Principles of Antiretroviral Therapy Christopher Behrens, MD Northwest AIDS Education & Training...

Principles of Antiretroviral Therapy

Christopher Behrens, MD

Northwest AIDS Education & Training Center

University of Washington

CBB/2002

Current Treatment Strategies

• DHHS Guidelines regarding when to initiate antiretroviral therapy

• Adherence

• Strategic antiretroviral combinations

• Popular regimens

• Follow-up monitoring

CBB/2002

HIV: Case History

A 29-year old woman comes to the clinic for routine HIV care; she has been HIV-infected for about 4 years, and has never received antiretroviral treatment. Her most recent CD4 count is 330 and her viral load is 88,000.

You explain the meaning of her CD4 count and viral load She asks you if you would recommend antiretroviral therapy

CBB/2002

Initiation of Antiretroviral Therapy

• Advantages– decrease viral load, increase

CD4 count

– prevent further damage to immune system

– immune reconstitution

– reduced morbidity & mortality (if effective)

– prevent viral heterogeneity

– decrease infectivity

• Disadvantages– toxicities, both short- &

long-term

– pill burden, lifestyle changes

– potential for developing resistance

– may limit future options

– potential for transmission of resistant virus

– cost

CBB/2002

Initiation of Antiretroviral Therapy: Key Considerations

• Symptoms & Opportunistic Infections

• CD4 count

• Viral Load

• Anticipated Adherence - patient ‘readiness’

CBB/2002

Indications for Initiation of Antiretroviral Therapy for HIV

Clinical Category CD4 count Viral Load Recommendation

Symptomatic (AIDS,severe Sx)

Any value Any value Treat

Asymptomatic, AIDS < 200/mm3 Any value Treat

Asymptomatic > 200/mm3

but < 350Any value Treatment should

generally be offered

Asymptomatic > 350/mm3 >30,000 bDNA or>55,000 PCR

Some experts wouldrecommend initiatingtreatment

Asymptomatic > 350/mm3 <30,000 bDNA or<55,000 PCR

Many experts woulddefer therapy andobserve

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6.

CBB/2002

Baseline CD4 Count and Survival after initation of HAART: prospective cohort of 715 patients

Survival in Years

Chen RY et al, 8th CROI, Chicago 2001

prop

orti

on s

urvi

ving

CD4 Count when Initiate HAART

< 50

51 - 200

201 - 350

> 350

0 1 2 3 4 5

0.0

0.5

1.0

CD4 > 200

CD4 50-199

CD4 < 50

Baseline CD4 Count and Survival after

Initiation of HAART

Pro

babi

lity

of

Sur

viva

l (%

)

Time From Start of HAART (months)

Cumulative Mortality by Baseline CD4 Count

JAMA. 2001;286:2568-2577

N = 1219 therapy-naïve individuals initiating HAARTin British Columbia1996 - 1999

====================

CBB/2002

Indications for Initiation of Antiretroviral Therapy for HIV

Clinical Category CD4 count Viral Load Recommendation

Symptomatic (AIDS,severe Sx)

Any value Any value Treat

Asymptomatic, AIDS < 200/mm3 Any value Treat

Asymptomatic > 200/mm3

but < 350Any value Treatment should

generally be offered

Asymptomatic > 350/mm3 >30,000 bDNA or>55,000 PCR

Some experts wouldrecommend initiatingtreatment

Asymptomatic > 350/mm3 <30,000 bDNA or<55,000 PCR

Many experts woulddefer therapy andobserve

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, February 5, 2001, Table 6.

CBB/2002

Time from initation of HAART (mos)

P

roba

bili

ty o

f S

urvi

val (

%)

JAMA. 2001;286:2568-2577

N = 1219 therapy-naïve individuals initiating HAARTin British Columbia1996 - 1999

Survival after Initiation of HAART

by Baseline CD4 Count

and Viral Load===================

Impact of CD4 and Viral Load on Initiation of HAART:

Summary

• The optimal time to initiate therapy is:– unclear– before CD4 drops below 200– probably when CD4 between 200 and 350– determined more by CD4 count than viral load

• Viral Load– predicts the slope of CD4 decline– may help determine whether to start closer to CD4

count of 200 or 350CBB/2002

HIV: Case History

A 29-year old woman comes to the clinic for routine HIV care; she has been HIV-infected for about 4 years, and has never received antiretroviral treatment. Her most recent CD4 count is 330 and her viral load is 88,000.

