Antiretroviral Therapy, 2010 Robert D. Harrington

Antiretroviral Therapy, 2010

Robert D. Harrington

Case 1

• A 23 year old man tested + for HIV in 2004. He moved to Arizona with the hope that a warmer environment would cure him of his HIV infection. However, over the past months he’s noted a variety of skin rashes, diarrhea and has lost 15 pounds. He returns to Seattle.

• On exam he is thin but not wasted, has poor dentition, severe xerosis and seborrheic dermatitis

Case 1

• His CD4 measures 400 cells/uL and his HIVRNA is 110,000 copies/mL

• Does he have AIDS?• Should he be offered antiretroviral therapy?


When to start?

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Pla

sma

HIV

RN

A

Plasma RNA Copies

CD4 Cells

4-8 Weeks Up to 12 Years 2-3 Years

CD

4 Cell C

ount

1,000

500

Intermediate Stage AIDS

HIV Infection: Pathogenesis

Typical Course

Viral set point

Anti-HIVT-cell response

Sero-conversionAntibody response

A lot of important stuff happens here

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10

100

1,000

10,000

100,000

1,000,000

10,000,000

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sma

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Plasma RNA Copies

CD4 Cells


CD

4 Cell C

ount

1,000

500

HIV-CTL Sero-conversion

Long Term Non-progression

Some CD4 death, good HIV-CTL, good HIV control

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Pla

sma

HIV

RN

A Plasma RNA Copies

CD4 Cells


CD

4 Cell C

ount

1,000

500

AIDS

CTL response

Sero-conversion

Rapid Progression

Lots of CD4 death, poor HIV-CTL, poor HIV control

Pre-HAART:CD4 and VL and HIV Progression

RT-PCR = reverse transcriptase–polymerase chain reaction. Mellors JW et al. Ann Intern Med. 1997;126(12):946-954; Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008.

85.5

40.1

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32.6

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Pro

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IDS

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)

bDNART-PCR

>30K 10-30K 3-10K 0.5-1K <-0.5K>55K 10-55K 7-20K 1.5-7K <1.5KBaseline c/mL >750

501- 351- 2

01- <200

750 500 3

50

Baseline CD4 (cells/mm3 )00

6060

8080

100100

2020

4040

MACS Cohort: Progression to AIDS in Pre-HAART EraMACS Cohort: Progression to AIDS in Pre-HAART Era

Impact of Age on Risk of HIV Progression

0

5

10

15

20

25

30

50 100 150 200 250 300 350 400 450 500

Age 25Age 55

Predicted 6-Month Risk of Progression to AIDS in Patient With HIV RNA of 30,000 c/mL

CD4 Cell Count (cells/mm3)

Pre

dic

ted

Ris

k (%

)

Phillips A et al. AIDS. 2004;18:51-58.

When to Initiate ARV Therapy: Starting at a Higher CD4 Count?

• Analysis of CD4-count recovery in ARV-treated patients (n=655) with sustained HIV RNA suppression (<400 c/mL) up to 6 years, stratified by BL CD4 counts

– >350 cells/mm3: CD4 counts significantly increased and returned to near-normal levels

– 201–350 and <200 cells/mm3: CD4 counts significantly increased and plateaued after 4 years below normal levels

• Differences in CD4 counts associated with differences in morbidity and mortality

Median CD4 Counts Over 6 YearsStratified by Baseline CD4 Count

900

800

700

600

500

400

300

200

100

00 1 2 3 4 5 6

Years After Starting HAART

CD

4 C

ou

nt

(cel

ls/m

m3 )

<200 201–350 >350

Moore RD, Keruly JC. Clin Infect Dis. 2007;44(3):441-446.

Johns Hopkins HIV Clinical CohortJohns Hopkins HIV Clinical Cohort

Early Vs Deferred HAART (Kitahata, et.al NEJM, 2009)

NA-ACCORD study• Observational study of 17,517 asymptomatic

patients in US and Canada• Two analyses:

– 1: Start HAART b/n 350-500 Vs deferred. • N= 8362, 2084 (25%) started at 350-500, 6278 deferred

• RR of death for deferred group 1.69 (P<0.001)

– 2: Start HAART at > 500 Vs deferred• N=9155, 2220 (24%) started at > 500, 6935 deferred

• RR of death for deferred group 1.94 (P<0.001)

When to Start?

