What Every Internist Should Know about HAART

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What Every Internist Should Know About HAART in
2003
Christopher Mathews, M.D. Director, Owen
Clinic University of California, San Diego
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Outline

• Historical milestones in HIV treatment
• Current treatment strategies
• Drug toxicities
• Resistance testing
• Drug interactions
• Medication Adherence
• Immune Recovery Inflammatory Diseases
• Resources for staying up to date

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Milestones of Therapy

• Licensure of antiretroviral agents in the United
  States
• Trends in virologic suppression among patients
  under care
• Trends in mortality

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Proportion of Patients with Undetectable Viral
Load, by Quarter Year
1.00
0.80
0.60
Proportion lt400 copies
0.40
0.20
1997Q1
1998Q1
1999Q1
2000Q1
2001Q1
2002Q1
Time in Quarter Years
Proportionlt400 copies,Owen Clinic, n4438
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Trends in Survival, Owen Clinic, 1990-1998
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Antiretroviral Treatment Strategies

• Viral targets for antiretroviral therapy
• Rationale for and timing of antiretroviral
  treatment

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HIV Life Cycle
Step 1 Fusion
Step 3 Integration
reverse transcriptase
HIV
Step 5 Packaging and Budding
Step 2 Transcription
Step 4 Cleavage
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Prognosis without HAART
Viral load gt60,000 20 - 60,000 6 - 20,000 1 -
5,000 lt1000
3-year probability of AIDS in 1604 men enrolled
in the Multicenter AIDS Cohort Study (MACS)
1984-1985 from Mellors Ann Int Med 1997
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Considerations in Initiating Therapy HIV
Asymptomatic

• Theoretical benefit
• No proven long-term clinical benefit for CD4 gt200
  cells/ml3
• Expert opinion advises initiation of therapy for
  CD4 lt350 cells/ml3 at any viral load
• Consider the viral load when gt 350 cells/ml3 CD4
  T cell
• The downside of antiretroviral regimens
• ? QOL
• Short- and long-term toxicities

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Risks and Benefits of Delayed Initiation of
Therapy

• Benefits of delayed therapy
• Avoid negative effects on quality of life (e.g.
  inconvenience)
• Avoid drug-related adverse events
• Delay in development of drug resistance
• Preserve maximum number of available and future
  drug options when HIV disease risk is greatest
• Risks of delayed therapy
• Possible risk of irreversible immune system
  depletion
• Possible greater difficulty in suppressing viral
  replication
• Possible increase risk of HIV transmission

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Risks and benefits of early initiation of therapy

• Benefits of early therapy
• Control of viral replication easier to achieve
  and maintain
• Delay or prevention of immune system compromise
• Lower risk of resistance with complete viral
  suppression
• Possible decreased risk of HIV transmission
• Risks of early therapy
• Drug-related reduction in quality of life
• Greater cumulative drug-related adverse events
• Earlier development of drug resistance, if viral
  suppression is suboptimal
• Limitation of future antiretroviral treatment
  options

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Goals of Therapy

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

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Tools to Achieve Goals of Therapy

• Maximize adherence to the antiretroviral regimen
• Rational sequencing of drugs
• Preservation of future treatment options
• Use of resistance testing in selected clinical
  settings

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Considerations in Initiating Therapy HIV
Asymptomatic

• Willingness of patient to begin and the
  likelihood of adherence
• Degree of immunodeficiency
• Plasma HIV RNA
• Risk of disease progression
• Potential risks and benefits

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Indications for ART in the Chronically
HIV-Infected Patient

• TREAT ALL
• (regardless of viral load)
• Symptomatic (AIDS, severe symptoms)
• Asymptomatic, CD4 lt200 cells/mm3
• Asymptomatic, CD4 gt200/mm3 but lt350 cells/ mm3
  
• Treatment should generally be offered, though
  controversy exists

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Indications for ART in the Chronically
HIV-Infected Patient

• TREAT
• Asymptomatic,
• CD4 gt350/mm3 and
• HIV RNAgt55,000(RT-PCR or bDNA)
• Some experts would recommend initiating
  therapy, recognizing that the 3 year risk of
  developing AIDS in untreated patients is gt30.
  In the absence of very high levels of plasma HIV
  RNA, some would defer therapy and monitor the
  CD4 and level of plasma HIV RNA more frequently.
  Clinical outcomes data after initiating therapy
  are lacking.