Would you suggest she start antiretroviral therapy?

CBB/2002

Initiation of Antiretroviral Therapy: Key Considerations

• Symptoms & Opportunistic Infections

• CD4 count

• Viral Load

• Anticipated Adherence - patient ‘readiness’

CBB/2002

Adherence

“Drugs don’t work if people don’t take them.”

- C. Everett Koop

CBB/2002

0

20

40

60

80

100

>95 90-95 80–90 70-80 <70

Pat

ient

s w

ith

HIV

RN

A<

400

cop

ies/

mL

, %

PI adherence, % (electronic bottle caps)

Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.

Virologic Control falls sharply with diminished adherence

CBB/2002

10% Adherence difference = 21% reduction in risk of AIDSAdherence and AIDS-Free Survival

Bangsberg D, et al. AIDS. 2001:15:1181

Pro

port

ion

AID

S-F

ree

Months from entry

P = .0012

0 5 10 15 20 25 30

0.00

0.25

0.50

0.75

1.00

AdherenceO 90–100%O 50–89%O 0–49%

Reasons for Non-Adherence: Clinician vs Patient Views

0

10

20

30

40

50

60

valu

e, %

No. of doses orpills

Side Effects Meal Instructions Schedulecomplexity

Other

ClinicanPatient

Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281CBB/2002

Predictors of Poor Adherence

• active alcohol1 or substance2 abuse

• work outside the home for pay1

• depressed mood1

• lack of perceived efficacy of HAART3

• lack of advanced disease4

• concern over side effects4

1. Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281. 2. Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407.3. Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588. 4. Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.

CBB/2002

Predictors of Poor Adherence, continued

• inability to fit medications into daily schedule

• tid dosing, food requirements1

1. Stone VE, et al. JAIDS 2001; 28:124-131

CBB/2002

Factors Associated with Higher Levels of Adherence

• twice-daily or once-daily regimens1,4

• belief in own ability to adhere to regimen1

• not living alone2

• dependent on a significant other for support2

• history of Opportunistic Infection or Advanced HIV disease3

1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125.

2. Morse EV et al, Soc Sci Med 1991;32:1161-1167. 3. Singh N, et al, AIDS Care 1996;8:261-269. 4. Stone VE, et al. JAIDS 2001; 28:124-131

CBB/2002

Factors Associated with Higher Levels of Adherence

• Belief in efficacy of antiretroviral therapy

• Belief that non-adherence will lead to viral resistance

Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.

Interventions Shown to Improve Adherence to Antiretrovirals

• medication alarms1

• education & counseling sessions2,3

• Directly Observed Therapy (DOT)4,5

1. Samet JH, et al. Am J Med. 1992;92:495-502. 2. Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4.3. Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; Abstract 595.4. Sorensen JL, et al. AIDS Care. 1998;10:297-312. 5. Wall TL, et al. Drug Alcohol Depend. 1995;37:261-269.

Self-Adminstered vs Directly Observed Therapy During Incarceration

0

102030405060708090

100

% w

ith

VL

< 5

0 co

pies

/mL

w4 w8 w16 w24 w48 w64 w72 w80 w88

DOT <50

SAT <50

Fischl et al 8th CROI, 2001 abstract 528

p < 0.01

N = 50 in each group

Putting it all Together

Practical Strategies to Improve Adherence

Improving Adherence: before Initiation of Therapy

Assess patient's understanding and acceptance of the regimens

Determine other medical barriers to adherence

Manage or refer for management of adherence-limiting co-morbid conditions

Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

Improving Adherence: before Initiation of Therapy

• Try to use simple regimens– bid or better– avoid food requirements if possible

• Clear & simple instructions

• Negotiated treatment plan

Improving Adherence: After Initiation of Therapy

• Close follow-up

• Ask patient to verbalize treatment regimen

• Education about adherence– re-emphasize importance of adherence at each

visit, even in patients with good virologic control

– review incidence & management of adverse effects often

Improving Adherence: After Initiation of Therapy

• consider cues to remind patients of dosing

• other reminders: alarms, watches, pagers

• consider recruiting family/friends as support

• referral to community support groups

• involve other members of the health care team

Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.

