Workshop HIV

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Workshop HIV co-infection

• Dr.K.Torpey Director of Family Health
  Int,Lusaka, Zambia
• Dr. M. Siwale Pediatrician, Lusaka Trust
  Hospital, Lusaka, Zambia
• Dr. S.Geelen Pediatric Infect Dis,
  CCPD/PharmAccess Foundation, Amsterdam Univ Med
  Center Utrecht, The Netherlands

The sponsors disclaim any liability for the
content of the presentation.
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• CASE Mister F

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Case Mr F

• 18 year-old-man
• complains about headache for the past few weeks
• mild fever
• vomits now and then
• Tested for HIV last week positive
• Has panicked, and thinks he will die

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Case Mr F

• Physical examination
• Young man in good physical health
• Mild neck stiffness

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Lab

• Hb 8.0 g/dL
• WBC 5.4 x 103/microl
• Liver function normal
• CD4 cells 43/mm3

What is your differential diagnosis? Additional
tests?
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Differential Diagnosis

• CNS infection Cryptococcal meningitis
  Bacterial meningitis Tuberculous meningitis
  Toxoplasmosis Other
• Other CNS abnormality Malignancy Vascular
  event

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• Cerebrospinal fluid
• White cells 43, 90 lymphocytes
• Protein 71 mg/dL
• Indian ink positive

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• Diagnosis
• Cryptococcal meningitis
• HIV WHO stage 4

• Treatment plan?
• For OI and HIV?

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Cryptococcal meningitis

• 5-8 of patients in US W-Europe
• Frequency higher in resource limited settings,
  reason unclear
• Most frequent cause of meningitis in patients
  with HIV
• Particularly if CD4 lt 100/mm3

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Cryptococcal meningitis

• Subacute course
• fever, headache, fatigue
• mental changes
• visual changes
• seizures
• Physical examination
• fever
• variable signs of meningismus and obtundation

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Cryptococcal meningitis

• CSF
• Increased intracranial pressure is common
• Usually mild pleiocytosis, mainly lymphocytes
• Increased protein
• Indian ink sensitivity 60-80
• Cryptococcal Antigen test sensitivity gt 95

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Mr F receives

• Fluconazole IV 800mg/day for 2 weeks
• Followed by oral 400mg/day for 8 weeks
• At the end of the treatment, Indian ink is
  negative
• Secondary prophylaxis oral fluconazole 200mg/day
• Is this therapy a good choice?

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Treatment Cryptococcal Meningitis

• 3 phases
• Induction 2 weeks, consolidation 6-8 weeks,
  maintenance (for life but if on ARV until CD4
  gt100-200 for 6 months)
• Most effective Amphotericin B ( 5
  Flucytosine)Alternative Fluconazole
• Lumbar taps if elevated intracranial pressure
• (gt 20 cm) (usually remove 20ml/session)
• Consider medical treatment for increased
  intracranial pressure if Lumbar puncture
  contraindicated (dexamethason plus mannitol).

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After 6 weeks Mr F starts HAARTd4T, 3TC and
NVPTiming and regimen OK?
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• Best time to start HAART in patient with advanced
  immunodeficiency and cryptococcal meningitis is
  not known
• First treat OI
• Need for delay in initiating HAART after
  diagnosis and treatment of cryptococcosis?

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• Follow-up 2 weeks later
• Good clinical condition, no complaints
• ALT 101 U/ml (nlt50)
• Cause?
• Strategy?

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• Cause increased ALAT?
• Drug-related?most likely candidates
  nevirapine fluconazole
• Other (e.g infection)

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• You decide to switch to efavirenz
• Is this a good choice?

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• Two weeks later Mr F is admitted with mild fever
  and a cranial nerve paralysis
• What is your differential diagnosis?
• What will be your strategy?

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Diagnostic problem

• Relapse of cryptococcal meningitis?
• IRIS?
• New OI?
• Vascular event?
• Other?

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Therapeutic dilemma

• Stop or continue HAART?
• Stop or change OI therapy?
• Add immunosuppressive or anti-inflammatory
  drugs?

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Follow-up Case Mr F

• CSF high pressure (28 cm), no cryptococci
  detected
• IRIS?
• Treatment
• restart high dose fluconazole
• continuation of HAART
• steroids???