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Indications for ART in the Chronically
HIV-Infected Patient

• DEFER TREATMENT
• Asymptomatic
• CD4 cells gt 350/mm3
• HIV RNA lt55,000(RT-PCR or bDNA)
• Many experts would defer therapy and observe,
  recognizing that the 3 year risk of developing
  AIDS in untreated patients is lt15.

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Initial TreatmentStrongly Recommended
One Choice Each From Column A and B

• Column B
• Didanosine Lamivudine
• Stavudine Lamivudine
• Stavudine Didanosine
• Zidovudine Lamivudine
• Zidovudine Didanosine

• Column A
• Efavirenz
• Indinavir
• Nelfinavir
• Ritonavir Saquinavir (SGC or HGC)
• Ritonavir Lopinavir
• Ritonavir Indinavir

Saquinavir-SGC, soft-gel capsule (Fortovase)
Saquinavir-HGC, hard-gel capsule (Invirase)
Co-formulated as Kaletra Based largely on
expert opinion
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Initial TreatmentAlternative Recommendation
One Choice Each From Column A and B

• Column A
• Abacavir
• Amprenavir
• Delavirdine
• Nelfinavir Saquinavir-SGC
• Nevirapine
• Ritonavir
• Saquinavir-SGC

• Column B
• Zidovudine Zalcitabine

• CONTRAINDICATED
• ART monotherapy
• Zidovudine and Stavudine
• exception for prevention of perinatal
  transmission (see ACOG guidelines)

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The Advantage of Sequencing Drugs

• To extend the overall long-term effectiveness of
  the available therapy options
• Delay the risk of certain side effects uniquely
  associated with a single class of drugs
• Anticipates up to 50 of failure rate and
  preserves future treatment options

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(Perrin Telenti. Science 19982801871-1873)
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Nucleoside Analogues (NAs) or NRTIs
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Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
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Protease Inhibitors (PIs)
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Dual Protease Inhibitor Combinations

• Exploits the enzyme inhibition properties of
  PIs, specifically RTV
• Lessens pill burden
• Theoretical ability to suppress resistant HIV
  strains by enhancement of PI plasma levels

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Basic Pharmacology Principles
Cmax
Drug Level
Cmin
IC90
Area of Potential HIV Replication
IC50
Dosing Interval
Time
Dose
Dose
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Indinavir/Ritonavir Pharmacokinetics
10,000
IDV/RTV q12h 800/200 High-fat Meal
800/100 High-fat Meal 400/400 High-fat
Meal IDV q8h 800 mg Fasted
IndinavirPlasmaConcentration(nM)
1,000
100
0
2
4
6
8
10
12
Time Postdose (hours)
6th Conference on Retroviruses and Opportunistic
Infections 1999. Abstract 362.
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Selected Antiretroviral Agent Toxicities

• Nucleoside analogs
• Mitochondrial toxicity
• Abacavir hypersensitivity
• Non-nucleoside RT inhibitors
• Nevirapine hepatotoxicity
• Protease inhibitors
• Lipodystrophy
• Metabolic abnormalities
• Indinavir nephropathy

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Mitochondrial Toxicity Syndromes

• Hyperlactatemia or lactic acidosis
• Hepatic steatosis
• Non-specific GI symptoms (bloating, nausea)
• Mild transaminase elevation
• Due to nucleoside analog HIV reverse
  transcriptase inhibitor therapy (D4T most
  commonly)
• May have normal anion gap despite elevated
  lactate.

