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/[email protected]
PEPLine (888) 448-4911
Warmline (800) 933-3413
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