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!