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Abacavir hypersensitity

• Occurs in up to 5 of patients
• Most common symptoms
• Fever, rash, nausea, malaise/fatigue, GI symptoms
• Respiratory symptoms may occur
• Onset usually first two weeks of therapy
• Symptoms worsen with each dose
• Can be fatal if continued or restarted
• NEVER re-challenge
• Patient counseling and follow-up mandatory
• HLA association

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Nevirapine Hepatotoxicity

• September 2000 two instances of life-threatening
  HEPATOTOXICITY in health-care workers taking NVP
  for PEP reported to CDC
• One of the two HCWs required a liver
  transplantation for fulminant hepatic failure
• Serious adverse effects associated with
  NVP-containing PEP regimens reported in 22 cases
  (16 occupational expsures)

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Protease Inhibitors Toxicities

• Hepatotoxicities
• especially with HCV coinfection
• Lipodystrophy
• Lipid abnormalities (?T total chol,
  ?triglycerides, ? HDL)
• Hyperglycemia, insulin resistance

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HAART Toxicities Lipodystrophy

• Body habitus changes
• Central fat accumulation
• Peripheral fat wasting
• Mixed pattern
• Risk factors
• female gender (maybe get it worse)
• older age
• HAART
• Protease Inhibitor use

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Dorsocervical fat pad (buffalo hump) in
HAART-treated patient
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Dorsocervical fat pad and gynecomastia in patient
on HAART
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Peripheral Lipoatrophy
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Facial Lipoatrophy
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HIV/HAART Toxicities Lipid Abnormalities

• Hypertriglyceridemia risk of pancreatitis
• Low HDL, high LDL
• Increased CAD not yet documented
• Generally treated w/ fibrates and/or statins
• Inconsistent results from switch studies
• Beware of CYP p450 drug interactions, risk of
  myositis and hepatitis

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HIV/HAART Toxicities Insulin Resistance

• Progression to frank diabetes mellitus possible
• Monitor with fasting glucose values
• Improvement often seen with switching from
  PI-based regimens
• Some success w/ metformin (Glucophage), although
  caution advised if on NRTIs with mitochondrial
  toxicity potential

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HIV-1 Drug Resistance Testing Clinical
Applications
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Technical Considerations Phenotype Assay Genotype Assay
Laboratory Requirements Both tests require highly specialized laboratories Both tests require highly specialized laboratories
Measurement Measures ability of patient virus-derived, PCR-amplified RT and protease to replicate in presence of specific drugs Measures genetic structure of the protease and RT genes
Availability and Cost 2 commercially available assays Antivirogram (Virco) PheonSense (Virologic) Cost 800 Multiple laboratories, kit-based or home brew Less expensive 350-500
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Technical Considerations Phenotype Assay Genotype Assay
Turn-around time Virologic 14 days Virco 4 weeks 10-14 days
Reproducibility Highly reproducible Repeat results vary lt2.5 fold from initial value Highly reproducible, but only with strict adherence to laboratory standards and experienced laboratory personnel Interlaboratory reproducibility varies from 50 to 99.6
Minimum RNA level to perform assay 500-1000 copies/mL 1000 copies/mL
Relationship between genotype and phenotype Concern how complex mutation patterns relate to phenotype Rule based vs. database derived genotypic interpretation (Virtual Phenotype) Concern how complex mutation patterns relate to phenotype Rule based vs. database derived genotypic interpretation (Virtual Phenotype)
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Assay Advantages Disadvantages
Genotypic Relatives simple to perform Widely available More rapid turn-around time Less expensive More sensitive for early resistance Use may improve virologic outcome Indirect measure of susceptibility Requires samples with plasma HIV RNA gt 1000 copies/mL Can only identify mutations that have been described and characterized complex interactions between mutations make interpretation difficult Insensitive to presence of minor variants May not correlate with phenotype False positives from lab contamination carryover
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Assay Advantages Disadvantages
Phenotypic Direct measure of susceptibility that assess net effect of mutations on drug susceptibility Provides data on cross-resistance More familiar results, intuitive to understand More useful when there are multiple mutations in both RT and protease Use on phenotyping may improve virologic outcome Insensitive to presence of minor variants Clinically significant cut-off values incompletely defined Time-consuming and expensive to perform Complexity of assays limits availability outside a few laboratories Slow turn-around time
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Take home messages

