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2nd Line ART Considerations for Resource-Limited Settings

2nd Line ART Considerations for Resource-Limited Settings

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2nd Line ART Considerations for Resource-Limited Settings

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  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” - 2007 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. 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

  18. 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 secondline regimensto 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 0 Poor Adherence Drug Resistance Failure

  26. How resistance develops: a bit more complicated 0 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. Women: stress of childcare Low income Lack of social support Support of family & friends Socioeconomic-related Factors: factors affecting adherence (+) effects (-) effects World Health Organization, 2003

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

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

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

  33. Forgetfulness Life stress Alcohol/recreational drug use Depression Hopelessness & negative feelings Positive beliefs regarding the efficacy of ARVs Patient-related factors (+) effects (-) effects 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. 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. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

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

  44. Detecting Treatment Failure Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)

  45. 2007 Caribbean Treatment Guidelines