Issues in Second

line ART failure

1

Yunus Moosa

08 September 2017

Dept of Infectious Diseases

UKZN

Overview

• Mechanism of drug resistance

• Limitations of ART resistance testing

• Third line ART drugs

• Illustrative clinical case – drug-drug

interactions

• Accessing third line agents in KZN

2

Goal of HAARTDurable Viral Suppression

Undetectable Levels

Halt disease progression

Immunological recovery

Reduce OIs

Reduce viraltransmission

Prevent drug resistance

Pathogenesis of ARV

Drug Resistance

Growth in the absence of inhibitory pressure

HIV multiplies freely taking the most optimum form for rapid growth wt.

As it proliferates, HIV undergoes spontaneous mutations in random genes due to error prone RT enzyme.

Growth in the presence of ARV pressure

ARVs kill all of the original wild type (wt) organisms

The mutated virus which is RESISTANT survives.

but

Growth in the presence of ARV pressure

• The mutated HIV grows and multiplies, even in the presence of ARVs.

This virus is now RESISTANT and will continue to replicate albeit at a slower rate due to reduced fitness.

Growth in the absence of ARVs Treatment Interruption

Wt. - replicative advantage

Wt. -dominant species

What viral load threshold is used to

define virologic failure in SA

Guidelines

A. 10000

B. 1000

C. 500

D. 200

Virologic failure

2 consecutive viral loads >1000cpm

How Does ART Resistance Develop?

Selective Pressure

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Poor Adherence

Insufficient Drug Level

Viral Replication in the

Presence of Drug

RESISTANT VIRUS

Social/Personal Issues

Regimen Issues

ToxicitiesPoor Potency

Wrong Dose

Host Genetics

Poor Absorption

Rapid Clearance

Poor Activation

Drug Interactions

Transmission

When faced with ART failure

need to consider HIV resistance

testing

There are limitations

to interpretation of

this test

Facts on ART resistance testing

• Minimum VL required 1000 cpm

• Measures dominant HIV strains (>20%)

• Does not detect virus in sanctuary sites

• Does not detect “archived” viruses

• Important to obtain comprehensive drug

history & outcome of past regimens

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Facts on ART resistance

testing

• Tells you what will not work, not what will work

• Most reliable for indicating Ω to drugs the patient is

currently on or recently discontinued

Resistance testing must be done

when the patient is on the failing

regimen

To decide on a new ART regimen

Need to know all ARVs patient has

experienced in the past

Need to know reasons for

discontinuation

Need to know regimen patient is on at

time of resistance testing

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Minimum time on second line

treatment before you consider

treatment failure from resistance?

A. 3 months

B. 6 months

C. 12 months

D. 18 months

E. 24 months

Diagnosis of second-line treatment failure

Important to Detect Treatment

Failure Early

• Morbidity/mortality from progression

• Further accumulation of mutations »

higher levels of drug resistance »

more difficult to construct new

regimen

• Potential for transmission of drug

resistant virus18

Resistance to 2nd Line

PI Based ART

Estimated Prevalence 14%–32%

Options for Novel Regimens and

New Drugs

Drug Class Drugs Available

Protease Inhibitors Darunavir/Ritonavir

(DRV/r)

Integrase Inhibitors Raltegravir (RAL)

Dolutegravir

Elvitegravir

Second Generation

NNRTI’s

Etravirine (ETV)

Darunavir

• Highly potent Protease Inhibitor

• Dose 600mg bd + Ritonavir 100mg bd

• Retains activity in the presence of resistance to other protease inhibitors (e.g. LPV/r and ATV/r)

• Drug interaction with Rifampicin (↓DRV levels)

• Important adverse effects:

– Diarrhoea, rash, hepatitis

Other PI exposure & DRV Ω

Extensive PI exposure - potential to

generate DRV resistance

Therefore persisting with a failing PI can

compromise DRVs.

