OR RCTtw OR cohorttw OR cross sectionaltw OR cross-sectionaltw OR case controltw OR non-randomtw or nonrandomtw OR observationaltw OR odds ratiotw OR hazard ratiotw OR risk ratiotw OR rate ratiotw OR confidence intervaltw OR prospectivetw OR experimenttw) NOT (animalsmh NOT humansmh) 3464436
2 HIV InfectionsMeSH OR HIVMeSH OR hivtw OR hiv-1tw OR hiv-2tw OR hiv1tw OR hiv2tw OR hiv infecttw OR human immunodeficiency virustw OR human immunedeficiency virustw OR human immuno-deficiency virustw OR human immune-deficiency virustw OR ((human immun) AND (deficiency virustw)) OR acquired immunodeficiency syndrometw OR acquired immunedeficiency syndrometw OR acquired immuno-deficiency syndrometw OR acquired immune-deficiency syndrometw OR ((acquired immun) AND (deficiency syndrometw)) OR "sexually transmitted diseases, viral"MESHNoExp) 276647
1 Search Cryptococc meningitis (cryptococcaceaeAll Fields OR cryptococcaceesAll Fields OR cryptococcaemiaAll Fields OR cryptococcalAll Fields OR cryptococcalesAll Fields OR cryptococccosisAll Fields OR cryptococcemiaAll Fields OR cryptococcenAll Fields OR cryptococciAll Fields OR cryptococciaAll Fields OR cryptococcicAll Fields OR cryptococcicaAll Fields OR cryptococcidaeAll Fields OR cryptococcidalAll Fields OR cryptococcinAll Fields OR cryptococciqueAll Fields OR cryptococcisAll Fields OR cryptococcoAll Fields OR cryptococcoalAll Fields OR cryptococcocalAll Fields OR cryptococcoceaeAll Fields OR cryptococcociAll Fields OR cryptococcocidalAll Fields OR cryptococcocisAll Fields OR cryptococcocusAll Fields OR cryptococcoisisAll Fields OR cryptococcolAll Fields OR cryptococcomAll Fields OR cryptococcomaAll Fields OR.AND ("intracranial hypertension"MeSH Terms OR ("intracranial"All Fields AND "hypertension"All Fields) OR "intracranial hypertension"All Fields OR ("raised"All Fields AND "intracranial"All Fields AND "pressure"All Fields) OR "raised intracranial pressure"All Fields OR "spinal puncture"MeSH Terms OR ("spinal"All Fields AND "puncture"All Fields) OR "spinal puncture"All Fields OR ("lumbar"All Fields AND "puncture"All Fields) OR "lumbar puncture"All Fields) 21252

• (PICOT 8)
• Databases (01 Jan 1980 15 Sept 2011)
• PubMed
• Conference Abstracts (CROI, IAS, Crypto meeting)

