Strategies for Antiretroviral Therapy in Adults

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Strategies for Antiretroviral Therapy in Adults

• Todd S. Wills, MD
• Assistant Professor of Internal Medicine
• Division of Infectious Diseases and International
  Medicine
• University of South Florida College of Medicine

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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 are no conflicts of interest
represented in the presentation.
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Objectives

• Understand goals of antiretroviral therapy
• Learn predictors of success with long term
  antiretroviral treatment
• Outline guidelines for initiation of
  antiretroviral medications
• Review recommended and alternative initial
  antiretroviral regimens
• Summarize medications to be avoided or used with
  caution
• Discuss treatment considerations in special
  populations

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Goals of Antiretroviral Therapy

• Improvement of quality of life
• Reduction of HIV-related morbidity and mortality
• Restoration and/or preservation of immunologic
  function
• Maximal and durable suppression of viral load

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Predictors of Long Term Success

• potency of antiretroviral regimen
• adherence to treatment regimen
• low baseline viremia
• higher baseline CD4 cell count and
• rapid (i.e. gt1 log 10 in 1-4 months) reduction of
  viremia in response to treatment

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Factors Influencing Therapeutic Success
With Undetectable Viral Load
0
100

• Late disease
• Antiretroviral experienced
• Low-potency regimen
• Highly toxic regimen
• Lack of patient education

Early disease Antiretroviral naive High-potency
regimen Minimally toxic regimen Patient education
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Tools to Achieve Treatment Goals

• Selection of ARV regimen
• Preservation of future treatment options
• Rational sequencing of therapy
• Maximizing adherence
• Use of resistance testing in selected clinical
  settings

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Predictors of Inadequate Adherence

• Regimen complexity and pill burden
• Poor clinician-patient relationship
• Active drug use or alcoholism
• Unstable housing
• Mental illness (especially depression)
• Lack of patient education
• Medication adverse effects
• Fear of medication adverse effects

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POOR Predictors of Adherence

• Age, race, sex, educational level, socioeconomic
  status, and a past history of alcoholism or drug
  use do NOT reliably predict suboptimal adherence.
• Higher SES and education levels and lack of
  history of drug use do NOT reliably predict
  optimal adherence.

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Predictors of Good Adherence

• Emotional and practical supports
• Convenience of regimen
• Understanding of the importance of adherence
• Belief in efficacy of medications
• Feeling comfortable taking medications in front
  of others
• Keeping clinic appointments
• Severity of symptoms or illness

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Mechanisms to Improve Adherence

• FLEXIBILITY
• Tailoring regimen to the patient
• Establish readiness to start therapy
• EDUCATION
• Potential drug toxicities
• Importance of adherence to avoid resistance
• Reinforce positive effects of therapy
• SUPPORT and REMINDER TOOLS
• Engage family and friends
• Calendars, pillboxes, alarms

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Antiretroviral TherapyWhen to Start
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Indications for Initiation of Therapy Chronic
Infection
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Indications for Initiation of Therapy Chronic
Infection
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Benefits and Risks of Deferred Therapy

• RISKS
• Possibility of irreversible immune system
  depletion
• Increased possibility of progression to AIDS
• Possible increased risk of HIV transmission

• BENEFITS
• Avoid negative effects on quality of life
• Avoid drug-related toxicity
• Preserve future drug options
• Delay development of drug resistance
• Decrease total time on medications

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Current Antiretroviral Medications

• NRTI
• Abacavir ABC
• Didanosine DDI
• Emtricitabine FTC
• Lamivudine 3TC
• Stavudine D4T
• Zidovudine ZDV
• Zalcitabine DDC
• Tenofovir TDF
• NNRTI
• Delavirdine DLV
• Efavirenz EFV
• Nevirapine NVP

• PI
• Atazanavir ATV
• Fosamprenavir FPV
• Indinavir IDV
• Lopinavir LPV
• Nelfinavir NFV
• Ritonavir RTV
• Saquinavir SQV
• Tipranavir TPV
• Fusion Inhibitor
• Enfuvirtide T-20

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Choosing The NRTI Backbone

• Typically two drugs
• Initial therapy with thymidine-sparing drugs
• Ease of dosing
• co-formulated agents
• Consideration of renal function

