Guideline Summary: Guideline Summary: When to Start ARTWhen to Start ART

Guidelines for the Use of Antiretroviral Agents

in Adults and Adolescents

Andy Catanzaro, MD

Infectious Diseases

acatanzaro@unityhealthcare.org

March 2012

OutlineOutline

Overview of HIV therapy Initiation of Therapy Special Issues

October 2011 www.aidsetc.org2

HIV TermsHIV Terms

October 20113 www.aidsetc.org

HIV Terms/Acronyms

ART: Antiretroviral Therapy

HIV Viral Load: amount of virus in the blood

Undetectable Viral Load: Goal of Therapy

CD4 Count: Immune Marker

Genotype: Sensitivity of the Virus to Medications

Goal of HIV Therapy:  Stop the Virus!

 

October 2011 www.aidsetc.org

What are ‘The Guidelines’ for HIV Therapy

Independent panel of experts

Review Current Literature on HIV

Make Recommendations

Strength of Evidence given for each guidance

(www.aidsinfo.nih.gov)

What the Guidelines AddressWhat the Guidelines Address

Baseline evaluation Laboratory testing When to initiate & change therapy Therapeutic options ART-associated adverse effects

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What the Guidelines AddressWhat the Guidelines Address

Treatment of acute HIV infection Special considerations (pregnant,

injection drug users, coinfected with HBV, HCV, or TB)

Preventing secondary transmission

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Websites to Access the GuidelinesWebsites to Access the Guidelines

http://aidsinfo.nih.gov http://www.aidsetc.org

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Goals of TreatmentGoals of Treatment

Improve quality of life Reduce HIV-related morbidity and mortality Restore and/or preserve immunologic

function Suppress HIV viral load Prevent HIV transmission

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Use of CD4 Cell Levels to Guide Use of CD4 Cell Levels to Guide Therapy DecisionsTherapy Decisions

CD4 count The major indicator of immune function Most recent CD4 count is best predictor of

disease progression A key factor in decision to start prophylaxis Important in determining response to ART

Adequate response: CD4 increase 50-150 cells/µL per year

*

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Studies in patients CD4>500Studies in patients CD4>500

Favor Treatment NA-ACCORD

Neutral on Treatment ART-CC CASCADE

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ART in Treatment Recommended for ART in Treatment Recommended for All PatientsAll Patients

CD4 count Strength of the Recommendation

Evidence for the Recommendation

<350 Strong Data from randomized clinical trials

350-500 Strong Data from non-randomized clinical trials

>500 Moderate Expert Opinion

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Use of HIV RNA Levels to Guide Use of HIV RNA Levels to Guide Therapy DecisionsTherapy Decisions

HIV RNA May influence choice of ART Critical in monitoring response to ART

Goal of ART: HIV RNA below limit of detection (ie, <20-75 copies/mL, depending on assay)

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Use of HIV RNA Levels to Guide Use of HIV RNA Levels to Guide Therapy Decisions Therapy Decisions (2)(2)

RNA monitoring Check at baseline Before initiating ART 2-4 weeks (not more than 8 weeks) after start or change of

ART, then every 4-8 weeks until suppressed to <200 copies/mL

Every 3-4 months with stable patients; may consider every 6 months for stable adherent patients with VL suppression >2-3 years

Isolated “blips” may occur (transient low-level RNA, typically <400 copies/mL), are not thought to predict virologic failure

ACTG defines virologic failure as confirmed HIV RNA >200 copies/mL

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When to Start ARTWhen to Start ART

Potent ART may improve and preserve immunefunction in most patients with virologic suppression, regardless of baseline CD4 count ART indicated for all with low CD4 count or symptoms Earlier ART may result in better immunologic responses

and better clinical outcomes Reduction in AIDS- and non-AIDS-associated morbidity and

mortality Reduction in HIV-associated inflammation and associated

complications

Reduction in HIV transmission

Recommended ARV combinations are considered to bedurable and tolerable

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When to Start ARTWhen to Start ART

Exact CD4 count at which to initiate therapy not known, but evidence points to starting at higher counts

Current recommendation: ART for all patients with CD4 Randomized control trial (RTC) data support benefit of ART if

