Highly Active Antiretroviral Treatment (HAART)

DHHS Guidelines 2009

Wayne Duffus, MD, PhD

May 25th 2010

FactorRecommendation

1998 2001 2002 2004 2007 2009

AIDS Treat Treat Treat Treat Treat Treat

CD4 count(cells/mm3)

• Treat <500

• Treat <200

• Offer <350

• Indiv. >350

• Treat <200

• Offer <350

• Indiv. >350

• Treat <200

• Offer <350

• Indiv. >350

• Treat <350• Risks/benefits

if >350

• Treat <350• Recommended

between 350 and 500

• >500 optional

Viral load (copies/mL)

>20,000 >55,000 > 100,000No specific viral load

No specific viral load

Other factors

• Pregnant women

• HBV coinfected

• HIVAN

• Pregnant women

• HBV coinfected

• HIVAN

When to Start: Evolution of DHHS Treatment Initiation Guidelines

Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 1998-2009.

2

Percent of subjects who have a CD4 cell count ≤500 cells/mm3

Per

cen

t o

f su

bje

cts,

%

CASCADE: Time Until CD4 Cell Count Declines to ≤500 Cells/mm3 After Seroconversion

• Time from seroconversion to first CD4 cell count ≤500 cells/mm3 analyzed from CASCADE cohort (N=11,702)

• 56.6% (n=6626) of subjects declined to CD4 cell count ≤500 cells/mm3 after a median of 20 months

• Predictors of more rapid CD4 cell count decline– Older age (HR 1.06, 1.03-1.09

per 10-years)– More recent seroconversion

by calendar year (HR 1.07, 1.06-1.08 per year)

Time after seroconversion, months

Lodi S, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOPEB050.3

6 12 24 36

8

28

57

70

0

20

40

60

80

100

• Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count normalization with earlier therapy

1Moore R, et al. Clin Infect Dis. 2007;44(3):441-446. 2Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Years on ART

Johns Hopkins HIV Clinical Cohort1

Mea

n C

D4

Cel

l C

ou

nt

(cel

ls/m

m3)

1000

800

600

400

200

0

0 48 96 144 192 240 288 336

ATHENA National Cohort2

Weeks From Starting ART

0 1 2 3 4 5

200

400

600

800

0

1000

Likelihood of Achieving a Normal CD4 Cell Count Depends on When You Start

<200

201-350

>350

<5050-200

200-350350-500≥500

4

ART in Patients >50 Years Old: ATHENA National Cohort

Mea

n C

D4

Co

un

t (c

ells

/mm

3 )

Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Median CD4 Response in Patients ≥50 Years of Age at the Start of ARTa

aSolid lines represent control patient group (male patients <50 years of age at the start of ART); dashed lines represent patients ≥50 year of age at the start of ART.

Years from Starting ART

<50 cells/mm3

50-200 cells/mm3

200-350 cells/mm3

350-500 cells/mm3

≥500 cells/mm3

0 1 2 3 4 65 7

1100

1000

900

800

700

600

500

400

300

200

100

0

5

ART in Patients >50 Years Old: ATHENA National Cohort

Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Median CD4 Response in Patients ≥50 Years of Age at the Start of ARTa

aSolid lines represent control patient group (male patients <50 years of age at the start of ART); dashed lines represent patients ≥50 year of age at the start of ART.

Years from Starting ART0 1 2 3 4 65 7

1100

1000

900

800

700

600

500

400

300

200

100

0Mea

n C

D4

Co

un

t (c

ells

/mm

3 )

6

<50 cells/mm3

50-200 cells/mm3

200-350 cells/mm3

350-500 cells/mm3

≥500 cells/mm3

ART in Patients >50 Years Old: ATHENA National Cohort

Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Median CD4 Response in Patients ≥50 Years of Age at the Start of ARTa

aSolid lines represent control patient group (male patients <50 years of age at the start of ART); dashed lines represent patients ≥50 year of age at the start of ART.

