PART 3 INITIATING THERAPY Objectives After completing this session the participant should be able to Discuss the goals of HIV treatment Understand when resistance testing should be performed ID: 1042173
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1. INITIAL MANAGEMENT OF THE PATIENT LIVING WITH HIVPART 3INITIATING THERAPY
2. ObjectivesAfter completing this session the participant should be able to:Discuss the goals of HIV treatment.Understand when resistance testing should be performed.Discuss the potential benefits and concerns for early treatment initiation.
3. Goals of TreatmentReduce HIV-related morbidity; prolong duration and quality of survivalRestore and/or preserve immunologic functionMaximally and durably suppress HIV viral loadPrevent HIV transmissionAETC NRC http://www.aidsetc.org February, 2013
4. Tools to Achieve Treatment GoalsSelection of ARV regimenMaximizing adherencePretreatment resistance testingAETC NRC http://www.aidsetc.org February, 2013
5. Improving AdherenceSupport and reinforcementSimplified dosing strategiesReminders, alarms, timers, and pillboxesOngoing patient educationTrust in primary care providerAETC NRC http://www.aidsetc.org February, 2013
6. Use of CD4 Cell Levels to Guide Therapy DecisionsCD4 countThe major indicator of immune function Most recent CD4 count is best predictor of disease progressionA key factor in determining urgency of ART or need for OI prophylaxisImportant in determining response to ARTAdequate response: CD4 increase 50-150 cells/µL per yearCD4 monitoringCheck at baseline (x 2) and at least every 3-6 months** May consider every 6-12 months in clinically stable patients on ART with sustained HIV RNA suppression and CD4 status well above threshold for opportunistic infection risk. AETC NRC http://www.aidsetc.org February, 2013
7. Use of HIV RNA Levels to Guide Therapy DecisionsHIV RNAMay influence decision to start ART and help determine frequency of CD4 monitoringCritical in determining response to ARTGoal of ART: HIV RNA below limit of detection (i.e., <20-75 copies/mL, depending on assay)Commercially available assays do not detect HIV-2AETC NRC http://www.aidsetc.org February, 2013
8. RNA monitoringCheck at baseline (x 2) Immediately before initiating ART2-4 weeks (not more than 8 weeks) after start or change of ART, then every 4-8 weeks until suppressed to <200 copies/mLEvery 3-4 months with stable patients; may consider every 6 months for stable adherent patients with VL suppression >2-3 yearsIsolated “blips” may occur (transient low-level RNA, typically <400 copies/mL), are not thought to predict virologic failureACTG defines virologic failure as confirmed HIV RNA >200 copies/mLUse of HIV RNA Levels to Guide Therapy Decisions (2)AETC NRC http://www.aidsetc.org February, 2013
9. Testing for Drug ResistanceBefore initiation of ART:Transmitted resistance in 6-16% of HIV-infected patientsIn absence of therapy, resistance mutations may decline over time and become undetectable by current assays, but may persist and cause treatment failure when ART is startedIdentification of resistance mutations may optimize treatment outcomesResistance testing (genotype) recommended for all at entry to careRecommended for all pregnant womenPatients with virologic failure:Perform while patient is taking ART, or ≤4 weeks after discontinuing therapyInterpret in combination with history of ARV exposure and ARV adherenceAETC NRC http://www.aidsetc.org February, 2013
10. Drug Resistance Testing: RecommendationsRECOMMENDEDCOMMENTAcute HIV infection, regardless of whether treatment is to be startedTo determine if resistant virus was transmitted; guide treatment decisions.If treatment is deferred, consider repeat testing at time of ART initiation.Genotype preferred.Chronic HIV infection, at entry into careTransmitted drug-resistant virus is common in some areas; is more likely to be detected earlier in the course of HIV infection.If treatment is deferred, consider repeat testing at time of ART initiation.Genotype preferred to phenotype.Consider integrase genotypic resistance assay if integrase inhibitor resistance is a concern.AETC NRC http://www.aidsetc.org February, 2013