Early Later

• Prevent Immune system destruction• More effective when started early• Mortality benefit• Prevent clinical “events”• Preserve HIV directed CTL

• Toxicities of treatment• Increased risk of resistance• Low rate of disease progression?• Cost

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Pla

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HIV

RN

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CD

4 Cell C

ount

500

CD4 Count, Viral Load and Clinical Course

1996: Treat Everyone!

- 350

- 200

2001

2004-5

Anti-retroviral Therapy: 2010

Simple RegimensDrugs Total daily pill count Dosing

• EFV - TDF/FTC 2 pills QD• R-ATZ - TDF/FTC 3 pills QD• R-LPV - TDF/FTC 5 pills QD• R-DRV – TDF/FTC 3 pills QD• R-FAMP - TDF/FTC 5 pills QD• EFV/TDF/FTC 1 pill QD• R-LPV - AZT/3TC 6 pills BID• EFV - AZT/3TC 3 pills BID• RLT – TDF/FTC 3 pills BID

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Pla

sma

HIV

RN

A Plasma RNA Copies


CD

4 Cell C

ount

500

CD4 Count, Viral Load and Clinical Course

1996: Treat Everyone!

- 350

- 200

2001

2004-5

2009-2010

DHHS Guidelines 2009: When To Start

Clinical Condition and/or CD4 Count Recommendations

• History of AIDS-defining illness

• CD4 count ≤500 cells/mm3

• Pregnant women

• Persons with HIV-associated nephropathy

• Persons co-infected with HBV, when HBV treatment is indicated

Initiate ART

Patients with CD4 >500 cells/mm3

• Optimal time to initiate ART not well defined

• Consider patient scenarios and co-morbidities

HBV = hepatitis B virus; ART = antiretroviral therapy.Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008.

When to Initiate ARV Therapy: Summary

• Initiating therapy with CD4 >500 cells/mm3 not currently recommended by all experts but may be considered in some motivated, adherent patients. Considerations include:– Age– Viral load - effect on rate of CD4 decline and clinical

events (SMART study)– Hepatitis co-infection– Transmission to uninfected partner

Egger M et al. Lancet. 2002;360(9327):119-129; US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008.

HIV: Practice and Prevention, 2010

What about starting HAART in the setting of an OI?

Case 2

• A 38 yo South African male presents with a 10 kg weight loss, 10 weeks of cough and intermittent fever. He has no past medical history.

• On exam he is thin, T 38.8 C, BP 100/70, HR 104, RR 20. He has prominent cervical adenopathy, oral thrush and course breath sounds over his R upper and mid lung zones.

Case 2

• What diagnostic tests do you want?• “HIV test is + and Sputum smear stains 3+ for AFB”

Case 2

• He is admitted to a hospital ward with similar patients and started on “RIPE” therapy.

• After a week his constitutional symptoms improve. His CD4 T-cell count measures 15 cells/uL.

• Should you prescribe HAART now?• What are you worried about?

Immune Reconstitution Syndrome

• TB-associated IRS in South Africa– 160 patients receiving Rx for

TB at the time HAART initiated

– Median CD4 68 – IRS in 12% overall, 32% in

those who started HAART within 2 months of TB Rx

– MV analysis: IRS risks• Low CD4• Early HAART – OR for

starting HAART < 30 days = 69.5

– 2 IRS deaths (both had disseminated TB

TB-IRS and CD4 and HAART

(Lawn, AIDS 2007;21:335-41)

SAPiT(Karim,CROI,2009,Abs36a)

• Open-label RCT• Patients

– Smear positive and on standard TB tx regimen– HIV positive with CD4 cell count < 500

• ART: ddI + 3TC + EFV once daily with TB DOT

• Endpoints– Primary: all cause mortality– Secondary: Tolerability, toxicity, viral load, CD4

count, TB outcomes and IRIS


Study Arms• Integrated TB-HIV treatment

1. ART initiated as soon as possible during the intensive phase of TB tx (first 8 weeks)

2. ART initiated after the intensive phase of TB tx

• Sequential – ART initiated after TB tx completed


Integrated Sequential

Initiated ART (n) 358 132

Completed (n) 94 (22%) 38 (18%)

