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DHHS Revised Adult and Adolescent Guidelines 1/29/2008. Swati Modi, M.D.

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DHHS Revised Adult and Adolescent Guidelines 1/29/2008

Swati Modi, M.D.

Faculty, Florida/Caribbean AETCAssistant Professor, University of Florida Center for HIV/AIDS Research, Education and Service (UF CARES), Pediatric Infectious Disease and Immunology, University of Florida College of Medicine, Jacksonville, Florida.

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Disclosure of Financial Relationships

This speaker has no significant financial relationships with commercial entities to disclose.

This slide set has been peer-reviewed to ensure that there areno conflicts of interest represented in the presentation.

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Course Objectives

As a result of attending this 1 hour course on HIV/AIDS, the participant will be able to:

Recognize current recommendation of when to start HIV therapy

Recognize current DHHS guidelines regarding preferred and alternative Anti-retroviral therapy and be familiar with antiretrovirals which are not recommended

Recognize when an HIV regimen is failing

Identify indications for drug resistance testing

Be familiar with implications of treatment interruption in HIV therapy and identify acute HIV syndrome

Identify and locate the latest Department of Health and Human Service adult and adolescent guidelines to treat HIV

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When to Start..

  • Current recommendation: ART for all patients with CD4 <350 cells/mm³, certain others regardless of CD4 depending on presence of co-morbid conditions.

  • Current recommendations no longer define a group of people who should not be treated

  • Other major determinant for timing of initiation of therapy:

    • Concern about adherence to therapy

    • Depression

    • Substance abuse

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Special considerations in patients presenting with an opportunistic disease

  • Early initiation of ART near time of initiation of OI treatment (within 1st 2 weeks) should be considered for most patients with an acute OI, excluding TB.

  • For TB disease, awaiting a response to OI therapy may be warranted before initiation of ART. Experts recommend making the decision based upon the immunological status of the patient:

    • CD4+ count <100 cells/μL: ART should be started after ≥2 weeks of TB treatment to reduce confusion about overlapping toxicities, drug interactions, and the occurrence of paradoxical reactions or IRIS

    • CD4+ count of 100–200 cells/μL: ART may be delayed until the end of the 2-month intensive phase of anti-TB treatment

    • CD4+ count >200 cells/μL: ART could be started during the anti-TB maintenance phase

    • CD4+ count >350 cells/μL: ART could be started after finishing anti-TB treatment

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Maintain higher CD4 count; prevent irreversible immune system damage

Decrease risk of HIV-associated complications

eg, TB, NHL, KS, peripheral neuropathy, HPV-associated malignancies, HIV-associated cognitive impairment

Decrease risk of nonopportunistic conditions and non-AIDS-associated conditions

eg, CV, renal, and liver disease; malignancies; infections

Decrease risk of HIV transmission

Potential Benefits of Early Therapy(CD4 count >350 cells/µL)

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ARV-related side effects and toxicities system damage

Drug resistance (attributable to ART failure)

Inadequate time to learn about HIV, treatment,and adherence

Increase in total time on ART; greater chance oftreatment fatigue

Current ART may be less effective or more toxicthan future therapies

Transmission of ARV-resistant virus, if incompletevirologic suppression

Potential Risks of Early Therapy(CD4 count >350 cells/µL)

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HAART at higher CD4 T-cells system damage

Treat all (regardless of CD4 count):

  • Pregnant women

  • HIV associated Nephropathy (HIVAN)

  • Co-Infection with hepatitis B, requiring treatment for HBV

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HIVAN (HIV Associated Nephropathy) system damage

  • HIVAN: Most common cause of Chronic Renal Failure in persons living with HIV infection.

  • More common in black than in white patients.

  • Not related to CD4 T-cell depletion, ongoing viral replication appears to be directly involved in renal injury.

  • Antiretroviral therapy in patients with HIVAN has been associated with preserved renal function and prolonged survival, and therefore should be initiated in individuals with diagnosis of HIVAN regardless of CD4 cell counts.

  • Keep in mind that NRTIs except Abacavir are renally excreted and so may require dose adjustment depending on creatinine clearance.

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HIV/HBV Co-Infection: system damage

  • Treat BOTH infections to prevent development of HBV resistant mutants

  • HBV resistance to lamivudine monoterapy: 40% at 2 years, 90% at 4 years

  • Elevation in transaminases: Think of IRIS vs. Antiretroviral therapy as a cause. However keep HBeAg seroconversion in mind.