11. RECOMMENDEDCOMMENTVirologic failure during ARTTo assist in selecting active drugs for a new regimen. Genotype preferred if patient on 1st or 2nd regimen; add phenotype if known or suspected complex drug resistance pattern.If virologic failure on integrase inhibitor or fusion inhibitor, consider specific genotypic testing for resistance to these to determine whether to continue them.(Coreceptor tropism assay if considering use of CCR5 antagonist; consider if virologic failure on CCR5 antagonist.)Suboptimal suppression of viral load after starting ARTTo assist in selecting active drugs for a new regimen.AETC NRC http://www.aidsetc.org February, 2013Drug Resistance Testing: Recommendations (2)
12. RECOMMENDEDCOMMENTPregnancyRecommended before initiation of ART or prophylaxis. Recommended for all on ART with detectable HIV RNA levels.Genotype usually preferred; add phenotype if complex drug resistance mutation pattern.AETC NRC http://www.aidsetc.org February, 2013Drug Resistance Testing: Recommendations (3)
13. NOT USUALLY RECOMMENDEDCOMMENTAfter discontinuation(>4 weeks) of ARVsResistance mutations may become minor species in the absence of selective drug pressurePlasma HIV RNA <500 copies/mLResistance assays cannot consistently be performed if HIV RNA is lowAETC NRC http://www.aidsetc.org February, 2013Drug Resistance Testing: Recommendations (4)
14. Other Assessment and Monitoring StudiesHLA-B*5701 screeningRecommended before starting ABC, to reduce risk of hypersensitivity reaction (HSR)HLA-B*5701-positive patients should not receive ABCPositive status should be recorded as an ABC allergyIf HLA-B*5701 testing is not available, ABC may be initiatedafter counseling and with appropriate monitoring for HSRCoreceptor tropism assayShould be performed when a CCR5 antagonist is being considered Phenotype assays have been used; genotypic test now available but has been studied less thoroughlyConsider in patients with virologic failure on a CCR5 antagonist (though does not rule out resistance to CCR5 antagonist)AETC NRC http://www.aidsetc.org February, 2013
15. Rationale for ARTEffective ART with virologic suppression improves and preserves immune function in most patients, regardless of baseline CD4 countEarlier ART may result in better immunologic responsesand clinical outcomesReduction in AIDS- and non-AIDS-associated morbidity and mortalityReduction in HIV-associated inflammation and associated complicationsART strongly indicated for all patients with low CD4 count or symptomsART can significantly reduce risk of HIV transmission Recommended ARV combinations are effective andwell toleratedAETC NRC http://www.aidsetc.org February, 2013
16. When to Start ARTExact CD4 count at which to initiate therapy not known, but evidence points to starting at higher countsCurrent recommendation: ART for allAETC NRC http://www.aidsetc.org February, 2013
17. Recommendations for Initiating ART ART is recommended for treatment:“ART is recommended for all HIV-infected individuals to reduce the risk of disease progression.”The strength of this recommendation varies on the basis of pretreatment CD4 count (stronger at lower CD4 levels)AETC NRC http://www.aidsetc.org February, 2013
18. ART is recommended for prevention:“ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.”AETC NRC http://www.aidsetc.org February, 2013Recommendations for Initiating ART
19. Rating Scheme for RecommendationsStrength of recommendation: StrongModerate OptionalQuality of evidence: ≥1 randomized controlled trials≥1 well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomesExpert opinionAETC NRC http://www.aidsetc.org February, 2013
20. Recommendations for Initiating ART: CD4 Count or Clinical Category Recommended for all CD4 counts: CD4 count <350 cells/µL (AI) CD4 count 350-500 cells/µL (AII) CD4 count >500 cells/µL (BIII)AETC NRC http://www.aidsetc.org February, 2013
21. Recommendations for Initiating ART: PreventionPerinatal transmissionRecommended for all HIV-infected pregnant women (AI)Sexual transmissionRecommended for all who are at risk of transmitting HIV to sexual partners (AI for heterosexuals, AIII for other transmission risk groups)AETC NRC http://www.aidsetc.org February, 2013