Back to the case

• You confirm her viral load and CD4 count; she keeps her follow-up appointments and appears to understand the importance of adherence. She has no significant co-morbid conditions or medications.

• What regimen would you recommend?

Highly Active Antiretroviral Therapy (HAART)

• Combination of at least 3 drugs, usually:– 2 NRTIs (the “NRTI backbone”), plus:

– 1 NNRTI or 1-2 PIs

• Therapy with only one or two agents allows HIV to overcome therapy through resistance mutations

Adapted from: Walker B. IDSA 1998

Classes of Antiretroviral Agents

RNA DNA

HIV

Nucleus

Host Cell

Nucleoside Analogues

Non-Nucleosides Protease Inhibitors

RT

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Nucleoside analogues that block translation of HIV RNA into DNA by inhibiting HIV Reverse Transcriptase enzyme– AZT (zidovudine; Retrovir)

– 3TC (lamivudine; Epivir)

– d4T (stavudine; Zerit)

– ddI (didanosine; Videx)

– Abacavir (Ziagen)

– ddC (zalcitabine; Hivid)

Tenofovir: a new NRTI

• Nucleotide Reverse Transcriptase Inhibitor

• one 300mg tablet daily with food

• well-tolerated and effective in clinical trials to date

• effective against many strains of HIV with NRTI resistance

• also active against hepatitis B

• generally being reserved for salvage therapy

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Also inhibit HIV Reverse Transcriptase, but at a different site than NRTIs– Efavirenz (Sustiva)– Nevirapine (Viramune)– Delavirdine (Rescriptor)

Protease Inhibitors (PIs)

• Block release of the assembled HIV virus particles from infected cells– Ritonavir (Norvir)– Saquinavir (Fortavase; Invirase)– Nelfinavir (Viracept)– Indinavir (Crixivan)– Amprenavir (Agenerase)– Lopinavir (co-formulated w/ ritonavir as Kaletra)

Ritonavir intensification of other Protease Inhibitors (PIs)

• Protease Inhibitors, like many medications, are metabolized in the liver by the cytochrome P450 enzyme complex

• Ritonavir inhibits this complex, thereby boosting serum levels of co-administered protease inhibitors

Basic Pharmacology Principles

IC90

IC50 Cmin

Cmax

Time

Drug Level

Dosing Interval

Area of Potential HIV Replication

Dose Dose

Cmax

Cmin

Time Postdose (hours)

0 2 4 6 8 10 12100

1,000

10,000

An Example of Ritonavir Boosting:Indinavir/Ritonavir BID PK Study

IDV/RTV q12h:

800/200 High-fat Meal

800/100 High-fat Meal 400/400 High-fat Meal

IDV q8h: 800 mg Fasted

IndinavirPlasma

Concentration(nM)

6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.

Ritonavir intensification of other Protease Inhibitors (PIs)

• This can be used to ease pill burden, dosing intervals, and potentially overcome HIV resistance among protease inhibitors

• This can also lead to potentially dangerous or fatal interactions with other medications and recreational drugs

So What to Start With?

• PI - based regimens (2 NRTIs + 1-2 PIs)

• NNRTI - based regimens (2 NRTIs + 1 NNRTI)

• NRTI - based regimens (3 NRTIs)

Protease Inhibitor -based regimens

The most clinical outcome data available for PI-based regimens

Allow deferral of NNRTIs

High genetic barrier to resistance (multiple mutations required)

high pharmacologic barrier to resistance for pharmaco-kinetically boosted PIs

Short-term side effects (esp. gastrointestinal)

Long-term metabolic/morphologic side effects

Inconvenience & adherence (schedule, pill burden, food requirements)

Drug-drug interactions

Advantages Disadvantages

NNRTI - based regimens

• Simpler regimens

• Fewer long-term toxicities

• Potent at high viral loads/low CD4+ cell counts (efavirenz)

• Allow deferral of PIs

• Fewer drug-drug interactions

• NNRTIs vary in potency; some may be less effective at high viral loads/low CD4+ counts (nevirapine, delavirdine)

• Low genetic barrier to resistance

• Extensive NNRTI cross-resistance

• toxicities: CNS, hyperlipidemia (efavirenz); rash (all); hepatotoxicity (NVP > EFV)