Years from Starting ART0 1 2 3 4 65 7

1100

1000

900

800

700

600

500

400

300

200

100

0Mea

n C

D4

Co

un

t (c

ells

/mm

3 )

7

<50 cells/mm3

50-200 cells/mm3

200-350 cells/mm3

350-500 cells/mm3

≥500 cells/mm3

D:A:D Study: Lower CD4 Count and Detectable Viral Load Associated With Increased Risk of Death

Smith C and D:A:D Study Group. 16th CROI; 2009; Montreal. Abstract 145.

HIV-RNA (log copies/mL) and ART Status

Ad

just

ed

Ra

te R

ati

o (

95

% C

l)

CD4

CD4 and HIV-RNA StatusCD4 and HIV-RNA Status

OverallOverall AIDSAIDS LiverLiver CVDCVD Non-AIDS MalignanciesNon-AIDS Malignancies

Per 100 <2.6 on >2.6 on <4 off 4-5 off >5 off0.1

0.5

1

5

10

8

HOPS Cohort: CD4 Count <350 Increases CVD Risk

• CD4 <350 cells/mm3 independently raised risk of new CVDa 80% in this analysis of 1697 patients1

• HOPS finding corroborated by the FIRST2 study– Patients with higher on-treatment CD4 cell count had lower risk of non-AIDS

events, including CVD2

Risk FactorHazard Ratio

for CVDa

Age 42 yr 2.5

Male sex 2.0

Smoking 2.0

Baseline CD4 count <350 cells/mm3

1.8

1Lichtenstein KA. 17th IAC; Mexico City, 2008. THPE0236. 2Baker JV. AIDS. 2008;22:841-848.

aCVD tracked as MI, CAD, PVD, TIA, angina, aortic aneurysm, coronary artery bypass, angioplasty.

HOPS Cohort1

9

Virologic Suppression (VS) Strategy

Continuous use of ARTto maintain viral load as low

as possible (n=2752)

Drug Conservation (DC) Strategy

Defer ART until CD4 count is <250; then episodic ART based on CD4 count to increase counts to >350

(n=2720)

CD4 cell count >350 cells/mm³N=5472

• Study was stopped January 2006 due to increased risk of progression of disease during the first 2 years of the trial for the DC versus the VS group

• Increased risk included progression of disease (the primary endpoint), and progression of major non-HIV/AIDS-related diseases

El-Sadr et al. New Engl J Med. 355(22): 2283-2296.

SMART: Study Design and Findings

10

SMART: Non-AIDS Event Rates With Continuous vs Deferred/Intermittent ART

• Significantly more individuals in DC arm developed major CV, renal, or hepatic disease than those in VS arm

• Significantly more individuals in DC arm experienced grade 4 event or death from any cause than individuals in VS arm

El-Sadr WM et al. N Engl J Med. 2006;355:2283-2296.

EndpointVS

(n=2752)DC

(n=2720)HR

(95% CI)P Value

Grade 4 event or death from any cause

164 205 1.3 (1.0-1.6) .03

Death by any cause 30 55 1.8 (1.2-2.9) .007

Major CV, renal, or hepatic disease 39 65 1.7 (1.1-2.5) .009

Fatal/nonfatal CV disease 31 48 1.6 (1.0-2.5) .05

Fatal/nonfatal renal disease

2 9 4.5 (1.0-20.9) .05

Fatal/nonfatal liver disease 7 10 1.4 (0.6-3.8) .46

11

SMART: Cumulative Probability of OI/Death With Continuous vs Deferred/Intermittent ART

• In January 2006, the study was modified to restart ART in DS group following the recommendations by the DSMB, and follow-up continued through July 2007

Cumulative Probability of OI/death From Any Cause Before Study Modification

Cumulative Probability of OI/death From Any Cause Following Study Modification

SMART Study Group. Ann Intern Med. 2008;149(5):289-299.