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Cryptococcal IRIS

• Usually CNS diseaseSometimes other
  manifestations
• Can be severe

Lortholary AIDS 2005, Shelburne CID 2005
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• CASE Mister K

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CASE Mr K

• 27 years old
• Born in Gabon
• Herpes Zoster 1 year ago
• Current complaint fatigue, weight loss, bouts
  of fever for the last few months

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• Physical examination
• Patient appears ill, T 39C
• Weight 42 kg, height 175 cm
• Scars of thoracic herpes zoster
• Heart lungs normal
• Abdominal examination normal

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• What laboratory tests will you request?

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• Lab
• Hb 9.0 g/dL, WBC 6.2 x 109/ml, platelets 256 x
  109/ml
• HIV rapid test positive
• CD4 185/mm3
• Chest X ray to follow

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Your differential diagnosis?
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Differential diagnosis

• Infection
• - M tuberculosis
• - Other infection causing lymphadenopathy
• Malignancy
• - Lymphoma
• - Kaposis sarcoma

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Your treatment strategy?

• In case of sputum smear
• Positive for acid fast bacilli
• Negative for acid fast bacilli

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How to exclude TB before starting ARV?

• Be aware in patients with chronic fever, cough,
  lymphadenopathies, weight loss, and Hb lt 8 g/dL
• Chest X-ray, AFB sputum
• Do not delay starting ARV if nothing found, but
  do very close clinical monitoring

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Treatment plan

• Patient has positive sputum smears
• Start TB treatment
• Start Cotrimoxazol prophylaxis
• HAART
• when to start?
• which regimen?

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HIV TB

• Optimal time to start HAART in patients treated
  for TB unknown
• Balance between risk of progression versus
• intolerance of regimen
• difficulty to adhere
• drug-drug interactions

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When to start HAART in TB patients

• Options
• start HAART and TB treatment together
• start HAART after acute, rifampicine containing
  phase e.g. 2 months
• start HAART after the end of TB treatment
• Remember
• HAART initiation is not an emergency

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TB when to start?

• Treat TB and follow-up
• Treat TB, after two months consider HAART
• Treat TB and start HAART after 2 weeks - 2 months

• CD4 gt 350 ?
• CD4 200-350 ?
• CD4 lt 200 ?

Remember Timing of HAART should be based on
clinical judgement. For extrapulmonary TB ASAP
WHO 2005
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Case Mr K contd

• Patient starts TB treatment
• How long will you continue TB-treatment in this
  patient?

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Case Mr K after 4 weeks TB treatment

• Improved clinical condition
• No fever
• Weight 1.5 kg
• Who would start and who would wait?
• What regimen would you choose?

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Case Mr K

• You decide to start HAART
• AZT 300 mg twice daily
• 3TC 150 mg twice daily
• Efavirenz 800 mg once daily
• Do you agree with this choice?

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Dose of Efavirenz (EFV) in case of
co-administration with rifampicin

• Rifampicin decreases level of EFV by 25
• Optimal dose of EFV not really known ?
• Best strategy still unknown
• Some advise to increase EFV does to 800 mg in
  patients gt 50 kg
• Others use regular dose EFV 600 mg

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• What if TB develops in a patient under HAART?
• Adapt HAART as necessary to avoid drug
  interactions

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Case Mr K contd

• After 2 months fever returns
• What is your differential diagnosis and what
  would you do?

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Causes of clinical worsening during TB treatment
and HAART

• Most likely
• Immune response inflammatory syndrome?
  (paradoxical reactions )
• Be aware of
• Drug-resistant TB
• Other (opportunistic) infections
• Adherence
• Drug interactions

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IRIS in TB HIV co-infection

• Mean onset of symptoms is 2 weeks
• Mean duration of symptoms is 3 weeks
• Most common symptoms include
• fever
• cervical lymphadenopathy
• intrathoracic lymphadenopathy
• Other manifstations have included
• focal cerebritis
• pulmonary disease / pleural effusions
• hepatospenomegaly

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TB HIV IRIS management

• No evidence based guidelines available yet
• Continue HAART if tolerated (but may need to
  stop if very severe!)
• Switch regimen if needed
• Continue TB medication
• Non-steroidal anti-inflammatory agents may help
• Add steroids if needed
• especially in case of severe dyspnea, TB
  meningitis
• high dose prednisone (1 mg/kg for 1-2 weeks,
  followed by tapering doses)

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Case Mr K contd

• Good adherence
• Other opportunistic infections not likely
• Symptomatic treatment
• Continuation of all medications
• Resolution of fevers and adenopathy in 3 weeks

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Case Mr G
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Case Mr G

• Male 24 years
• HIV infected, diagnosed 5 years ago,
• Medical history 
• Recurrent oral candidiasis
• TB (treatment completed)
• Currently ARV naive
• Physical examination ? No abnormalities

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Case Mr G

• Decreasing CD4
• Recent value 180/mm3 ? indication HAART
• Basic laboratory evaluation
• Full blood count normal
• Creatinin normal
• Liver ALT 125 U/l

Conclusion?
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Hepatitis?Possible causes?
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Hepatitis

• Infection (HBV, HCV, opportunistic infection)
• Drug toxicity
• Alcohol
• Steatosis
• Auto-immune
• Malignancy
• Other

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• Which additional diagnostic investigations are
  available in your setting to evaluate further
  the cause of the hepatitis?

