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

New and investigational ARV agents

New strategies for OI management

Common management challenges

Typical CD4 Response to HAART

Challenges of HAART

Complexity

Toxicity

Accessibility

Incomplete efficacy

Viral resistance

What’s a Clinician to Do?

Expanding number of agents adds complexityMinimal clinical experience when drugs released adds toxicity riskShortage of outcomes data adds uncertainty

New ARV Treatment Strategies and Concepts

Adherence to treatment

ARV resistance and resistance testing

Interrupting ARV therapy

Treating primary HIV infection

Adherence

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

C. Everett Koop

Reasons for Non-Adherence: Clinician vs Patient Views

0

10

20

30

40

50

60

valu

e, %

No. of doses orpills

Side Effects Meal Instructions Schedulecomplexity

Other

Clinican

Patient

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

Viral Suppression And Adherence By Refill Records

0

10

20

30

40

50

60

70

80

90

95-100% 90-95% 80-90% 70-80% < 70%

Adherence, by prescription refill

% A

chie

ving

<50

0 co

pies

/mL

N = 504 pts on HAART

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

Measuring Adherence: Electronic Bottle Caps

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

MEMScaps, Aardex Corp.

0

20

40

60

80

100

>95 90-95 80–90 70-80 <70

Pat

ient

s w

ith

HIV

RN

A<

400

cop

ies/

mL

, %

PI adherence, % (electronic bottle caps)

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

Viral Suppression And Adherence By MEMS

10% adherence difference = 21% reduction in risk of AIDS

Bangsberg D, et al. AIDS. 2001:15:1181

Pro

port

ion

AID

S-F

ree

Months from entry

P = .0012

0 5 10 15 20 25 30

0.00

0.25

0.50

0.75

1.00

AdherenceO 90–100%O 50–89%O 0–49%

Adherence and AIDS-Free Survival

Why Does HAART Fail?

ARV Resistance

What Is Resistance?

Viral replication in the presence of drug pressure

Basic Pharmacology Principles

IC90

IC50

Cmin

Cmax

Time

Drug Level

Dosing Interval

Area of Potential HIV Replication

Dose Dose

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’

HIV-1 Quasi Species in Untreated and Treated HIV Infection:

Heterogeneity vs. Selection of Resistant Strains

acute chronic AIDS

Time

V. Simon, MD

Pla

sma

vir

em

ia

Development of Drug Resistance

Antiretroviral Resistance Testing

Goals Improve virologic control and immunologic

benefitMinimize exposure to ineffective agents

OptionsGenotypePhenotype “Virtual phenotype”

DefinitionsGenotype 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 presence

of 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

Availability

Turnaround time 2 weeks

Mutations may precede phenotypic resistance

Lower cost

GENOTYPE

Requires expert interpretation

Measures susceptibility indirectly

Insensitive for detecting minor species

Does not assess interactions among mutations

Does not address drug levels

Measures susceptibility directly

Results are easier to interpret

PHENOTYPE

Restricted availability

Turnaround time 2–4 weeks

Insensitive for detecting minor species

Clinically significant cutoff values may not be defined for some drugs

More expensive

Fast results (2 weeks)

Moderate costVIRTUAL

PHENOTYPE

Measures susceptibility indirectly

Insensitive for detecting interactions between mutations

Strengths Weaknesses

HIV Drug Resistance Assays: DHHS Recommendations

Clinical Situation Recommendation/Rationale

Virologic failure during ART

Determine role of resistance in failure or suboptimal viral suppression

Maximize number of active drugs

Acute HIV infection

Assess possibility of drug-resistant HIV transmission

Treat accordingly

Chronic HIV infection prior to treatment initiation

After D/C ART

Plasma HIV RNA <1000 copies/mL

Uncertain prevalence of resistant virus/assays may not detect minor quasispecies

Assays may not detect certain quasi-species in the absence of selective pressure

HIV RNA too low for reliable detection with current assays

Re

com

me

nd

ed

Op

tion

al

No

t G

en

era

lly R

eco

mm

en

de

d

Resistance Testing Factors

CostTimeAccessTechnical limitations Thresholds Partial resistance

Mutations yet to be identified New drugs Different sequence regions for old drugs

Uncertain clinical impact

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 RedistributionSyndromes 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 useMechanism unknown

Fat Redistribution Syndromes

Cervico-dorsal Fat Pad

Central Fat Accumulation

Facial Lipoatrophy

Abnormal Insulin and Glucose Metabolism

Associated with ARVs, especially PIsMechanism 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

Mechanism unknownPrevalenceClinical syndromesHypertriglyceridemiaHypercholesterolemiaMixed

? Impact on CV riskManage per AHA guidelines

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

Class toxicity of NRTIs (Black Box warning)Incidence est. 4/1000 patient-yearsRisk factorsOlder ageFemale genderddI, ddC, or d4T use > 3 monthsddI+d4T in pregnancy

Lactic Acidosis: Clinical Presentation

Acute or subacute onsetVarying 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

Management Of Lactic Acidosis

Be alert to symptomsStop ARVs if symptomatic and lactate elevatedMay 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

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

Avascular Necrosis of the Hip

Osteopenia and Avascular Necrosis of the Radial Head

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

Should “Failing” HAART Be Stopped?

Better to stay on some ARV regimen than noneResistance mutations may impair viral

“fitness”Specific mutations may enhance response

to specific ARV agentsCD4 count gains may be sustained despite

incomplete viral suppression

Deeks, et al. NEJM 2/15/01

Antiretroviral Therapy: Persistent Uncertainties

When to start

What to start with

When to change

What to change to

When to stop (if ever)

ARV Treatment Interruption

Treatment Interruption Rationale

Enhance HIV-specific immune response In primary infection In chronic infection

Reduce treatment-associated complicationsToxicityCostTreatment fatigue

Treatment Interruption Target Groups

ARV treatment fully suppressiveStarted during acute infectionStarted after infection chronic

ARV treatment not fully suppressive

Structured Treatment Interruptions

Treatment Interruptions: Real Risks And Theoretical BenefitsReal 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

Structured Treatment Interruptions: Conclusions

Still experimental

Rapidly evolving field

Stay tuned!

ARVs For Acute HIV Infection

Primary HIV Infection Rash

Primary HIV Infection Oral Ulcers

Natural History of HIV Infection

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

New ARV Agents

New ARV Agents

T-20

Atazanavir

Capravirine

Phos-Amprenavir

Tipranivir

New OI Management Strategies

Stopping primary prophylaxis

Stopping secondary prophylaxis

Immune restoration syndromes

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

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

Local expert cliniciansRegional and local AIDS Education and Training CentersNational 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/hivcntrAkindrick@nccc.ucsf.edu

PEPLine (888) 448-4911

Warmline (800) 933-3413