Cu

mu

lati

ve

Pro

ba

bil

ity

of

Op

po

rtu

nis

tic

Dis

ea

se

or

De

ath

*

Participants in the risk set, n

DC group 1892 1297 957VS group 1914 1305 978

Time from Randomization (mo)

DC group 2508 2446 2414VS group 2617 2567 2528

Participants in the risk set, n

Time from Study Modification (mo)

Overall HR, 2.9 (Cl, 1.9-4.5); P <.001

Change in HRs (log-time term); P = .23

Overall HR, 1.4 (Cl, 1.0-2.0); P = .04

Change in HRs (log-time term); P = .290.06

0.04

0.02

0

0 6 12 18

0.06

0.04

0.02

0

0 6 12 18

DC Group

VS Group

HR, 3.7 (Cl, 1.6-8.4); P=.003

HR, 3.9 (Cl, 1.8-8.5); P<.001

HR, 2.1 (Cl, 1.1-4.2); P=.04

HR, 1.2 (Cl, 0.7-2.2); P=.55

HR, 1.3 (Cl, 0.8-2.3); P=.32

HR, 2.2 (Cl, 1.1-4.3); P=.034

12

Association Between Current CD4 Cell Count and Non-AIDS Complications

StudyNon-AIDS

malignanciesRenal

disease/deathCVD

events/deathLiver disease/

death

FIRST Yes Yes Trend, NS No

D:A:D Yes Yes Trend, NS Yes

CASCADE Yes NA Yes Yes

SMART Trend, NS Trend, NS Trend, NS Yes

Phillips A et al. 15th CROI; 2008; Boston. Abstract 8.

Is Lower Current CD4 Cell Count Significantly Associated With Increased Risk of non-AIDS Events?

13

ART-CC: Prognosis Based on CD4 Count at Initiation of ART

Sterne J et al. CROI 2009. Abstract 72LB. Graphic reproduced with permission for educational use only.Sterne J et al. Lancet. 2009;373(9672):1352-63.

CD4 Threshold

Comparison(CD4

cells/mm3)HRa (95% CI)

1-100 vs 101-200 3.35 (2.99-3.75)

101-200 vs 201-300

2.21 (1.91-2.56)

201-300 vs 301-400

1.34 (1.12-1.61)

251-350 vs 351-450

1.28 (1.04-1.57)

351-450 vs 451-550

0.99 (0.76-1.29)

aAdjusted for lead-time and unobserved events.

0.5

1.0

2.0

4.0

500 400 300 100

HR

fo

r A

IDS

or

De

ath

a

200 0

14

Guidelines Outline

• Overview

• Initiation of Therapy

• Management of the Treatment-Experienced Patient

• Special Issues

What the Guidelines Address

• Baseline evaluation

• Laboratory testing (HIV RNA, CD4 cell count, resistance)

• When to initiate therapy

• When to change therapy

• Therapeutic options

• Adherence

• ART-associated adverse effects

What the Guidelines Address (2)

• Treatment of acute HIV infection

• Special considerations in adolescents, pregnant women, injection drug users, HIV-2 infection, and patients coinfected with HIV and HBV, HCV, or TB

• Preventing secondary transmission

Goals of Treatment

• Improve quality of life

• Reduce HIV-related morbidity and mortality

• Restore and/or preserve immunologic function

• Maximally and durably suppress HIV viral load

• Prevent HIV transmission

Tools to Achieve Treatment Goals

• Selection of ARV regimen

• Maximizing adherence

• Pretreatment resistance testing

Predicting Adherence: Individual and Psychosocial Factors

Not Predictive

Negative Effect

Positive Effect

Race

Gender

Disease stage

History of substance abuse

Active IDU

Active alcohol abuse(>14 drinks/week)

Untreated psychiatric disease

Patient belief in HAART

Physician expertise

Social supports

Adherence to office visits

Most Common Reasons for Nonadherence

• Vacations/away from home

• Forgetting to take a dose (timing)