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Parameters used to assess liver damage

• ALT
• Hepatitis serology
• Liver histology
• In resource rich settings also HBV and HCV-PCR

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Patient Mr G Hepatitis serology

• Hepatitis B

Hepatitis A IgG positive Hepatitis C IgG
negative
Conclusion?
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Conclusion

• HIV and HBV co-infection
• Possible chronic active hepatitis

Patient refuses liver biopsy HBV-DNA-PCR not
available
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• Consequences of HIV HB co-infection?

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Hepatitis B HIV co-infection

• In HIV-infected person ?
• Increased risk of chronicity after HBV exposure
• Enhanced HBV replication levels may result in
  progression of more severe liver fibrosis
• Increased risk of HBV-associated end-stage liver
  disease if chronic HBV infection is present

Soriano et al, AIDS 2005, p 221
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Prevention

• If the individual has been at risk for Hepatitis
  B infection, which is the case for many
  HIV-infected patients, then HBV serologic status
  should be determined
• Those who are seronegative should be offered
  immunization.

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Case Mr G contd
Your treatment strategy?
Remember HAART was indicated in this patient
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If possible choose regimen with agents active
against both infections

• Which antiviral agents are active against both
  HIV and HBV?

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Agents with anti-HIV plus anti-HBV activity

• Nucleoside analogues
• Lamivudine 300 mg a dayEmtricitabine 200 mg a
  day
• Lamivudine and emtricitabine are
  interchangeable, not additive because of low
  genetic barrier for HIV resistance
• Nucleotide analoguesTenofovir 300 mg a day

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HIV-HBV co-infection and HAART indicated
Preferred combination (if available) Tenofovir
Lamivudine 3rd antiretroviral
agent or Tenofovir Emtricitabine 3rd
antiretroviral agent
Soriano et al, AIDS 2005, p 221
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HIV-HBV co-infectionHAART not yet indicated

• Best strategy not really known
• Consider anti-HBV therapy if evidence of liver
  disease
• In resource rich settings agents with activity
  against HBV but not against HIV are used (e.g.
  interferon)
• If no specific anti-HBV agents are
  availablechoose between watchful waiting
  strategyorconsider initiating HAART with agents
  active against HIV plus HBV

Soriano et al, AIDS 2005, p 221
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Caution

• Do not use lamivudine or emtricitabine
  monotherapy
• ?
• HIV resistance mutations will be selected rapidly
• HBV resistance mutations will also be selected,
  albeit more slowly

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Is hepatoxicity of HAART a problem in
HIV-HBV-co-infected patients?
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Hepatotoxicity of HAART in HIV-HBV co-infected
patients

• Liver enzyme elevations after initiation of
  HAART are more frequent in patients with chronic
  hepatitis B infection

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Hepatotoxicity of HAART

• Significant hepatoxicity occurs in 5-10
• of HIV-positive individuals initiating HAART
• Causes of hepatoxicity may differ
• Direct injury from prescribed drugs
• Immune reconstitution phenonema
• Allergy/hypersensitivity

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Hepatotoxicity of HAART in HIV-HBV co-infected
patients

• Use drugs with more hepatotoxic profiles with
  caution e.g.
• Nevirapine
• Efavirenz
• Full-dose ritonavir

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Whether to continue or discontinue drugs depends
on most likely cause

• Direct toxicity - antiretroviral drug suspected ?
  discontinue suspected drug
• Immune reconstitution most likely ? continue as
  long as patient remains asymptomatic and
  transaminase levels do not rise above 10 times
  the upper limit of normal (grade 4 toxicity)
• Hypersensitivity suspected ? liver enzyme
  elevations often seen in context of a more
  generalized reaction ? discontinue suspected drug
  e.g. nevirapine, abacavir

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Remember

• Carefully choose
• When to start anti-HIV and/or anti-HBV therapy
• Which drugs to use
• Carefully monitor for hepatotoxic side effects