NRTI - based regimens (AZT + 3TC + Abacavir)

• Allows deferral of PIs and NNRTIs

• Simple, low pill burden

• Well tolerated

• minimal long-term toxicity

• virtually no drug interactions

• Limited data, no clinical endpoint data

• Relative potency and durability not established

• Efficacy at high viral loads questionable

• Abacavir hypersensitivity


Recommended Antiretroviral Combinations for Initial Therapy

Column A Column BEfavirenz Stavudine + lamivudineIndinavir Stavudine + didanosineNelfinavir Zidovudine + lamivudineRitonavir + indinavir Zidoviduine + didanosineRitonavir + lopinavir Didanosine + lamivudineRitonavir + saquinavir

Choose one from Column A and one from Column B

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, August 13, 2001, Table 12.

Effect of Baseline Viral Load on Efficacy

• Inverse Association– Nelfinavir– Indinavir– Nevirapine– Delavirdine– triple NRTI

• No Association– Efavirenz– Lopinavir/ritonavir

(Kaletra)

• Unknown Association– dual PI combination

Choice of initial regimen by baseline Viral Load

• VL > 100,000• Proven

– LPV/RTV + 2 NRTIs

– Efavirenz + 2 NRTIs

• Unproven

– Boosted PI + 2 NRTIs

– 3 NRTIs + PI

– 3 NRTIs + Nevirapine

– NRTI/NNRTI/PI

• VL < 100,000– LPV/RTV + 2 NRTIs

– Efavirenz + 2 NRTIs

– Nevirapine + 2 NRTIs

– 1-2 PIs + 2 NRTIs

– AZT/3TC/Abacavir

Popular Initial HAART Regimens: Efavirenz + 2 NRTIs

• d4T/3TC/Efavirenz– highly potent– generally well tolerated– CNS side effects from efavirenz

• AZT/3TC/Efavirenz (or Combivir/Efavirenz)– low pill burden– more side effects from AZT

DHS/ARV Rx /PP

Efavirenz: Study 006

90%

79% 75%64%

43% 47%

0

20

40

60

80

100

Patie

nts %

On Treatment ITT (NC=F)

48 Week Data: HIV RNA < 50 copies/ml

AZT + 3TC + EFV

AZT + 3TC + IDV

EFV + IDV

From: Staszewski S. N Engl J Med 1999;341:1865-73.

Patients (N=450)- CD4 > 50 cells/mm3

- HIV RNA > 10,000 copies/ml- Naive to PI, non-nucleoside, and 3TC

Regimens- AZT + 3TC + IDV - EFV + IDV - AZT + 3TC + EFV

AZT/3TC/EFVAZT/3TC/IDVEFV/IDV

90

Undetectable VL at 48 Weeks

64

AIDS 2001 December 7;15(18):2385-2395

Kaplan–Meier plot showing the percentage of patients with virological failure by time from start of the non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen, according to use of nevirapine or efavirenz.

Popular Initial HAART Regimens

• d4T/3TC/Nevirapine, AZT/3TC/Nevirapine– fewer CNS side effects– more hepatotoxic– Nevirapine may be less potent than efavirenz

• d4T/3TC/Nelfinavir, AZT/3TC/Nelfinavir– more experience with PIs as third agent– Nelfinavir preserves future PI options– higher pill burden; diarrhea common

Popular Initial HAART Regimens

• d4T/3TC/Kaletra, AZT/3TC/Kaletra– Kaletra a potent and well-tolerated PI– maintains high efficacy even in patients with

baseline VL > 100,000– many clinicians prefer to save Kaletra for

salvage therapy

Other Initial HAART Regimens

• Trizivir (AZT/3TC/ABC)– simplest regimen available with lowest pill count– not considered first-line option– efficacy not well established– consider for patients with low VL who need very

simple regimen– beware of ABC hypersensitivity

Abacavir: Study 3005AZT + 3TC + ABC vs AZT + 3TC + IDV

69

82

4046

31

45

0

10

20

30

40

50

60

70

80

90

100

As Rx ITT ITT

AZT/3TC/ABC

AZT/3TC/IDV

• Patients (N = 562)– therapy-naïve adults

– HIV VL > 10,000

– CD4 > 100

• Regimens– AZT + 3TC + Abacavir

– AZT + 3TC + Indinavir

VL > 100,000

% o

f pa

tient

s w

ith V

L <

50

48 week data: HIV VL < 50

Staszewski, S. JAMA 2001;285:1155-63.