• Fatigue

• Conflict with eating

• Ran out of medications

• Side-effects

• Doubts about efficacy

Improving Adherence

• Support and reinforcement

• Simplified dosing strategies

• Reminders, alarms, timers, and pillboxes

• Ongoing patient education

• Trust in primary care provider

Use of CD4 Cell Levels to Guide Therapy Decisions

• CD4 count– The major indicator of immune function – Most recent CD4 count is best predictor of

disease progression– A key factor in decision to start ART or OI

prophylaxis– Important in determining response to ART

• Adequate response: CD4 increase 50-150 cells/µL per year

• CD4 monitoring– Check at baseline (x2) and at least every

3-6 months

Use of HIV RNA Levels to Guide Therapy Decisions

• HIV RNA– May influence decision to start ART and help

determine frequency of CD4 monitoring– Critical in determining response to ART

• Goal of ART: HIV RNA below limit of detection (ie, <40-75 copies/mL, depending on assay)

• RNA monitoring– Check at baseline (x2) – Immediately before initiating ART– 2-8 weeks after start or change of ART– Every 3-6 months with stable patients

Testing for Drug Resistance

• Before initiation of ART:– Transmitted resistance in 6-16% of HIV-infected

patients

– In absence of therapy, resistance mutations may decline over time and become undetectable by current assays, but may persist and cause treatment failure when ART is started

– Identification of resistance mutations may optimize treatment outcomes

– Resistance testing (genotype) recommended for all at entry to care

– Recommended for all pregnant women

Testing for Drug Resistance

• Patients with virologic failure:– Perform while patient is taking ART, or ≤4 weeks

after discontinuing therapy

– Interpret in combination with history of ARV exposure and ARV adherence

Drug Resistance Testing: RecommendationsRECOMMENDED COMMENT

Acute HIV infection, regardless of whether treatment is to be started

To determine if resistant virus was transmitted; guide treatment decisions.

If treatment is deferred, consider repeat testing at time of ART initiation.

Genotype preferred.

Chronic HIV infection, at entry into care

Transmitted drug-resistant virus is common in some areas; is more likely to be detected earlier in the course of HIV infection.

If treatment is deferred, consider repeat testing at time of ART initiation.

Genotype preferred.

Suboptimal suppression of viral load after starting ART

To assist in selecting active drugs for a new regimen.

RECOMMENDED COMMENT

Virologic failure during ART

To assist in selecting active drugs for a new regimen.

Genotype preferred if patient on 1st or 2nd regimen; add phenotype if known or suspected complex drug resistance pattern.

If virologic failure on integrase inhibitor or fusion inhibitor, consider testing for resistance to these to determine whether to continue them.

Coreceptor tropism assay if considering use of CCR5 antagonist.

Drug Resistance Testing: Recommendations (2)

RECOMMENDED COMMENT

Pregnancy Recommended before initiation of ART or prophylaxis.

Recommended for all on ART with detectable HIV RNA levels.

Genotype usually preferred; add phenotype if complex drug resistance mutation pattern.

Drug Resistance Testing: Recommendations (3)

Drug Resistance Testing: Recommendations (4)

NOT USUALLY RECOMMENDED

COMMENT

After discontinuation(>4 weeks) of ARVs

Resistance mutations may become minor species in the absence of selective drug pressure

Plasma HIV RNA <500 copies/mL

Resistance assays cannot consistently be performed if HIV RNA is low

Other Assessment andMonitoring Studies

• HLA-B*5701 screening– Recommended before starting abacavir, to reduce risk

of hypersensitivity reaction (HSR)– HLA-B*5701-positive patients should not receive ABC– Positive status should be recorded as an ABC allergy– If HLA-B*5701 testing is not available, ABC may be initiated

after counseling and with appropriate monitoring for HSR

• Coreceptor tropism assay– Should be performed when a CCR5 antagonist

is being considered – Requires plasma HIV RNA ≥1,000 copies/mL– Consider in patients with virologic failure on a

CCR5 antagonist

When to Start ART

• Potent ART may improve and preserve immune function in most patients with virologic suppression, regardless of baseline CD4 count– ART indicated for all with low CD4 count or symptoms

