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

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

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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