ARV failure and resistance for the paediatrician
Douglas Watson, M.D.University of Maryland
11 December 2013
REVERSE TRANSCRIPTASE INHIBITORS (NRTIs & NNRTIs)
PROTEASE INHIBITORS
Attachment Inhibitors
Integrase inhibitors
Fusion Inhibitors
HIV DRUG TARGETS
Antiretrovirals in the U.S.- 2013Nucleoside analogues (NRTIs)Zidovudine (ZDV, AZT, Retrovir)Lamivudine (3TC, Epivir)Tenofovir (TDF, Viread)Emtricitabine (FTC, Emtriva)Abacavir (ABC, Ziagen)Stavudine** (D4T, Zerit)Didanosine** (DDI, Videx)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)Efavirenz (EFV, Sustiva)Nevirapine (NVP, Viramune) Etravirine (ETV, Intelence)Delavirdine** (DLV, Rescriptor)Rilpivirine (Edurant)
Protease inhibitorsLopinavir/ritonavir (LPV/r, Kaletra)Atazanavir (ATV, Reyataz)Fosamprenavir (fAMP, Lexiva)Darunavir (DRV, Prezista)Tipranavir* (TPV, Aptivus)Saquinavir* (SQV, Invirase)Nelfinavir* (NFV, Viracept)Indinavir** (IDV, Crixivan)
Integrase inhibitorsRaltegravir (RAL, Isentress)ElvitegravirDolutegravir (Tivacay)
Attachment inhibitor Maraviroc (Selzentry)
Fusion inhibitorEnfuvirtide* (T-20, Fuzeon) P450 inhibitor (for “boosting” PIs)
Ritonavir (RTV or r, Norvir)Cobicistat*Uncommonly used. **No useful role
WHO 2013 recommendations for 1st-line ART in children < 3 y of age
• “ABC should be considered the preferred NRTI whenever possible.”
• LPV//r should not be given to infants < 14 d of age or in premature infants until after 14 d after their due date
WHO 2013: Start with LPV/r and switching to NNRTI?
NOTE: •The quoted study enrolled only children with history of SD NVP exposure•The quoted study used < 50 copies/ml as primary endpoint and < 1,000 c/ml as secondary endpoint- NOT < 400 c/ml as stated above. •The switch-to-NVP group had fewer cases of VL > 50 but more cases of VL > 1,000 and more resistance than group that stayed on LPV/r
WHO 2013 recommendations for 1st line ART in children > 3 y of age
Adherence failurePotency failure
Virologic failure
Immunologic failure
Clinical failure
Treatment failure: progressive steps, different definitions
Genotypic failure (resistance)
Expected fall in viral loadTime Log fold
drop in viral load
Fold-drop in viral load
Viral load (example)
Viral load (example)
0 -- -- 600,000 100,000
1 month 2 100+ < 6,000 < 1,000
3 months 3 1,000 600 100
6 months 4 10,000 60 <50
If viral load at these follow up times is 3-fold or more than these examples, full suppression not likely
10
100
1000
10000
100000
1000000
-20 0 20 40 60 80 100 120 140 160 180Days
HIV viral load response to D4T/3TC/NFV/NVPTherapy started at day 0 (6 weeks old)
Vir
al lo
ad
CD
4 C
ou
nt
Start ZDV/3TC/NVP
Nonadherence
NVP resistance
3TC resistance
Gradual ZDV resistance
Clinical deterioration
1 year 2 years
Course of treatment failure
ABC
NNRTI (NVP or EFV)Blocks reverse transcriptase
by binding at active site
NRTI (such as ABC(P3) is added onto cDNA chain, blocking further
reverse transcription
cDNA
Mechanism of reverse transcriptase inhibitors
NRTI = Nucleoside reverse transcriptase inhibitorNNRTI = Non-nucleoside reverse transcriptase inhibitor
HIV reverse
transcriptase
The K103N mutation: how it can take over
Nevirapine
Resistant 103N HIV
Sensitive K103 HIV wild type (wt)
NVP blocks sensitive HIV, not resistant HIV
In presence of NVP, only the resistant virus grows. Soon almost all virus is resistant!
