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Resistance

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					Resistance
Chris Hoffmann
Aurum Institute
Johns Hopkins Hospital
Resistance

   Resistance background & theory

   Elevated viral loads in practice

   Managing suspected resistance
Definition

   The ability of a pathogen to survive and/or multiply
    despite administration & absorption of a drug given
    in doses equal to or higher than those usually
    recommended but within the limit of tolerance of
    the subject
                            (WHO 1986)
HIV enzymes
Reverse Transcriptase

   Enzymes are
    proteins made
    up of a chain of
    amino acids
    that then fold
    to create a 3-D
    structure.
Resistance mutations

   When RNA or DNA is replicated errors
    can be introduced.
   HIV reverse transcriptase is the
    enzyme that replicates HIV RNA.
   HIV reverse transcriptase is prone to
    make errors. 1 error in every 8,000
    base pairs copied.
Mutations in HIV

   The RNA of HIV is approximately
    8,000 base pairs long (compare with
    billions in humans)

   In an infected person, not on ART
    there are about 10000000000 (1010)
    HIV produced per day.
Every mutation occurs
every day
   All possible single mutations occur
    100,000-1,000,000 times a day
    (1010/10,000)
   So, every day an HIV infected person
    not on ART produces 100,000 HIV
    with the M184V mutations causing
    resistance to epivir.
Most mutations die off

   Most mutations are weaker than the
    original virus and do not effectively
    reproduce if there is no selective
    pressure.
Selection of resistance
Selective pressure
Selective pressure by
epivir



         Epivir   Epivir   Untreated
Multiple mutations – less
likely to occur
   A combination of 2 specific mutations
    will occur randomly 10-100 times a
    day [1010/(10,000 x 10,000)]

   A combination of 3 specific mutations
    will occur randomly once every 100
    days [1010/(10,000 x 10,000 x
    10,000)]
Why should we care
about resistance??
1.   Drugs being used become ineffective
2.   Mutations may have cross-resistance
     with 2nd line drugs
How to prevent
resistance
   Give combination of drugs that require more
    mutations than will occur randomly in any
    patient (>3).

   Give combination of drugs that will rapidly
    cause decrease in HIV levels.

   Give combination of drugs that will maintain
    low viral load
How LOW is LOW enough

   With lower HIV level, fewer different
    mutations are occurring every day
    making formation of mutations less
    likely.
      Resistance With Low-
      Level HIV Viremia
   80% of patients with VL <10,000
    developed new RT or PI mutations over
    8 months 1

   90% of patients with VL <1,000
    developed resistance over 14 months                   2




1 Kantor, 9th CROI; 2002; Seattle. Abstract 566.
2 Coakley 9th CROI; 2002; Seattle. Abstract 556.; 2002;
Undetectable Viral Load

   No resistance with undetectable viral
    load (VL < 50 copies/mL)
   No resistance with occasional „blips‟




Nettles, 2005
 How much adherence?




Only if enough medication is being taken
to select for resistant species.
Aurum Experience

   Do we have resistance?

   Do we always have resistance when
    the viral load is going up?
Why does viral load go up

   Missed medications (not good enough
    adherence)
   Resistance to medications
   Laboratory error
Aurum Workplace

   Failures (VL > 1000 x1)            579
   Failures (VL > 1000 x2)            338



   Changed to 2nd line                 46
   Changed to 2nd line after 2 VL>1000 38
   Median days to change 128 (IQR: 50-335)
Resistance testing (only
changed to 2nd line)

   18 subjects tested
   15/18 had high level resistance against
    1 or more agents
   15/15 any high level NNRTI resistance
    (resistance to Stochrin or nevirapine)
   13/15 M184V (resistance to epivir)
   6/15 any TAMs
   (similar to experience in Uganda,
    elsewhere)
Do we always have
resistance??
Suppression of HIV RNA
after failure
                    Fraction re-
                    suppressing (after 1
                    or more VL > 1000)
No regimen change   0.37
(group 1)
Regimen change      0.68
Suppression of HIV RNA
after failure
                    Fraction re-         Fraction re-
                    suppressing (after 1 suppressing (after 2
                    or more VL > 1000) or more VL > 1000)
No regimen change   0.37                 0.13
(group 1)
Regimen change      0.68                 0.70
What to do??
   Adherence, Adherence, Adherence
Definitions of virologic
failure (after suppression)
   WHO: single viral load > 10,000
   IAS: 2 sequential viral loads > 400
   Others: 1 viral load > 1000
What to do??
                 Measure Viral Load


