2nd line art considerations for resource-limited settings

2nd Line ART Considerations for Resource-Limited

Settings

August 2007

Chris Behrens MD

I-TECH/University of Washington

Distance Learning Clinical Seminar Series

2

Outline of this Talk

Introductory Case

Definitions 1st line vs 2nd line regimens

Preferred vs alternate regimens

Treatment failure

Virologic failure

Immunologic failure

Clinical failure

Resistance patterns associated with treatment failure

Implications for 2nd line regimens

Cases

3

Case You are working in a resource-limited setting where

the number of ARVs available is limited, and resistance testing is not available.

A patient who was started on a HAART regimen of AZT + 3TC + NVP six months ago responded well initially but is now showing clear clinical signs of treatment failure, and admits to poor adherence over the past three months.

CD4 and viral load testing confirm failure of his first regimen.

Drugs available to you: AZT, 3TC, d4T, ddI, NVP, EFV, RTV, IDV, NFV

What would you suggest for his next HAART regimen?

Are there any additional ARVs that you would advise your National AIDS Programme to make available for patients such as this?

Definitions

5

Some Key Definitions 1st line regimen: “the initial regimen prescribed for a

naïve patient when the patient fulfills national clinical and laboratory criteria to start ART.”

2nd line regimen: “the next regimen used in sequence immediately after first-line therapy has failed”

Treatment failure: “the loss of antiretroviral efficacy [that] triggers the switch of the entire regimen from first to second line”

Note: single substitutions of ARVs (usually within the same class) for toxicity, drug-drug interactions, or intolerance to not indicate a 2nd line regimen is being used.

WHO: Prioritizing Second Line ART within a Public Health Approach, 2007

6

Key Definitions, continued

Preferred Regimen: a first- or second-line regimen that is preferred per national/regional guidelines on the basis of efficacy, tolerability, cost, etc.

Example preferred first-line regimen: AZT + 3TC + EFV

Alternate Regimen: a first- or second-line regimen that can be reasonably used instead of the preferred regimen if deemed necessary by the prescribing clinician (e.g., due to considerations of toxicity; drug availability; convenience of dosing; co-morbid illnesses; etc.)

Example Alternate first-line regimen: AZT + 3TC + NFV

7

Key Definitions, continued

Treatment Failure: “loss of antiretroviral (ARV) efficacy, prompting a

switch of the entire regimen from first- to second-line.” - WHO, 2007

“absence of a sustained favourable response to antiretroviral therapy” - 2007 Caribbean Guidelines

How do we recognize Treatment Failure?

Clinical Failure

Immunologic Failure

Virologic Failure

8

Detecting Treatment FailureTable 14 - Clinical, CD4 Cell Count and Virological Definitions of Treatment Failure for Patients on a First-Line Antiretroviral Regimen (adapted from WHO Guidelines Š 2006 Revision) Clinical failure a New or recurrent WHO stage 4 condition b c

Immunologic failure d Fall of CD4 count to pre-therapy baseline (or below); or

50% fall from the on-treatment peak value (if known) ; or

Persistent CD4 levels < 100 cells/mm3 e

Virologic failure Persistently elevated viral load f

a. Current event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS) b. Certain WHO cl inical stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may be an

indication of treatment failure and thus require consideration of second-line therapy. c. Some WHO clinical stage 4 conditions (lymph node TB, uncomplicated TB pleural disease, esophageal

candidiasis, recurrent bacterial pneumon ia) may not be an indicator of treatment failure and thus no t require consideration of second-line therapy.

d. Without concomitant infection to cause transient CD4 cell decrease. e. Some experts consider that patients with persistent CD4 c ell count <50/mm3 after 12 months on AR T

may be more appropr iate f. The optimal viral load value at which A RT should be sw itched has not been defined. However, values

of more than 10,000 copie s/ml have been associated with subsequent clinical progres sion and appreciable CD4 cell count decline. A more conservative approach would be to define virologic failure as anything short of full viral suppression, i.e. any persistently detectable viral load (see text)

2007 Caribbean HIV Treatment Guidelines, p. 28

Integrating clinical status, CD4 cell count and viral load to guide ART switching

Failure criteria WHO Stage 1 WHO Stage 2 WHO Stage 3 WHO Stage 4

CD4 failure b

(Viral load testing not available)

Do not switch regimen. Follow patient for development of clinical signs or symptoms.Repeat CD4 in 3 months.

Do not switch regimen. Follow patient for evidence of further clinical progression.Repeat CD4 in 3 months.

Consider switcha to second- line regimen.

Recommend switcha to second- line regimen.

CD4 failure b

and viral load failure c

Consider switcha to second-line regimen.

Consider switcha to second-line regimen.

Recommend switcha to second-line regimen.