Mortality (rate per 100 person-yrs)

5.2 12.1 HR 0.44(CI 0.2-0.8, p=0.003)



Timing of HAART

#142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164)

• Randomized study of ARV given within 14 days of Rx for OI Vs delayed (at least 4 wks)

• Patients with TB excluded• Primary endpoint: 48 week combination of 3 categorical

variables – 1. Death or alive with new AIDS diagnosis – 2. Alive with HIV RNA > 50 and no new AIDS diagnosis– 3. Alive with HIV RNA < 50 and no new AIDS diagnosis

Timing of HAART

#142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164)

• Patients (N=282)– Median age 38– Median CD4 = 29 and log10 HIV RNA level = 5.07– OIs

• PCP 63%• Cryptococcal meningitis 13%• Pneumonia 10%

– Median time to starting ART 12 Vs 45 days

Timing of HAART

• No significant difference between immediate Vs delayed for the composite endpoint

• Immediate arm had fewer deaths/new AIDS diagnosis

• Immediate arm had longer time to death/new AIDS diagnosis (HR 0.53)

P=0.035

ACTG 5164: Results

Early Vs Delayed HAART in Patients with Cryptococcal Meningitis in Africa

(Macadzange,CROI,2009,Abs 38cLB)

• Open Label RCT

• Patients: Adults with HIV and Cryptococcal meningitis (CSF CrAg or India ink positive)

• All received Fluconazole 800 mg PO once daily x 10 wks + aggressive pressure management

• Followed by maintenance fluconazole 200 mg

• Intervention: d4T, 3TC, NVP

– EARLY: Immediate start with initial fluconazole

– DELAYED: Start after initial 10 wks of fluconazole

• Primary Outcome: Mortality after 2 years



TOTAL: 50 patientsOverall 2-yr Mortality: 62%

EARLY 27 patients

Median Survival: 35 days*

2-yr Mortality: 87%**

DELAYED23 patients

Median Survival: 274 days

2-yr Mortality: 37%

*Comparison of median survival, p=0.03**Comparison of 2-yr Mortality, p=0.002



All but 2 deathsdue to Cryptococcus

Other 2 deaths ascribed to TB-IRIS

Baseline CD4 cells similarin those who died in each group

Starting HAART in the setting of an OI

• The initiation of HAART in the setting of most OIs should not be delayed beyond 2 to 8 weeks

• Concerns about precipitating IRIS are overdone – except with cryptococcal meningitis

Case 1 (continued): Should HAART be interrupted?

• Patient #1 was started on HAART at the last visit.

• His CD4 rose to 520 cells/uL and his plasma HIV RNA level became undetectable.

• However, 8 months later he complains of “medication fatigue”, is worried he will miss doses and wonders if he should take a drug holiday.

• What should you advise?

NO!

SMART: Risk of Opportunistic Disease or Death With Continuous vs Episodic Therapy

Among those on antiretroviral therapy at baseline.El-Sadr WM et al. N Engl J Med. 2006;355(22):2283-2296.

Endpoint

OI or death

Nonserious OI-related events

Death from any cause

OI/death by baseline VL*

≤400 c/mL

>400 c/mL

OI/death by race

Black

Other

Favors Viral Suppression ►

►

Favors Drug

Conservation

Hazard Ratio: DC/VS (95% CI)

2.6

1.8

3.6

0.1 1 10

4.0

1.2

3.7

2.1 P=.02

P<.001

P<.001

P<.001

P=.007


Choosing a regimen?

