Transcript Clinical Significance of HIV-1 Drug Resistance

Clinical Significance of HIV-1
Drug Resistance
Daniel R. Kuritzkes, MD
Section of Retroviral Therapeutics
Brigham and Women’s Hospital
Harvard Medical School
Consequences of ongoing
viral replication during HAART
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Accumulation of drug resistance mutations
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Development of cross-resistance within multiple
drug classes
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Greater difficulty in re-establishing virologic control
with future regimens
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Decline in CD4 count leading to disease progression
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Factors contributing to incomplete
suppression of virus replication
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Inadequate adherence
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Pharmacologic factors
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Host factors
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Inadequate ARV potency
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Transmitted drug resistance
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Managing drug-resistant HIV-1
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Goal of therapy: complete virologic suppression
Use resistance testing to guide regimen selection
Combine new drugs with other active agents
– Ritonavir-boosted PI
– NRTI without cross-resistance
– Newer drugs (2nd-generation NNRTI, integrase
inhibitors, entry inhibitors)
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Use at least two or three active drugs to
maximize success of 2nd and later ART regimens
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ARV Drug Resistance in ResourceLimited Settings
South Africa Resistance Cohort Study:
Specific aims
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Estimate prevalence of drug resistance among
patients receiving sub-optimal ART
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Estimate prevalence of drug resistance among
previously treated patients
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Estimate impact of drug resistance on response
to national ART program
Marconi et al Clin Infect Dis 2008
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S. African Resistance Cohort Study
Selected Patient Characteristics at Study Entry
Mean age (years)
37.3
Male sex (%)
47.8
Black race (%)
93.9
Median CD4 cell count (cells/mm3)
162
Median plasma HIV-1 RNA (log10 copies/mL)
4.29
Median duration of HAART (months)
10.8
Prior single- or dual-drug ART (%)
15.7
Marconi et al Clin Infect Dis 2008
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Resistance mutations by regimen
Marconi et al Clin Infect Dis 2008
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Risk factors associated with resistance
Marconi et al Clin Infect Dis 2008
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Adjusted odds ratio for drug resistance*
Relationship between plasma viremia and
risk of antiretroviral drug resistance
9
8
7
6
5
4
3
2
1
0
0
20
40
60
80
100
Plasma HIV-1 RNA copies/mL (thousands)
*compared to patients with VL>100,000 copies/mL
Modeled from Marconi et al Clin Infect Dis 2008
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24-week follow-up of SARCS patients
% Viral Suppression (<50 c/ul)
24-Week ITT Viral Suppression (VL<50 c/ml)
and Baseline HIV-1 Drug Resistance
100%
65%
69%
37%
75%
All subjects
>1 Major Mutation
50%
No Drug Resistance
25%
0%
P=.01
Murphy R et al AIDS 2010; 24:1007-12.
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Resistance after 2nd-line ART failure
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302 patients on 2nd-line ART in Gugulethu
– Viral sequencing performed on samples from 33 adults with
confirmed virologic failure
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Mean duration of prior ART 23 months
Time from initiating 2nd-line ART to VF ~10 mo
– Plasma obtained 7 mo after VF
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22 patients (67%) had wild-type virus at time of
2nd virologic failure
– No major PI resistance mutations found
Levinson et al CROI 2011
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Conclusions
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Data suggest non-adherence plays a major role in
treatment failure
Adherence interventions rather than regimen
switch may be more appropriate for some patients
Resistance testing may help avoid unnecessary
switching to expensive 2nd- and 3rd-line regimens
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Resistance after Single-Dose Nevirapine
NVP resistance in women and infants after
sdNVP prophylaxis in HIVNET 012
Eshleman et al AIDS 2001; 15:1951-7.
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ACTG A5208: Primary endpoint
Lockman et al N Engl J Med 2010;363:1499-509.
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Association between NVP exposure and
virologic response in A5208
Lockman et al N Engl J Med 2010;363:1499-509.
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Effect of minority NNRTI-resistant
variants on NVP ART after sdNVP
Boltz et al PNAS 2011; 108:9202-7.
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Percent of women with NVP
resistance at week 6
TOPS: Preventing NNRTI resistance after
single-dose NVP for PMTCT
60%
50%
40%
30%
20%
10%
0%
NVP
NVP-CBV4
NVP-CBV7
Overall efficacy of ZDV/3TC “tail” = 85.6%
McIntyre et al PLoS Medicine 2009; 6:e1000172
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MOMS Study (ACTG A5207)1
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Pregnant women who were to receive sdNVP for
pMTCT randomized to 7 or 21 days of a post-NVP
“tail” consisting of:
– AZT/3TC
– TDF/FTC
– LPV/r
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487 women randomized
– 422 received study treatment
– 63% received ZDV pre-partum
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NVP resistance emerged in 5 women (4 in 7-day
and 1 in 21-day arms; p=NS)
– No difference between regimens
– Similar trends observed in minority variant analysis2
1McMahon
2Hong
et al CROI 2011.
et al. Antiviral Ther 2011; 16 (Suppl 1): A15.
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Conclusions
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In the absence of virologic monitoring, failure of
1st-line regimens is associated with a high
incidence of ARV resistance
PI resistance at 2nd-line failure is uncommon
Absence of resistance suggests non-adherence
and may predict future non-adherence
Better regimens are needed to prevent resistance
in the context of pMTCT
– PROMISE study is addressing this need
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Acknowledgments
BWH
Vince Marconi
Richard Murphy
Roger Paredes
Sébastien Gallien
MGH
Bruce Walker
Elena Losina
Zhigang Lu
Bingxia Wang
Julie Levinson
Ken Freedberg
St. Mary’s Hospital
Doug Ross
Scott Carpenter
Kofi Koranteng-Apeagyi
Nelson Mandela School of Medicine
Michelle Gordon
University of Cape Town
Catherine Orrell
Robin Wood
Funding
NIAID, Gilead, CDC, Elizabeth Glaser
Pediatric AIDS Foundation, Mark
Schwartz Global Health Fellowship
McCord Hospital
Henry Sunpath
Jane Hampton
Janet Giddy
Helga Holst
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