                     >1000?
               yes             no

         Adherence             Continue with monitoring, adherence etc
         intervention


 Recheck viral load in 2-4 m


          >1000?
                        no
       yes

       Consider regimen change
How much cross
resistance is there?
   Epivir resistance (1 mutation)  epivir
   Stochrin resistance (1 mutation) 
    Stochrin & Nevirapine
   AZT resistance (>3 mutations)  AZT,
    d4T, abacavir, tenofovir, didanosine
   Stavudine (same mutations as for
    AZT)
   Kaltra (multiple mutations)  other
    protease inhibitors
   Nelfinavir (2 mutations)  other PIs
Resistance to 1st Line
   AZT, 3TC, EFV 

   d4T, 3TC, NVP 

    – EFV/NVP resistance (K103N etc)
          Cross resistance to EFV/NVP
    – 3TC resistance (M184V)
          Cross resistance to FTC
    – AZT/d4T Gradual accumulation of thymidine
      associated mutations (TAMs)
          Cross resistance to tenofovir, abacavir, ddI
Choice of 2nd line

   Either AZT or d4T or abacavir
   Plus either abacavir or didanosine
   Plus Protease inhibitor (Kaletra)
Resistance to 2nd line

   Workplace: Kaletra, didanosine,
    abacavir
   Government: Kaletra, AZT, didanosine
2nd line failure

   Abacavir, didanosine: L74V, K65R
    – Cross resistance: abacavir, didanosine,
      K65R: tenofovir
   PI: some cross resistance to other PIs,
    require multiple mutations. PIs which
    include ritonavir (boosted PIs) can fail
    without detectable resistance
Options after 2nd line
failure
   Few NRTI options
   NO NNRTI options
   Few PI options
Failure of ABC, ddI,
Kaletra
   Probable mutations L74V, Kaletra
    resistance. (plus K103N, M184V from
    1st line)

   Options: tenofovir, AZT, epivir, plus
    boosted PI: saquinavir + RTV 100
    twice daily.
Failure of AZT, ddI,
Kaletra
   Probable mutations: L74V, TAMS,
    Kaletra resistance

   Options: more limited: consider
    tenofovir, epivir, AZT, & boosted PI
Adherence

   Failure of one regimen suggests
    inadequate adherence
   Prior inadequate adherence predicts
    future adherence problems
   Patients on 2nd line regimens need
    extra help with adherence
No fully active options

   “salvage” therapy should be continued
    even if no fully suppressive ART
    – Include epivir
        Non-suppressive ART




(Deeks, 2005)




                   (Castagna 2006)
When to test resistance

   Failure of 2nd line, consider testing
    (esp with government 2nd line)
   If 1st & 2nd line not working &
    adherence is thought to be good
   REMEMBER: resistance reservoir is
    permanent
Summary - 1

   Resistance mutations occur rapidly
    because of RT errors and huge
    number of new virions produced each
    day
   Reduce resistance mutations by
    – Use of a potent regimen with multiple
      active agents
    – Maintain excellent adherence
Summary - 2

   If 1 viral load is elevated  adherence
    intervention and recheck VL in 2 to 4
    months.
   If 2 sequential viral loads are elevated
    (>1000)  change regimen
Summary - 3

   Failure of 1st line leads to NNRTI and
    epivir resistance (no resistance testing
    needed)
   If all therapy failed, can still consider
    epivir therapy.
Future directions

   Further studies on Aurum patients
    with treatment failure to assess
    resistance development

   Therapies with lower cross resistance
    with other drugs
    – Tenofovir or abacavir plus Epivir plus
      Stochrin
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