Approval of Antiretrovirals: 1987-2008

ZDVddI

ddCd4T

SQV3TC

RTVIDVNVP

NFVDLV

EFVABC

APV

LPV/RTV

TDF

TPVDRV

ATVFPVENFFTC

Years

0

5

10

15

20

25

1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007-

2008

RTGMVCETR

Adapted from clincaloptions.com/hiv (Oct, 2007)

NRTI

NNRTI

PI

FUSION INHIBITOR

CCR5 BLOCKER

INTEGRASE INHIBITOR

Antiretroviral Therapy

Five Drug Classes

• Nucleoside Reverse Transcriptase Inhibitors (NRTI)

• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

• Protease Inhibitors (PI)

• Integrase Inhibitors

• Cell Entry Inhibitors

HIV Life Cycle


NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)

AZT (zidovudine; Retrovir)3TC (lamivudine; Epivir)

d4T (stavudine; Zerit)ddI (didanosine; Videx)

Abacavir (Ziagen)ddC (zalcitabine; Hivid)

Tenofovir (Viread)*Emtricitabine (Emtriva)


NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)

Fixed Combinations

Combivir (AZT and 3TC)

Epzicom (3TC and ABC)

Trizavir (AZT, 3TC and ABC)

Truvada (FTC and TDF)


NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

Efavirenz (Sustiva)Nevirapine (Viramune)Delavirdine (Rescriptor)

Etravirine (Intelence)

Efavirenz + Tenofovir + FTC (Atripla)


PROTEASE INHIBITORS

Ritonavir (Norvir)

Saquinavir (Fortavase; Invirase)

Nelfinavir (Viracept)

Indinavir (Crixivan)

Fosamprenavir (Lexiva)

Lopinavir/ritonavir (Kaletra)

Atazanavir (Reyataz)

Tipranavir (Aptivus)

Darunavir (Prezista)


CELL ENTRY INHIBITORS

T-20 (Enfuvirtide)• Synthetic peptide – blocks gp41 mediated fusion

• Subcutaneous injection twice/day

• Indicated for “salvage therapy” (use with at least one other active drug or in patients with high risk of disease progression/death)

Maraviroc (Selzentry)

• Only effective against HIV isolates that utilize CCR5 co-receptor

• Must screen patients for the absence of CXCR4 using virus

• Not clear where to use it since “salvage patients” more likely to have CXCR4 virus


INTEGRASE INHIBITORS

Raltegravir (Isentress)• Only member of its class, twice a day medicine• Initially approved for salvage therapy, now

recommended as a preferred drug for initial treatment


Choosing a regimen:

NNRTI or PI?

NNRTI or PI?

NNRTIs• High efficacy

• Simplicity—lowest pill burden

• Relatively well tolerated

• Limited toxicity

• Low genetic barrier to resistance

• Drug-drug interactions

PIs• High efficacy• Getting simpler, but

regimen ≥3 pills per day• High genetic barrier to

resistance• Relatively well tolerated

except for GI• Fat accumulation and lipid

problems persist• Drug-drug interactions,

especially with RTV

GI = gastrointestinal; RTV = ritonavir.Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008.


Choosing a regimen:

Which NRTIs?

Weighing the Options: TDF/FTC vs ABC/3TC

Regimen Advantages Disadvantages

ABC/3TC

High level of efficacy in clinical trials with EFV or boosted PIs

Similar efficacy to TDF/FTC in HEAT regardless of BL HIV-1 RNA

HSR can be safely avoided with HLA-B*5701 assay

Preferred option only in IAS-USA guidelines

Potential for HSR reaction to ABC Inferior response in pts with BL HIV-1

RNA > 100,000 c/mL in ACTG 5202 Association with risk of MI in some

studies

TDF/FTC

High level of efficacy in clinical trials with EFV or boosted PIs

Coformulated with EFV as QD regimen

Preferred option in DHHS and IAS-USA guidelines

Caution in pts with renal insufficiency Long-term nephrotoxicity and tubular

toxicity not fully understood Should not be coadministered with

other nephrotoxic drugs Bone toxicity

Initiating Antiretroviral Therapy

DHHS Recommendations (2009)Preferred Regimens

NNRTI-Based

EFV QD + TDF/FTC

PI-BasedAtazanavir/R QD + TDF/FTCDarunavir/R QD + TDF/FTC

Integrase-BasedRaltegravir BID + TDF/FTC

Initiating Antiretroviral Therapy

DHHS Recommendations (2009): Never use

• As components of a regimen– DDI/D4T (toxicity)– D4T/AZT (compete for activation)– FTC/3TC (same drug)– Efavirenz: if pregnant or potentially pregnant (category D)– Nevirapine: women with CD4 > 250 or men with CD4 > 400

