1. 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?

4. 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” Caribbean Guidelines
How do we recognize Treatment Failure?
Clinical Failure
Immunologic Failure
Virologic Failure

8. Detecting Treatment Failure
2007 Caribbean HIV Treatment Guidelines, p. 28

9. 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.
Consider switcha to second- line regimen.
Recommend switcha to second- line regimen.
and viral load failure c
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
Viral Load
Clinical Status
CD4 Count
Time
Tx Failure
Immunologic detection
Clinical detection
Virologic detection

11. 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
Viral Load
Clinical Status
CD4 Count
Time
Tx Failure
Immunologic detection
Clinical detection
Virologic detection

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

17. 2007 Caribbean HIV Treatment Guidelines
1. 3TC may be added to any of the above regimens. Some expert clinicians suggest continuing 3TC therapy even for patients in whom 3TC resistance is likely due to reduced replicative capacity induced by the signature 3TC resistance mutation (see text for further explanation).
2. PI/r = RTV-boosted PI (e.g. LPV/r; IDV/r; SQV/r). Insufficient data exist to recommend one r/PI combination over another. NFV can be substituted where a cold chain of refrigeration does not exist and where the heat-stable version of LPV/r is not available.
3. Dosage of ddI should be lowered to 250mg when combined with TDF.
2007 Caribbean HIV Treatment Guidelines

18. 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 or
TDF + ABC or
TDF + 3TC (± AZT) c
PI/r d
TDF + 3TC a + (NVP or EFV)
ddI + 3TC (± AZT) c
ABC + 3TC a + (NVP or EFV)
ddI + 3TC (± AZT) c or
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.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

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

24. What causes Treatment Failure in the first place?

25. How resistance develops: the simple model
Poor Adherence
Drug Resistance
Failure

26. How resistance develops: a bit more complicated
Social/personal issues
Regimen issues
Poor potency
Toxicities
Wrong dose
Poor adherence
Host genetics
Poor absorption
Insufficient drug level
Rapid clearance
Viral replication in the
presence of drug
Poor activation
Resistant virus
Drug interactions

27. The Five Dimensions of Adherence
World Health Organization, 2003

28. Factors affecting adherence

29. Socioeconomic-related Factors: factors affecting adherence
(+) effects
(-) effects
Women: stress of childcare
Low income
Lack of social support
Support of family & friends
World Health Organization, 2003

30. Health care team/health system-related factors
(+) effects
(-) effects
Lack of clear instructions from health professionals
Poor implementation of educational interventions
Good relationship between patient and physician
Support of nurses and pharmacists
World Health Organization, 2003

31. Condition-related factors
(+) effects
(-) effects
asymptomatic
Symptomatic
Understanding the relationship between adherence and viral load
World Health Organization, 2003

32. Therapy-related factors
(+) effects
(-) effects
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
World Health Organization, 2003

33. Patient-related factors
(+) effects
(-) effects
Forgetfulness
Life stress
Alcohol/recreational drug use
Depression
Hopelessness & negative feelings
Positive beliefs regarding the efficacy of ARVs
World Health Organization, 2003

34. 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
World Health Organization, 2003

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
World Health Organization, 2003

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
World Health Organization, 2003

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
World Health Organization, 2003

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
World Health Organization, 2003

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

41. Second line ARV drugs in adults and adolescents
Standard second-line option if NRTI/NNRTI approach were used in first-line therapy
ddI or TDF
PI/r*
EFV or NVP
NRTI sparing option if the triple NRTI approach were used in first-line therapy
ABC or 3TC (±AZT)#
* 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 switching
regimen b d
Treat and manage staging event and monitor responseAssess and offer adherence support
Check CD4 cell count (if available) c d
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
Check CD4 cell count (if available) c
Assess and offer adherence support
Clinical stages refer to the clinical stage while on ART for at least 6 months (termed T1, T2, T3, T4)
Differentiation of opportunistic infections from immune reconstitution syndrome is necessary.
Treat and manage the staging event before measuring CD4 cell count.
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.
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.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

43. (CD4 and VL not available) Immunologic and Virologic Failure
When to Switch from 1st Line to 2nd Line ARV Regimens for Treatment Failure
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
Consider Switch 3 4
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.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

44. Detecting Treatment Failure
Clinical, 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
This event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS)
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;
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;
Without concomitant infection to cause transient CD4 cell decrease.
Some experts consider that patients with persistent CD4 cell count <50/mm3 after 12 months on ART may be more appropriate.
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.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

45. 2007 Caribbean Treatment Guidelines