Total of records 768
Records excluded 730
Full-text articles obtained 28
16
What do key Guidelines say?
IDSA 2010 Recommend daily lumbar punctures for initial management and until the opening pressure is stable
CDC 2009 Recommend daily lumbar punctures for initial management and until the opening pressure is stable
MSF 2006 No specific recommendation
South African guidelines 2007 No specific recommendation
European Mycoses Group 2008 No specific recommendation
Jackson review 2010 No specific recommendation
17
Summary of evidence
Newton 2001 RCT n22 Placebo-controlled trial of Acetazolamide for elevated ICP in CM terminated prematurely as high incidence of adverse events in the acetazolamide group.
Orem 2005 RCT n18 Compared serial LPs acetazolamide vs monitoring LP (on days 7,14, 70). Lower opening pressure in treatment arm (mean fall 53 vs 46mm CSF) , but no differences in mortality.
Graybill 2000 Cohort within RCT n41 of 110 10/41 gt35cm CSF treated with high-dose steroids 66 with successful clinical response vs. 86 in steroid non-recipients (p0.001)
In one case report, Dexamethasone is used with favourable results in C gatti CNS infection in non-immunocompromised patients with altered mental status. In one case report, Dexamethasone is used with favourable results in C gatti CNS infection in non-immunocompromised patients with altered mental status. In one case report, Dexamethasone is used with favourable results in C gatti CNS infection in non-immunocompromised patients with altered mental status. In one case report, Dexamethasone is used with favourable results in C gatti CNS infection in non-immunocompromised patients with altered mental status.
18
Summary of evidence
Graybill 2000, Bicanic 2009, Sun 2004, Andrade 2006 Observational n221 n163 n35 n34 Opening pressure decreased with serial lumbar punctures, with clinical improvement, however no significant difference in overall mortality
Shoham 2005 Observational n26 Lack of adherence to guidelines for raised intracranial pressure management was associated with worse neurological outcomes.
Six case reports (one in paediatric non-HIV patients) report successful use of devices (lumbar drain, reservoirs and VP shunts) in management of raised ICP in CM. Six case reports (one in paediatric non-HIV patients) report successful use of devices (lumbar drain, reservoirs and VP shunts) in management of raised ICP in CM. Six case reports (one in paediatric non-HIV patients) report successful use of devices (lumbar drain, reservoirs and VP shunts) in management of raised ICP in CM. Six case reports (one in paediatric non-HIV patients) report successful use of devices (lumbar drain, reservoirs and VP shunts) in management of raised ICP in CM.
19
Recommendations for control of CSF pressure

• Control of the CSF pressure is one of the most
  critical determinants of outcome for CM.
• In settings where an lumbar puncture is readily
  available, we recommend an initial LP, both for
  diagnosis and measurement of the opening
  pressure.
• We recommend that CSF opening pressure is
  measured with every LP that is performed.
• If the opening pressure is gt 25 cm CSF and
  symptoms (in the lateral recumbent position)
• We recommend in patients with raised ICP pressure
  and symptoms relieving pressure by drainage of a
  volume sufficient to reduce the CSF pressure to
  lt20 cm (or by 50 if it is very high), but no
  more than 30ccs on each occasion.
• In patients with persistent symptoms consistent
  with raised ICP, We recommend repeat daily or
  alternate daily LPs until symptoms have subsided
  for gt2 days, (or CSF pressure is consistently lt
  25 cm).
• We do not recommend the use of drugs (mannitol,
  acetozolamide, steroids) for management of raised
  ICP.
• With refractory raised ICP (where normal values
  are not achieved despite repeated LPs and optimal
  antifungal therapy), we recommend referral to or
  discussion with an experienced centre, where a
  temporary lumbar drain or ventriculoperitoneal
  shunt may be considered.

20
Recommendations Cerebral Cryptococcoma

• Induction option 1,2a or 2b for at least 6 weeks
  (differentiate from tuberculoma, toxo, lymphoma)
• Corticosteroids for mass effect and surrounding
  oedema. Consider CT in setting where available
  and focal neurology/SOL suspected.
• Move to PICOT 3 (Initial treatment)

21

• PICOT 9 What is the optimal approach to
  diagnosis and management of microbiological
  treatment failure or relapse?

22
PICOT 9 framework

• What is the optimal approach to diagnosis and
  management of microbiological treatment failure
  or relapse?