Abacavir (Ziagen) Hypersensitivity

Incidence and Timing- Incidence < 3%- Onset typically within 4 weeks

Symptoms- Rash- Fever - Nausea- Throat/mouth lesions- Conjunctivitis/respiratory symptoms

Re-challenge can be fatal!

DHS/ARV Rx/PPFrom: Hetherington S, et al. 12th World AIDS Conference, Geneva, 1998: Abstract 12353

HIV Case continued

You decide to start her on d4T (stavudine) plus 3TC (lamivudine) plus Efavirenz.

What are your goals of therapy? What follow up labs do you arrange, and when?

DHS/ARV Rx/PP

Antiretroviral Therapy: Optimal Response

10

100

1000

10000

100000

1000000

0 1 2 3 4 5 6 7 8

Months

HIV

RN

A

Medications Started

50 50

Several trials indicate the need to achieve better viral suppression, i.e. < 50 cps/ml

AVANTI-2 (AZT/3TC/IDV)INCAS (AZT/ddI/NVP)

484032261680

100

0

20

40

60

80

0 8 16 24 32 40 48

0 8 16 24 32 40 48

All trials combined

Weeks

00 8 16 24 32 40 48

20

40

60

80

100AVANTI-3 (AZT/3TC/NFV)

Weeks

Pro

port

ion

of

su

bje

cts

wit

h

su

sta

ined

vir

olo

gic

su

ccess*

(%) Viral load Nadir

20 copies/ml21–400 copies/ml>400 copies/ml

*HIV-1 RNA <1000 copies/mlMontaner J. 12th World AIDS Conference Geneva 1998 AETC NRC Training Slide

Follow-up Laboratory Testing

• Viral load & CD4 counts, initially q month after starting therapy; can space out to q3mo if doing well

• Goals are undetectable viral load (<50 copies/mL) and rise in CD4 count

• CBC, electrolytes, LFTs at regular intervals to monitor for toxicity, also when signs or symptoms develop

Initial Antiretroviral Therapy: Summary

• When to initiate therapy is controversial, but probably best to start while CD4 > 200

• HAART consists of at least 3 drugs, generally from 2 or more classes

• consider adherence and baseline viral load when designing initial regimen

• goal is undetectable viral load (< 50 copies/mL) and rise in CD4 count

• monitor closely after initiation of therapy

Back to the Case

• She does well on her regimen of d4T, 3TC and Kaletra

• Her viral load rapidly drops to undetectable within 4 months

• At the same time, her CD4 count rises to 390

Antiretroviral Therapy: Intermittent Viremia (“blips”)

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

Case continued

• At her next blood draw, her viral load is 100 copies/mL

• what do you do?

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

Antiretroviral Therapy: Intermittent Viremia (“blips”)

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

Predictive Value of Intermittent Viremia

• Methods– N=241 adults on ARV Rx*

– HIV VL<50 at start of study

– “viral blip” defined as transient VL>50

– virologic failure = VL>200 on 2 consecutive values

• Follow-up at 6 months– 96 (40%) of 241 had “blips”

– 145 (60%) had no “blips” 1014

0

10

20

30

40

50

Vir

olog

ic F

ailu

re (

%)

Virologic Failure

Viral BlipNo Viral Blip

* AZT + 3TC + Indinavir (ACTG 343)

Havlir DV et al. JAMA 2001;276:171.

Antiretroviral Therapy: Low-level Viremia

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

Predictive Value of Low-Level Viremia

• Methods– N=1858 adults on HAART

– HIV VL <50 copies/mL x 2 at outset

– low level rebound: VL = 51-500

– blip: rebound followed by VL < 50

– virologic failure: VL > 500 x 2

• Follow-up at 6 months– 604 (33%) with low-level

rebound

22

85

0

5

10

15

20

25

30

35

40

45

50

Vir

olog

ic F

ailu

re (

per

100

pers

on-y

ears

) Sustained low level rebound

Single viral blip

No viral blip

Greubl G et al. 8th CROI, 2001: Abstract 522

Virologic Failure

Salvage Antiretroviral Therapy

Guiding Principles, Strategies and

the Role of Resistance Testing

DHS/ HIV/PP

HIV: Case History

A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm3 is started on a regimen of AZT (zidovudine) plus 3TC (lamivudine) plus Nevirapine. He has an initial excellent response: HIV viral load < 50 at months 3, 6, and 9, and his CD4 count rises to 247. At the 12 month visit, he admits to missing some doses in the past month.

