1. Management of the Treatment-Experienced Patient Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents December 2009 AETC NRC Slide Set

2. December 2009 2 www.aidsetc.org These slides were developed using the December 2009 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the field of HIV care is rapidly changing, users are cautioned that the information in this presentation may become out of date quickly.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 About This Presentation

3. December 2009 3 www.aidsetc.org The Treatment-Experienced Patient: Contents  Considerations  Evaluation and Management of Treatment Failure  Virologic Failure  Testing for Resistance  Immunologic Failure  Treatment Interruption or Discontinuation

4. December 2009 4 www.aidsetc.org 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

5. December 2009 5 www.aidsetc.org 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

6. December 2009 6 www.aidsetc.org 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 clinical progression

7. December 2009 7 www.aidsetc.org 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

8. December 2009 8 www.aidsetc.org 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)

9. December 2009 9 www.aidsetc.org Virologic Failure  Incomplete virologic response:  In patient on initial ART, HIV RNA >400 copies/mL after 24 weeks on therapy or >50 copies/mL by 48 weeks (confirm with second test)  Virologic rebound:  Repeated detection of HIV RNA after virologic suppression (eg, >50 copies/mL)

10. December 2009 10 www.aidsetc.org 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

11. December 2009 11 www.aidsetc.org 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

12. December 2009 12 www.aidsetc.org 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

13. December 2009 13 www.aidsetc.org 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, 2nd 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

14. December 2009 14 www.aidsetc.org Virologic Failure: Management (3)  Previous treatment with low-level viremia (50- 1,000 copies/mL):  “Blips” (isolated HIV RNA of <1,000 copies/mL): no change in ART required  Persistent low-level viremia: management unclear; many experts would not change ART and would follow closely  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)

15. December 2009 15 www.aidsetc.org Virologic Failure: Management (4)  Previous treatment and drug resistance:  Goal: resuppress HIV RNA maximally (<50 copies/mL)  Change regimen early to prevent further resistance  Especially consider stopping NNRTI, raltegravir, and enfuvirtide in a failing regimen  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 resistance mutations

16. December 2009 16 www.aidsetc.org Virologic Failure: Management (5)  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 for accumulating additional resistance mutations  Consult with experts

17. December 2009 17 www.aidsetc.org Virologic Failure: Management (6)  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

18. December 2009 18 www.aidsetc.org Virologic Failure: Management (7)  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

19. December 2009 19 www.aidsetc.org 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)

20. December 2009 20 www.aidsetc.org Genotyping  Detects drug resistance mutations in specific genes (eg, reverse transcriptase, protease, integrase)  Sequencing or probing  Results within 1-2 weeks  Interpretation of mutations and cross- resistance is complex  Consultation with specialists is recommended

21. December 2009 21 www.aidsetc.org 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

22. December 2009 22 www.aidsetc.org Drug Resistance Testing: Limitations  Lack of uniform quality assurance  Relatively high cost  Insensitivity for minor viral species (<10-20%)

23. December 2009 23 www.aidsetc.org Drug Resistance Testing  Resistance assays recommended in virologic failure  Should be performed while patient is taking ARV 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

24. December 2009 24 www.aidsetc.org 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  Requires plasma HIV RNA ≥1,000 copies/mL  Consider in patients with virologic failure on a CCR5

25. December 2009 25 www.aidsetc.org 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

26. December 2009 26 www.aidsetc.org 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

27. December 2009 27 www.aidsetc.org 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

28. December 2009 28 www.aidsetc.org 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, improve ART adherence, avoid long-term toxicities, reduce risk of virologic failure  Consider known or suspected drug resistance in making decisions

29. December 2009 29 www.aidsetc.org 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  Caution in patients with ARV resistance mutations  After simplification, monitor in 2-6 weeks (laboratory and clinical)

30. December 2009 30 www.aidsetc.org 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)

31. December 2009 31 www.aidsetc.org 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 substitution of shorter half-life ARVs (see below)

32. December 2009 32 www.aidsetc.org 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

33. December 2009 33 www.aidsetc.org 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

34. December 2009 34 www.aidsetc.org 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

35. December 2009 35 www.aidsetc.org 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

36. December 2009 36 www.aidsetc.org 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

37. December 2009 37 www.aidsetc.org 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

38. December 2009 38 www.aidsetc.org 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

39. December 2009 39 www.aidsetc.org 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

40. December 2009 40 www.aidsetc.org Websites to Access the Guidelines  http://www.aidsetc.org  http://aidsinfo.nih.gov

41. December 2009 41 www.aidsetc.org About This Slide Set  This presentation was updated by Susa Coffey, MD, for the AETC National Resource Center in December 2009.  See the AETC NRC website for the most current version of this presentation. http://www.aidsetc.org