hiv drug resistance.hope its useful to those who need it

1. HIV DRUG RESISTANCE AND ITS
MANAGEMENT
DR MIKHIN GEORGE THOMAS

2. Classification of HIV
• Fami ly: Ret rovi r idae
• Subgroup: Lent ivi rus
2

3. 3

4. 4
Integrase
protease

5. • 1990s- Monotherapy
• 1995- dual NRTI
• 1995- Protease inhibi tors
• 1996 - HAART

6. Primary resistance
• Zidovudine-1993
• Some strains of HIV -naturally resistant to some antiretroviral drugs.
• HIV type 2 - intrinsically resistant to most non nucleoside reverse-transcriptase
inhibitors

7. COMBINATION THERAPY
• Multiple mechanisms (each requiring different mutations) are
required for resistance to occur to all drugs in the regimen
• Multiple drugs suppress viral replication more effectively than single
agents

8. Concept of induced resistance
High levels of virus production and turnover
 The viral population in an infected person is
highly heterogeneous
Half-life of infected cells is remarkably short (1-
2days)
The reverse transcription of viral RNA into DNA is
notoriously prone to error-one mutation for each
viral genome transcribed.

9. UNDER THESE CIRCUMSTANCES
• Selective advantage conferred by the mutation
• The prevalence of the mutant within the virus population
• Level of drug at the site of HIV replication
• Time for which the drug is available at the site

10. CONCEPT OF HALF LIFE
• Longer the hal f l i fe the more chance of
cumulat ive mutat ions
•More t ime the drug is avai lable,vi rus has better
chance at developing mutat ions whi le the wi ld
st rain stays suppressed.
• NRTI AND Ral tegravi r.

11. • Shorter half life
• No replicative advantage over the wild strain.
• Protease inhibitors

12. Tenofovir

15. STRATEGIES
• Two NRTIs plus an NNRTI
• Two NRTIs plus a PI
• Two NRTIs plus an integrase inhibitor (INI)
• Three or four NRTIs (triple nuke, quadruple nuke)
• Experimental combinations (nuke-sparing, intensive approaches)
• Problematic primary therapies to be avoided

16. Drugs Mechanisms of Action Mechanisms of Resistance
Nucleoside analogues
Zidovudine
Stavudine
Lamivudine
Didanosine
Zalcitabine
Abacavir
Analogues of normal
nucleosides
Active as triphosphate
derivatives
Incorporated into nascent
viral DNA
Prematurely terminate
HIV DNA synthesis
Thymidine analogue
mutations .
M184V or Q151M
complex mutations
impair
incorporation of
nucleoside analogues
Nucleotide analogues
Tenofovir
K65R impairs
incorporation of tenofovir
into DNA
Thymidine analogue
mutations often
associated
with cross-resistance to
tenofovir

19. Drugs Mechanism of action Mutation
NNRTI
Nevirapine
Efavirenz
Delavirdine
HIV Bind a hydrophobic
pocket of type 1 reverse
transcriptase. Block
polymerization of viral
DNA.Inactive against HIV
type 2
Mutations reduce affinity
of the inhibitors for the
enzyme. Single mutations
generally sufficient to
induce high level of
resistance
Protease inhibitors
S a q u i n a v i r
R i t o n a v i r
I n d i n a v i r
Ne l f i n a v i r
Amp r e n a v i r
L o p i n a v i r
Structure derived from
natural peptide substrate
of the HIV type 1protease.
Bind the active site of the
protease
Mutations reduce affinity
of the inhibitors for the
enzyme.High-level
resistance requires
accumulation of mutations
Fusion inhibitors
Enfuvirtide
36-Amino-acid peptide derived
from the HR2 domain of
glycoprotein 41.Interferes with
glycoprotein 41–dependent
membrane fusion
Mutations affect HR1, a
domain of glycoprotein 41
whose interaction with HR2
promotes membrane fusion

21. AVOIDABLE MISTAKES IN FIRST-LINE THERAPY
• Mono- or dual therapy as well as a gradual introduction of
therapy – Always start with a complete ART regimen
• Starting at a lowered dose (except for nevirapine)
• T-20, delavirdine, tipranavir, etravirine, maraviroc
• Ritonavir (not tolerated – only for use as low-dose booster)

22. • AZT+d4T (antagonistic effects)
• D4T in general
• Simultaneous introduction of ABC and NNRTIs without prior
HLA testing (allergy potential)
• Efavirenz+nevirapine (too toxic)
• Efavirenz or nevirapine+raltegravir (low resistance barrier)

23. CROSS-RESISTANCE
•Resistance to drugs to which a virus has never
been exposed, results from mutations that have
been selected for by the use of another drug.

24. MONITORING PATIENTS ON FIRST LINE ART
FOR FAILURE
• Good adherence is the key to maintaining the
Fi rst l ine ART for longer durat ion.
• Good adherence is requi red for Second l ine ART
to ensure vi ral suppression and increase
survival .