• Resistance testing is most useful in determining
  if a reason for current regimen failure is
  resistance
• Implication Test on a stable regimen for at
  least 1 month
• Susceptibility to an agent the patient previously
  took but is not currently on does not rule out
  resistance
• Reversion to wild type

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Take home messages

• Resistance tests evaluate the predominant
  circulating quasispecies
• Detection of minor species varies by drug and by
  laboratory (ENVA-2 data)
• Interpretations of mutational patterns
  (genotypes) are ruled-based
• in vitro susceptibility (phenotype) may vary
  considerably among samples with same genotype
  pattern

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Take home messages

• Susceptibility cutoffs on phenotype reports
  have not been uniformly validated against
  clinical response
• Sometimes a drug will work even though the report
  suggests reduced susceptibility (e.g. by
  increasing Cmin through pharmacologic boosting
  strategies)

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Take home messages

• Situations when a drug might be used even though
  resistance is highly likely
• Continue 3TC to enhance response to tenofovir or
  adefovir or ZDV
• Continue 3TC if patient also has Hepatitis B
• Maintain drug selection of resistant but less fit
  virus

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Take home messages

• Gene charts (rules for interpreting genotype
  patterns) may not yet reflect evolving knowledge
  of new mutations, transitional mutations and
  complex mutational interactions

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Take home messages

• Resistance is not the only reason for regimen
  failure
• Adherence
• Drug interactions
• Pharmacologic factors
• phosphorylation inhibition/competition
• cellular factors (P-glycoprotein)
• protein binding
• Regimen potency

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Antivirogram Report
All 14 approved NRTIs, NNRTIs PIs reported
(plus adefovir)
Richman, 11/99
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VircoGEN II
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Richman, 11/99
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Drug Interactions and Cytochrome p450 Systems
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Cytochrome P-450, HIV-1 Protease Inhibitors and
NNRTIs
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Drug Interactions and PK

• Never prescribe a new drug to a patient on
  antiretroviral therapy without first checking for
  potential drug interactions
• Be aware of variable pharmakokinetic patterns
  among antiretroviral agents
• e.g. Stopping all drugs at once may result in
  functional monotherapy for several days with
  NNRTIs

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Treatment Adherence
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Treatment Adherence(Altice Friedland. Ann
Intern Med 1998129503-505)

• compared with therapies for other chronic
  diseases, which are often forgiving of lapses in
  adherence, HIV therapy is unforgiving.
• Nonadherence may mean
• Not taking medication at all
• Taking reduced amounts
• Not taking doses at prescribed frequencies or
  intervals
• Not matching medication to food requirements

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Factors affecting Adherence (Mehta et al,AIDS,
1997)

• Demographics
• Psychiatric illness
• Substance Abuse
• Health beliefs
• benefits
• risksside effects
• barriers
• suspectibility/severity
• cues to action
• self efficacy

• Social support
• Motivation
• Knowledge
• Regimen complexity
• Provider interactions
• Extrinsic factors
• cost
• access
• Symptoms

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Average Treatment Completion, by Week after ART
Start or Change, Owen Clinic 1998
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Immune Recovery Inflammatory Diseases
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Table 1 Clinical Presentation of Specific
Opportunistic Infections in HIV-1-infected
Patients with and without Highly Active
Antiretroviral Therapy
DeSimone et al. Ann Intern Med 2000133447-454
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Good Web Sites for Physician Education about HIV
Care

• AIDS Education and Training Centers
• www.aidsetc.org
• HIV/AIDS Treatment Information Services
• http//www.aidsinfo.nih.gov/
• Johns Hopkins AIDS Service
• http//www.hopkins-aids.edu
• HIV insite
• http//hivinsite.ucsd.edu
• JAMA HIV/AIDS Information Center
• http//www.ama-assn.org/special/hiv/hivhome.htm