– Earlier ART may result in better immunologic responsesand better clinical outcomes

• Reduction in AIDS- and non-AIDS-associated morbidity and mortality

– Reduction in HIV-associated inflammation and associated complications

• Reduction in HIV transmission

– Recommended ARV combinations are considered to bedurable and tolerable

When to Start ART

• Exact CD4 count at which to initiate therapy not known, but evidence points to starting at higher counts

• Current recommendation: ART for all patients with CD4 <500 cells/µL

• For patients with CD4 >500 cells/µL, 50% of the panel recommend ART, 50% consider ART to be optional

– Randomized control trial (RTC) data support benefit of ART if CD4 350

– No RTC data on benefit of ART at CD4 >350, but observational cohort data

• Currently available ARVs are effective and well tolerated

Potential Benefits of Early Therapy (CD4 count >500 cells/µL)

• Cohort study data show survival benefit if ART initiated at CD4 count >500 cells/µL

• Earlier ART may prevent HIV-related end organ damage; deferred ART may not reliably repair damage acquired earlier – Increasing evidence of direct HIV effects on

various end organs and indirect effects via HIV-associated inflammation

– End organ damage occurs at all stages of infection

Potential Benefits of Early Therapy (CD4 count >500 cells/µL) (2)

• Potential decrease in risk of many complications, including:– HIV-associated nephropathy– Liver disease progression from hepatitis B or

hepatitis C– Cardiovascular disease– Malignancies (AIDS defining and non-AIDS

defining)– Neurocognitive decline– Blunted immunological response due to ART

initiation at older age– Persistent T-cell activation and inflammation

Potential Benefits of Early Therapy (CD4 count >500 cells/µL) (3)

• Prevention of sexual and bloodborne transmission of HIV

• Prevention of mother-to-child transmission of HIV

Potential Limitations of Early Therapy (CD4 count >500 cells/µL)

• ARV-related toxicities

• Drug resistance

• Nonadherence to ART

• Cost

Recommendations for Initiating ART

Clinical Category or CD4 Count Recommendation

•History of AIDS-defining illness

•CD4 count <350 cells/µL

•CD4 count 350-500 cells/µL

•Pregnant women

•HIV-associated nephropathy (HIVAN)

•Hepatitis B (HBV) coinfection, when HBV treatment is indicated*

Initiate ART

* Treatment with fully suppressive drugs active against both HIV and HBV is recommended.

Recommendations for Initiating ART (2)

Clinical Category or CD4 Count Recommendation

CD4 count >500 cells/µL, asymptomatic, without conditions listed above

50% of the Panel favors starting ART; 50% views ART as optional

Recommendations for Initiating ART (3)

• “Patients initiating ART should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence.”

• Patients may choose to postpone ART

• Providers may elect to defer ART, based on patients’ clinical and/or psychosocial factors

Consider More Rapid Initiation of ART

• Pregnancy

• AIDS-defining condition

• Acute opportunistic infection

• Lower CD4 count (eg, <200 cells/µL)

• Rapid decline in CD4

• Higher viral load

• HIVAN

• HBV coinfection when HBV treatment is indicated

Consider Deferral of ART

• Clinical or personal factors may support deferral of ART– If CD4 is low, deferral should be considered only

in unusual situations, and with close follow-up

• When there are significant barriers to adherence

• If comorbidities complicate or prohibit ART

• “Elite controllers” and long-term non-progressors

Current ARV Medications

NRTI• Abacavir (ABC)

• Didanosine (ddI)

• Emtricitabine (FTC)

• Lamivudine (3TC)

• Stavudine (d4T)

• Tenofovir (TDF)

• Zidovudine (AZT, ZDV)

NNRTI• Delavirdine (DLV)

• Efavirenz (EFV)

• Etravirine (ETR)

• Nevirapine (NVP)

PI• Atazanavir (ATV)

• Darunavir (DRV)

• Fosamprenavir (FPV)

• Indinavir (IDV)

• Lopinavir (LPV)

• Nelfinavir (NFV)