Recommend switcha

to second-line regimen.

a Switching from first- to second-line regimen for treatment failure should not be done until the first regimen has been given sufficient time to succeed. This should be a minimum 6 month period. With only one second-line regimen available in most circumstances, premature switching should be avoided.b CD4 failure is defined as a fall to (or below) the pre-treatment baseline or a 50% drop from the on-treatment peak level or persistent levels < 100 cells/mm3.c Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on therapy.

Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

10

Time-Sensitivity of different failure definitions for detecting Tx Failure

Tx Failure

Virologic detection

Immunologic detection

Clinical detection

Time

Viral LoadClinical Status

CD4 Count

Why is it helpful to diagnose Tx Failure

as soon as possible?

Evolution of ART resistance is time-sensitive!

12

HIV develops resistance to different ARVs at different rates

In the setting of treatment failure, HIV evolves resistance rapidly (within weeks) to:

3TC or FTC

EFV or NVP

However, resistance evolves more slowly (weeks to months) to:

AZT, d4T, TDF, ABC, or ddI

Protease inhibitors

13

Implications for 2nd line regimens

Common first line regimens in Caribbean, Africa, India:

AZT + 3TC + EFV

AZT + 3TC + NVP

d4T + 3TC + EFV

d4T + 3TC + NVP

In the setting of 1st line treatment failure:

Resistance will develop rapidly (weeks) to 3TC, EFV, and NVP

Resistance will develop more gradually (months) to AZT and d4T

14

Implications for 2nd line regimens, continued If treatment failure is detected early:

3TC and the NNRTI (NVP/EFV) are lost; but

Other NRTIs (AZT, d4T, TDF, ABC, ddI) likely retain partial, if not full, activity

Efficacy of 2nd line regimen using PI + 2 or more NRTIs highly likely

If treatment failure is detected late: 3TC and NVP/EFV are lost;

Other NRTIs more likely to be lost as well due to serial accumulation of resistance mutations to (AZT or d4T) which confer cross-resistance to other NRTIs as well

Efficacy of 2nd line regimen using PI + 2 or more NRTIs less likely

Hence, periodic virologic screening of patients on HAART may better preserve 2nd line regimen options

15

Time-Sensitivity of different failure definitions for detecting Tx Failure

Tx Failure

Virologic detection

Immunologic detection

Clinical detection

Time

Viral LoadClinical Status

CD4 Count

16

Empiric design of 2nd line regimens, when resistance testing is not available

172007 Caribbean HIV Treatment Guidelines

Detailed recommendations for switching to Second line ARV regimens in adults and adolescents

First Line Regimen

Second Line Regimen

RTI Component PI Component b

Standard Strategy

(AZT or d4T) + 3TC a + (NVP or EFV)ddI + ABC orTDF + ABC orTDF + 3TC (± AZT) c

PI/r dTDF + 3TC a + (NVP or EFV)

ddI + ABC orddI + 3TC (± AZT) c

ABC + 3TC a + (NVP or EFV)ddI + 3TC (± AZT) c orTDF + 3TC (± AZT) c

Alternative Strategy

(AZT or d4T) + 3TC a + (TDF or ABC) (EFV or NVP) ± ddI

a 3TC and FTC are considered interchangeable because they are structurally related and share pharmacological properties and resistance profile.b NFV does not need refrigeration and can be used as a PI alternative in places without cold chain.c 3TC can be considered to be maintained in second line regimens to potentially reduce the viral fitness, confer residual activity and maintain pressure on the M184V mutation to improve viral sensitivity to AZT or TDF. AZT may prevent or delay the emergence of K65R mutation.d There are insufficient data to detect differences among available RTV-boosted PIs (ATV/ r, FPV/r, IDV/r , LPV/r and SQV/r ) and the choice should be based on individual program priorities (see text). In the absence of a cold chain, NFV can be employed as the PI component but it is considered less potent than a RTV-boosted PI.


19

Case 1

40 yo man with AIDS and PCP is started on d4T + 3TC + Efavirenz after completing PCP therapy. Baseline CD4 count is 120 cells/mm3

He responds initially with weight gain and a rise in his CD4 count to 330 six months after starting HAART

He returns another six months later, and his CD4 count has dropped to 140; he has lost weight as well.

You explore adherence issues and he admits to erratic adherence due to medication access problems.

20

Case 1: 40 yo male failing initial HAART regimen of d4T/3TC/EFV You do not have access to resistance assay testing,

and treatment options are limited.

High-level resistance to which of his current medications is most likely? d4T

3TC

EFV

d4T and 3TC

3TC and EFV

High level resistance to all of his initial ARVs is likely

21

Case 1: 40 yo male failing initial HAART regimen of d4T/3TC/EFV

Which of the following regimens would you recommend for this patient?

