hiv care 2010: the 3 rd revolution in hiv treatment
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HIV Care 2010: The 3 rd Revolution in HIV treatment. Chris Farnitano, MD Noon Conference February 11, 2010. Learning Objectives. Be familiar with recent advances in anti-HIV medications Know the new threshold for initiating HIV treatment according to the December, 2009 DHHS guidelines - PowerPoint PPT PresentationTRANSCRIPT
HIV Care 2010:The 3rd Revolution in HIV treatment
Chris Farnitano, MD
Noon Conference
February 11, 2010
Learning Objectives
Be familiar with recent advances in anti-HIV medications
Know the new threshold for initiating HIV treatment according to the December, 2009 DHHS guidelines
Be able to discuss the reasons for these more aggressive treatment guidelines
Case Study: D.T.
Ms. D. T. is a 51 y.o. woman diagnosed HIV+ in 1994 with T cells=232 at that time
Long history of antiviral therapy:
Case Study: D.T.
Antiviral History:Nukes tried:
– zidovudine, lamivudine, stavudine, – didanosine, abacavir
Non-nukes tried:– nevirapine
Case Study: D.T.
Antiviral History:Protease inhibitors tried:
– saquinavir, indinavir, nelfinavir, ritonavir, amprenavir, lopinavir, azatanavir,
Novel agents tried:– hydroxyurea
Case Study: D.T.
Genotype/Phenotype testing results:– Resistant to all nukes except tenofovir– Resistant to non-nukes– Multiple PI mutations, resistant to all protease
inhibitors unless boosted with ritonavir
Case Study: D.T.
June, 2008:T cells = 62HRNA = 6320On dialysis for HIV nephropathyPatient absolutely refuses to take even the lowest
dose of ritonavir due to diarrhea and nausea “Even looking at the Norvir pill makes me
vomit”
Case Study: D.T.
What to do now?
The first revolution in HIV care: Slowing the damage to the immune function, delaying death from AIDS:
1987:AZT (zidovudine) becomes the first FDA-approved anti-HIV drug
1989: FDA approves aerosolized pentamidine for PCP prophylaxis
1989: CDC recommends use of TMP/SMZ (Septra/Bactrim) for PCP prophylaxis– PCP prophylaxis adds 2 years to HIV+ pt lifespan
1991:DDI (didanosine) approved by FDA
US AIDS Cases and Deaths
The 2nd revolution in HIV care:Restoring the damaged immune system,Improving health of HIV+s
1995: lamivudine approved by FDA1995: saquinavir approved as first protease
inhibitor1996: nevirapine approved as first non-
nuke drug1996: ritonavir, indinavir approved
The 3rd revolution in HIV care:Preventing immune related damage
June, 06: Darunavir, protease inhibitor with efficacy against highly PI-resistant virus, approved by FDA
August, 07: Maravaroc, first CCR5 co-receptor blocker approved
October, 07: Raltegravir, first integrase inhibitor approved
January, 08: Etravirine, first of 2nd generation non-nukes approved
The 3rd revolution in HIV care:Preventing immune related damage
December, 09: DHHS revises guidelines on when to start therapy:
2009 guidelines
Why the change?
Better, less toxic drugsIncreased recognition of harms of
uncontrolled viral replicationAccumulating data showing better
outcomes with earlier therapy(Public health benefit?)
Better, less toxic drugs
June, 2006: Darunavir, protease inhibitor with efficacy against highly PI-resistant virus, approved by FDA
August, 07: Maravaroc, first CCR5 co-receptor blocker approved
October, 07: Raltegravir, first integrase inhibitor approved
January, 08: Etravirine, first of 2nd generation non-nukes approved
Better, less toxic drugs: darunavir
Prezista (darunavir) protease inhibitor
-1 tablet (600 mg) twice a day with food– Take with 1 tablet Norvir (ritonavir 100mg)
twice a day– Works against protease inhibitor resistant
virus– SE: rash, abd pain, constipation, headache
Better, less toxic drugs: maraviroc
Selzentry (maraviroc) CCR5 co-receptor blocker– Take 1 tablet (300mg) with or without food twice a
day
– 150mg bid c ritonavir boosted protease inhibitors
– 600 mg bid c etravarine or efavarenz
– 150 mg bid c ritonavir and etravarine
– dose adjustment also needed with clarithromycin, itraconazole
Better, less toxic drugs: maraviroc
Selzentry (maraviroc) CCR5 co-receptor blocker– need CCR5 tropism assay to see if will
respond– 80% of treatment experienced patients with
Tcells<100 have CXCR4 virus– SE: uncommon: cough 5-10%, dizziness,
fever, rare liver toxicity
HIV tropism assay
Better, less toxic drugs: raltegravir
Isentress (raltegravir) integrase inhibitor– 1 tablet (400 mg) twice a day with or without
food– SE: uncommon: nausea, dizziness– Avoid dosing with metal ions (calcium, ant-
acids)
Better, less toxic drugs: raltegravir
Better, less toxic drugs: etravirine
Intelence (etravirine) non-nucleoside reverse transcriptase inhibitor– 2 tablets (100 mg each) twice a day with food– Effective against 1st gen NNRTI resistant virus
(K103N, Y181C)– SE: 10-18% of men and 34% women get transient
rash– Contraindicated with atazanavir, fosamprenavir,
tipranavir (levels markedly incr or dec.)