CD4 count 350 cells/µL No RTC data on benefit of ART at CD4 counts of >350 cells/µL,

but observational cohort data exist

Currently available ARVs are effective and well tolerated

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Potential Benefits of Early Therapy Potential Benefits of Early Therapy (CD4 count >500 cells/µL)(CD4 count >500 cells/µL)

Cohort study data show survival benefit if ART initiated at CD4 count >500 cells/µL

Earlier 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 inflammation

End organ damage occurs at all stages of infection

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Potential Benefits of Early Therapy Potential Benefits of Early Therapy (CD4 count >500 cells/µL) (CD4 count >500 cells/µL) (2)(2)

Potential decrease in risk of many complications, including: HIV-associated nephropathy Liver disease progression from hepatitis B or

hepatitis C Cardiovascular disease Malignancies (AIDS defining and non-AIDS defining) Neurocognitive decline Blunted immunological response owing to ART

initiation at older age Persistent T-cell activation and inflammation

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Potential Benefits of Early Therapy Potential Benefits of Early Therapy (CD4 count >500 cells/µL) (CD4 count >500 cells/µL) (3)(3)

Prevention of sexual and blood borne transmission of HIV

Prevention of mother-to-child transmission of HIV

Prevention of transmission to a sexual partner

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Potential Limitations of Early TherapyPotential Limitations of Early Therapy (CD4 count >500 cells/µL)(CD4 count >500 cells/µL)

ARV-related toxicities Drug resistance Non-adherence to ART Cost

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Recommendations for Initiating ART Recommendations for Initiating ART (3)(3)

Patients may choose to postpone ART Providers may elect to defer ART, based on

patients’ clinical or psychosocial factors caveat: do we really know who is ready?

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Consider More Rapid Initiation of ART Consider More Rapid Initiation of ART (e.g. before the genotype is available)(e.g. before the genotype is available)

Pregnancy Acute opportunistic infection Lower CD4 count (eg, <200 cells/µL) Rapid decline in CD4 Higher viral load HIV Associated Nephropathy HBV coinfection when HBV treatment is indicated

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Consider Deferral of ARTConsider Deferral of ART

Clinical or personal factors may support deferral of ART If CD4 count is low, deferral should be considered

only in unusual situations, and with close follow-up

When there are significant barriers to adherence If comorbidities complicate or prohibit ART “Elite controllers” and long-term nonprogressors

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Initial ART Regimens: DHHS CategoriesInitial ART Regimens: DHHS Categories Preferred

Randomized controlled trials show optimal efficacy and durability

Favorable tolerability and toxicity profiles

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Initial Treatment: Choosing RegimensInitial Treatment: Choosing Regimens

3 main categories: 1 Non-nucleoside Reductase Inhibitor + 2 Nucleside

Reductase Inhibitor (NRTI) 1 Protease Inhibitor + 2 NRTIs 1 Integrase Inhibitor + 2 NRTIs

Combinations preferred for most patients (Bias: Once Daily Preferred by patients)

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Initial Therapy: Fixed Dose CombinationsInitial Therapy: Fixed Dose Combinations

Preferred:TDF/FTC(Truvada)

Once-daily dosing High virologic efficacy Active against HBV Potential for renal toxicity

Alternative:ABC/3TC(Epzicom)

Once-daily dosing Risk of hypersensitivity reaction if positive for

HLA-B*5701 Possible inferior efficacy if baseline HIV RNA

>100,000 copies/mL Active against HBV

Acceptable:ZDV/3TC(Combivir)

Twice-daily dosing Preferred for pregnant women More toxicities than TDF/FTC or ABC/3TC

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Initial Regimens: PreferredInitial Regimens: Preferred

NNRTI based EFV/TDF/FTC (Atripla) 1,

Protease Inhibitor based

ATV/r (Reyataz/Norvir) + TDF/FTC (Truvada)DRV/r (Prezista/Norvir) + TDF/FTC (Truvada)²

Integrase Inhibitor based

RAL (Isentress BID) + TDF/FTC (Truvada)

Pregnant women LPV/r (Kaletra BID) + ZDV/3TC (Combivir)²

1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception.27

October 2011 www.aidsetc.org

Drug-Drug Interactions

Too Common

Always check new medications

Resources: Guidelines, Uptodate, Epocrates

Websites to Access the GuidelinesWebsites to Access the Guidelines

http://www.aidsetc.org http://aidsinfo.nih.gov

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