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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. Overview. New concepts and strategies in HIV antiretroviral therapy Long-term toxicities of ARV therapy

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advances in hiv treatment haart and its complications

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

overview
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
challenges of haart
Challenges of HAART
  • Complexity
  • Toxicity
  • Accessibility
  • Incomplete efficacy
  • Viral resistance
what s a clinician to do
What’s 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
new arv treatment strategies and concepts
New ARV Treatment Strategies and Concepts
  • Adherence to treatment
  • ARV resistance and resistance testing
  • Interrupting ARV therapy
  • Treating primary HIV infection
adherence

Adherence

“Drugs don’t work if people don’t take them.”

C. Everett Koop

reasons for non adherence clinician vs patient views
Reasons for Non-Adherence: Clinician vs Patient Views

Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281

viral suppression and adherence by refill records
Viral Suppression And Adherence By Refill Records

N = 504 pts on HAART

% Achieving <500 copies/mL

Adherence, by prescription refill

Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056.

measuring adherence electronic bottle caps
Measuring Adherence: Electronic Bottle Caps
  • Caps harbor chips that register each time a bottle is opened or closed

MEMScaps, Aardex Corp.

viral suppression and adherence by mems
Viral Suppression And Adherence By MEMS

Patients with HIV RNA<400 copies/mL, %

PI adherence, % (electronic bottle caps)

Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.

adherence and aids free survival

Adherence

O 90–100%

O50–89%

O 0–49%

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. 2001:15:1181

what is resistance
What Is Resistance?
  • Viral replication in the presence of drug pressure
basic pharmacology principles
Basic Pharmacology Principles

Cmax

Drug Level

Cmin

IC90

Area of Potential HIV Replication

IC50

Dosing Interval

Time

Dose

Dose

how does resistance develop
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’
slide25
HIV-1 Quasi Species in Untreated and Treated HIV Infection:Heterogeneity vs. Selection of Resistant Strains

chronic

AIDS

acute

Plasma viremia

Time

V. Simon, MD

antiretroviral resistance testing
Antiretroviral Resistance Testing
  • Goals
    • Improve virologic control and immunologic benefit
    • Minimize exposure to ineffective agents
  • Options
    • Genotype
    • Phenotype
    • “Virtual phenotype”
definitions
Definitions
  • Genotype
    • Virus nucleotide sequence from which a protein’s 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
genotype vs phenotype
Genotype Vs Phenotype

Strengths

Weaknesses

hiv drug resistance assays dhhs recommendations
HIV Drug Resistance Assays: DHHS Recommendations

Recommended

Optional

Not Generally Recommended

resistance testing factors
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
long term complications of hiv and arv therapy
Long-Term Complications of HIV and ARV Therapy
  • Body habitus changes
  • Insulin resistance/hyperglycemia/diabetes
  • Hyperlipidemia
  • Lactic acidosis
  • Hepatic steatosis
  • Osteopenia
  • Avascular necrosis
abnormal fat redistribution
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
abnormal insulin and glucose metabolism
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
hyperlipidemia
Hyperlipidemia
  • Mechanism unknown
  • Prevalence
  • Clinical syndromes
    • Hypertriglyceridemia
    • Hypercholesterolemia
    • Mixed
  • ? Impact on CV risk
  • Manage per AHA guidelines
hyperlipidemia treatment considerations
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
lactic acidosis and hepatic steatosis
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 > 3 months
    • ddI+d4T in pregnancy
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

Lactic Acidosis: Clinical Presentation
management of lactic acidosis
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
delayed onset nrti toxicity
Delayed Onset NRTI Toxicity
  • Hypothesized due to toxic effects of NRTIs on human mitochondria
    • NRTIs inhibit DNA polymerase γ required for mDNA synthesis
  • Clinical syndromes
    • Pancreatitis
    • Myopathy
    • Peripheral neuropathy
    • Bone marrow toxicity
  • “D” drugs especially implicated
changing therapy considerations
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

Changing Therapy:Considerations
should failing haart be stopped
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

antiretroviral therapy persistent uncertainties
Antiretroviral Therapy: Persistent Uncertainties
  • When to start
  • What to start with
  • When to change
  • What to change to
  • When to stop (if ever)
treatment interruption rationale
Treatment Interruption Rationale
  • Enhance HIV-specific immune response
    • In primary infection
    • In chronic infection
  • Reduce treatment-associated complications
    • Toxicity
    • Cost
    • Treatment fatigue
treatment interruption target groups
Treatment Interruption Target Groups
  • ARV treatment fully suppressive
    • Started during acute infection
    • Started after infection chronic
  • ARV treatment not fully suppressive
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

Treatment Interruptions: Real Risks And Theoretical Benefits
structured treatment interruptions conclusions
Structured Treatment Interruptions: Conclusions
  • Still experimental
  • Rapidly evolving field
  • Stay tuned!
the berlin patient
The Berlin Patient

Lisziewicz J et al. NEJM 1999; 340: 1683-1684.

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

ARV Therapy for Primary Infection
new arv agents68
New ARV Agents
  • T-20
  • Atazanavir
  • Capravirine
  • Phos-Amprenavir
  • Tipranivir
new oi management strategies
New OI Management Strategies
  • Stopping primary prophylaxis
  • Stopping secondary prophylaxis
  • Immune restoration syndromes
common management challenges
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
resources for hiv aids clinicians
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)
consultation services for hiv aids clinicians
Consultation Services For HIV/AIDS Clinicians
  • Local expert clinicians
  • Regional and local AIDS Education and Training Centers
  • National HIV Telephone Consultation Service (Warmline)
    • (800) 933-3413
  • National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline)
    • (888) HIV-4911
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

[email protected]

PEPLine (888) 448-4911

Warmline (800) 933-3413

National HIV/AIDS Clinicians’ Consultation Center
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