2nd Line ART Considerations for Resource-Limited Settings August 2007 Chris Behrens MD I-TECH/University of Washington Distance Learning Clinical Seminar Series

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

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

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

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

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

Detecting Treatment Failure 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. 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)

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

Why is it helpful to diagnose Tx Failure as soon as possible? Evolution of ART resistance is time-sensitive!

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

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

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

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

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

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

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)

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.

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

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)

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?

Extra slides

What causes Treatment Failure in the first place?

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

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

The Five Dimensions of Adherence World Health Organization, 2003

Factors affecting adherence

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

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

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

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

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

Interventions to improve adherence

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

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

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

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

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

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)

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.

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)

(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)

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)

2007 Caribbean Treatment Guidelines