• As a regimen– Mono, dual or triple NRTI– DDI/TDF + NNRTI– Tipranavir as part of initial regimen in ARV naïve patient

Conclusions

• A patient’s CD4 T-cell count is used to stage disease and determine the need for ART. The current threshold for initiating treatment is < 500 cells– Factors to consider include viral load, rate of CD4 decline,

co-morbidities, transmission risk, age, patient readiness and the likelihood of adherence - may want to start at CD4 > 500

• Therapy should be considered permanent – (Smart study)• TDF/FTC in once-daily fixed-dose combination plus an EFV

or ATZ/r or DRV/r or RAL are proven and preferred initial choices

• Combination therapy with newer agents can be effective for patients with highly drug resistant virus


Failure and Drug Resistance

Case 3

• A 38 year old man with AIDS was started on HAART (EFV, TDF, FTC) a year ago with an excellent response: his HIV RNA dropped from 248,000 copies to < 30 copies and his CD4 increased from 87 to 360 cells.

• Unfortunately, he’s missed several recent appointments and when he finally does make it to the office you find he has thrush and seborrheic dermatitis. His CD4 count has decreased to 240 cells and his HIV RNA is now detectable at 37,000 copies.

• What is going on?

• What, in particular, are you worried about?


Insufficient drug level

Viral replication in the presence of drug

Resistant virus

Poor adherence

Social/personal issuesRegimen issues

ToxicitiesPoor potency

Wrong dose

Host genetics

Poor absorption

Rapid clearance

Poor activation

Drug interactions

Adherence and Drug Resistance Relationship

00.10.20.30.40.50.60.70.80.9

1

0 10 20 30 40 50 60 70 75 80 85 90 95 100

Adherence

Res

ista

nce

When to Use Resistance TestingPatient Status IAS-USA1 DHHS2 European3

Primary/acute Recommend Recommend‡ Recommend

Post-exposure prophylaxis — — Recommend

Chronic, treatment naïve Consider* Recommend‡ Strongly consider*

Failure Recommend Recommend Recommend

Pregnancy Recommend† Recommend Recommend†

Pediatric — — Recommend†

*Especially if exposure to someone receiving antiretroviral drugs is likely or if prevalence of drug resistance in untreated patients ≥5% (European: ≥10%); †When viral load is detectable; ‡December 1, 2007: The panel recommends performing genotypic drug resistance testing for all treatment-naïve patients entering into clinical care, regardless of whether antiretroviral therapy is to be initiated. This recommendation is based on the fact that transmitted resistance mutation may be detected at a time point more proximal to the time of infection than later. Repeat testing may be considered at the time when therapy is to be initiated.1. Hirsch MS et al. Clin Infect Dis. 2003;37(1):113-128; 2. Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008; 3. Vandamme AM et al. Antivir Ther. 2004;9(6):829-848.

Overview of Antiretroviral Resistance Testing

How do we test for resistance?

GenotypePhenotypeVirtual Phenotype

Genotypic Resistance Assay

• Sequence relevant portions of the HIV genome (env and pol – included RT, PR, Int)

• Detect and report variations in the sequences of these genes that are known or suspected to confer antiretroviral resistance

AAA GAC AGTAAA GAC AGTAAA GAC AGTAAA GAC AGT AAAAAA AAACAC AGAGCCAAAAAA AAACAC AGAGCC

LysLysLysLys AspAspAspAsp SerSerSerSer LysLysLysLys AsnAsnAsnAsn SerSerSerSer

Codon Silent MutationMutation Silent Mutation

Adapted from Winters. Reviewed in Wilson. AIDS Read 2000;10:469.