AZT/ddI/NVP

d4T/ddI/NVP

AZT/3TC/Indinavir

AZT/ddI/r-lopinavir

AZT/3TC/Abacavir (Trizivir)

22

Case 2 You are working in a resource-limited setting where

the number of ARVs available is limited, and resistance testing is not available.

A patient who was started on a HAART regimen of AZT + 3TC + NVP six months ago responded well initially but is now showing clear clinical signs of treatment failure, and admits to poor adherence over the past three months.

CD4 and viral load testing confirm failure of his first regimen.

Drugs available to you: AZT, 3TC, d4T, ddI, NVP, EFV, RTV, IDV, NFV

What would you suggest for his next HAART regimen?

Are there any additional ARVs that you would advise your National AIDS Programme to make available for patients such as this?

23

Extra slides

What causes Treatment Failure in

the first place?

25

How resistance develops: the simple model

Poor Adherence

Drug Resistance

Failure

How resistance develops: a bit more complicated

Insufficient drug level

Viral replication in the presence of drug

Resistant virus

Poor adherence

Social/personal issuesRegimen issues

ToxicitiesPoor potency

Wrong dose

Host genetics

Poor absorption

Rapid clearance

Poor activation

Drug interactions

27

The Five Dimensions of Adherence

World Health Organization, 2003

Factors affecting adherence

29

Socioeconomic-related Factors: factors affecting adherence

Women: stress of childcare

Low income

Lack of social support

Support of family & friends

(-) effects (+) effects


30

Health care team/health system-related factors

Lack of clear instructions from health professionals

Poor implementation of educational interventions

Good relationship between patient and physician

Support of nurses and pharmacists

(-) effects


(+) effects

31

Condition-related factors

asymptomatic Symptomatic

Understanding the relationship between adherence and viral load



32

Therapy-related factors

Complex treatment regimens

Close monitoring

Severe lifestyle alterations

Adverse events & effects of treatment

Lack of clear instructions regarding how to take the medications

Less frequent dosing

Fewer pills per day

Fewer dietary restrictions

Fitting medication to individual’s lifestyle

Belief that medications are effective



33

Patient-related factors

Forgetfulness

Life stress

Alcohol/recreational drug use

Depression

Hopelessness & negative feelings

Positive beliefs regarding the efficacy of ARVs



Interventions to improve adherence

35

Interventions to improve adherence: Socioeconomic Factors

Family preparedness

Mobilization of community-based organizations;

Intensive education on use of medicines for patients with low literacy

Assessment of social needs


36

Interventions to improve adherence: Health system-related factors

Good patient-physician relationship

Multidisciplinary care

Training of health professionals on adherence, adherence education, and monitoring adherence

Training caregivers

Identification of treatment goals and development of strategies to reach them

Management of disease and treatment in conjunction with the patients

Ready availability of information

Non-judgemental attitude & assistance

Rational selection of medications


37

Interventions to improve adherence: condition-related factors

Education on use of medications

Supportive medical consultation

Screening for co-morbidities

Attention to mental illness

Attention to alcohol/drug abuse


38

Interventions to improve adherence: therapy-related factors

Simplification of regimens

Education on use of medications

Assessment & management of side effects

Patient-tailored prescriptions

Medications for symptoms

Education on adherence

Continuous monitoring & re-assessment of treatment

Management of side effects


39

Interventions to improve adherence: patient-related factors

Monitoring drug/alcohol use

Psychiatric consultation as needed

Behavioral & motivational intervention

Counseling/psychotherapy

Telephone counselling

Memory aids & reminders

Self-management of disease & treatment


40

ARV combinations not recommended

d4T + AZT - both drugs work through common metabolic pathways [A-II]

d4T + ddI a - these drugs have overlapping toxicities [A-II]

TDF + 3TC + ABC b − this regimen selects for the K65R mutation and high incidence of

early virologic failure [A-III]

TDF + 3TC + ddI c - this regimen selects for the K65R mutation and high incidence of

early virologic failure [A-III]

TDF + ddI + NNRTI d - these regimens are associated with a high incidence of early

virological failure [A-III]

a. Didanosine (ddI) is an adenosine analogue NRTI which is generally reserved for second-line regimens

b. Data from three clinical trials in adults involving the combination of TDF + ABC + 3TC demonstrated high rates of virological failure and drug resistance. Given these concerns and the lack of clinical data, this NRTI backbone should not be used in treatment-naïve patients . Another report confirms that ABC and TDF select for the K65R mutation, which reduces susceptibility to both drugs

c. A pilot study resulted in a high incidence of K65R mutation and virologic failure (insert ref 117 from 2006 DHHS guidelines)

d. The use of TDF + ddI with boosted PIs can be considered with caution and close monitoring until more data become available [B-IV]. The ddI dose should be adjusted accordingly with body weight when used concomitantly with TDF to reduce its toxicity risk