22. Recommendations for Initiating ART: Considerations“Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence.”Patients may choose to postpone ARTProviders may elect to defer ART, based on an individual patient’s clinical or psychosocial factorsAETC NRC http://www.aidsetc.org February, 2013
23. Potential Benefits of Early Therapy Untreated HIV may be associated with development of AIDS and non-AIDS-defining conditionsEarlier ART may prevent HIV-related end-organ damage; deferred ART may not reliably repair damage acquired earlier Increasing evidence of direct HIV effects on various end organs and indirect effects via HIV-associated inflammationEnd-organ damage occurs at all stages of infectionAETC NRC http://www.aidsetc.org February, 2013
24. Potential decrease in risk of many complications, including:HIV-associated nephropathyLiver disease progression from hepatitis B or CCardiovascular diseaseMalignancies (AIDS defining and non-AIDS defining)Neurocognitive declineBlunted immunological response owing to ART initiation at older agePersistent T-cell activation and inflammationAETC NRC http://www.aidsetc.org February, 2013Potential Benefits of Early Therapy (2)
25. CD4 count 350 cells/µL or history of AIDS-defining illness:Randomized control trial (RCT) data show decreased morbidity and mortality with ART CD4 count 350-500 cells/µL:RCT data as well as nonrandomized trials and cohort data support morbidity and perhaps mortality benefit of ARTAETC NRC http://www.aidsetc.org February, 2013Potential Benefits of Early Therapy: Supporting data
26. CD4 count >500 cells/µLCohort study data are not consistent; some show survival benefit if ART initiatedOther considerations (eg, potential benefit of ART on non-AIDS complications, HIV transmission risk) support recommendation for ARTAETC NRC http://www.aidsetc.org February, 2013Potential Benefits of Early Therapy: Supporting data (2)
27. ARV-related toxicitiesNonadherence to ARTDrug resistance CostPotential Concerns about Early Therapy AETC NRC http://www.aidsetc.org February, 2013
28. Consider More-Rapid Initiation of ARTPregnancyAIDS-defining conditionAcute opportunistic infection Lower CD4 count (eg, <200 cells/µL)Acute/recent infectionRapid decline in CD4Higher viral load (eg, >100,000 copies/mL)HIVANHBV coinfectionHCV coinfectionAETC NRC http://www.aidsetc.org February, 2013
29. Consider Deferral of ARTClinical or personal factors may support deferral of ARTIf CD4 count is low, deferral should be considered only in unusual situations, and with close follow-upWhen there are significant barriers to adherence If comorbidities complicate or prohibit ART“Elite controllers” and long-term nonprogressorsAETC NRC http://www.aidsetc.org February, 2013
30. Current ARV MedicationsNRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV) NNRTI Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV)PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV) Integrase Inhibitor (II) Raltegravir (RAL) Elvitegravir* (EVG)Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) * EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTCAETC NRC http://www.aidsetc.org February, 2013
31. Case Study Discussion
32. Case 1A 32 year old woman presents for FU care. She was dx 8 mo ago. After returning for the confirmatory results she has missed her next 2 appointments. She admits to THC use and states she last had a beer 4 days ago. She is anxious, talkative, and smells of ETOH. Her CD4 count is 448 and the HIV RNA is 88,375. The Genotype indicates no drug resistance. She has Medicaid and states she is eager to start medication today.Discuss your concerns for this patient and how you would address them.How do you address her eagerness to start ARV’s.
33. Websites to Access the Guidelineshttp://aidsinfo.nih.govhttp://www.aidsetc.orgAETC NRC http://www.aidsetc.org February, 2013
34. Howard University HURB 11840 7th Street NW, 2nd FloorWashington, DC 20001202-865-8146 (Office)202-667-1382 (Fax)www.capitolregiontelehealth.orgwww.aetcnmc.org