HIV

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HIV Malaria Interactions Drug therapy
S. H. Khoo University of Liverpool
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Menu

• Anti-retroviral therapy
• HIV treatment failure
• pharmacology of HIV therapy
• Interactions with anti-malaria therapy
• pharmacokinetic interactions
• pharmacodynamic interactions
• direct disease interactions
• anti-viral effects of malaria drugs
• anti-malarial effects of HIV drugs
• co-trimoxazole
• overlapping syndromes

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Anti-retroviral therapy

• NRTI NNRTI PI
• zidovudine nevirapine saquinavir
• lamivudine efavirenz ritonavir
• didanosine delavirdine indinavir
• zalcitabine nelfinavir
• stavudine lopinavir
• abacavir amprenavir
• emtricitabine atazanavir
• tenofovir
• ART 2 NA PI, or
• 2 NA NNRTI or
• other combinations

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Anti-retroviral therapy

• NRTI NNRTI PI
• zidovudine nevirapine saquinavir
• lamivudine efavirenz ritonavir
• didanosine delavirdine indinavir
• zalcitabine nelfinavir
• stavudine lopinavir
• abacavir amprenavir
• emtricitabine atazanavir
• tenofovir
• rash, n v rash, n v rash, n v
• neuropathy p450 / p450
• mitochondrial ? lipids
• toxicity ? glucose
• lipodystrophy

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Leading Causes of Death (aged 25-44 ) USA,
1982-1998
National Center for Health Statistics National
Vital Statistics System
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Specific prescribing issues in developing
countries

• Effect of gender, body weight, ethnicity
• Interactions with TB medications, traditional
  medications, etc
• Need to be dosed with food
• Fixed dose combinations
• Drug quality
• Shelf life storage
• monitoring
• Second line role of protease inhibitors ?

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Durability of HAART
Remaining on HAART
Proportion of Patients
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HIV treatment failure

• Host
• adherence
• PK variability

• Drug
• inadequate
• potency
• sanctuary sites

• Virus
• resistance

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How much adherence is enough ?
Paterson 2000
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PK of ARVs

• Large intra-individual variability
• Significant proportion of individuals with low /
  high levels

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PK of ARVs

• Effect of ethnicity, gender and body weight
• Ethnicity
• ?EFV in Africans (? 2B6 polymorphism)
• (?) NVP in Africans
• ? IDV peaks in Thais
• Different toxicity profile
• (lipo, hypersensitivity, hepatitis)
• Gender
• ? Levels in women (NVP/ EFV/ ?LPV)
• ? ZDV/3TC triphosphates in women
• Body weight
• Differences for Pis NNRTIs ?

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Drug Metabolizing Enzymes

• Extended known polymorphisms that affect
  activity.
• Polymorphisms present in all (?) enzymes.

Wilson et al. Nature Genetics 29265, 2001.
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STOP Study
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STOP Study
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STOP Study

• Of 10 patients stopping therapy
• 5 had EFV T½ 40-50 h
• 5 had EFV T½ 100 h
• 4 / 5 Black African women
• 3 had EFV levels in the therapeutic range at 2
  w

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HIV drugs must ...

• suppress viral replication completely
• penetrate all reservoirs in sufficient
• concentrations

Sanctuary
Blood
Drug
failure to do so will establish a sanctuary
site
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How Common is Resistance ?
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Does low adherence lead to resistance ?

• Paradoxes
• Very non-adherent patients fail with WT virus

• Highly adherent patients on PIs fail with
  resistance
• SF (n 148) Bangsberg et al. AIDS
  2003171925-32
• CCTG (n 205) Miller et al. Antiviral Ther
  20038S167
• London Walsh et al. J AIDS 200230278-87
• Vancouver (n 1219) Harrigan et al. 2nd IAS
  Paris 2003 LB12
• M98-863 (n 653) King et al. Antiviral Ther
  20038S118

• Very non-adherent patients on NNRTIs fail with
  resistance
• Single dose perinatal NVP studies e.g. HIVNET
  012
• Dybul et al. JID 2003188388-96
• Sethi et al. CID 2003371112-18
• Parienti et al. CID 2004 (in press)

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PI resistance as a function of adherence
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Adherence - resistance relationship
Risk of resistance
20 40 60 80 100
Adherence ()
Bangsberg, Moss Deeks. JAC 2004
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Menu

• Anti-retroviral therapy
• HIV treatment failure
• pharmacology of HIV therapy
• Interactions with anti-malaria therapy
• pharmacokinetic interactions
• pharmacodynamic interactions
• direct disease interactions
• anti-viral effects of malaria drugs
• anti-malarial effects of HIV drugs
• co-trimoxazole
• overlapping syndromes

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Anti HIV effect of malarial drugs

• In-vitro
• CLQ and hydroxyCLQ exert modest antiHIV effect
• some additivity with ZDV or ddI /- HU
• Sperber 1993, Boelart 2001
• Liverpool data suggest these effects are modest

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Anti HIV effect of malarial drugs

• In-vivo
• n38 randomised to HCQ/placebo (8w)
• (? HIV by culture but variability in
  methodology)
• Sperber 1995
• n72 randomised to HCQ/ZDV (16w)
• (? HIV VL 0.4 vs 0.6 log)
• Sperber 1997
• n22 open label HCQ ddI HU (48w)
• (? HIV VL 1.3 log at 48w but no control)
• Paton 2002
• Role of CLQ in the ART era ? (specific scenarios
  ?)

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Missing drug doses with different half lives
Day 1
Day 2
Drug concentration
IC90
Mut IC90
Zone of potential replication
IC50
WT IC50
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0
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48
36
Time (hours)
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Inadequate drug levels may result in resistance
Drug level
Periodically inadequate drug levels
Mutant selected with reduced susceptibility
Rebound with highly resistant organism
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Overlapping Syndromes
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Conclusions

• Large gaps in knowledge
• gender, ethnicity, body weight
• drug penetration (breast milk, genital tract,
  etc)
• interactions (quinine, artemether,
  lumefantrine)
• Co-trimoxazole
• Shared problems of adherence and resistance
• ? sharing of strategies
• and surveillance programmes
• Shared problems of ensuring drug quality
• Urgent need for disseminating prescribing
  knowledge

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