P I C O
Adult and paediatric HIV-infected and HIV-uninfected patients undergoing therapy for symptomatic cryptococcal meningitis or non-meningeal cryptococcal disease who have failed treatment or relapsed Amphotericin and fluconazole High dose oral fluconazole Symptomatic CSF reduction. Mortality Decreased ICP Neurological deficits Serious adverse events Duration of hospitalisation
23
Searches
Search PubMed Strategy Result
4 Search((1) AND 2) AND 3. Limits Publication date from 1980/1/1 to 2011/09/15 124
3 (randomized controlled trialpt OR controlled clinical trialpt OR randomizedtw OR randomisedtw OR randomtw OR placebotw OR drug therapysh OR randomlytw OR trialtw OR RCTtw OR cohorttw OR cross sectionaltw OR cross-sectionaltw OR case controltw OR non-randomtw or nonrandomtw OR observationaltw OR odds ratiotw OR hazard ratiotw OR risk ratiotw OR rate ratiotw OR confidence intervaltw OR prospectivetw OR experimenttw) NOT (animalsmh NOT humansmh) 3464436
2 HIV InfectionsMeSH OR HIVMeSH OR hivtw OR hiv-1tw OR hiv-2tw OR hiv1tw OR hiv2tw OR hiv infecttw OR human immunodeficiency virustw OR human immunedeficiency virustw OR human immuno-deficiency virustw OR human immune-deficiency virustw OR ((human immun) AND (deficiency virustw)) OR acquired immunodeficiency syndrometw OR acquired immunedeficiency syndrometw OR acquired immuno-deficiency syndrometw OR acquired immune-deficiency syndrometw OR ((acquired immun) AND (deficiency syndrometw)) OR "sexually transmitted diseases, viral"MESHNoExp) 276647
1 Search Cryptococc meningitis (cryptococcaceaeAll Fields OR cryptococcaceesAll Fields OR cryptococcaemiaAll Fields OR cryptococcalAll Fields OR cryptococcalesAll Fields OR cryptococccosisAll Fields OR cryptococcemiaAll Fields OR cryptococcenAll Fields OR cryptococciAll Fields OR cryptococciaAll Fields OR cryptococcicAll Fields OR cryptococcicaAll Fields OR cryptococcidaeAll Fields OR cryptococcidalAll Fields OR cryptococcinAll Fields OR cryptococciqueAll Fields OR cryptococcisAll Fields OR cryptococcoAll Fields OR cryptococcoalAll Fields OR cryptococcocalAll Fields OR cryptococcoceaeAll Fields OR cryptococcociAll Fields OR cryptococcocidalAll Fields OR cryptococcocisAll Fields OR cryptococcocusAll Fields OR cryptococcoisisAll Fields OR cryptococcolAll Fields OR cryptococcomAll Fields OR cryptococcomaAll Fields OR.AND antifungal agents"MeSH Terms OR ("antifungal"All Fields AND "agents"All Fields) OR "antifungal agents"All Fields OR "antifungal"All Fields OR "antifungal agents"Pharmacological Action) AND failureAll Fields) OR "recurrence"MeSH Terms OR "recurrence"All Fields OR "relapse"All Fields OR treatment failure"MeSH Terms OR ("treatment"All Fields AND "failure"All Fields) OR "treatment failure"All Fields 19456

• (PICOT 9)
• Databases (01 Jan 1980 15 Sept 2011)
• PubMed
• Conference Abstracts (CROI, IAS, Crypto meeting)

Total of records 124
Records excluded 106
Full-text articles obtained 15
24
Summary of evidence
Perfect 2003 Open label trial n 18 refractory 39 (7/18) efficacy (composite of clinical, mycological, radiological) of voriconazole (IV 4-6 mg/kg/day then oral 200mg bid or 400mg bid loading)
Pitisuttihum2005 Open label clinical trial n 29 refractory CM Posaconazole 800mg/day for 1 year. Clinical success in 14 (48).
Bicanic 2006 Observational n 27 (32 episodes) relapse CM treated with fluc 76 of relapses associated with fluconazole resistance.
25
What do key Guidelines say? (Persistence)
IDSA 2010 (persistence) Check mesures to improve immune status Reinstitute induction phase Consider increasing AmB dose up to 1mg/kg/d Ideally, check for MIC change (gt3-dilution suggests drug resistance)
CDC 2009 (failure) Start treatment with AmB /- 5FC until clinical response
MSF 2006 No specific recommendation
South African guidelines 2007 No specific recommendation
European Mycoses Group 2008 No specific recommendation
Jackson review 2010 No specific recommendation
26
What do key Guidelines say? Relapse
IDSA 2010 (relapse) Restart induction phase Determine susceptibility of the relapse isolate After induction, consider salvage with flu or one of the newer azoles
CDC 2009 No specific recommendation
MSF 2006 No specific recommendation
South African guidelines 2007 No specific recommendation
European Mycoses Group 2008 No specific recommendation
Jackson review 2010 No specific recommendation
27
Recommendations Definitions of Persistent and
relapsed infection

