Management of the Treatment-Experienced Patient

1. Management of the Treatment-Experienced Patient Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents March 2012 AETC NRC Slide Set

2. About This Presentation These slides were developed using the March 2012 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the field of HIV care is rapidly changing, users are cautioned that the information in this presentation may become out of date quickly.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 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 www.aidsetc.org

4. Treatment-Experienced Patients • In clinical studies of ART, most patients maintained virologic suppression for at least 3-7 years • Appropriate initial ARV regimens should suppress HIV indefinitely, assuming adequate adherence • In patients with suppressed viremia: • Assess adherence frequently • Simplify ARV regimen as much as possible • Patients with ART failure: assess and address aggressively 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 • Provider experience 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 examination for signs of clinicalprogression 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 www.aidsetc.org

8. Types of Treatment Failure • Virologic failure: • Inability to achieve or maintain suppression of HIV RNA (to <200 copies/mL) • 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) www.aidsetc.org

9. Virologic Failure • Incomplete virologic response: • HIV RNA >200 copies/mL after 24 weeks on ARV regimen (confirm with second test) • Virologic rebound: • Repeated detection of HIV RNA after virologic suppression (eg, >200 copies/mL) • Virologic blip: • Isolated detectable HIV RNA level followed by a return to virologic suppression • Persistent low-level viremia: • Confirmed detectable HIV RNA <1,000 copies/mL www.aidsetc.org

10. Virologic Failure (2) • Optimal time to change ART not known • Ongoing viral replication promotes selection of drug resistance mutations • Some recommend change for any repeated detectable HIV RNA, after suppression to <50 copies/mL • “Blips” (single, isolated HIV RNA of <1,000 copies/mL) usually not associated with subsequent virologic failure • Management of HIV RNA in range of >48 to <200 copies/mL is unclear; risks of drug resistance and virologic failure are not defined • Predictive value of HIV RNA thresholds of <200 copies/mL and <50 copies/mL are the same 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 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 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 and drugs with new mechanisms of action (eg, integrase inhibitor, CCR5 antagonist, fusion inhibitor, second-generation NNRTI) 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 www.aidsetc.org

14. Virologic Failure: Management (3) • Low-level viremia (48-1,000 copies/mL): • “Blips” (isolated HIV RNA of <1,000 copies/mL): no change in ART required • HIV RNA >48 and <200 copies/mL: no consensus; follow HIV RNA over time to assess need for ART changes • Persistent HIV RNA >200 copies/mL: development of resistance likely: resistance testing if possible, consider ART change www.aidsetc.org

15. Virologic Failure: Management (4) • Repeated detectable viremia (>1,000 copies/mL) and 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) www.aidsetc.org

16. Virologic Failure: Management (5) • Repeated detectable viremia (>1,000 copies/mL) and drug resistance: • Goal: resuppress HIV RNA maximally (<48 copies/mL) • Change regimen early to prevent further resistance • Especially consider stopping NNRTI, RAL, and ENF in a failing regimen www.aidsetc.org

17. Virologic Failure: Management (6) • Extensive prior treatment and highly drug-resistant HIV: • If viral suppression is not possible (≥2 fully active agents are not available), goals are to preserve immunologic function, prevent clinical progression • Reasonable to continue the same regimen and follow closely, depending on stage of HIV disease • Even with partial virologic suppression, ART decreases risk of HIV progression • Immunologic and clinical benefit if HIV RNA <10,000-20,000 copies/mL • Risk of accumulating additional resistance mutations • Consult with experts www.aidsetc.org

18. Virologic Failure: Management (7) • Previous treatment and suspected drug resistance, presenting to care in need of ART but with limited information about past ARV history • Obtain medical records and prior resistance test results, if possible • If ARV and resistance history is not available, consider restarting the most recent ARV regimen and assessing drug resistance in 2-4 weeks to guide choice of next regimen www.aidsetc.org

19. Virologic Failure: Management (8) • Discontinuing ART • Discontinuation or interruption in ART is not recommended: • May lead to rapid increase in HIV RNA and decrease in CD4 count (even in patients with ongoing viremia on ART) • Increases risk of clinical progression www.aidsetc.org

20. 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) www.aidsetc.org

21. Genotyping • Detects drug resistance mutations in specific genes (eg, reverse transcriptase, protease, integrase) • Order specific genotype for integrase inhibitor resistance, if suspected (standard genotype tests only RT and PR genes) • Sequencing or probing • Results within 1-2 weeks • Interpretation of mutations and cross-resistance is complex • Consultation with specialists is recommended www.aidsetc.org

22. 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 www.aidsetc.org

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

24. 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 • In patients failing integrase inhibitor-containing regimen, consider genotypic testing for II resistance • 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 www.aidsetc.org

25. Coreceptor Tropism Assay • Test for tropism before using CCR5 antagonist • 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 • Standard phenotypic assay requires plasma HIV RNA ≥1,000 copies/mL • Proviral DNA assay can be used if HIV RNA is below limit of detection (not clinically validated) • Consider in patients with virologic failure on a CCR5 antagonist (does not rule out resistance) www.aidsetc.org

26. 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 of: • AIDS-related complications • Non-AIDS events www.aidsetc.org

27. 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, interferon, cancer chemotherapy, prednisone) • Persistent immune activation www.aidsetc.org

28. Immunologic Failure: Management • No consensus • Discontinue medications that decrease CD4 cells, if possible • Otherwise, it is unclear whether change of ART in patients with virologic suppression will improve immunologic status • Immune-based therapies: unproven benefit; should be used only in clinical trials • IL-2 showed no clinical benefit despite increases in CD4 counts www.aidsetc.org

29. Regimen Simplification • Changing an effective ARV regimen to: • Reduce pill burden • Reduce dosing frequency • Reduce drug-drug interactions • Enhance tolerability • Decrease food and fluid requirements • Goals: improve patient’s quality of life, maintain ART adherence, avoid long-term toxicities, reduce risk of virologic failure • Consider known or suspected drug resistance in making decisions www.aidsetc.org

30. Regimen Simplification (2) • Types of substitution • Within class: substitution of a new agent or coformulation, or change from BID to QD dosage • 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 • Caution in patients with ARV resistance mutations • After simplification, monitor in 2-6 weeks (laboratory and clinical) www.aidsetc.org

31. 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) www.aidsetc.org

32. 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) www.aidsetc.org

33. Interruption of ART: After Pregnancy • In 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 www.aidsetc.org

34. 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 cannot be recommended outside clinical trials www.aidsetc.org

35. 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 www.aidsetc.org

36. 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 www.aidsetc.org

37. 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 www.aidsetc.org

38. 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 www.aidsetc.org

39. 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 www.aidsetc.org

40. 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 www.aidsetc.org

41. Websites to Access the Guidelines • http://www.aidsetc.org • http://aidsinfo.nih.gov www.aidsetc.org

42. About This Slide Set • This presentation was updated by Susa Coffey, MD, for the AETC National Resource Center in March 2012. • See the AETC NRC website for the most current version of this presentation: http://www.aidsetc.org www.aidsetc.org