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Changes in HIV Clinical Epidemiology with Therapy
• Certain opportunistic diseases essentially disappeared
- CMV, MAC rare. KS uncommon and
• Some conditions relatively unchanged
- NHL, community acquired pneumonia
HIV Science: Open Issues
• The degree and quality of immune repair following ARV therapy
• Mechanisms of HIV pathogenesis: Is HIV non-cytopathic?
• HIV reservoirs and eradication
• Early events in HIV infection: The "real" receptor and HIV, antiretroviral, protease inhibitors, AIDS, protase
How Long Does Treatment Benefit on Immune System Persist?
• Uncertain
- CD4 rises in vast majority of aggressively treated patients- Rise as good with incomplete viral response
- CD4 count stable for 18+ months even after plasma virus becomes detectable
• Implications for considering treatment changes significant. If very prolonged, may wait longer to
CDC Spectrum of Disease Study
• Prospectively following 44,672 patients at 100 sites. Medical record audits
• ARV therapy decreases mortality
- One drug by 62%, two by 76%, three by 85% • Greater fall in MAC in gay men than IDU
• Risk of PCP directly related to CD4# and an increase to a "safe" level following ARV therapy as protective as in untreated
Controversies in HIV Treatment
• When is it best to start treatment
• More options for initial therapy
• Increasing complexity of treatment monitoring. What is success? - Ultrasensitive RNA assays Resistance testing
The Ideal Time to Treat HIV
• Before any significant risk for serious complications
• Before immune system is irreversibly damaged at a clinically significant level
• Before HIV evolves to more virulent form
• Before disease progression to point that compromises therapy response
• When patient is fully committed to regimen
The Problem of Eradication
• May be various types of latently infected cells in reservoir
• 1/10,000 CD4 Ro+ cells have integrated latent HIV
- Total population about 1 M, larger number cells in blood have inducible HIV but non-integrated- Reservoir of comparable size in acute infection
• Estimate 23-27 years to eliminate pool but may be less if replication is an important source of replenishing pool
Usual Choices for Initial Therapy
• Two nucleoside RT inhibitors and one protease inhibitor
- Variation is to use two PIs to increase either potency or convenience
• Two nucleoside RT inhibitors and one non-nucleoside RT inhibitor
• Less proven options:
- Above with hydroxyurea, nnRTI+PI, three RTIs
Options for Initial Therapy
How to Monitor HIV Therapy
• Baseline CD4, plasma viral load
• Plasma viral load after 4 weeks
- Want to see at least 0.5 log reduction
• Plasma viral load after 8 weeks
- Want <500 copies to predict 75% probability of suppression below 50 copies at 24 weeks
• CD4 cell counts with any plasma viral load
- Want >250 cells by 3 weeks
Ultrasensitive HIV RNA Assays
• More sensitive limits (20-200 copies/mL) monitors more aggressive therapy
• Evidence that suppression below this level is important
- Limits resistance evolution- Prolongs duration of suppression
• Adds some complexity to therapy
- Longer time to reach treatment goal- Intermittent detection
- Uncertainty of clinical utility
(80% below 500 copies also below 50 copies)
Dangers in HIV Therapy
• Treatment may allow selection of chug resistant viruses
- May result in disease progression- May lead to community multidrug resistance if transmitted
• Treatment may have toxicities after long-term use
Transmission of Drug-Resistant HIV
• Hecht et al reported on case of acute infection with multiple resistant HIV
- Virus shared resistant genotype with source (heavily treated patient with high viral load)- Resistant genotype and phenotype to RT and protease drugs
- Slower response to conventional aggressive therapy
• Similar reports from Swiss study
Long-Term Protease Toxicities
• Lipodystrophies (84%, severe in 12%)
• Glucose intolerance/diabetes mellitus (23%)
• Hyperlipidemias (90%)
• Cutaneous reactions (dry skin, ingrown mils)
Proportions are those of Cart et al. Many groups report lower rates.
A New Contender for Initial Therapy?
The Role of the Non-Nucleoside Reverse-Transcriptase Inhibitors (NNRTIs)
• Three drugs in the United States
- Nevirapine, delavirdine, efavirenz- Chemical structure, dosing, toxicity, effect on cytochrome p450 differs. All cross resistance and high level resistance can happen quickly
- Potency high in vitro. Never directly compared in vivo but general belief that EFV>NVP>DLV
- Use in initial therapy increasing even before Geneva given concerns, re: PI toxicities
Efavirenz Triple Therapy Results
% <400 copies at 24 wks (% <40)
On treatment LOCF N=F
Arm A = ZDV + 3TC + El~g0 (76) 88 (62) 74
Arm B = EFV + IND 90 (64) 72 ($0) 65
Arm C -- ZDV + 3TC + INId0 (72) 65 (48) 55
On treatment only uses available data (least stringent). LOCF assumes last known value (RNA, CD4), continues into future. N=F assumes treatment failure after data is missing (most stringent), CD4 rise of 140 cells in each group
Triple Therapy With No Protease or nnRTI
• Fischl et t al reported on a trial of ZDV+3?C+ the new RTI, abacavir
• 173 patients, no prior therapy, randomized to ZDV+3TC vs ZDV+$TC+ABC
• At 16 weeks, 75%<400 (54%<50) with three drugs vs only 35% <400 with two drugs
• Advantage is simplicity; 6 tabs da/ly total in a BID regimen that can be taken with food
• ABC hypersensitivity in about 3% (early)
Hydroxyurea
• No independent HIV activity
• Increases effective intracellular level of nucleosides (especially ddI) by reducing concentration of competing substrate
• In ACTG 307, significantly increased antiviral potency of ddI but blocked CD4 increase
• No known resistance and may restore ddl sensitivity
• Toxicity includes neutropenia, alopecia
"Compacting" HIV Treatment
• Realize that adherence can be improved with easier regimens; fewer pills, less frequent dosing, less dietary restriction
• BID regimens increasingly of interest:
- ZDV, 3TC, d4T, ddl, nevirapine, efavirenz, ritonavir all BID (or QD, for some)- Preliminary BID data promising with nelfinavir, indinavir, saquinavir-sgc
When Has Treatment Failed?
• Possibilities
- Plasma viral load above detection limits- Viral load becomes detectable after initial response
- CD4 count falls or fails to rise
- Resistance tests show sentinel mutations in patient with stable viral load
- Patient experiences toxicity or clinical progression
Applying Resistance Testing in Clinical Management
• Baseline testing in acute HIV infection
• Community monitoring of resistance prevalence to recommend best initial therapy
• Testing at time of virologic failure to select drugs to discontinue
• Testing at time of therapy change to select best regimen
New Life for the Salk Vaccine?
• Valentine et al treated 43 patients with PI regimen with or without killed vaccine (RernuneTM) at 4, 16, 28 wks
• Both groups had similar RNA, CD4 effects at wk 20
• RemuneTM group had better immune parameters including HIV antigen response. This crossed HIV clades.