  • Discontinuation of emtricitabine, lamivudine, and tenofovir may potentially cause serious hepatocellular damage resulting from reactivation of HBV

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Antiretroviral therapy system damage

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Sites of Action of ART system damage

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Considerations in Choosing Regimen system damage

  • Comorbidities

  • Adherence potential

  • Dosing convenience

  • Potential adverse effects

  • Potential drug interactions

  • Pregnancy potential

  • Results of drug resistance test

  • Gender and CD4 count, if considering nevirapine

  • HLA B*5701 testing, if considering abacavir


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Tests Prior to Initiating Therapy system damage

  • HLA-B*5701 screening

    • Recommended before starting abacavir, to reduce riskof hypersensitivity reaction (HSR)

    • HLA-B*5701-positive patients should not receive ABC

    • Positive status should be recorded as an ABC allergy

    • If HLA-B*5701 testing is not available, ABC may be initiatedafter counseling and with appropriate monitoring for HSR

  • Coreceptor tropism assay

    • Should be performed when a CCR5 antagonistis being considered

    • Consider in patients with virologic failure on aCCR5 antagonist

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ADVANTAGES system damage

Long half-lives

Less metabolic toxicity (dyslipidemia, insulin resistance) than with some PIs

PI options preserved for future use


Low genetic barrier to resistance - single mutation

Cross-resistance among most NNRTIs

Rash, hepatotoxicity, neuropsychiatric side effects

Potential drug interactions (CYP450)

Antiretroviral Components in Initial Therapy: NNRTIs


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ADVANTAGES system damage

Higher genetic barrier to resistance

PI resistance uncommon with failure (boosted PI)

NNRTI options preserved for future use


Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance)

GI intolerance

Potential for drug interactions (CYP450), especially with ritonavir

Antiretroviral Components in Initial Therapy: PIs


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ADVANTAGES system damage

Established backbone of combination therapy

Minimal drug interactions

PI and NNRTI preserved for future use


Lactic acidosis and hepatic steatosis reported with most NRTIs (rare)

Triple NRTI regimens show inferior virologic response compared with efavirenz- and indinavir-based regimens*

ARV Components in Initial Therapy: NRTIs

* Triple NRTI regimen of abacavir + lamivudine + zidovudine to be used only when a preferred or alternative NNRTI- or PI-based regimen cannot or should not be used as first-line therapy.


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Antiretroviral Components Recommended for Treatment of HIV-1 Infection in Treatment Naïve Patients


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Cardiovascular Safety of Abacavir (ABC) Infection in Treatment Naïve Patients

  • D:A:D study group reported their analysis of association of NRTI use and risk of myocardial infarction (MI)

  • A separate analysis conducted by GlaxoSmithKline using their internal database containing data from 54 clinical trials and post-marketing reports: GlaxoSmithKline did not find any evidence of an increase in cardiovascular disease in their clinical trials among patients who received ABC.

  • HEAT study: Abacavir/lamivudine noninferior to tenofovir/emtricitabine in combination with once-daily Kaletra

  • At this point, preliminary information available from these studies does not warrant a change in its current recommendations regarding the use of antiretroviral drugs in adults and adolescents

  • Clinicians should consider all available information so that the optimal therapeutic choice for each patient is based on individual patient characteristics and the potential risks and benefits of each treatment component


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ARVs Not Recommended in Initial Treatment (1) Infection in Treatment Naïve Patients

*Should not be given to pregnant women


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ARVs Not Recommended in Initial Treatment (2) Infection in Treatment Naïve Patients


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ARVs Not Recommended as Part of Infection in Treatment Naïve PatientsAntiretroviral Regimen


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Antiretroviral Regimens or Components That Should Infection in Treatment Naïve PatientsNot Be Offered At Any Time

When constructing an antiretroviral regimen for an HIV-infected pregnant woman, please consult “Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States” in http://www.aidsinfo.nih.gov/guidelines/.

When considering an antiretroviral regimen to use in post-exposure prophylaxis, please consult “Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis” in CDC MMWR Recommendations and Reports. September 30, 2005/54 (RR 09); 1–17 and “Management of Possible Sexual, Injection-Drug-Use, or Other Non-occupational Exposure to HIV, Including Considerations Related to Antiretroviral Therapy” in CDC MMWR Recommendations and Reports. January 21, 2005/54 (RR 02); 1–19.

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Should Not Be Offered at Any Time Infection in Treatment Naïve Patients

  • Efavirenz in pregnancy and in women with significant potential for pregnancy: associated with significant teratogenic effects

  • Nevirapine initiation in treatment-naïvewomen with CD4 >250 cells/mm³ or men with CD4 >400 cells/mm³: Greater risk of symptomatic, including serious and life-threatening, hepatic events have been observed in these patient groups. Nevirapine should be initiated only if the benefit clearly outweighs the risk

  • Atazanavir + indinavir: Both can cause grade 3 to 4 hyperbilirubinemia and jaundice. Additive/Worsening effect?


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Comparison of Different Classes: The Trials Infection in Treatment Naïve Patients

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NNRTI Vs PI based Regimen as Infection in Treatment Naïve PatientsFirst Line Therapy

  • A1424-034 study demonstrated comparable virologic and immunologic responses with atazanavir and efavirenz based regimens

  • ACTG A5142- better virologic responses with efavirenz based regimen compared with lopinavir/ritonavir based regimen, but better CD4 responses and less resistance following virologic failure with lopinavir/ritonavir plus two NRTIs.

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NNRTI Vs PI based Regimen as First Line Therapy Infection in Treatment Naïve Patients

  • Drug resistance to most PIs requires multiple mutations in the HIV protease, and it seldom develops following early virologic failure, especially when ritonavir boosting is used.

