hiv drug resistance and its management
TRANSCRIPT
HIV DRUG RESISTANCE AND ITS MANAGEMENT
DR MIKHIN GEORGE THOMAS
Classification of HIV
• Family: Retrovir idae
• Subgroup: Lentivirus
2
3
4
Integrase
protease
• 1990s- Monotherapy
• 1995- dua l NRTI
• 1995- Protease inh ib i tors
• 1996 - HAART
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
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
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.
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
CONCEPT OF HALF LIFE
• Longer the half l i fe the more chance of
cumulative mutations
• More t ime the drug is avai lable,virus has better
chance at developing mutations while the wild
strain stays suppressed.
• NRTI AND Raltegravir.
• Shorter half life
• No replicative advantage over the wild strain.
• Protease inhibitors
Tenofovir
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
Drugs Mechanisms of Action Mechanisms of Resistance
Nucleoside analogues
ZidovudineStavudineLamivudineDidanosineZalcitabineAbacavir
Analogues of normal nucleosidesActive as triphosphate derivativesIncorporated into nascent viral DNAPrematurely terminate HIV DNA synthesis
Thymidine analogue mutations .M184V or Q151M complex mutations impairincorporation of nucleoside analogues
Nucleotide analoguesTenofovir
K65R impairs incorporation of tenofovirinto DNAThymidine analogue mutations often associatedwith cross-resistance to tenofovir
Drugs Mechanism of action Mutation
NNRTINevirapineEfavirenzDelavirdine
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 inhibitorsS a q u i n a v i rR i t o n a v i rI n d i n a v i rN e l f i n a v i rA m p r e n a v i rL 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
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)
• 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)
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.
MONITORING PATIENTS ON FIRST LINE ART FOR FAILURE
• Good adherence is the key to maintaining the
First l ine ART for longer duration.
• Good adherence is required for Second l ine ART
to ensure viral suppression and increase
survival .
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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
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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
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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
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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
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)
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
•Adherence should be assessed and optimized
• Intercurrent OI treated and resolved
• IRIS excluded
ART TREATMENT FAILURE AND WHEN TO SWITCH
•HIV replication is not fully suppressed
• Failure to access care
•Discontinuation
•Non-adherence to ART
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.
CLINICAL SIGNS OF TREATMENT FAILURE
Occurrence of new Ols or malignancy
Recurrence of previous Ol
Onset or recurrence or WHO stage 3 conditions
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
VIROLOGICAL FAILURE
•PVL value of more than 5,000 copies/mL at six
months after the initiation of ART
•Blips
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.
MULTICLASS RESISTANCE
• Phenotypic and genotypic resistance to all three classes of drugs
• Higher risk of clinical progression and death
• Susceptible contacts
• Salvage therapy
•Multi drug therapy
•MEGA HAART
•Quadruple NRTI
•Protease inhibitors- Tipranavir/r and Darunavir/r
•NNRTI- Etravirine
•CCR5 antagonist- Maraviroc
• Integrase inhibitor- Raltegravir
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
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
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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
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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
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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