Management of the Treatment-Experienced Patient

1. Management of the Treatment-Experienced Patient Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents November 2008 AETC NRC Slide Set

2. About This Presentation These slides were developed using the November 2008 guidelines. The intended audience is clinicians involved in the care of patients with HIV. Because the field of HIV care is rapidly changing, users are cautioned that the information in this presentation may become out of date quickly. It is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. – AETC National Resource Center http://www.aidsetc.org AETC National Resource Center, www.aidsetc.org

3. The Treatment-Experienced Patient: Contents • Considerations • Evaluation and Management of Treatment Failure • Virologic Failure • Testing for Resistance • Immunologic Failure • Treatment Interruption or Discontinuation AETC National Resource Center, www.aidsetc.org

4. Treatment-Experienced Patients • In clinical studies of ART, most patients maintained virologic suppression for 3-7 years • Patients with suppressed viremia: • Assess adherence frequently • Simplify ARV regimen as much as possible • Patients with ART failure: assess and address aggressively AETC National Resource Center, www.aidsetc.org

5. Treatment-Experienced Patients: ARV Treatment Failure • Causes of treatment failure include: • Patient factors (eg, CD4 nadir, pretreatment HIV RNA, comorbidities) • Drug resistance • Suboptimal adherence • ARV toxicity and intolerance • Pharmacokinetic problems • Suboptimal drug potency AETC National Resource Center, www.aidsetc.org

6. ARV Treatment Failure: Assessment • Review medical history • HIV RNA, CD4 changes over time • HIV-related clinical events • ARV treatment history • Results of previous resistance tests • Adherence, tolerability, concomitant medications(look for adverse drug-drug interactions) • Comorbidities • Physical exam for signs of clinicalprogression AETC National Resource Center, www.aidsetc.org

7. ARV Treatment Failure: Assessment (2) • Possible causes: • Suboptimal adherence • Medication intolerance • Pharmacokinetic issues • Suboptimal drug potency • Viral resistance • Approach depends on cause of regimen failure and remaining ARV options AETC National Resource Center, www.aidsetc.org

8. Types of Treatment Failure • Virologic failure: • HIV RNA >400 copies/mL after 24 weeks, >50 copies/mL after 48 weeks, or>400 copies/mL after viral suppression • Immunologic failure: • Failure to achieve and maintain adequate CD4 increase despite virologic suppression • Clinical progression: • Occurrence of HIV-related events(after ≥3 months on therapy; excludes immune reconstitution syndromes) AETC National Resource Center, www.aidsetc.org

9. Virologic Failure • Incomplete virologic response: • In patient on initial ART, HIV RNA >400 copies/mL after 24 weeks on therapy or >50 copies/mL by48 weeks (confirm with second test) • Virologic rebound: • Repeated detection of HIV RNAafter virologic suppression(eg, >50 copies/mL) AETC National Resource Center, www.aidsetc.org

10. Virologic Failure (2) • Optimal time to change ART not known • Some recommend change for any repeated detectable HIV RNA, after suppression to <50 copies/mL • Ongoing viral replication promotes selection of drug resistance mutations • “Blips” (single, isolated HIV RNA of <1,000 copies/mL) usually not associated with subsequent virologic failure AETC National Resource Center, www.aidsetc.org

11. Virologic Failure: Assessment • Assess drug resistance: • Drug resistance testing • Treatment history • Previous resistance test results • Drug resistance usually is cumulative – consider all treatment history and test results AETC National Resource Center, www.aidsetc.org

12. Virologic Failure: Management • Clarify goals: aim to reestablish maximal virologic suppression (eg, <50 copies/mL) • Evaluate remaining ARV options • Newer agents have expanded treatment options • Base ARV selection on medication history, resistance testing, expected tolerability, adherence, and future treatment options • Avoid treatment interruption, which may cause rapid worsening of CD4, HIV RNA, and clinical status AETC National Resource Center, www.aidsetc.org

13. Virologic Failure: Management (2) Changing an ARV Regimen General principles: • Add at least 2 (preferably 3) fully active agents to an optimized background ARV regimen • Determined by ARV history and resistance testing • Consider potent RTV-boosted PIs, drugs with new mechanisms of action (eg, fusion inhibitor, CCR5 inhibitor, integrase inhibitor) plus an optimized ARV background • In general, 1 active drug should not be added to a failing regimen (drug resistance is likely to develop quickly) • Consult with experts AETC National Resource Center, www.aidsetc.org