  • Resistance to efavirenz or nevirapine, however, is conferred by a single mutation in reverse transcriptase, and develops rapidly following virologic failure

  • In terms of convenience, NNRTI-based regimens are among the simplest to take, particularly with the coformulated tablet containing tenofovir, emtricitabine, and efavirenz, which allows for once daily dosing with a single pill.

  • PI-based Currently preferred regimens are usually used with ritonavir (Boosting), may be dosed once- or twice daily, and generally require more pills in the regimen.

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Measurement of Success of ART Regimen Infection in Treatment Naïve Patients

  • HIV RNA less than 400 copies/mL after 24 weeks

  • HIV RNA less than 50 copies after 48 weeks

  • Achieve and maintain adequate CD4 increase with virologic suppression

  • Avoidance of HIV-related events

    • After 3 months of therapy

    • Does not include immune reconstitution syndromes


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Indicators of Antiretroviral Treatment Failure Infection in Treatment Naïve Patients

  • HIV RNA greater than 400 copies/mL after 24 weeks

  • HIV RNA greater than 50 copies/mL after 48 weeks

  • Rebound in viral load after suppression

  • Failure to achieve and maintain adequate CD4 increase despite virologic suppression

  • Clinical progression of HIV despite treatment


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Drug Resistance Testing: Recommendations Infection in Treatment Naïve Patients

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Drug Resistance Testing: Recommendations (2) Infection in Treatment Naïve Patients

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Clinical Progression Infection in Treatment Naïve Patients

  • Occurrence or recurrence of HIV-related events (after at least 3 months on an antiretroviral regimen), excluding immune reconstitution syndromes

  • Management:

    • Rule out immune reconstitution syndrome which may respond toanti-inflammatory treatment

    • may not warrant a change in therapy in the setting of suppressed viremia and adequate immunologic response

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Special Issues Infection in Treatment Naïve Patients

  • Treatment Interruptions

  • Acute HIV infection

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Treatment Interruption Infection in Treatment Naïve Patients

  • No treatment interruption except if the patient is too sick or needs a surgery or part of a clinical trial

  • May cause viral rebound, immune decompensation and clinical progression, development of drug resistance, increases risk of HIV transmission

  • Increases risk of HIV and non-HIV related complications

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Short Term Interruption in ART Infection in Treatment Naïve Patients

  • In case of life threatening toxicity: Stop all drugs simultaneously

  • If it is planned short term interruption

    • When all ARVs have similar half-lives: Stop all drugs simultaneously

    • When ARVs have different half-lives: stopping all drugs at same time may result in functional monotherapy. Consider staggered discontinuation

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ART Interruptions: ARV Specific Issues Infection in Treatment Naïve Patients

  • Discontinuation of Efavirenz, Etravirine or Nevirapine: All have long half lives. Consider stopping them before the NRTI component to avoid potential mono therapy. Or Consider substitution of a NNRTI with a PI for a period of time before stopping all ARVs

  • If the Nevirapine has been discontinued for more than 2 weeks, it should be restarted with the usual dose escalation period

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Interruption of ART: ARV-Specific Issues Infection in Treatment Naïve Patients

Discontinuation of emtricitabine, lamivudine, or

tenofovir in patients with hepatitis B:

  • 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

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Fever Infection in Treatment Naïve Patients




Myalgia or arthralgia



Nausea and vomiting


Weight loss


Neurological symptoms

Acute Retroviral Syndrome: Common Signs and Symptoms

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Acute HIV Infection: Diagnosis Infection in Treatment Naïve Patients

  • Maintain high level of suspicion in patients with compatible clinical syndrome + risks

  • Plasma HIV RNA + HIV antibody test

    • Often, detectable HIV RNA with negative or indeterminate HIV antibody test

    • Low-positive HIV RNA (<10,000 copies/mL) may be false positive

    • Qualitative HIV RNA test can be used

    • If diagnosis is made by HIV RNA testing, confirmatory serologic testing should be performed subsequently

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Possible Benefits: Infection in Treatment Naïve Patients

Decrease the severity of acute disease

Alter the viral “set point”

Reduce the rate of mutation by suppressing viral replication

Preserve immune function

Reduce risk of viral transmission

Possible Risks:

Drug-related toxicity

Earlier emergence of drug resistance

Limitation of future treatment options

Potential need for indefinite treatment

Adverse effects on quality of life

Acute HIV Infection: Treatment

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Acute HIV: Treatment Regimen Infection in Treatment Naïve Patients

  • ARV regimen selection and monitoring are same as for chronic infection

  • Resistance testing (genotype) is recommended before ART selection

  • Resistance to NNRTIs is more common than resistance to PIs; consider using PI-based regimen if ART is initiated before resistance test results are available


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Websites to Access the Guidelines Infection in Treatment Naïve Patients

  • http://www.aidsetc.org

  • http://aidsinfo.nih.gov

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Thank you!! Infection in Treatment Naïve Patients