Advances In HIV Treatment: HAART And Its Complications

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Advances In HIV Treatment HAART And Its
Complications

• Amy V. Kindrick, M.D., M.P.H.
• National HIV/AIDS Clinicians Consultation Center
• April 26, 2003

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Overview

• New concepts and strategies in HIV antiretroviral
  therapy
• Long-term toxicities of ARV therapy
• New and investigational ARV agents
• New strategies for OI management
• Common management challenges

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Typical CD4 Response to HAART
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Challenges of HAART

• Complexity
• Toxicity
• Accessibility
• Incomplete efficacy
• Viral resistance

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Whats a Clinician to Do?

• Expanding number of agents adds complexity
• Minimal clinical experience when drugs released
  adds toxicity risk
• Shortage of outcomes data adds uncertainty

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New ARV Treatment Strategies and Concepts

• Adherence to treatment
• ARV resistance and resistance testing
• Interrupting ARV therapy
• Treating primary HIV infection

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Adherence

• Drugs dont work if people dont take them.
• C. Everett Koop

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Reasons for Non-Adherence Clinician vs Patient
Views
Chesney M. Adherence to antiretroviral therapy.
12th World AIDS Conference, 1998 Geneva. Lecture
281
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Viral Suppression And Adherence By Refill Records
N 504 pts on HAART
Achieving lt500 copies/mL
Adherence, by prescription refill
Montessori, V, et al. XII International
Conference on AIDS, Durban, South Africa, 2000.
Abstract MoPpD1056.
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Measuring Adherence Electronic Bottle Caps

• Caps harbor chips that register each time a
  bottle is opened or closed

MEMScaps, Aardex Corp.
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Viral Suppression And Adherence By MEMS
Patients with HIV RNAlt400 copies/mL,
PI adherence, (electronic bottle caps)

Paterson, et al. 6th Conference on Retroviruses
and Opportunistic Infections 1999 Chicago, IL.
Abstract 92.
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Adherence and AIDS-Free Survival
10 adherence difference 21 reduction in risk
of AIDS
1.00
0.75
Proportion AIDS-Free
0.50
0.25
P .0012
0.00
0
5
10
15
20
25
30
Months from entry
Bangsberg D, et al. AIDS. 2001151181
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Why Does HAART Fail?
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ARV Resistance
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What Is Resistance?

• Viral replication in the presence of drug pressure

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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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How Does Resistance Develop?

• High replication and transcription error rates
  generate mutant HIV variants
• Spontaneously generated variants often contain
  mutations that confer survival advantage in the
  presence of antiretroviral agents
• Poor adherence or suboptimal regimens can lead to
  resistance and viral breakthrough

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HIV-1 Quasi Species in Untreated and Treated HIV
InfectionHeterogeneity vs. Selection of
Resistant Strains
acute
chronic
AIDS
Plasma viremia
Time
V. Simon, MD
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Development of Drug Resistance
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Antiretroviral Resistance Testing

• Goals
• Improve virologic control and immunologic benefit
• Minimize exposure to ineffective agents
• Options
• Genotype
• Phenotype
• Virtual phenotype

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Definitions

• Genotype
• Virus nucleotide sequence from which a proteins
  amino acids can be deduced
• Mutations reported as change in the deduced amino
  acid sequence, e.g., Met184Val
• Specific mutations confer phenotypic resistance
• The phenotype is always derived from the genotype
• Phenotype
• Relative growth of the virus in the presenceof
  different drug concentrations
• Usually reported as the drug concentration that
  inhibits virus replication by 50 (IC50), or the
  fold increase in IC50

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Genotype Vs Phenotype
Strengths
Weaknesses
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HIV Drug Resistance Assays DHHS Recommendations
Recommended
Optional
Not Generally Recommended
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Resistance Testing Factors

• Cost
• Time
• Access
• Technical limitations
• Thresholds
• Partial resistance
• Mutations yet to be identified
• New drugs
• Different sequence regions for old drugs
• Uncertain clinical impact

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Complications Of HIV And ARV Therapy
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Long-Term Complications of HIV and ARV Therapy

• Body habitus changes
• Insulin resistance/hyperglycemia/diabetes
• Hyperlipidemia
• Lactic acidosis
• Hepatic steatosis
• Osteopenia
• Avascular necrosis

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Abnormal Fat Redistribution

• Syndromes
• Abnormal fat accumulation
• Buffalo hump
• Increased abdominal girth
• Increased breast size
• Peripheral fat wasting
• Sunken cheeks
• Thin extremities
• Prominent peripheral musculature and veins
• Prevalence unknown (est. 2 to 80)
• Increased with duration of HIV infection ARV tx
  
• Associated with PI and NRTI use
• Mechanism unknown

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Fat Redistribution Syndromes
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Cervico-dorsal Fat Pad
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Central Fat Accumulation
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Facial Lipoatrophy
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Abnormal Insulin and Glucose Metabolism

• Associated with ARVs, especially PIs
• Mechanism unclear
• ?PI inhibition of glut-4 transporter
• Risk factors
• Older age
• African American ethnicity
• Clinical syndromes
• Insulin resistance
• Hyperglycemia
• Type 2 diabetes
• Treat as usual

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Hyperlipidemia

• Mechanism unknown
• Prevalence
• Clinical syndromes
• Hypertriglyceridemia
• Hypercholesterolemia
• Mixed
• ? Impact on CV risk
• Manage per AHA guidelines

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Hyperlipidemia Treatment Considerations

• Risk of increased insulin resistance with niacin
• Increased risk of myopathy and rhabdomyolysis
• Interactions between ARVs and statins
• Prefer pravastatin or atorvastatin
• Avoid lovastatin and simvastatin
• Interactions between statins and fibrates
• May respond to ARV change