Reporting: GSS

• Mutations are scored with a number for each drug. Sum of mutation scores for each drug yields the interpretation:

• Several GSSs– French National Agency for AIDS Research:

www.hivfrenchresistance.org– International AIDS Society – USA mutation list:

www.iasusa.org/resistance_mutations– Rega Institute: www.rega.kuleuven.be/cev– Stanford: www.hivdb.stanford.edu

http://www.hivfrenchresistance.org/

http://www.iasusa.org/resistance_mutations

http://www.rega.kuleuven.be/cev

http://www.hivdb.stanford.edu/

Reporting: GSS

• Stanford HIV Resistance Database:

– 0-9 No resistance– 10-14 Possible low level resistance– 15-29 Low level resistance– 30-59 Intermediate resistance– > 60 High level resistance

Phenotypic Resistance

Testing• Tests viability of a synthetic

version of the patient’s HIV in the presence of antiretroviral agents

• Similar to traditional bacterial antibiotic susceptibility assays

• Results reported as fold-change in susceptibility to antiretroviral agents

Phenotypic Resistance Reporting• Phenotype generates IC50 (or IC90) for chimeric

virus to each drug• Patient’s virus IC50 divided by the IC50 of WT

virus and ratio expressed as fold change (FC)• Relationship of FC to resistance for each drug is

determined separately and based on clinical data. When no clinical data are available…. then called R if IC50 is > 2SD of IC50 of WT virus

• PSS (Phenotypic Susceptibility Score) – just add the number of active drugs in a regimen: e.g. 0 is no active drugs, 3 is three active drugs

Inhibitory Quotients

• IQ = ratio of drug concentration/drug susceptibility

• gIQ = drug trough concentration/# drug RAMs

• v(or p)IQ = drug trough concentration/FC times IC50 for resistant virus (for PIs=550 ng/mL)

• IQs may be better predictors of response

Etravirine

• Duet I & II – ETV+OBR Vs placebo+OBR in pts with 1 nnRTI

RAM and 3 PI RAM.

– OBR = 2nRTI + R-DRV +/- T-20

– Results at 48 weeks• Overall 60% Vs 40% were < 50

• If PSS of OBR was 0 – then 33% Vs 0%

• If PSS was > 2 – then 76% Vs 60%

• Resistance: 103N has no effect, need > 3 RAMs to be fully R

• ARV DI – don’t use with TPV (a P450 3A4 inducer)

Tipranavir

• Resist I & II – TPV+OBR Vs comparitor PI+OBR in pts with 3 class

experienced patients and PI resistance.

– Results at 156 weeks• 14% Vs 7.5% < 50

• Both arms better with T-20

• Reduced activity with FC > 2 and no activity with FC > 8

– Patients with TPV failure – little effect on DRV susceptibility

– Increased lipids (RTV 200 bid), increased bleeding (incl ICH), more hepatitis, cannot use with other PIs (induces P450)

Darunavir

• Power I & II– DRV+OBR Vs comparitor PI+OBR in 3 class

experienced patients with PI resistance– Results at 48 weeks: 48% Vs 10% < 50

• Titan– DRV Vs LPV in experienced patients (LPV naïve)

– Results at 48 wks: 71% Vs 60% < 50

– Patients who failed – fewer RAMs on DRV (better protection?)

• Artemis– DRV (QD) Vs LPV in naïve patients

– Results at 48 wks: 84% Vs 78% < 50

Darunavir

• Resistance - phenotype

• Resistance – genotype– Multiple RAMs– Decreased susceptibility with > 3 and fully

resistant with > 5 mutations

FC < 2 2-4 3-4 > 4

Mutation 11I, 54V, 73S, 89V

32I, 33F, 47V

54M, 76V, 84V

50V

FC < 10 susceptible, > 10 and < 40 reduced susceptibility, > 40 resistant (PhenoSense scores > 98 as fully resistant)

Raltegravir

• Benchmark I & II: RAL+OBR Vs placebo +OBR in 3 class resistant patients– Results at 48 weeks: % < 50

• Overall 65% Vs 31%

• OBR included both DRV and T-20: 89% Vs 66%

• OBR includes neither DRV or T-20: 60% Vs 20%

• ARNS 138: 3 class R but ND on T-20: change to RAL or stay on T-20– No difference at 24 weeks

Raltegravir

• Switchmark I & II– Suppressed on LPV+2nRTI: change LPV to

RAL or not– At 24 weeks 87% (LPV) Vs 81% (RAL): RAL

inferior to LPV– Patients who failed in RAL arm had more nRTI

and nnRTI RAMs – suggesting RAL did not protect nRTIs as well as LPV (however, patients randomized to RAL had had more nRTI failing regimens at baseline)