Raltegravir• Integrase Strand Transfer Inhibitor

• (INSTI) - 400mg bid

• Potential drug interaction with Rifampicin

(↓RAL levels)

• With RIF – dose 800 bid vs. 400 bid (reflate

study)

• Important adverse effects: rash, hepatitis

• New drug class – no resistance at baseline

Dolutegravir

• Integrase inhibitor - Dose 50mg daily

• Potential drug interaction with Rifampicin (↓DTG

levels) **

• Needs to be adequately evaluated in patients on

treatment for TB (INSPIRING study)

• Important adverse effects: insomnia and headache

• New drug class – no resistance at baseline

RAL vs. DTG

• Raltegravir has low genetic barrier to

resistance - single mutation resistance

• Once vs. twice daily dosing**

• DTG is preferred INSTI

Etravirine

• 2nd Generation NNRTI

• Dose 200mg bid

• Can retain activity in the presence of

resistance to EFV/NVP (depends on

mutation profile)

• C/I with Rifampicin (↓ETR levels)

• Important adverse effects: rash

Etravirine• More robust than NVP or EFV.

• Works in the presence of single mutations: L100I, K103N, Y188L

or G190A/S

• Mutations associated with Etravirine resistance:

• F227C

• Combination K103N + L101I

• Combination of 3 mutations: V90I, A98G, L100I,

K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S.

What contributes to Resistance?

A. Sub-optimal potency of regimen

B. Non adherence

C. Malabsorption

D. Drug interactions

E. All of the above

What is the main cause of 2nd line

treatment failure

A. Sub-optimal potency of regimen

B. Non adherence

C. Malabsorption

D. Drug interactions

E. Resistant virus

Factors that Contribute to

Resistance

Resistant Virus

Drug interactions

Malabsorption

Non adherence

Sub-optimal potency of regimen

Conundrum

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Deciding between

Resistance vs. non- adherence

Which of the following is most

effective means (>90%) of

predicting non-adherence

A. Direct questioning

B. Pill counts

C. Clinic Attendance

D. Script refills

E. All of the above

F. None of the above

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Resistance at second-line failure in SA

Resistance to PIs in adults failing 2nd line ART is not common

Interpret cautiously - short duration of second-line ART

Bias – poorly compliant patients go onto 2nd line ART

Study author N Criteria for

genotype

Duration on

second-line

ART (median)

Drug resistance

Wallis 75 2 x VL >5000 16 months39% no major DR mutations

7% major PI mutations

Levison 33 2 x VL >1000 10 months67% no major DR mutations

No major PI mutations

Sigaloff 15 1 x VL >1000 >12 months40% no major DR mutations

7% major PI mutations

Sources: AIDS Res Treat 2011; 769627. PLoS ONE 2012; 3: e32144. JID 2012; 205: 1739-44

Message

• Many treatment failures occur with no significant mutations non-adherence

• Resistance testing is effective but expensive means to determine adherence

• Cost benefit favors resistance testing

Factors that Contribute to

Resistance

Resistant Virus

Drug interactions

Malabsorption

Non adherence

Sub-optimal potency of regimen

Case 1

• 36 yr. old male- Baseline CD4 = 9

• 09/2009 – started D4T, 3TC, EFV took for 2/12

• 08/2010 started TDF, 3TC, EFV

• 07/2011 failing Regimen 1

• 07/2011 started on AZT, 3TC, LPV/r – 4/52 – An.

Case 1

• 08/2011 switched to ABC, 3TC, LPV/r

• 09/2011 TB – on ATT till 04/2012

• 05/2012 VL > 106 CD4

Was ATV/r a good choice?

A. Yes

B. No

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ATV/r/TDF/3TC

• VL remained between 105 and 106 cpm

• Repeated adherence counseling still not

suppressed

• Genotyped in Jan 2013

ATV/r/TDF/3T

C

Genotyped: Jan 2013

Case 1 progress

Based on genotype

TDF/3TC/RAL/DRV/r

Clinical chart - UPDATE

August 2014 VL

Which TB drug is associated

with PI failure

A. Isoniazid

B. Ethambutol

C. Pyrazinamide

D. Rifampicin

Which PI can be used with

Rifampicin based ATT

A. Lopinavir/ritonavir

B. Darunavir/ritonavir

C. Atazanavir/ritonavir

D. Indinavir/ritonavir

The only PI that can be used

with rifampicin.

