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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 l.jpg

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 l.jpg
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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Challenges of HAART

  • Complexity

  • Toxicity

  • Accessibility

  • Incomplete efficacy

  • Viral resistance


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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


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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 don’t work if people don’t 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 <500 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 RNA<400 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

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




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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’


Slide25 l.jpg
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



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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 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


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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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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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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 > 3 months

    • ddI+d4T in pregnancy


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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


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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 γ required for mDNA synthesis

  • Clinical syndromes

    • Pancreatitis

    • Myopathy

    • Peripheral neuropathy

    • Bone marrow toxicity

  • “D” drugs especially implicated




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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


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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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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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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


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Structured Treatment Interruptions: Conclusions

  • Still experimental

  • Rapidly evolving field

  • Stay tuned!






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The Berlin Patient

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


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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



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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)

    • (800) 933-3413

  • National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline)

    • (888) HIV-4911


National hiv aids clinicians consultation center l.jpg

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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