wt always present
Drug resistance mutations in Thai patients failing D4T/3TC/NVP for an average of 4-5 months by viral load monitoring. Sungkanuparph S. CID 2007; 44:447–52
Stavudine(D4T)
Zidovudine(AZT)
Abacavir(ABC)
Tenofovir(TDF)
Didanosine(DDI)
Lamivudine(3TC) or Emtricitabine (FTC)
Thymidine analogue mutations(TAMS)ResistanceAZTD4TTDF
TAMS +184VResistance3TC, FTC > D4T, DDI, AZT, ABC > TDF
K65RResistanceTDF, ABC, DDID4T3TC, FTC
HypersensitivityAZT
L74V+ M184VResistanceABCDDI3TC FTC
HypersensitivityAZTTDF
M184VResistance3TCFTC
HypersensitivityTDF > AZT > D4T
Q151MResistanceAZT, D4T,DDI, ABC >TDF, 3TC, FTC
Nucleoside reverse transcriptase inhibitor resistance and cross-resistance
Summary: NRTI resistance patterns & options
Regimen Common pattern Other patterns
Geno Resistance Options* Geno Resistance Options*
D4T/3TC M184V,
TAMS
3TC >
D4T, ZDV, ABC, DDI >TDF
TDF/3TC (+/-ZDV)>
(ZDV/3TC/ABC)
(how good depends on # of TAMS)
K65R, M184V
or
M184V, Q151M
3TC, TDF, ABC, DDI, d4T
3TC, ZDV, D4T, DDI, ABC, (TDF)
ZDV/3TC
(TDF/3TC)
ZDV/3TC “ “ “
TDF/3TC K65R,
(M184V)
3TC, TDF, ABC, DDI, d4T
ZDV/3TC
ABC/3TC M184V, L74V
3TC, ABC, DDI
ZDV/3TC M184V, K65R
3TC, TDF, ABC, DDI, d4T
ZDV/3TC
DDI/3TC M184V, L74V
3TC, ABC, DDI
ZDV/3TC
*Options: Underline = excellent, () = weak, others fair
NNRTI resistance• 1st generation (nevirapine, efavirenz, delavirdine)
– High potency but low genetic barrier to resistance– Most commonly K103N- resistance to all 1st generation– NVP also selects for Y181C (especially in newborns) which has
mild effect on EFV but associated with increased failures– Other mutation patterns also seen
• 2nd generation (Etravirine)– NO EFFECT of K103N– Resistance increases with other NNRTI mutations- 3 or more
yield
Protease inhibitor resistance• Some PIs select for drug-specific mutations (e.g. NFV,
ATV)• Some PIs can be boosted or unboosted (ATV, fAPV)-
low-level resistance may be clinically significant if not boosted
• Boosted PIs more durable• Resistance to LPV requires 5-10 mutations• Virologic failure while receiving LPV/r usually due to
nonadherence• Prolonged virologic failure while on LPV/r eventually
will lead to LPV resistance
Drug resistance testing
• Commercial methods start with RT PCR of bulk virus in plasma
• Not sensitive to minor strains- e.g. genotyping (sequencing) cannot detect strain representing < 10-25% of circulating virus
• When to get resistance testing (resource-rich)– Baseline: resistant strains (especially NNRTI resistance)
circulating in population
– Whenever resistance suspected (e.g. failing and patient appears adherent)
– Selective pressure- patient taking medication
HIV drug resistance genotype• RT PCR bulk plasma virus to produce cDNA• Sequence pol gene• Derive predicted amino acid sequence• Identify mutations known to confer resistance (e.g.
Stanford database, IAS-USA, etc.)• Virtual phenotype™ genotype interpretation
– Identified set of significant mutations is matched with massive database of genotype-phenotype correlations
– Reported as predicted fold resistance (used to also give number of matches)
– Fold-resistance interpreted according to in vitro or clinical measure of activity
IAS-USA, Topics in HIV Medicine, March 2013
Interpretation of resistance testing
• Complete treatment and viral load history are essential
• What is current regimen and is patient taking it?
• Many resistance mutations cause decreased viral fitness: if there is not selective pressure, wild-type virus rapidly outgrows mutant, but archive of mutant remains
WHO 2013
Johnny B. Goode
• Newly infected adolescent
• CD4 = 320, VL = 58,000
• Prescribed TDF/FTC/ATV/r
• VL 1 month later = 5,200
• VL at 2 months = 4,000
• Genotype is wild-type
• How do you interpret this situation?
• How to proceed?
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