Maraviroc

• Motivate I & II– MRV+OBR Vs placebo+OBR in 3 class R pts– At baseline 56% R5 and 44% X4 or DM, at d0 –

additional 8% had DM– Results: at 48 wks: 44% Vs 17% < 50

• Merit– MRV Vs EFV in naïve patients– Results

• VL < 100,000: MRV=EFV, VL > 100,000: MRV < EFV

• When Trofile ES used to categorize pts: MRV=EFV

Maraviroc

• MRV resistance: 2 mechanisms– Switch to X4 or DM virus– Mutations in V3 region (or gp 41): allow virus to

bind CCR5 even with MRV around• No good GSS for these mutations yet

• PhenoSense for these viruses shows reduced or saturable inhibition rather than R-shift in IC50

• Dosing: MRV is substrate of P450– TPV: use 300 bid (standard)– Other PIs: use 150 bid– NNRTIs: use 600 bid

Take-home Points for Resistance Testing

• Some nRTI mutations (e.g. 215Y, 208Y) lead to hyper-susceptibility to nnRTIs

• TAMs (41L, 67N, 70R, 210W, 215Y/F, 219Q/E) can lead to some R to all nRTIs

• 184V alone does not confer R to abacavir but can in the presence of TAMs

• 184V can delay the emergence of TAMs• 215A/C/D/E/G/H/I/L/N/S/V are revertant

mutations … from 215Y on the way back to WT• AZT or TAMs prevent the emergence of 65R


• 103N does not affect etravirine. 181C/I/V, 100I, 101P and 190S do, but not completely – need combination of 3 or 4 RAMs to knock it out

• Patients failing nnRTI regimens more likely to have nRTI RAMs than patients failing PI regimens

• PI mutations can be major (appear early and contribute to R) or minor (appear late and may increase fitness).

• Most who fail PI regimens will not have RAMs


• The Resist and Power studies demonstrate the superiority of TPV and DRV over other PIs

• DRV mutations – need 3 for FC > 10 (diminished susceptibility) and 5 for FC > 40 (complete R)

• TPV resistance requires multiple RAMs and mutations are relatively unique among PIs – so TPV remains active after failure on other PIs


• T-20 resistance primarily due to mutations in gp41 and can occur easily (like nnRTIs)

• Maraviroc R usually due to X4 or DM virus – new Trofile ES detects most (Motivate update). However there are viruses with mutations in gp120 that will allow the virus to bind CCR5 in the presence of maraviroc

• Raltegravir R occurs via 1 of 3 major mutational pathways (148H/K/R, 155H, 143R/H/C) plus 1 or more minor mutations….and can occur easily (like nnRTIs) (Switchmark)

ARNS 139: TRIO Study

• Observational study 103 patients failing HAART with 3 class resistant HIV (but not R to RAL or ETV or DRV)

• Treated with RAL+ETV+DRV with OBR (12% on T-20)

• Results: at 48 weeks 86% were < 50

From CLIN INFECT DIS 49(9):1441-1449. © 2009 by the Infectious Diseases Society of America. All rights reserved. For permission to reuse, contact [email protected].

ARNS 139: TRIO Study

Percent with VL < 50 CD4 and VL on Treatment

Case 4

• 48 yo HIV+ male just moved from SF to Seattle. He’s been on lots of ARVs over the years – was never very adherent, mostly because the meds made him nauseated. He identifies AZT, 3TC, ddI, d4T, NVP, IDV, SQV and LPV/r as medications he’s taken before.

• He is currently taking Atripla (likes 1 pill per day) but has a VL of 24K, a genotype that reveals 184V and 103N mutations and a Trofile ES showing only R5 virus.

Case 4

• Which regimen would you recommend:– AZT + TDF/FTC + ETV

– AZT + TDF/FTC + ETV + MRV

– AZT + TDF/FTC + RAL

– AZT + TDF/FTC + R-ATZ

– AZT + TDF/FTC + R-DRV

Case 4

• Which regimen would you recommend:– AZT + TDF/FTC + ETV (maybe not fully supported

nnRTI – easy to fail?)

– AZT + TDF/FTC + ETV + MRV (OK but lots of pills)

– AZT + TDF/FTC + RAL (maybe not fully supported Raltegravir – easy to fail?)

