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Advances in hiv treatment
1. 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
2. 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
11. 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
12. New ARV Treatment
Strategies and Concepts
Adherence to treatment
ARV resistance and resistance testing
Interrupting ARV therapy
Treating primary HIV infection
14. Reasons for Non-Adherence:
Clinician vs Patient Views
0
10
20
30
40
50
60
value,%
No. of doses or
pills
Side Effects Meal Instructions Schedule
complexity
Other
Clinican
Patient
Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281
15. 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
%Achieving<500copies/mL
N = 504 pts on HAART
Montessori, V, et al. XII International Conference on AIDS, Durban, South Africa, 2000. Abstract MoPpD1056.
17. 0
20
40
60
80
100
>95 90-95 80–90 70-80 <70
PatientswithHIVRNA
<400copies/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
18. 10% adherence difference = 21% reduction in risk of AIDS
Bangsberg D, et al. AIDS. 2001:15:1181
ProportionAIDS-Free
Months from entry
P = .0012
0 5 10 15 20 25 30
0.00
0.25
0.50
0.75
1.00
Adherence
O 90–100%
O 50–89%
O 0–49%
Adherence and AIDS-Free Survival
24. 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’
25. HIV-1 Quasi Species in Untreated
and Treated HIV Infection:
Heterogeneity vs. Selection of Resistant Strains
acute chronic AIDS
Time
V. Simon, MD
Plasmaviremia
31. 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 presence
of different drug concentrations
Usually reported as the drug concentration that inhibits
virus replication by 50% (IC50), or the fold increase in
IC50
32. 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 cost
VIRTUAL
PHENOTYPE
Measures susceptibility indirectly
Insensitive for detecting interactions
between mutations
Strengths Weaknesses
33. 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
RecommendedOptionalNotGenerallyRecommended
36. Long-Term Complications of
HIV and ARV Therapy
Body habitus changes
Insulin resistance/hyperglycemia/diabetes
Hyperlipidemia
Lactic acidosis
Hepatic steatosis
Osteopenia
Avascular necrosis
37. 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
43. 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
45. 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
46. 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
48. 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
49. 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
52. 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
53. 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
57. Treatment Interruption Target
Groups
ARV treatment fully suppressive
Started during acute infection
Started after infection chronic
ARV treatment not fully suppressive
66. 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
70. 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
71. 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)
72. 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
73. 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@nccc.ucsf.edu
PEPLine (888) 448-4911
Warmline (800) 933-3413
Notas do Editor
Not Over
Date of first publication: 2/1/99 Keywords: Adherence, antiretroviral therapy, viral load Subject: Degree of adherence needed for optimal viral suppression Title: “What degree of adherence is needed?” Discussion and teaching points: How much adherence is needed for optimal viral load suppression is addressed in the graph from Paterson which shows that the best performance was achieved in patients who by self-report and MEMS-caps were found to have >95% adherence, I.e. Better than 95% of doses were taken during the 3 months of study. Sig- nificant differences were observed between >95%, 90-95%, 80-90%, 70-80%, and <70% adherence, as shown. Note that <70% adherence was associated with only 10% of patients achieving a viral load below detection. Author(s): Paterson et al. Sources: University of Pittsburgh Sponsors: NA
Currently, there are three commonly used resistance analyses: 1) determination of the viral genotype; 2) assessment of the viral phenotype in vitro; and 3) determination of a "virtual" phenotype based on genotypic assessment. Each of the three above-listed approaches has distinct strengths and weaknesses. Assessments based on determination of the viral genotype are readily available, provide relatively rapid results, and have low to moderate cost. Knowing the viral genotype may also permit prediction of future phenotypic resistance. Weaknesses of these approaches include requirement for expert interpretation, and the facts that they only indirectly measure resistance, do not take into account interactions among mutations, and do not include information about antiretroviral drug levels. Phenotypic resistance analysis measures susceptibility directly, and thus results are relatively easy to interpret. However, phenotypic testing is expensive and not widely available. In addition, its turnaround time is relatively long, it is insensitive to minor species, and clinically significant cutoff values may not be established for all drugs.
Considerations for Changing a Failing Regimen As with the initiation of antiretroviral therapy, the decision to change regimens should be approached with careful consideration of several complex factors. These factors include: recent clinical history and physical examination; plasma HIV RNA levels measured on two separate occasions; absolute CD4+ T lymphocyte count and changes in these counts; remaining treatment options in terms of potency, potential resistance patterns from prior antiretroviral therapies and potential for compliance/tolerance; assessment of adherence to medications; and preparation of the patient for the implications of the new regimen which include side effects, drug interactions, dietary requirements and possible need to alter concomitant medications. Failure of a regimen may occur for many reasons, including initial viral resistance to one or more agents, altered absorption or metabolism of the drug, multi-drug pharmacokinetics that adversely affects therapeutic drug levels, and poor patient adherence to a regimen. In this regard, it is important to carefully assess patient adherence prior to changing antiretroviral therapy; health care workers involved in the care of the patient, such as the case manager or social worker, may be of assistance in this evaluation. Clinicians should be aware of the prevalence of mental health disorders and psychoactive substance use disorders in certain HIV-infected persons; inadequate mental health treatment services may jeopardize the ability of such individuals to adhere to their medical treatment. Proper identification of and intervention in these mental health disorders can greatly enhance adherence to medical HIV treatment. It is important to distinguish between the need to change therapy due to drug failure versus drug toxicity. In the latter case, it is appropriate to substitute one or more alternative drugs of the same potency and from the same class of agents as the agent suspected to be causing the toxicity. In the case of drug failure where more than one drug had been used, a detailed history of current and past antiretroviral medications, as well as other HIV-related medications, should be obtained. Testing for antiretroviral drug resistance may also be very helpful in maximizing the number of active drugs in a regimen (see Testing ). Viral resistance to antiretroviral drugs is an important, but not the only, reason for treatment failure. Genetically distinct viral variants emerge in each HIV-infected individual over time after initial infection. Viruses with single drug resistant mutations exist even prior to therapy, but are selected for replication by antiviral regimens that are only partially suppressive. The more potent a regimen is in durably suppressing HIV replication, the less likely the emergence of resistant variants. Thus the goal of therapy should be to reduce plasma HIV RNA to below detectable limits using the most sensitive assay available (<50 copies/mL), thereby providing the strongest genetic barrier possible to the emergence of resistance.
As everyone here knows, state of the art HIV therapy changes at lightning speed. Much of antiretroviral treatment of HIV infected is guided by outcome based studies. The story is different for post-exposure prophylaxis. Most of what we know about how to provide PEP comes from the original case control study of HCWs, anecdotes, animal data, and perinatal prophylaxis studies. Because infection is a rare event, thankfully, there is very little outcome data. This is striking contrast to the information available how to use antiretroviral therapy as treatment, as opposed to prevention where there is an relative abundence of outcome data. Many clinicians have tried to bridge this gap by extrapolating treatment data to prevention strategies. Thus, the rapid changes in antiretroviral use as treatment leads to rapid changes in antretroviral use as prevention. As a result, PEP in practice is likely to move quite rapidly. However the biology as well as the risk-benefit decision is quite different between treatment and prevention. Not all extrapolations from treatment data to prevention strategies may or may not be rational. As a result PEP in practice is likely to be different that PEP guidelines. What I would like to do today is to describe PEP in practice. I will focus mostly on PEP treatment decisions which have not been addressed by the quidelines.