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HIV

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Anti HIV effect of malarial drugs. In-vitro. CLQ and hydroxyCLQ exert modest antiHIV effect ... drug penetration (breast milk, genital tract, etc) ... – PowerPoint PPT presentation

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Title: HIV


1
HIV Malaria Interactions Drug therapy
S. H. Khoo University of Liverpool
2
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

3
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

4
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

5
Leading Causes of Death (aged 25-44 ) USA,
1982-1998
National Center for Health Statistics National
Vital Statistics System
6
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 ?

7
Durability of HAART
Remaining on HAART
Proportion of Patients
8
HIV treatment failure
  • Host
  • adherence
  • PK variability
  • Drug
  • inadequate
  • potency
  • sanctuary sites
  • Virus
  • resistance

9
How much adherence is enough ?
Paterson 2000
10
PK of ARVs
  • Large intra-individual variability
  • Significant proportion of individuals with low /
    high levels

11
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 ?

12
Drug Metabolizing Enzymes
  • Extended known polymorphisms that affect
    activity.
  • Polymorphisms present in all (?) enzymes.

Wilson et al. Nature Genetics 29265, 2001.
13
STOP Study
14
STOP Study
15
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

16
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
17
How Common is Resistance ?
18
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)

19
PI resistance as a function of adherence
20
Adherence - resistance relationship
Risk of resistance
20 40 60 80 100
Adherence ()
Bangsberg, Moss Deeks. JAC 2004
21
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

22
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23
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24
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

25
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
    ?)

26
Missing drug doses with different half lives
Day 1
Day 2
Drug concentration
IC90
Mut IC90
Zone of potential replication
IC50
WT IC50
12
0
24
48
36
Time (hours)
27
Inadequate drug levels may result in resistance
Drug level
Periodically inadequate drug levels
Mutant selected with reduced susceptibility
Rebound with highly resistant organism
28
Overlapping Syndromes
29
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

30
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