New drugs darunavir and raltegravir move into preferred first line therapy
Options for Once-daily Therapy
Options with evidence of QD efficacy:– TDV + FTC*
– TDV + DDI
– TDV + 3TC
– DDI + 3TC
– ABC + 3TC
EFV*ATV/rtv*DRV/rtv*NVPF-AMP/rtvSQV/rtvLPV/rtv
+
*indicates preferred regimen for initial therapy, DHHS guidelines
Most patients can control their virus
Why the change?
Better, less toxic drugs
Increased recognition of harms of uncontrolled viral replication
Accumulating data showing better outcomes with earlier therapy
(Public health benefit?)
Increased recognition of harms of uncontrolled viral replication
NeuropathyNephropathyAcceleration of liver disease in Hep B/C co-
infected Increased risk of many different cancersAccelerated atherosclerosisCNS dysfunctionMalaise, fatigue, lipodystrophy
Increased recognition of harms of uncontrolled viral replication
Why the change?
Better, less toxic drugsIncreased recognition of harms of
uncontrolled viral replication
Accumulating data showing better outcomes with earlier therapy
(Public health benefit?)
NA-ACCORD analysis
Analysis of 17,517 asymptomatic HIV+ US and Canada– Antiretroviral naive– Compare mortality between those starting
ART at:• <350 (deferred) vs• CD4 350-500• CD4 >500
– Kitahata, NEJM, 2009
NA-ACCORD analysis: Retrospective case control study
Higher risk of death in deferred ART group vs >350 CD4– CD4 <350 vs 350-500 N=8362
• Relative risk 1.69 (95% CI 1.26-2.26) of death
– CD4 <500 vs >500 N=9155• Relative risk 1.94 (95% CI 1.37-2.79) of death
– Other predictors of mortality: older age, injection drug use and HCV
When to Start Consortium: Prospective case matched study
When to Start Consortium
Why the change?
Better, less toxic drugsIncreased recognition of harms of
uncontrolled viral replicationAccumulating data showing better
outcomes with earlier therapy
(Public health benefit?)
Can more aggressive treatment break the back of the epidemic?
Can more aggressive treatment break the back of the epidemic?Model for Elimination of HIV Transmission:
Generalized epidemic in South Africa (17% prevalence):
Developed model to predict outcomes
Population aged 15 and above
Annual HIV testing
Treat for all newly identified cases
Assume infectiousness falls to 1% of pre-ART
HIV elimination defined as reduction in incidence <1/1000 people/year
Granich, Lancet, 2009
Can more aggressive treatment break the back of the epidemic?
Can more aggressive treatment break the back of the epidemic?
Can more aggressive treatment break the back of the epidemic?
Universal HIV testing and immediate ART combined with other prevention interventions
• 95% reduction in new HIV cases in 10 years
• Incidence reduced from 15-20,000 to 1000 per million
• Prevalence less than 1% by 2050
• Initial resources higher but over time, given the reduction in HIV incidence, this approach may provide cost savings
• Estimated costs are within UNAIDS estimates for Universal Access for a population this size.
Case Study: D.T.
Genotype/Phenotype testing results:– Resistant to all nukes except tenofovir– Resistant to all 1st gen. non-nukes– Multiple PI mutations, resistant to all protease
inhibitors unless boosted with ritonavir
Case Study: D.T.
June, 2008:T cells = 62HRNA = 6320On dialysis for HIV nephropathyPatient absolutely refuses to take even the lowest
dose of ritonavir due to diarrhea and nausea “Even looking at the Norvir pill makes me
vomit”
Case Study: D.T.
What to do now?
Case Study: D.T.
Started on tenofovir/lamivudine, etravarine, raltegravir
Tolerates well with no noticeable side effects
Case Study: D.T.
3 months later:– T Cells= 148
– Viral load <48
18 months later:– T Cells= 382
– Viral load <48
Patient in UCSF transplant program, awaiting donation of living related donor kidney (cousin)
It’s an infection, stupid, so treat it!
Hope!