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Choosing the First Regimen

• NNRTI and PI options both reasonable
• Additional Considerations
• Co-morbidities
• Sequencing Options
• NNRTI low barrier to resistance

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Important Co-Morbidities

• Cardiovascular Disease
• Lipid sparing drugs
• Hepatic Disease
• Hepatotoxicity
• Potential HBV
• co-infection
• Polypharmacy
• Drug-interactions

• Renal Disease
• Dose modifications
• Contraindicated agents
• Neuropathy
• Psychiatric Disease
• GERD
• Pregnancy/ Child Bearing Age

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Important Dose Adjustments

• NRTIs in renal insufficiency
• Dose adjustment for all except abacavir
• Didanosine when used with tenofovir
• Avoid if possible higher rate of virologic
  failure when used with NNRTI
• Atazanavir RTV when used with tenofovir

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Initial Treatment Preferred Regimens
NNRTI-Based
pills/day
PI-Based

• Avoid in pregnant women and women with pregnancy
  potential.

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Initial Treatment Alternative Regimens
NNRTI-Based
pills/day

• Avoid in pregnant women and women with pregnancy
  potential.
• Monitor closely for nevirapine-associated
  hepatotoxicity.

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Initial Treatment Alternative Regimens
PI-Based
pills/day
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Initial Treatment Alternative Regimens

PI-Based
pills/day
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Initial Treatment Alternative Regimens
NRTI-Based
pills/day
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 in Initial Therapy
NNRTIs

• ADVANTAGES
• Less dyslipidemia
• NVP better than EFV
• Less fat maldistribution than in PI-based
  regimens
• PI options preserved for future use

• DISADVANTAGES
• Resistance - single mutation
• Cross-resistance among NNRTIs
• Rash hepatotoxicity
• Potential drug interactions (CYP450)

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Antiretroviral Components in Initial Therapy PIs

• DISADVANTAGES
• Metabolic complications (fat maldistribution,
  dyslipidemia, insulin resistance)
• Greater potential for drug interactions (CYP450),
  especially with ritonavir

• ADVANTAGES
• Longest prospective data
• NNRTI options preserved for future use

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Antiretroviral Components in Initial Therapy
NRTIs

• DISADVANTAGES
• Lactic acidosis and hepatic steatosis reported
  with most NRTIs (rare)
• Triple NRTI regimens show inferior virologic
  response compared with efavirenz- and
  indinavir-based regimens

• ADVANTAGES
• Established backbone of combination therapy
• Minimal drug interactions
• PI and NNRTI preserved for future use

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NOT Recommended in Initial Treatment
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NOT Recommended in Initial Treatment
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NOT offered at any time

• Regimens not recommended
• Monotherapy (except possibly in prevention of
  perinatal HIV transmission)
• Dual NRTI therapy
• 3-NRTI regimen of abacavir tenofovir
  lamivudine
• 3-NRTI regimen of didanosine tenofovir
  lamivudine

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Monitoring Antiretroviral Therapy
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Use of HIV RNA CD4 T Cell Levels to Guide
Therapy Decisions

• Syndrome consistent with acute HIV infection
• Initial evaluation of new HIV diagnosis
• Every 3-4 months in the untreated patient
• Immediately prior to initiating therapy
• 2-8 weeks after initiating therapy
• Every 3-4 months in patients on therapy
• As clinically indicated

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Identifying Treatment Failure

• Virologic Failure
• incomplete or lack of HIV RNA response to
  antiretroviral therapy
• Incomplete Virologic Response (treatment naïve)
• repeated HIV RNA gt400 copies/mL after 24 weeks
• or gt50 copies/mL by 48 weeks
• Virologic Rebound
• repeated detection of HIV RNA after initial
  suppression
• Immunologic Failure
• failure to increase CD4 cell count by 25-50
  cells/mm3 above the baseline count over the first
  year.
• Mean expected increase approximately 150
  cells/mm3 / yr
• Clinical Progression

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Causes of Treatment Failure

• baseline patient factors
• higher pretreatment or baseline HIV RNA level
• lower pretreatment or nadir CD4 cell count
• prior AIDS diagnosis
• co-morbidities
• presence of drug resistant virus
• incomplete medication adherence
• drug side effects and toxicity
• suboptimal pharmacokinetics
• suboptimal potency of the antiretroviral regimen