• We recommend the following diagnostic criteria
  for persistent or relapsed infection
• Persistent infection
• Lack of clinical improvement after two weeks (?
  or Persistent symptoms after 4 weeks) of
• appropriate antifungal therapy at an effective
  dose,
• appropriate management of raised ICP
• exclusion of raised ICP or IRIS
• positive CSF culture.
• Relapsed or recurrent infection
• Re-appearance of signs or symptoms after previous
  full resolution following treatment of initial
  episode.
• A definitive diagnosis of relapse can only be
  made on the basis of a positive culture after a
  previously negative one (if available).
• Positive India ink, and abnormal CSF microscopy
  are insufficient to diagnose a microbiological
  relapse

28
Recommendations

• We recommend the following diagnostic steps
• An LP with measurement of opening pressure and
  CSF examination and culture in all patients with
  suspected persistent or relapsed CM, to confirm
  diagnosis, exclude other causes of deterioation
  or meningitis, (and obtain isolate for
  fluconazole susceptibility testing).
• Establish potential reasons for persistence or
  relapse (inadequate initial induction,
  consolidation or maintenance therapy (drug, dose
  and/or duration) failure of adherence to
  treatment regimen azole resistance drug
  interaction or IRIS.
• Referral to a centre with access to both AmB and
  minimum toxicity management and monitoring, and
  access to fungal culture susceptibility
  testing.

29
Recommendations 1

• We recommend the following treatment/management
  steps for suspected persistent/relapse infection
• If received AmB (option 1,2a,2b), Restart
  induction treatment with AmB and either
  Flucytosine or Fluconazole, and/or for a longer
  duration of 4-10 weeks, or until CSF
  sterilization/clinical improvement is achieved.
• If received Fluconazole therapy (option 3), then
  induction treatment with AmB regimen. Fluconazole
  monotherapy is not recommended in patients with
  persistent or relapsed infection, unless previous
  fluconazole was at low dose (less than 800mg per
  day). Then if only options, 1200mg fluconazole
  for at least four weeks. Dose adjustment required
  with nevirapine.

30
Recommendations 2

• We recommend the following treatment/management
  steps
• Address contributory factors such as compliance
  or drug interactions
• Therapy with newer azoles such as voriconazole or
  posaconazole, liposomal amphotericin, may be
  considered, if available, for those who can not
  tolerate AmB or have refractory infection.
• Initiation of first or second line ART after two
  weeks of optimal antifungal therapy, if evidence
  of ART treatment failure.

31
Research Gaps

• Comparative trials of salvage therapy in patients
  with persitent or relapsed infection.
• Data on use of newer azoles (voriconazole or
  posaconazole) for those who can not tolerate AmB
  or have refractory infection.
• Optimal timing of first or second line ART for
  salvage antifungal therapy.

32

• PICO 10 What is the optimal management of
  Cryptococcal meningitis IRIS?

33
PICO 10 framework

• PICO 10 What is the optimal approach to
  diagnosis and management of Cryptococcal
  meningitis IRIS?