– AZT + TDF/FTC + R-ATZ (OK but has seen multiple PIs)

– AZT + TDF/FTC + R-DRV (OK, probably the best)

Case 4

• He’s started on AZT + TDF/FTC + ETV + MRV and is quickly suppressed but then tires of the pill burden, becomes less adherent and fails. Repeat testing reveals DM virus that now has 65R and 181C in addition to 184V and 103N

• Now you recommend:– RAL + ETV + R-DRV

– RAL + ETV + R-TPV

– RAL + T-20 + R-TPV

– 3TC + ETV + R-DRV

– 3TC montherapy

Case 4

• He’s started on AZT + TDF/FTC + ETV + MRV and is quickly suppressed but then tires of the pill burden, becomes less adherent and fails. Repeat testing reveals DM virus that now has 65R and 181C in addition to 184V and 103N

• Now you recommend:– RAL + ETV + R-DRV (OK)

– RAL + ETV + R-TPV (DRV preferred over TPV and shouldn’t use TPV with ETV)

– RAL + T-20 + R-TPV (would work but nasty)

– 3TC + ETV + R-DRV (only 2 active drugs)

– 3TC montherapy (not yet)

Case 4

• He’s started on RAL + ETV + R-DRV and does well – is suppressed at 6 months. Then takes up methamphetamine, his adherence suffers and he fails with X4-using, multi-drug R virus: 65R, 184V, 100I, 103N, 181C, 190S and a PhenoSense for DRV with a FC of 100 (fully resistant)

• Now what would you choose:– R-TPV + T-20 + 3TC

– 3TC alone

Combination rules

• When constructing a salvage regimen best to have 2 (and preferably 3) fully active drugs

• 184V virus is less fit….good reason to use 3TC or FTC

• 184V delays emergence of TAMs and AZT or TAMs delay emergence of 65R…so use of 3TC or FTC with AZT and TDF is good combination

• ABC and TDF both select for 65R so best to avoid if using alone with an nnRTI

• If using an nnRTI or RAL – make sure regimen is fully supported (3 active drugs)

Combination rules

• If going to a second PI – use DRV first (better tolerated than TPV)

• Combination of RAL, ETV and DRV particularly effective salvage for patients with multi-drug resistant virus (Trio study)

• Save TPV and T-20 until the end


Drug interactions

Case 5

• A 25 year old woman is recently diagnosed with advanced HIV. Her CD4 count is 10, her plasma HIV RNA level is > 1,000,000.

• Her PMH is notable for GERD, anxiety, opiate addiction, hyperlipidemia, primary pulmonary hypertension, hepatitis C, hepatitis B and a seizure disorder.

• Current medications are omeprazole, diazepam, methadone, lovastatin, sildenafil, dilantin, pegylated interferon, ribavirin and estridiol.

• Besides bactrim and azithromycin you prescribe HAART selecting ddI, 3TC and atazanavir/ritonavir.

• The clinic pharmacist approaches you shaking her head in disgust. What is the problem?

Case 5

Drug Interactions• NNRTIs (EFV and NVP) induce the cytochrome P450 system• Protease inhibitors (esp RTV) inhibit the cytochrome P450 system• Ribavirin increases the toxicity due to ddI • NNRTIs decrease estradiol concentrations and, paradoxically, so do

protease inhibitors• Methadone metabolism is increased by NNRTIs and variably affected

by protease inhibitors• Atazanavir absorption is decreased with co-administration of PPI

• Watch out for significant drug interactions with all antiretrovirals, especially those metabolized through the cytochrome P450 system

Case 5

For this patient:• Change omeprazole to ranitidine• Change diazepam to lorazepam• Watch for methadone withdrawl• Change lovastatin to pravistatin• Talk to pulmonologist about sildenafil dose• Transition from dilantin to other anticonvulsant (Keppra)• Don’t use ddI with ribavirin• Don’t use 3TC alone in patient with hepatitis B• Don’t rely on OCPs alone for birth control in patient on

HAART

Madison Clinic Website

www.madisonclinic.org

Documents

Antiretroviral Therapy, 2010 Robert D. Harrington