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Use of Drug Resistance Testing
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Testing for Drug Resistance

• Adjunct to guide antiretroviral therapy
• Combine with obtaining a drug history and
  maximizing drug adherence
• Research supports use in certain settings
• Genotyping vs. phenotyping
• Limitations of resistance testing and specific
  indications

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Changing Treatment for Virologic Failure

• perform resistance testing
• Use the treatment history and past and current
  resistance test results to identify active agents
  (preferably 3 or more) to design a new regimen
• If three active agents cannot be identified,
  consider pharmacokinetic enhancement of protease
  inhibitors
• Adding a drug with a new mechanism of action
  (e.g. HIV entry inhibitor)
• In general, one active drug should not be added
  to a failing regimen because drug resistance is
  likely to develop quickly

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Second Regimens

• Goal of therapy remains full virologic
  suppression
• Changes typically due to toxicity or virologic
  failure
• Resistance testing crucial in guiding regimen
  changes

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Changes based on toxicity

• Best to change drugs when viral load fully
  suppressed
• Primary reasons for changes
• Intolerable, but benign, side-effects
• Hematologic abnormalities
• Metabolic abnormalities
• hepatotoxicity

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NRTI changes based on toxicity

• AZT hematologic toxicity, GI side effects,
  headaches
• D4T long term neuropathy, hyperlipidemia,
  mitochondrial toxicity, lipodystrophy
• DDI neuropathy, pancreatitis, mitochondrial
  toxicity
• ABC hypersensitivity reactions
• TDF renal failure (Fanconis syndrome)
• 3TC/FTC limited toxicity

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NRTI changes based on toxicity

• Favor change from thymidine to non-thymidine
  based drug if feasible
• AZT less implicated in long-term toxicities than
  D4T
• May consider elective therapy change prior to
  emergence of toxicity
• Beware of previous drug exposure
• ? Archived resistance

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NRTI changes due to Virologic Failure

• Guide decisions based on assessment of adherence,
  and resistance testing if feasible
• 3TC/FTC most implicated in earliest development
  of resistance
• Prolonged sub-optimal regimen increases risk for
  TAMs and may significantly compromise future
  choices
• Must consider possibility of virologic failure
  early

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3rd / Salvage Regimens

• Goal full viral suppression vs. improved viral
  control
• PK enhancement
• Therapeutic drug monitoring
• Re-treatment with prior medications
• Multi-drug regimens (limited by complexity,
  tolerability)
• New ARV drugs, e.g., enfuvirtide, tipranavir,
  TMC-114, investigational drugs
• Treatment interruptions not recommended

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Immune Restoration Syndrome

• Collection of inflammatory disorders associated
  with paradoxical worsening of preexisting
  infectious processes following ART in HIV
  infected patients

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Diagnostic criteria Immune Restoration

• AIDS with low pre treatment CD4 count except TB
• Rapid virological response to ART with decrease
  of the VL and increase of CD4
• Association between ART and the clinical features
  of the illness
• Clinical manifestation of inflammatory condition
• Absence of drug resistant infection, bacterial
  superinfection or drug allergy

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Immune Restoration Syndrome - Management

• Treatment of the underling opportunistic
  infection
• Continue ART if possible. D/C ART if life
  threatening immune restoration syndrome and treat
  the underliying infection for a period of time
  before resuming ART (not an option in PML)
• Corticosteroids and NSAIDs

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Special Populations
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Death from End-Stage Liver Disease HIV
patients
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Hepatitis B Co-Infection

• Not candidate for HIV treatment by CD4 (CD4 gt350
  in US)
• Consider treatment with agent active only against
  HBV
• Interferon alfa, adefovir
• Candidate for both HIV/HBV treatment
• Agents active against HIV and HBV
• Lamivudine, emtricitabine, tenofovir
• Combination therapy vs. HBV if possible

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Hepatitis C Co-Infection

• Combination therapy
• Ribavirin (1000 1200 mg/d) PLUS
• Interferon (IFN)
• Conventional IFN 3 million units 3x/wk
• Pegylated IFN alfa 2b (1mg/kg/wk)
• Pegylated INF alfa 2a (180 mg/wk)
• 48 week treatment course regardless of genotype
  in HIV patients
• HCV treatment preceding HAART may decrease
  antiretroviral related liver function
  abnormalities
• ARVs prior to HCV treatment when CD4 count is low
  improves eventual response to HCV therapy

