1. Clinical Significance of HIV-1 Drug Resistance
Daniel R. Kuritzkes, MD
Section of Retroviral Therapeutics
Brigham and Women’s Hospital
Harvard Medical School

2. Consequences of ongoing viral replication during HAART
Accumulation of drug resistance mutations
Development of cross-resistance within multiple drug classes
Greater difficulty in re-establishing virologic control with future regimens
Decline in CD4 count leading to disease progression
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3. Factors contributing to incomplete suppression of virus replication
Inadequate adherence
Pharmacologic factors
Host factors
Inadequate ARV potency
Transmitted drug resistance
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4. Managing drug-resistant HIV-1
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)
Use at least two or three active drugs to maximize success of 2nd and later ART regimens
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5. ARV Drug Resistance in Resource-Limited Settings

6. South Africa Resistance Cohort Study: Specific aims
Estimate prevalence of drug resistance among patients receiving sub-optimal ART
Estimate prevalence of drug resistance among previously treated patients
Estimate impact of drug resistance on response to national ART program
Marconi et al Clin Infect Dis 2008
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7. S. African Resistance Cohort Study
Selected Patient Characteristics at Study Entry
Mean age (years)
Male sex (%)
Black race (%)
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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8. Resistance mutations by regimen
Marconi et al Clin Infect Dis 2008
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9. Risk factors associated with resistance
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Marconi et al Clin Infect Dis 2008

10. Relationship between plasma viremia and risk of antiretroviral drug resistance
Adjusted odds ratio for drug resistance*
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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11. 24-week follow-up of SARCS patients
Murphy R et al AIDS 2010; 24:
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12. Resistance after 2nd-line ART failure
302 patients on 2nd-line ART in Gugulethu
Viral sequencing performed on samples from 33 adults with confirmed virologic failure
Mean duration of prior ART 23 months
Time from initiating 2nd-line ART to VF ~10 mo
Plasma obtained 7 mo after VF
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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13. Conclusions
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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14. Resistance after Single-Dose Nevirapine

15. NVP resistance in women and infants after sdNVP prophylaxis in HIVNET 012
Eshleman et al AIDS 2001; 15:
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16. ACTG A5208: Primary endpoint
Lockman et al N Engl J Med 2010;363:
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17. Association between NVP exposure and virologic response in A5208
Lockman et al N Engl J Med 2010;363:
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18. Effect of minority NNRTI-resistant variants on NVP ART after sdNVP
Boltz et al PNAS 2011; 108:
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19. TOPS: Preventing NNRTI resistance after single-dose NVP for PMTCT
Percent of women with NVP
resistance at week 6
Overall efficacy of ZDV/3TC “tail” = 85.6%
McIntyre et al PLoS Medicine 2009; 6:e
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20. MOMS Study (ACTG A5207)1
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
487 women randomized
422 received study treatment
63% received ZDV pre-partum
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 et al CROI 2011.
2Hong et al. Antiviral Ther 2011; 16 (Suppl 1): A15.
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21. Conclusions
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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22. Acknowledgments BWH Vince Marconi Richard Murphy Roger Paredes
Sébastien Gallien
MGH
Bruce Walker
Elena Losina
Zhigang Lu
Bingxia Wang
Julie Levinson
Ken Freedberg
McCord Hospital
Henry Sunpath
Jane Hampton
Janet Giddy
Helga Holst
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
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