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Lactic Acidosis And Hepatic Steatosis

• Class toxicity of NRTIs (Black Box warning)
• Incidence est. 4/1000 patient-years
• Risk factors
• Older age
• Female gender
• ddI, ddC, or d4T use gt 3 months
• ddId4T in pregnancy

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Lactic Acidosis Clinical Presentation

• Acute or subacute onset
• Varying symptoms, including
• Malaise a/o fatigue
• Abdominal pain
• Nausea a/o vomiting
• Anorexia
• Hepatomegaly
• Breathlessness

• Abnormal laboratory values
• Elevated serum lactate
• Anion gap
• Transaminitis
• Low serum bicarbonate
• Elevated amylase/lipase

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Management Of Lactic Acidosis

• Be alert to symptoms
• Stop ARVs if symptomatic and lactate elevated
• May consider continuing ARVs if
• Symptoms absent or mild
• Lactate only minimally elevated (e.g., 2-4
  mmol/l)
• ddI, d4T can be replaced
• Anecdotal treatments for mild disease
• L-carnitine
• Riboflavin
• Thiamine

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Delayed Onset NRTI Toxicity

• Hypothesized due to toxic effects of NRTIs on
  human mitochondria
• NRTIs inhibit DNA polymerase ? required for mDNA
  synthesis
• Clinical syndromes
• Pancreatitis
• Myopathy
• Peripheral neuropathy
• Bone marrow toxicity
• D drugs especially implicated

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Avascular Necrosis of the Hip
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Osteopenia and Avascular Necrosis of the Radial
Head
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Changing TherapyConsiderations

• Recent clinical history and physical examination
• Two plasma HIV RNA levels
• CD4 T cell count
• Remaining treatment options

• Drug failure or drug toxicity?
• Medication adherence
• Pharmacology drug interactions
• Resistance profile
• Patient preference

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Should Failing HAART Be Stopped?

• Better to stay on some ARV regimen than none
• Resistance mutations may impair viral fitness
• Specific mutations may enhance response to
  specific ARV agents
• CD4 count gains may be sustained despite
  incomplete viral suppression

Deeks, et al. NEJM 2/15/01
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Antiretroviral Therapy Persistent Uncertainties

• When to start
• What to start with
• When to change
• What to change to
• When to stop (if ever)

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ARV Treatment Interruption
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Treatment Interruption Rationale

• Enhance HIV-specific immune response
• In primary infection
• In chronic infection
• Reduce treatment-associated complications
• Toxicity
• Cost
• Treatment fatigue

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Treatment Interruption Target Groups

• ARV treatment fully suppressive
• Started during acute infection
• Started after infection chronic
• ARV treatment not fully suppressive

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Structured Treatment Interruptions
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Treatment Interruptions Real Risks And
Theoretical Benefits

• Real Risks
• Loss of viral suppression
• Development of resistance
• Repopulation of reservoirs
• Acute antiretroviral syndrome
• CD4 cell decline
• Loss of immune responses
• Pharmacokinetic issues
• Increased transmission
• Disease progression
• Death

• Theoretical Benefits
• Reduced drug exposure
• Minimize resistance
• Minimize toxicity
• Maximize tolerability
• Reduced costs
• Increased access to drugs
• Improved adherence
• Better QOL
• Enhanced immune function
• Long-term viral control off ARVs

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Structured Treatment Interruptions Conclusions

• Still experimental
• Rapidly evolving field
• Stay tuned!

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ARVs For Acute HIV Infection
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Primary HIV Infection Rash
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Primary HIV Infection Oral Ulcers
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Natural History of HIV Infection
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The Berlin Patient
Lisziewicz J et al. NEJM 1999 340 1683-1684.
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ARV Therapy for Primary Infection

• Pros
• May prevent immune system damage
• May allow control of viremia without ARVs

• Cons
• No obvious end point
• Risk of cumulative ARV toxicity
• Risk of suboptimal adherence leading to emergence
  of resistance

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New ARV Agents
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New ARV Agents

• T-20
• Atazanavir
• Capravirine
• Phos-Amprenavir
• Tipranivir

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New OI Management Strategies

• Stopping primary prophylaxis
• Stopping secondary prophylaxis
• Immune restoration syndromes

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Common Management Challenges

• Coinfection with viral hepatitis
• More rapid hepatitis progression
• Increased risk of ARV-associated hepatotoxicity
• Increased risk of toxicity associated with
  hepatitis treatment
• Pregnancy
• Tolerability
• Teratogenicity
• Metabolic toxicity
• Transmission

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Resources for HIV/AIDS Clinicians

• Handbooks
• Sanford Guide to HIV/AIDS Therapy
• The Medical Management of HIV Infection
• Internet
• HIV InSite (http//hivinsite.ucsf.edu)
• Medscape (www.medscape.com)
• HIV/AIDS Treatment Information Service
  (www.hivatis.org)
• Johns Hopkins (www.hopkins-aids.edu)
• National HIV/AIDS Clinicians Consultation Center
  (www.ucsf.edu/hivcntr)

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Consultation Services For HIV/AIDS Clinicians

• Local expert clinicians
• Regional and local AIDS Education and Training
  Centers
• National HIV Telephone Consultation Service
  (Warmline)
• [phone]
• National Clinicians Post-Exposure Prophylaxis
  Hotline (PEPline)
• (888) HIV-4911

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National HIV/AIDS Clinicians Consultation Center

• A Joint Program of UCSF
• and San Francisco General Hospital
• Supported by HRSA and CDC
• http//www.ucsf.edu/hivcntr
• Akindrick_at_nccc.ucsf.edu
• PEPLine [phone]
• Warmline [phone]

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