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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. Accumulation of drug resistance mutations
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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 • 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 DRK/Rome IAS/20.07.11
Factors contributing to incomplete suppression of virus replication • Inadequate adherence • Pharmacologic factors • Host factors • Inadequate ARV potency • Transmitted drug resistance DRK/Rome IAS/20.07.11
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 DRK/Rome IAS/20.07.11
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 DRK/Rome IAS/20.07.11
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 DRK/Rome IAS/20.07.11
Resistance mutations by regimen Marconi et al Clin Infect Dis 2008 DRK/Rome IAS/20.07.11
Risk factors associated with resistance DRK/Rome IAS/20.07.11 Marconi et al Clin Infect Dis 2008
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 DRK/Rome IAS/20.07.11
24-week follow-up of SARCS patients P=.01 Murphy R et al AIDS 2010; 24:1007-12. DRK/Rome IAS/20.07.11
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 DRK/Rome IAS/20.07.11
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 DRK/Rome IAS/20.07.11
NVP resistance in women and infants after sdNVP prophylaxis in HIVNET 012 Eshleman et al AIDS 2001; 15:1951-7. DRK/Rome IAS/20.07.11
ACTG A5208: Primary endpoint Lockman et al N Engl J Med 2010;363:1499-509. DRK/Rome IAS/20.07.11
Association between NVP exposure and virologic response in A5208 Lockman et al N Engl J Med 2010;363:1499-509. DRK/Rome IAS/20.07.11
Effect of minority NNRTI-resistant variants on NVP ART after sdNVP DRK/Rome IAS/20.07.11 Boltz et al PNAS 2011; 108:9202-7.
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:e1000172 DRK/Rome IAS/20.07.11
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. DRK/Rome IAS/20.07.11
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 DRK/Rome IAS/20.07.11
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 Acknowledgments DRK/Rome IAS/20.07.11