Lopinavir/ritonavir (aluvia)

How should dose adjust when

using Rifampicin and Aluvia?

A. Double the dose of aluvia (4 bid)

B. Double dose the Rifafour

C. Dose aluvia three times a day (2 tds)

D. Further increase ritonavir (LPV 400 +

ritonavir 400 bid)

E. None of above

Current Strategy

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What alternate to rifampicin?

A. Rifabutin

B. Double dose rifampicin

C. Rifapentine

D. Riftimaxcid

How do you dose rifabutin?

A. 600mg daily

B. 450mg daily

C. 300mg daily

D. 150mg daily

E. 150mg three time as week

F. I don’t care!

Main toxicities: Rifabutin

• Uveitis

• Hepatotoxicity

• Neutropenia.

CASE 2

• Ms NC 40 yr. old

• Diagnosed Jan 2008 during pregnancy –

received stat dose NVP

• April 2008- started d4T/3TC/NVP

• 2013 – d4T replaced with TDF (lipodystrophy)

• March 2013 - VL 65030 -AZT/3TC/LPV/r

• June 2013 – VL 157

Case 2

• Sept 2013 –carbamazepine for pain related to

fracture of left tibia following MVA (2007)

Date Viral load

17/09/2014 732

28/05/2014 1752

06/09/2015 2520

09/12/2015 18300

02/03/2016 16200

• 2016 referred to ID- second line failure

Be vigilant for concomitant

drugs and ALWAYS check for

drug-drug interactions

Guidelines for Second and Third

Line Regimens

• Use at least 2 and preferably 3 active drugs

• Based on ART history & genotype

• Using a new drug not previously experienced

does not mean drug is fully active due to class

resistance and or archived resistance

Algorithm for choosing 3rd line agents

• Potential low level resistance: >10 to =15 to =30 to =60

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Eligible for third line ART?

PI score ≥15

DRV/r

PLUS

3TC/FTC

PLUS

AZT/TDF (lowest score)

Add RAL/DTG

Add ETR

TDF/AZT >29

&

DRV ≥15

&

ETR ≤29

TDF/AZT (30-59)

or

DRV ≥15

Process to follow

56Genotyping

Clinic

CentralCoordinator

Local

Pharmaceutical

services

• Fill in PDF form on computer and email to

third line coordinator

TLART@health.gov.za

• Include electronic copy of genotype

mailto:TLART@health.gov.za

Motivation Forms

• Patients details

• Facility details

• Past ART - drugs/duration/ why discontinued

• Adherence details

• Concomitant medication

• Serial recent CD4/VL/ Safety bloods (ALT, Cr, WCC)

• HBV status

• Genotype

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Key Learning Points

• Non adherence is still the main cause of

failure of 2nd line treatment

• Beware of drug-drug interactions when failing

second line treatment

• Beware of complexities of TB treatment when

using 2nd & 3rd line ART

• Unadjusted LPV/r drives 2nd line resistance

• Simple algorithm for deciding on third line Rx

• Follow the national process to access drugs

Contact Numbers

• Adult ID Helpline: 0800 111 740

• Department of Virology: 0800 113 000031 240 2599/ 031 240 6000 / 031 240 2794

• The Secretariat: Ruth Lancaster

– TLART@health.gov.za• Ashwin Bhagwandin

– ashbhagwandin@gmail.com

– Wk. 031 4698397

– Cell: 083 465 5107

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mailto:TLART@health.gov.zamailto:ashbhagwandin@gmail.com

Acknowledgements

• Richard Lessells

• Bernadett Gosnell

• Justen Manasa

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