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Drug-Drug Interactions and the Pharmacotherapy of HIV Infect.ppt
1. Case Study #1
• 42 yo HIV(+) AA female, initiated EFV + 3TC +
TDF
• VL decreased from 120,000 to < 50 c/mL after 3
months
• Week 2: Complained of dizziness, insomnia,
impaired concentration. At Month 3, 6, and 12,
problems have subsided to a degree but remain
a significant concern
• Decided to switch to ATV/r + TDF/FTC
• After 1 month, CNS symptoms have resolved,
but VL increased from < 50 to 60,000 copies/mL
2. Case Study #1 (cont)
• What are the possible causes of virologic
failure in this individual?
– Adherence
– Virologic
– Pharmacokinetic
• Residual induction effect of efavirenz
• Drug-drug interaction with atazanavir and tenofovir
3. Efavirenz Concentrations and
Polymorphisms in CYP2B6
Haas DW, et al. AIDS. 2004;18:2391-2400.
All Subjects European
Americans
African
Americans
250
200
150
100
50
0
GG GT TT GG GT TT GG GT TT
CYP2B6 G516T genotype
Efavirenz
AUC
0-24hr
(g
x
hr/mL)
4. CYP2B6 516G>T and Predicted
Post-D/C Plasma EFV
Concentrations
Ribaudo HJ, et al. Submitted.
Each panel shows predicted post-
discontinuation EFV concentrations
Panel A: Subjects with GG at
CYP2B6 position 516;
median t1/2 = 23 hr (IQR, 18-35 hr)
Panel B: Subjects with GT at
CYP2B6 position 516;
median t1/2 = 27 hr (IQR, 19-31 hr)
Panel C: Subjects with TT at
CYP2B6 position 516;
median t1/2 = 48 hr (IQR, 38-77 hr)
n = 78
Days since last dose
Days since last dose
Days since last dose
0 3 6 9 12 15 18 21 24 27
10,000
1000
100
10
A
B
C
10,000
1000
100
10
10,000
1000
100
10
n = 60
n = 14
0 3 6 9 12 15 18 21 24 27
0 3 6 9 12 15 18 21 24 27
EFV
(ng/mL)
EFV
(ng/mL)
EFV
(ng/mL)
5. Case Study #3
• 35 yo Caribbean male admitted to isolation ward with
3-wk history of productive cough and fever. Chest x-ray
shows large left upper lobe infiltrate; acid-fast smear of
the sputum is positive
• Patient was working construction in the US and staying
with relatives; plans to return home ASAP
• Consumes alcohol regularly but denies IDU. Sexually
active. Takes no prescription medications.
• Evaluation: oral thrush; left upper lobe consolidation;
HIV(+) with CD4 23, VL 216,000
6. Case Study #3 (cont)
• TB therapy initiated (rifampin, isoniazid, pyrazinamide
and ethambutol). After 2 wks, sputum is negative for
mycobacteria. Fevers resolved and oral candidiasis
responded to topical nystatin
• Plans made for discharge with continued TB therapy;
patient is anxious to start HIV therapy
• Would you:
– Avoid ARV therapy until 6 months of TB therapy is complete
– Start ARV therapy with ATV/r 300/100 mg QD, and TDF 300 mg,
and FTC 200 mg QD
– Start EFV 600 mg QD + TDF 300 mg, and FTC 200 mg QD
7. Case Study #3 (cont)
• Decision made to start therapy with EFV +
TDF/FTC. Upon checking the DHHS
guidelines, you learn that rifampin lowers
the AUC of efavirenz by 25%
• Would you:
– Increase the dose of efavirenz to 800 mg/day
– Maintain the dose of efavirenz at 600 mg/day
8. Efavirenz and Rifampin - 1
• Rifampin lowers the AUC of efavirenz by 25%.
• Longitudinal cohort study (n = 255) in India found no
difference in CD4+ cell response at 9 months in
HIV(+)TB cohort who received EFV 600 mg/day with RIF
vs HIV cohort who received EFV[1]
• 84 Thai HIV/TB coinfected patients receiving RIF
randomized to EFV 600 vs 800 mg/d plus d4T and 3TC[2]
– No difference in CD4 and TB cure rate with 38 wks of follow-up
– No difference in EFV conc: 3.02 vs 3.39 mg/L
– No difference in % with EFV conc < 1 mg/L: 8% vs 0%
– Mean body weight, ≈ 50 kg
1. Patel A, et al. J AIDS. 2004;37:1166-1169.
2. Manosuthi W, et al. IAC 2004. Abstract MoOrB1013.
9. Efavirenz and Rifampin -2
• A survey of the Liverpool TDM database
examined 111 pts receiving EFV (600 or 800
mg) with RIF vs 360 pts only receiving EFV[1]
– Overall, no difference in EFV conc observed:
median values 2.7 mg/L and 2.6 mg/L for 600 and
800 mg, respectively
– Patients < 60 kg had higher EFV conc (> 4 mg/L)
– Proportion of patients with EFV conc outside of 1-
4 mg/L range same with both doses
– Data indicate the efavirenz-rifampin interaction in
individual patients is highly variable[2]
1. Almond L, et al. Clin Pharm Workshop 2005. Abstract 19.
2. Friedland G, et al. CROI 2005. Abstract 891.
10. EFV and RIF – Author’s Suggestions
for Patient Management
• If < 60 kg, standard EFV dose may be adequate
• If on RIF therapy:
– Consider an empiric EFV dose increase to 800 mg/day
• If on EFV, and RIF-based TB therapy to be added:
– Consider an empiric EFV dose increase to 800 mg/d
• Monitor for EFV tolerance, primarily CNS symptoms:
– If tolerance acceptable, continue 800 mg/day
– If tolerance unacceptable after 2-4 wks, decrease to 600 mg/day
• Monitor as appropriate for HIV and TB response
11. Summary
• Not all drug-drug interactions can be predicted
• Clinical significance cannot be excluded simply
on the basis of magnitude of change in concs
• Knowledge of drug concentrations will contribute
to an understanding of the overall effects of an
antiretroviral regimen
• Pharmacologic characteristics of combination
antiretroviral regimens need to be sufficiently
understood prior to use in HIV-infected pts