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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
Zidovudine, Retrovir, retrover, AZT, ZDV, didanosine, Videx, ddI, zalcitabine, Hivid, ddC, stavudine, Zerit, zeret, d4T, lamivudine, Epivir, epevir, 3TC, nevirapine, Viramune, delavirdine, Rescriptor, efavirenz, Sustiva, indinavir, Crixivan, crixavan, ritonavir, Norvir, saquinavir, Fortovase, nelfinavir, Viracept, adefovir, adofovir, Preveon, abacavir, amprenavir, Agenerase
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 Zidovudine, Retrovir, retrover, AZT, ZDV, didanosine, Videx, ddI, zalcitabine, Hivid, ddC, stavudine, Zerit, zeret, d4T, lamivudine, Epivir, epevir, 3TC, nevirapine, Viramune, delavirdine, Rescriptor, efavirenz, Sustiva, susteva, indinavir, Crixivan, crixavan, ritonavir, Norvir, saquinavir, Fortovase, nelfinavir, Viracept, adefovir, adofovir, Preveon, abacavir, amprenavir, Agenerase
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.