• Ritonavir (RTV)

• Saquinavir (SQV)

• Tipranavir (TPV)

Integrase Inhibitor (II)• Raltegravir (RAL)

Fusion Inhibitor• Enfuvirtide (ENF, T-20)

CCR5 Antagonist• Maraviroc (MVC)

Initial ART Regimens: DHHS Categories

• Preferred– Randomized controlled trials show optimal efficacy

and durability– Favorable tolerability and toxicity profiles

• Alternative– Effective but have potential disadvantages

– May be the preferred regimen in individual patients

• Acceptable– Less virologic efficacy, lack of efficacy data, or

greater toxicities

• May be acceptable but more definitive data are needed

Initial Treatment: Choosing Regimens

• 3 main categories:– 1 NNRTI + 2 NRTIs– 1 PI + 2 NRTIs– 3 NRTIs

• Combination of NNRTI or PI + 2 NRTIs preferred for most

patients

• Fusion inhibitor, CCR5 antagonist, integrase inhibitor not recommended in initial ART

• Few clinical end points to guide choices

• Advantages and disadvantages to each type of regimen

• Individualize regimen choice

Preferred Regimens

PI-basedATV + (3TC or FTC) + (AZT, d4T, ABC or ddI) or

(TDF+RTV 100 mg/d)LPV/r + (3TC or FTC) + (d4T, ABC, TDF or ddI)

FPV or FPV/r or IDV/r or NFV or SQV/r + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)

Alternative RegimensNNRTI-based

EFV + (3TC or FTC) + (ABC, ddI or d4T)NVP + (3TC or FTC) + (AZT, d4T, ddI,

ABC or TDF)

EFV +(3TC or FTC) + (AZT or TDF)

LPV/r +(3TC or FTC) + AZT

3 NRTI-based

ABC + AZT + 3TC – only when a preferred or an alternative NNRTI- or PI-based regimen

cannot or should not be used

DHHS Guidelines for the Use of ARV Agents in HIV-1-Infected Adults and Adolescents; May 2006.

DHHS Guidelines: Recommended Regimens for Treatment-Naïve Patients

Initial Treatment: Preferred

NNRTI based •EFV/TDF/FTC1,2

PI based •ATV/r + TDF/FTC²•DRV/r (QD) + TDF/FTC²

II based •RAL + TDF/FTC²

Pregnant Women •LPV/r (BID)³ + ZDV/3TC

1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception.

2. 3TC can be used in place of FTC and vice versa.

Initial Treatment: Alternatives

NNRTI based •EFV¹ + (ABC/3TC) or (ZDV/3TC)²•NVP4 + ZDV/3TC

PI based •ATV/r + (ABC/3TC) or (ZDV/3TC)2,3

•FPV/r (QD or BID) + (ABC/3TC) or (ZDV/3TC) or (TDF/FTC)2,3

•LPV/r (QD or BID) + (ABC/3TC) or (ZDV/3TC) or (TDF/FTC)2,3

•SQV/r + TDF/FTC2

1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception.

2. 3TC can be used in place of FTC and vice versa.

3. ABC should not be used in patients who test positive for HLA B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease.

4. NVP should not be started if pre-ARV CD4 >250 in women or >400 in men.

Initial Treatment: Acceptable

NNRTI based •EFV¹ + ddI + (3TC or FTC)

PI based •ATV + (ABC/3TC) or (ZDV/3TC)2,3

1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception.

2. 3TC can be used in place of FTC and vice versa.

3. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease .

Initial Treatment: May Be Acceptable but More Definitive Data Needed

PI based •DRV/r + (ABC/3TC) or (ZDV/3TC)1,2

•SQV/r + (ABC/3TC) or (ZDV/3TC)1,2

CCR5 Antagonist based

•MVC + ZDV/3TC1,3

II based •RAL + (ABC/3TC) or (ZDV/3TC)1

1. 3TC can be used in place of FTC and vice versa.

2. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease.