What would you do? Would you change his regimen?

Salvage Antiretroviral Therapy: Indications

• Virologic breakthrough on previously successful regimen (viral failure)

• Failure to ever achieve desired level of virologic suppression

• immune deterioration (falling CD4 count) despite viral suppression

• adherence or intolerance problems with initial regimen

DHS/ARV Rx/PP

Antiretroviral Therapy: Viral Failure

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

DHS/ARV Rx/PP

Antiretroviral Therapy: Failure to Suppress

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

Salvage Antiretroviral Therapy: Guiding Principles

• Always confirm viral failure with repeat viral load measurements

• Re-visit adherence issues

• Try to correct adherence problems before starting a salvage regimen


• for adherence or intolerance problems, can change single agent in the regimen as long as resistance is not suspected

• for cases of viral failure or failure to achieve sustained virologic suppression, must change at least two of the agents; an entirely new regimen is best though not always feasible

• beware of cross-resistance within a class


• trials have demonstrated the clinical benefit of resistance testing in designing salvage regimens, but resistance testing can miss minor resistant variants of HIV

• trials have also demonstrated the clinical benefit of expert assistance in designing salvage regimens


• Many patients have limited salvage options; it is sometimes rational to continue a ‘failing’ regimen in order to maintain partial viral suppression

• discontinuation of HAART should be considered for patients experiencing return to viral baseline and declining CD4 count who do not have rational salvage options

DHS/ HIV/PP

HIV: Case History

A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm3 starts on a regimen of Zidovudine (AZT) plus Lamivudine (3TC) plus Nevirapine and has an initial excellent response (HIV RNA < 50 at months 3, 6, and 9; CD4 count rises to 247). At the 12 month visit, he admits to missing some doses in the past month

What would you do? Would you change his regimen?

DHS/ HIV/PP

HIV: Case History

You re-address his adherence problems You continue his current regimen but order a viral

load and CD4 count. His 12 month HIV RNA level comes back at 624

copies/mL; CD4 count is essentially unchanged.

What would you do?

HIV Case continued

• The viral load is repeated 2 weeks later and returns at 822 copies/ml.

• Would you change his regimen?• Would you order a resistance test?

DHS/ARV Rx/PP

HIV Case continued

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

Antiretroviral Resistance Testing

• due to HIV’s high transcription error rate and high level of replication, mutant HIV variants constantly generated

• these variants often contain mutations that confer variable levels of resistance to antiretroviral agents

• poor adherence or suboptimal regimens can lead to resistance and ‘viral breakthrough’

HIV Case continued

Wild-type HIV

Resistant HIV

Pre-treatment: wild-type

On Treatment: resistance

Poor Adherence

Antiretroviral Resistance Testing

• Goal of resistance testing is to identify these resistance-conferring mutations in order to more intelligently design a ‘salvage’ regimen

• Studies have documented clinical benefit of resistance testing

• Expert advice on interpretation of the genotype carries a similar and additive benefit as well

Summary of Randomized Controlled Trials of Resistance Testing

Study N Primaryendpoint

Study Arms Change in viralload (log10)

% with undetectable VL

VIRADAPT 108 24 weeks Genotype + expert advicevs

SOC (no expert advice)

-1.15 vs –0.67(p=0.05)

32% vs 14% <200 copies/mL(p=0.67)

GART 153 4-8 weeks Genotype + expert advicevs


-1.19 vs –0.61(p < 0.001)

N/A

Havana 274 24 weeks Genotype +/- expert advicevs

SOC (+/- expert advice)

-1.1 vs –0.8(p=0.02)

58% vs 42% <400 copies/mL(p=0.01)

Expert advice +/- genotypevs

SOC (no expert advice) +/-genotype

-1.0 vs –0.9(p=0.03)

59.1% vs 41.1% <400 copies/mL(P = .003)