14. Virologic Failure: Management (3) • Previous treatment with no resistance identified: • Evaluate accuracy of resistance test; assess adherence • Consider resuming same regimen or starting new regimen and repeating genotype in 2-4 weeks • Consider intensification with 1 drug (eg, TDF)or PK enhancement (RTV boosting of PI) • Previous treatment and drug resistance: • Goal: resuppress HIV RNA maximally(<50 copies/mL) • Change regimen early to prevent further resistance AETC National Resource Center, www.aidsetc.org

15. Virologic Failure: Management (4) • Extensive prior treatment and drug resistance: • Goal: resuppress HIV RNA maximally (<50 copies/mL) • New ARVs make this possible in many patients • If viral suppression is not possible, goals are to preserve immunologic function, prevent clinical progression • Even partial virologic suppression yields clinical benefits • Risk for accumulating additional resistancemutations AETC National Resource Center, www.aidsetc.org

16. Virologic Failure: Management (5) • No available regimen that contains≥2 fully active agents: • Reasonable to observe patient on the same regimen, depending on stage of HIV disease • Continuing therapy, even with ongoing viremia, decreases risk of disease progression • Immunologic and clinical benefit if HIV RNA <10,000-20,000 copies/mL AETC National Resource Center, www.aidsetc.org

17. Testing for Drug Resistance • Recommended in case of virologic failure, to determine role of resistance and maximize the number of active drugs in a new regimen • Combine with obtaining a drug history and maximizing drug adherence • Perform while patient is taking ART (or within 4 weeks of regimen discontinuation) AETC National Resource Center, www.aidsetc.org

18. Genotyping • Detects drug resistance mutations in specific genes(eg, reverse transcriptase and protease) • Sequencing or probing • Results within 1-2 weeks • Interpretation of mutations and cross-resistance is complex • Consultation with specialists is recommended AETC National Resource Center, www.aidsetc.org

19. Phenotyping • Measures the ability of viruses to grow in various concentrations of ARV drugs • Results within 2-3 weeks • More expensive than genotyping • The ratio of the IC50s of the test and reference viruses is reported as the fold increase in IC50, or fold resistance • Interpretation may be complex • Consultation with specialists is recommended AETC National Resource Center, www.aidsetc.org

20. Drug Resistance Testing: Limitations • Lack of uniform quality assurance • Relatively high cost • Insensitivity for minor viral species (<10-20%) AETC National Resource Center, www.aidsetc.org

21. Drug Resistance Testing • Resistance assays recommended in virologic failure • Should be performed while patient is takingARV regimen, or ≤4 weeks of stopping ART • Unreliable if HIV RNA <500-1,000 copies/mL • Interpret in combination with history of ARV exposure and ART adherence • Data suggesting the absence of resistance should be interpreted carefully in relation to the treatment history AETC National Resource Center, www.aidsetc.org

22. Coreceptor Tropism Assay • Should be performed when CCR5 antagonist is being considered • MVC should be given only to patients with exclusive CCR5 tropism • Current commercially available tropism assay is 100% sensitive for CXCR5 clones that make up ≥0.3% of the population • Consider in patients with virologic failure on a CCR5 AETC National Resource Center, www.aidsetc.org

23. Immunologic Failure • Failure to achieve and maintain adequate CD4 response despite virologic suppression • Persistently low CD4 count while on suppressive ART is associated with increased risk for • AIDS-related complications • Non-AIDS events AETC National Resource Center, www.aidsetc.org

24. Immunologic Failure (2) • Factors associated with immunologic failure: • CD4 count <200 cells/µL at ART initiation • Older age • Coinfection (HCV, other) • Medications (eg, ZDV; TDF + ddI) • Persistent immune activation AETC National Resource Center, www.aidsetc.org

25. Immunologic Failure: Management • No consensus • Unclear whether change of ART in setting of virologic suppression will improve immunologic status • Immune-based therapies: unproven benefit; should be used only in clinical trials AETC National Resource Center, www.aidsetc.org

26. Regimen Simplification • Changing a suppressive ARV regimen to: • Reduce pill burden • Reduce dosing frequency • Enhance tolerability • Decrease food and fluid requirements • Goals: improve patient’s quality of life, improve ART adherence, avoid long-term toxicities, reduce risk of virologic failure AETC National Resource Center, www.aidsetc.org