3. Tropism testing required before treatment with MVC; use only if only CCR5-tropic virus is present.

Initial Treatment: Use with Caution

NNRTI based •NVP + ABC/3TC1,2,3,4

•NVP + TDF/FTC1,2,3,4,5

PI based •FPV + (ABC/3TC) or (ZDV/3TC)1,2,3,6

1. 3TC can be used in place of FTC and vice versa.

2. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease.

3. NVP and ABC both can cause hypersensitivity reaction in first few weeks of treatment.

4. NVP should not be started if pre-ARV CD4 >250 in women or >400 in men.

5. Early virologic failure in some patients; larger studies under way.

6. Virologic failure may select mutations that confer cross-resistance to DRV.

ARVs Not Recommended inInitial Treatment

High rate of early virologic failure

• ddI + TDF

Inferior virologic efficacy

• ABC + 3TC + ZDV as 3-NRTI regimen• ABC + 3TC + ZDV + TDF as 4-NRTI regimen• DLV• NFV• SQV as sole PI (unboosted)• TPV/r

High incidence of toxicities

• d4T + 3TC• IDV/r• RTV as sole PI

ARVs Not Recommended inInitial Treatment (2)

High pill burden/Dosing inconvenience

• IDV (unboosted)

Lack of data in initial treatment

• ABC+ TDF• ABC + ddI• DRV (unboosted)• ENF (T-20)• ETR

No benefit over standard regimens

• 3-class regimens• 3 NRTIs + NNRTI

ARV Medications: Should Not Be Offered at Any Time

• ARV regimens not recommended:– Monotherapy with NRTI*– Dual-NRTI therapy– 3-NRTI regimen (except ABC + 3TC + ZDV or possibly

TDF + 3TC + ZDV, when other regimens are not desirable)

* If ZDV monotherapy is being considered for prevention of mother-to-child transmission, see Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.

ARV Medications: Should Not Be Offered at Any Time (2)

• ARV components not recommended:– ddI + d4T– FTC + 3TC– d4T + ZDV– DRV, SQV, or TPV as single PIs

(unboosted)

ARV Medications: Should Not Be Offered at Any Time (3)

• ARV components not recommended:

– EFV during pregnancy and in women with significant potential for pregnancy

– NVP initiation in women with CD4 counts of >250 cells/µL or in men with CD4 counts of >400 cells/µL

– ETR + unboosted PI

– ETR + RTV-boosted ATV, FPV, or TPV

– 2-NNRTI combination

ARV Components in Initial Therapy: NNRTIs

ADVANTAGES• Long half-lives

• Less metabolic toxicity (dyslipidemia, insulin resistance) than with some PIs

• PIs and II preserved for future use

DISADVANTAGES• Low genetic barrier to

resistance – single mutation

• Cross-resistance among most NNRTIs

• Rash; hepatotoxicity

• Potential drug interactions (CYP450)

• Transmitted resistance to NNRTIs more common than resistance to PIs

ARV Components in Initial Therapy: PIs

ADVANTAGES• Higher genetic barrier

to resistance

• PI resistance uncommon with failure (boosted PI)

• NNRTIs and II preserved for future use

DISADVANTAGES• Metabolic complications

(fat maldistribution, dyslipidemia, insulin resistance)

• GI intolerance

• Potential for drug interactions (CYP450), especially with RTV

ARV Components in Initial Therapy: II (Raltegravir)

ADVANTAGES• Virologic response

noninferior to EFV

• Fewer adverse events than with EFV

• Fewer drug-drug interactions than with PIs or NNRTIs

• NNRTIs and PIs preserved for future use

DISADVANTAGES• Less experience with IIs,

limited data

• Twice-daily dosing

• Lower genetic barrier to resistance than PIs

• No data with NRTIs other than TDF/FTC in initial therapy

ARV Components in Initial Therapy: Dual-NRTI Pairs

ADVANTAGES• Established backbone

of combination therapy

• Minimal drug interactions

DISADVANTAGES• Lactic acidosis and

hepatic steatosis reported with most NRTIs (rare)