P I C O
Adult and paediatric HIV-infected patients undergoing therapy for cryptococcal meningitis with increased ICP and immune reconstitution syndrome Protocol-driven CSF reduction Adjunct ICP reduction (lumbar drain, VP, shunt) Steroid therapy Mannitol therapy Antifungal treatment intensification Symptomatic CSF reduction Mortality Decreased ICP Neurological deficits Serious adverse events
34
Searches
Search PubMed Strategy Result
4 Search((1) AND 2) AND 3. Limits Publication date from 1980/1/1 to 2011/09/15 254
3 (randomized controlled trialpt OR controlled clinical trialpt OR randomizedtw OR randomisedtw OR randomtw OR placebotw OR drug therapysh OR randomlytw OR trialtw OR RCTtw OR cohorttw OR cross sectionaltw OR cross-sectionaltw OR case controltw OR non-randomtw or nonrandomtw OR observationaltw OR odds ratiotw OR hazard ratiotw OR risk ratiotw OR rate ratiotw OR confidence intervaltw OR prospectivetw OR experimenttw) NOT (animalsmh NOT humansmh) 3464436
2 HIV InfectionsMeSH OR HIVMeSH OR hivtw OR hiv-1tw OR hiv-2tw OR hiv1tw OR hiv2tw OR hiv infecttw OR human immunodeficiency virustw OR human immunedeficiency virustw OR human immuno-deficiency virustw OR human immune-deficiency virustw OR ((human immun) AND (deficiency virustw)) OR acquired immunodeficiency syndrometw OR acquired immunedeficiency syndrometw OR acquired immuno-deficiency syndrometw OR acquired immune-deficiency syndrometw OR ((acquired immun) AND (deficiency syndrometw)) OR "sexually transmitted diseases, viral"MESHNoExp) 276647
1 Search Cryptococc meningitis (cryptococcaceaeAll Fields OR cryptococcaceesAll Fields OR cryptococcaemiaAll Fields OR cryptococcalAll Fields OR cryptococcalesAll Fields OR cryptococccosisAll Fields OR cryptococcemiaAll Fields OR cryptococcenAll Fields OR cryptococciAll Fields OR cryptococciaAll Fields OR cryptococcicAll Fields OR cryptococcicaAll Fields OR cryptococcidaeAll Fields OR cryptococcidalAll Fields OR cryptococcinAll Fields OR cryptococciqueAll Fields OR cryptococcisAll Fields OR cryptococcoAll Fields OR cryptococcoalAll Fields OR cryptococcocalAll Fields OR cryptococcoceaeAll Fields OR cryptococcociAll Fields OR cryptococcocidalAll Fields OR cryptococcocisAll Fields OR cryptococcocusAll Fields OR cryptococcoisisAll Fields OR cryptococcolAll Fields OR cryptococcomAll Fields OR cryptococcomaAll Fields OR.AND "immune reconstitution inflammatory syndrome"MeSH Terms OR ("immune"All Fields AND "reconstitution"All Fields AND "inflammatory"All Fields AND "syndrome"All Fields) OR "immune reconstitution inflammatory syndrome"All Fields) OR "iris"MeSH Terms OR "iris"All Fields) AND ("therapy"Subheading OR "therapy"All Fields OR "treatment"All Fields OR "therapeutics"MeSH Terms OR "therapeutics"All Fields) 148

• (PICOT 10)
• Databases (01 Jan 1980 15 Sept 2011)
• PubMed
• Conference Abstracts (CROI, IAS, Crypto meeting)

Total of records 254
Records excluded 210
Full-text articles obtained 32
35
Proposed case definition for Cryptooccal
paradoxical IRIS in HIV
36
Proposed case definition for Cryptococcal
ARV-related or unmasking IRIS in HIV
37
Recommendations

• We recommend the following steps
• LP to exclude other pathology, to measure ICP
• We recommend against discontinuation of ART with
  paradoxical or unmasking IRIS.
• Initiation or continuation of appropriate
  antifungal therapy as for PICOT 3.
• No specific treatment recommendations for minor
  IRIS manifestations, as self-limiting in days or
  weeks
• For major complications, such as raised ICP,
  which fail to respond to usual management,
  consider short course oral steroid therapy with
  prednisolone 1 mg/kg/day or dexamethasone for at
  least one week with tapering over 2-6 weeks.
• No specific recommendation can be given for use
  of NSAIDs or thalidomide.

38
Research Gaps

1. RCT for different management options