25. 25
In Which Conditions is DR Less Likely?
Medication Factors
 All patients treated with 3 or more drugs
 Use of appropriate drug regimens
 Can reliably suppress HIV replication to levels of
<50 copies/ml
 Use of fixed-dose combinations to support
adherence

26. 26
In Which Conditions is DR Less Likely?
Systems Factors
 Limited number of regimens
 Trained personnel
 Supervision and monitoring
 Adequate lab services
 Drug supply and delivery systems

27. 27
In Which Conditions is DR Less Likely?
Patient Factors
 Adherence to treatment regimen
 Avoiding interruption of treatment, even if only a
few days
 Regular follow-up (going to clinic)
 Staying on uninterrupted first-line ART as long as
possible

28. 28
In Which Conditions is DR More Likely?
 Treatment with <3 drugs
 Inappropriate selection of drugs
 Adding one drug to a failing regimen
 Interruption of treatment (even for a few
days)
 Prolonging a failing regimen

29. Clinical monitoring and staging
New or recurrent event on ART Recommendations Additional Management Options
Asymptomatic (T1) Do Not switch regimen Maintain schedule follow-up
visits, including CD4
monitoring (if available)
Stage 2 event (T2) Do Not switch regimen Treat and manage staging event
Check if on treatment for at
least six months
• Assess continuation of
reintroduction of OI prophylaxis
• Schedule earlier visit for
clinical review and consider CD-
4 (if available)

30. Stage 3 event (T3) Consider switching regimen Stage 2+
• Assess continuation of
reintroduction of OI prophylaxis
Stage 4 event (T4) Switching regimen Treat and manage staging event
and monitor response
• Check if on treatment for at least
six months
• Assess continuation of
reintroduction of OI prophylaxis
• Check CD4 cell count (if
available)c
• Assess and other adherence
support

31. • Adherence should be assessed and
optimized
• Intercurrent OI treated and resolved
• IRIS excluded

32. ART TREATMENT FAILURE AND WHEN TO SWITCH
•HIV replication is not fully suppressed
• Failure to access care
•Discontinuation
•Non-adherence to ART

33. IDENTIFYING TREATMENT FAILURE
• New OIs/recurrence/clinical events after 6 months on First line ART(
after ruling out IRIS).
• Progressive CD4count decline.
• Slow/no clinical improvement over 6-12 months, associated with
stationary CD4, despite good adherence.
• Clinical deterioration in spite of good adherence to therapy.

34. CLINICAL SIGNS OF TREATMENT FAILURE
 Occurrence of new Ols or malignancy
 Recurrence of previous Ol
 Onset or recurrence or WHO stage 3 conditions

35. IMMUNOLOGICAL FAILURE
• A return to, or fall below, the pre-therapy CD4 baseline after at least 6
months of therapy
• A 50% decline from the on-treatment peak CD4 value (if known)
• A persistent CD4 count of less than 100 cells/mm3 after 6–12 months
of therapy

36. VIROLOGICAL FAILURE
• PVL value of more than 5,000 copies/mL at six
months after the initiation of ART
• Blips

46. ARCHIVED POPULATIONS OF VIRUS
• Minority populations of virus expressing a variety of distinct
combinations of resistance mutations are generally present and can
continue to evolve
• Reservoir for the generation of novel resistance genotypes
• Viral genomes are continually being archived as latently integrated
proviruses in resting cells.

47. MULTICLASS RESISTANCE
• Phenotypic and genotypic resistance to all three classes of drugs
• Higher risk of clinical progression and death
• Susceptible contacts
• Salvage therapy

48. •Multi drug therapy
•MEGA HAART
•Quadruple NRTI

49. • Protease inhibitors- Tipranavir/r and Darunavir/r
•NNRTI- Etravirine
• CCR5 antagonist- Maraviroc
• Integrase inhibitor- Raltegravir

51. Highly drug resistant HIV
• Preserve immunological function
• Prevent clinical progression
• Maintain treatment with a failing regimen such as with
lamivudine and thus preserve immunological function and
prevent new resistance mutations against other class of
drugs

52. MOTHER TO CHILD TRANSMISSION
•Seen in 20 to 70 % women put on Sd-NVP
•No reduction in efficacy for next pregnancy
•Inappropriate use of adult formulation

53. 53
Types of Resistance Assays
 Genotypic Testing: Prediction of phenotype based
on sequence
 Phenotypic Testing: Measure of susceptibility to
specific drugs
– Recombinant Assays: RT/PCR portion of patient virus
and transfer into a vector

54. 55
Clinical Use of Resistance Data
 Resistance tests are most accurate in assessing resistance to current
regimen
 Absence of resistance to previously used drug does not rule out
reservoirs of resistant virus that might emerge after re-initiation of that
drug
 If resistance to given drug has ever been detected, that drug should
probably not be used again, even if current test results suggest viral
susceptibility

55. 56
GENO vs PHENO?
 A gross oversimplification:
– Utility of genotypic testing greatest earlier in treatment
continuum
– Utility of phenotypic testing increases with subsequent
treatment rounds
Genotypic testing
Phenotypic testing
Treatment rounds
Utility
Increasing Genetic Complexity