27. Regimen Simplification (2) • Types of substitution • Within class: substitution of a new agent or coformulation • Out-of-class: eg, change from PI to NNRTI or agent from another class • Reducing number of active drugs in ARV regimen: simplification to boosted-PI monotherapy is not recommended • After simplification, monitor in 2-6 weeks (laboratory and clinical) AETC National Resource Center, www.aidsetc.org

28. Interruption of ART • May cause viral rebound, immune decompensation, and clinical progression • Not recommended as a treatment strategy; increases risk of HIV- and non-HIV-related complications • Potential risks and benefits vary according to patient’s clinical and immunologic status, duration of interruption, and other factors • Short-term treatment interruptions may be necessary (eg, drug toxicity, inability to take oral medications, nonavailability of drugs) AETC National Resource Center, www.aidsetc.org

29. Interruption of ART: Short-Term Considerations for stopping ART • In case of severe or life-threatening toxicity: • Stop all drugs simultaneously • Planned short-term interruption • When all ARVs have similar half-lives: • Stop all drugs simultaneously • When ARVs have different half-lives: • Stopping all ARVs simultaneously may result in functional monotherapy • Consider staggered discontinuation, or substitutionof shorter half-life ARVs (see below) AETC National Resource Center, www.aidsetc.org

30. Interruption of ART: After Pregnancy • Women who started ART during pregnancy to decrease risk of mother-to-child transmission • If pretreatment CD4 is above currently recommended ART starting levels and patient wishes to stop therapy after delivery AETC National Resource Center, www.aidsetc.org

31. Interruption of ART: Long-Term Potential risks, including: • Viral rebound • CD4 decline • Acute retroviral syndrome • Disease progression, death • Development of drug resistance • Increase in risk of HIV transmission Treatment discontinuation should be avoided outside clinical trials AETC National Resource Center, www.aidsetc.org

32. Interruption of ART: Long-Term (2) Several scenarios: • Patients who started ART during acute HIV infection • Optimal duration of treatment and consequences of discontinuation are unknown; studies ongoing • Patients with treatment failure, extensive ARV resistance, and few available treatment options • Partial virologic suppression from ART has clinical benefit • Avoid treatment interruption AETC National Resource Center, www.aidsetc.org

33. Interruption of ART: Long-Term (3) • Patients on ART with CD4 count above levels recommended for starting therapy; baseline CD4 count either above or below recommended threshold: • Several studies of structured treatment interruptions show increased risk of disease progression and death • Avoid treatment interruption AETC National Resource Center, www.aidsetc.org

34. Interruption of ART: ARV-Specific Issues Discontinuation of EFV, ETR, or NVP: • These ARVs have long half-lives; stopping drugs in an ART regimen simultaneously may result in functional monotherapy or dual therapy • The optimal interval between stopping these and other ARVs is not known • Consider substitution of a PI for the NNRTI for a period of time before stopping all ARVs AETC National Resource Center, www.aidsetc.org

35. Interruption of ART: ARV-Specific Issues (2) Discontinuation and reintroduction of NVP: • If NVP has been interrupted for more than 2 weeks, it should be restarted with the usual dosage escalation period AETC National Resource Center, www.aidsetc.org

36. Interruption of ART: ARV-Specific Issues (3) Discontinuation of FTC, 3TC, or TDF in patients with HBV: • Flare of hepatitis may occur on discontinuation of any of these ARVs • Monitor closely • Consider initiating adefovir for HBV treatment • Entecavir should not be used in patients not on suppressive ART AETC National Resource Center, www.aidsetc.org

37. Interruption of ART: Patient Counseling If therapy must be discontinued, counsel patients on: • Need for close clinical and laboratory monitoring • Risks of treatment interruption • Behavioral guidelines to reduce risk of HIV transmission AETC National Resource Center, www.aidsetc.org

38. Websites to Access the Guidelines • http://www.aidsetc.org • http://aidsinfo.nih.gov AETC National Resource Center, www.aidsetc.org

39. About This Slide Set • This presentation was updated by Susa Coffey, MD, for the AETC National Resource Center in November 2008. • See the AETC NRC website for the most current version of this presentation. http://www.aidsetc.org AETC National Resource Center, www.aidsetc.org