Clinical Significance of HIV-1 Drug Resistance

Clinical Significance of HIV-1 Drug Resistance

Daniel R. Kuritzkes, MDSection of Retroviral Therapeutics

Brigham and Women’s HospitalHarvard Medical School

DRK/Rome IAS/20.07.11

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


Factors contributing to incomplete suppression of virus replication Inadequate adherence Pharmacologic factors Host factors Inadequate ARV potency Transmitted drug resistance


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

ARV Drug Resistance in Resource-Limited Settings


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


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



Resistance mutations by regimen



Risk factors associated with resistance



Relationship between plasma viremia and risk of antiretroviral drug resistance

0123456789

0 20 40 60 80 100

Plasma HIV-1 RNA copies/mL (thousands)

Adj

uste

d od

ds ra

tio fo

r dru

g re

sist

ance

*

Modeled from Marconi et al Clin Infect Dis 2008

*compared to patients with VL>100,000 copies/mL


24-week follow-up of SARCS patients

24-Week ITT Viral Suppression (VL<50 c/ml) and Baseline HIV-1 Drug Resistance

65% 69% 37%

0%

25%

50%

75%

100%

% V

iral S

uppr

essi

on (<

50 c

/ul)

All subjects >1 Major MutationNo Drug Resistance

Murphy R et al AIDS 2010; 24:1007-12.

P=.01


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


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

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.


ACTG A5208: Primary endpoint

Lockman et al N Engl J Med 2010;363:1499-509.


Association between NVP exposure and virologic response in A5208

Lockman et al N Engl J Med 2010;363:1499-509.


Effect of minority NNRTI-resistant variants on NVP ART after sdNVP

Boltz et al PNAS 2011; 108:9202-7.


TOPS: Preventing NNRTI resistance after single-dose NVP for PMTCT

0%

10%

20%

30%

40%

50%

60%

NVP NVP-CBV4 NVP-CBV7

Per

cent

of w

omen

with

NV

P re

sist

ance

at w

eek

6

Overall efficacy of ZDV/3TC “tail” = 85.6%McIntyre et al PLoS Medicine 2009; 6:e1000172


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.


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


AcknowledgmentsBWHVince MarconiRichard MurphyRoger ParedesSébastien Gallien

MGHBruce WalkerElena LosinaZhigang LuBingxia WangJulie LevinsonKen Freedberg

McCord HospitalHenry SunpathJane HamptonJanet GiddyHelga Holst

St. Mary’s HospitalDoug RossScott CarpenterKofi Koranteng-Apeagyi

Nelson Mandela School of MedicineMichelle Gordon

University of Cape Town Catherine OrrellRobin Wood

FundingNIAID, Gilead, CDC, Elizabeth Glaser Pediatric AIDS Foundation, Mark Schwartz Global Health Fellowship

Documents

Clinical Significance of HIV-1 Drug Resistance