ARGENTA 174 6 months Genotype + expert advicevs


N/A 21% vs 17% <500 copies/mL(p=NS)

VIRA3001 274 16 weeks Phenotype (no expert advice)vs


-1.23 vs -0.87(P = .004)

45% vs 34% <400 copies/mL(P = 0.099)

NARVAL 541 12 weeks Genotype (no expert advice)vs

phenotype plus expert advicevs


N/A 41% vs 33% vs 34% <200 copies/mL(P =0.249)

Antiretroviral Resistance Testing: Guidelines for Implementation

Clinical Setting/Recommendation Rationale

Recommended Virologic failure during HAART

Suboptimal suppression of viral load after initiation of HAART

Determine the role of resistance in drug failureand maximize number of active drugs in a newregimen if indicated

Determine the role of resistance and maximizenumber of active drugs in new regimen

Consider Acute (Primary) HIV Infection Determine if drug resistant virus was transmitted

and design initial regimen accordingly

Not Generally Recommended Chronic HIV infection prior to initiation of HAART

After discontinuation of drugs

Plasma viral load < 1000 copies/mL

Current assays unlikely to detect minor drugresistant quasispecies

Resistant quasispecies tend to become minorspecies in the absence of selective drug pressure,making detection by current assays unlikely

Current assays unreliable at low viral loads

DHS/ARV Rx/PP

Antiretroviral Therapy: Viral Failure

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

DHS/ARV Rx/PP

Antiretroviral Therapy: Failure to Suppress

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

DHS/HIV/Resistance /PP

HIV Primary Infection Isolates

2

1

7

2

6

0

2

4

6

8

10

Res

ista

nt

Iso

late

s %

NRTI NNRTI PI

1996-1998

1999-2000

3

From: Little SJ. JAMA 1999;282:1142-9.Little SJ. 8th Conf Retrovirus. Abstract 756

N = 108 PatientsNewly HIV-Infected Phenotypic Data: 10-fold Resistance

Resistance Testing: Acute vs. Chronic HIV Infection

Wild-type HIV

Resistant HIV

Acute HIV Chronic HIV

No Therapy

Resistance Testing: On (Failing) Therapy vs Off Therapy

Wild-type HIV

Resistant HIV

On Therapy Off Therapy

ARV Rx stopped

Resistance Testing: Genotypic Assays

Reports mutations in Reverse Transcriptase & Protease genes

Generally require > 1,000 copies/mL Turn-around time of approximately two weeks cost: around $400 several trials have demonstrated clinical

benefit

Resistance Testing: Phenotypic Assays

Determine amount of drug required to suppress HIV replication in vitro

intuitively simpler but less clinical experience, less data demonstrating benefit

Generally require > 1,000 copies/mL turn-around time of approximately four weeks cost: close to $1,000

Genotyping vs Phenotyping

• discordance common between the two assays• genotypic assays suffer from complexity of

interpretation, potentially unknown interactions between various mutations

• phenotypic assays suffer from lack of consensus on susceptibility cut-offs for most agents, inability to delineate mutation patterns underlying resistance, high cost, and lengthy turn-around time

HIV Resistance TestingVirtual Phenotype

Genotype

ProteaseRTHIV

Access Data

Genotype & Phenotype Data

Virtual PhenotypeWild-type HIV

Resistant HIV

HIV Case continued

• You obtain a genotype which shows the K103N mutation in the Reverse Transcriptase Gene

• Would you change the nevirapine in his regimen to efavirenz?

Salvage Regimens & Resistance Testing: Key Points

• Consider salvage regimens for virologic failure, failure to suppress, immune deterioration, or inadherence/toxicity

• resistance testing is indicated for virologic failure, failure to suppress, and acute HIV infection

• expert advice has proven clinical benefit in interpreting resistance tests and designing salvage regimens

Consultation Services for Clinicians Caring for Patients with HIV/AIDS

• Northwest AETC– (206) 994-8773 pager, (206) 731-1058 VM

• University of Washington MEDCON– (800) 326-5300

• National HIV Telephone Consultation Service (Warmline)– (800) 933-3413

• National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline)– (888) HIV-4911

Principles of Antiretroviral Therapy Christopher Behrens, MD Northwest AIDS Education & Training...

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