Treatment-Experienced Patients

• In clinical studies of ART, most patients maintained virologic suppression for at least 3-7 years

• Appropriate initial ARV regimens should suppress HIV indefinitely, assuming adequate adherence

• In patients with suppressed viremia:– Assess adherence frequently– Simplify ARV regimen as much as possible

• Patients with ARV failure: assess and address aggressively

Treatment-Experienced Patients: ART Failure

• Causes of treatment failure include:– Patient factors (eg, CD4 nadir, pretreatment HIV RNA,

comorbidities)

– Drug resistance

– Suboptimal adherence

– ARV toxicity and intolerance

– Pharmacokinetic problems

– Suboptimal drug potency

– Provider experience

Treatment-Experienced Patients: ART Failure (2)

• Virologic failure: – HIV RNA >400 copies/mL after 24 weeks, >50

copies/mL after 48 weeks, or >400 copies/mL after viral suppression

• Immunologic failure: – Failure to achieve and maintain adequate CD4

increase despite virologic suppression

• Clinical progression: – Occurrence of HIV-related events (after ≥3 months on

therapy; excludes immune reconstitution syndromes)

Treatment-Experienced Patients: Virologic Failure

• Incomplete virologic response: – In patient on initial ART, HIV RNA >400

copies/mL after 24 weeks on therapy or >50 copies/mL by 48 weeks (confirm with second test)

• Virologic rebound:– Repeated detection of HIV RNA after virologic

suppression (eg, >50 copies/mL)

Treatment-Experienced Patients: Virologic Failure (2)

• Assess drug resistance: – Drug resistance test– Prior treatment history– Prior resistance test results

• Drug resistance usually is cumulative – consider all previous treatment history and test results

Treatment-Experienced Patients: Virologic Failure (3)

• Management:– Clarify goals: aim to reestablish maximal

virologic suppression (eg, <50 copies/mL)

– Evaluate remaining ARV options• Newer agents have expanded treatment

options

– Base ARV selection on medication history, resistance testing, expected tolerability, adherence, and future treatment options

– Avoid treatment interruption, which may cause viral rebound, immune decompensation, clinicalprogression

Virologic Failure: Changing an ARV Regimen

• General principles:– Add at least 2 (preferably 3) fully active agents to an

optimized background ARV regimen• Determined by ARV history and resistance testing

– Consider potent RTV-boosted PIs, drugs with new mechanisms of action (eg, integrase inhibitor, CCR5 antagonist, fusion inhibitor, 2nd generation NNRTI) + optimized ARV background

– In general, 1 active drug should not be added to a failing regimen (drug resistance is likely to develop quickly)

– Consult with experts

0

10

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30

40

50

60

70

80

90

100

If you were to take a certain number of pills each day, how would you prefer them to be administered?

All at once

Divided and taken twice a day

% p

atie

nts

pre

ferr

ing

>8 pills 8 pills 6 pills 4 pills 3 pills

31%

69%

38%

62% 59%

41%

84%

16%

93%

7%

Patients Prefer Once-daily With Low Pill Burden

Moyle G et al. Paper presented at: 6th International Congress on Drug Therapy in HIV Infection; Glasgow, Scotland; November 17-21, 2002. Poster 99.

Regimen Simplification

• Changing a suppressive ARV regimen to:– Reduce pill burden – Reduce dosing frequency– Enhance tolerability– Decrease food and fluid requirements

• Goals: improve patient’s quality of life, improve ART adherence, avoid long-term toxicities, reduce risk of virologic failure

Regimen Simplification (2)

• Types of substitution– Within class: substitution of a new agent or co-

formulation – Out-of-class: eg, change from PI to NNRTI or

agent from another class– Reducing number of active drugs in ARV

regimen: simplification to boosted-PI monotherapy is not recommended

• After simplification, monitor in 2-6 weeks (laboratory and clinical)

Websites to Access the Guidelines

• http://www.aidsetc.org

• http://aidsinfo.nih.gov