ABC or 3TC (±AZT)#

ddI or TDF

EFV or NVPNRTI sparing option if the triple NRTI approach were used in first-line therapy

Standard second-line option if NRTI/NNRTI approach were used in first-line therapy

Second line ARV drugs in adults and adolescents

PI/r*

* Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r, LPV/r and SQV/r) are considered as the key component in second-line regimens and its use should be reserved for this situation. LPV/r is the only PI currently available as a FDC and a new formulation that doesn't need refrigeration was recently launched. In the absence of a cold chain and where the new LPV/r formulation is not available, NFV can be employed as the PI component but it is considered less potent than a RTV-boosted PI.

# The use of 3TC (±AZT) are listed for “strategic” use as resistance to both drugs is predicted to be present following failure on the respective first-line regimen listed. 3TC will maintain the M184V mutation which may potentially decrease viral replicative capacity as well as induce some degree of viral resensitization to AZT or TDF; AZT may prevent or delay the emergence of the K65R mutation. However, it must be stressed that the clinical efficacy of this strategy in this situation has not been proven.

42

Clinical staging events to guide decision-making on ART switching

New or recurrent event on ART a Recommendations Additional management options

Asymptomatic(T1)

Do not switch regimen

• Maintain scheduled follow up visits including CD4 monitoring (if available) • Continue to offer adherence support

Stage 2 event(T2 )

Do not switch regimen b

Treat and manage staging eventAssess and offer adherence support • Check if on treatment at least 6 months • Assess continuation or reintroduction of OI prophylaxis • Schedule earlier visit for clinical review and consider CD4 (if available) c

Stage 3 event(T3)

Consider switchingregimen b d

Treat and manage staging event and monitor responseAssess and offer adherence support

• Check if on treatment at least 6 months • Check CD4 cell count (if available) c d

• Assess continuation or reintroduction of OI prophylaxis• Institute more frequent follow up

Stage 4 event(T4)

Switch regimen b e

Treat and manage staging event and monitor responseCheck if on treatment at least 6 months

• Assess continuation or reintroduction of OI prophylaxis• Check CD4 cell count (if available) c

• Assess and offer adherence support

a. Clinical stages refer to the clinical stage while on ART for at least 6 months (termed T1, T2, T3, T4)b. Differentiation of opportunistic infections from immune reconstitution syndrome is necessary.c. Treat and manage the staging event before measuring CD4 cell count.d. Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of treatment failure, and thus not

require consideration of second-line therapy; response to appropriate therapy should be used to evaluate the need for switching of therapy.e. Some stage 4 conditions (simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis, recurrent bacterial pneumonia) may

not be an indicator of treatment failure and thus not require consideration of second-line therapy; response to appropriate therapy should be used to evaluate the need to switch of therapy.


WHO Clinical Staging

Clinical Failure(CD4 and VL not

available)

Immunologic Failure

(VL not available)

Immunologic and Virologic

Failure(CD4 and VL available)

1 N/A Do Not Switch Consider

Switch

2 N/A Do Not Switch Consider Switch

3Consider Switch

Switch Switch

4Switch Switch Switch

When to Switch from 1st Line to 2nd Line ARV Regimens for Treatment Failure

Clinical failure is defined as a occurrence of new or recurrent WHO clinical stage 3 or 4 event (excluding IRIS).

CD4 failure is defined as a fall to (or below) the pre-treatment baseline or a 50% drop from the on-treatment peak level or persistent levels < 100 cells/mm3.

Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on therapy.


44

Detecting Treatment FailureClinical, CD4 Cell Count, and Virological Definitions of Treatment Failure

for Patients on a First-Line Antiretroviral Regimen

Clinical failure a Occurrence of new or recurrent WHO stage 4 condition b c

CD4 cell failure d Fall of CD4 count to pre-therapy baseline (or below) or 50% fall from the on-treatment peak value (if known) or Persistent CD4 levels < 100 cells/mm3 e

Virological failure Plasma viral load >10,000 copies/ml f

a. This event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS)b. Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of

treatment failure, and thus not require consideration of second-line therapy; c. Some stage 4 conditions ( EPTB: simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis,

recurrent bacterial pneumonia) may not be an indicator of treatment failure and thus not require consideration of second-line therapy;

d. Without concomitant infection to cause transient CD4 cell decrease.e. Some experts consider that patients with persistent CD4 cell count <50/mm3 after 12 months on ART may be more

appropriate.f. The optimal viral load value at which ART should be switched has not been defined. However, values of more than 10,000

copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline.


452007 Caribbean Treatment Guidelines

2nd line art considerations for resource-limited settings

Documents