Download 3rd revolution in HIV Treatment

HIV Care 2010:
rd
The 3 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 = 62
 HRNA = 6320
 On dialysis for HIV nephropathy
 Patient 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 FDA
1995: saquinavir approved as first protease
inhibitor
1996: nevirapine approved as first nonnuke drug
1996: 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 coreceptor 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 drugs
Increased recognition of harms of
uncontrolled viral replication
Accumulating 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 coreceptor 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, antacids)
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*
NVP
F-AMP/rtv
SQV/rtv
LPV/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
 Neuropathy
 Nephropathy
 Acceleration of liver disease in Hep B/C coinfected
 Increased risk of many different cancers
 Accelerated atherosclerosis
 CNS dysfunction
 Malaise, fatigue, lipodystrophy
Increased recognition of harms
of uncontrolled viral replication
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?)
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 drugs
Increased recognition of harms of
uncontrolled viral replication
Accumulating 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 = 62
 HRNA = 6320
 On dialysis for HIV nephropathy
 Patient 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!