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Women of Child Bearing Age

• goals of treatment are the same as for other
  adults and adolescents
• Efavirenz should be avoided if
• desire for pregnancy
• Patient does not use effective and consistent
  contraception.
• For the woman who is pregnant, an additional goal
  of therapy is prevention of mother-to-child
  transmission (PMTCT)
• goal of viral suppression to lt1,000 copies/mL
• Clinicians should consult the most current PHS
  guidelines when designing a regimen for a
  pregnant patient

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Conclusions

• Antiretroviral therapy improves clinical outcomes
  in patients with HIV infection
• Therapy success depends on patient adherence and
  medication potency
• Short- and Long-term drug toxicities should be
  considered in treatment decisions
• Monitoring of CD4 count and viral load allows for
  early detection of virologic failure and
  treatment changes as appropriate
• Resistance testing is an important tool for
  constructing antiretroviral regimens after
  treatment failure

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CASES
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ARV Management Case

• 32y/o Asian MSM male last HIV test 4 yrs. ago
  presents now newly diagnosed HIV with CD4 230
  cells/mm3 and HIV-1 RNA of 824,000 copies/mL
  repeated and confirmed in this range within 30
  days of 1st visit.
• Hepatitis C Neg, Hepatitis B surface antigen
  with HBV DNA level of gt4.5 log10 copies/mL.
• Family history of Diabetes, FBS is normal

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ARV Management Case

• Pt. c/o fatigue but no other sxs.
• Occasional THC and daily alcohol.
• Because of his work schedule he admits adhering
  to AM meds will be troublesome with his rush to
  get to work
• He agrees though to begin CART but fears
  lipodystrophy signs he has seen in friends on ARV
  therapy.

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ARV Management Case

• Which of the following regimens do you recommend?
• Tenofovir/emtricitabine FDC Efavirenz
• Abacavir/lamivudine Nevirapine
• Zidovudine/lamivudine FDC lopinavir/ritonavir

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ARV Management Case

• At week 12, patient admits cocaine use on
  weekends and non-compliance with ARV. Drug and
  ETOH counseling begins
• At week 28, VL is 3124 copies/mL and CD4 is 355
  cells/mm3.
• HBV has declined to 2 log10 copies/mL (original
  4.5 log10)
• A genotype is ordered

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ARV Management Case

• Genotype test reveals
• RTI mutation K65R, L100I, K103N, and M184V.

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ARV Management Case

• The treatment team considers his extensive drug
  and adherence counseling to be fairly successful,
  and you decide to change his regimen without
  further delay.

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Which of the following new regimens do you
recommend?

• Zidovudine/lamivudine/abacavir fosamprenavir
• Tenofovir/emtricitabine Zidovudine
  atazanavir/ritonavir
• Tenofovir stavudine lopinavir/ritonavir

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ARV Management Case

• The patient feels well but has scleral icterus
• Bilirubin level is 6.6 mg/dL his indirect
  bilirubin level is 6.1 mg/dL
• You reassure the patient that this is only a
  cosmetic problem, and he agrees to wait and see
  if it resolves.
• After 16 weeks the icterus is somewhat better.
  Indirect bilirubin is 4.8 mg/dL,
• His boss is complaining about his appearance
  because he has to interact with customers.

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ARV Management Case

• He has been frequently missing doses due to his
  concern about his yellow eyes.
• HIV-1 RNA viral load is 1200 copies/mL and his
  CD4 cell count is 461 cells/mm3
• A genotype reveals
• same reverse transcriptase mutations
• protease mutation, N88S.

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Which of the following regimens do you recommend
now?

• Discontinue atazanavir continue
  tenofovir/emtricitabine and zidovudine
• Discontinue atazanavir continue
  tenofovir/emtricitabine and zidovudine add
  fosamprenavir/ritonavir
• Discontinue atazanavir discontinue
  tenofovir/emtricitabine continue zidovudine add
  tenofovir add lopinavir/ritonavir

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Case Summary

• Choose regimens addressing the patients schedule
  and concerns
• Once daily dosing when possible
• Combination therapy for hepatitis B is likely to
  be more effective, although not yet proven
• Resistance testing at regimen failure to guide
  future regimen selection.