Antiretroviral Therapy

DHHS Guidelines

Guidelines for the Use of Antiretroviral Agents in Adults

and Adolescents

II. Background and Principles:Contents

Goals of therapy Adherence Risks and benefits of early or

delayed therapy Testing viral load and CD4+ T cell Resistance testing

Risks and Benefits of Delayed Initiation of Therapy

BENEFITS Avoid negative effects

on quality of life Avoid drug-related

adverse events Delay in development

of drug resistance Preserve maximum

number of available and future drug options when HIV disease risk is highest

RISKS Possible risk of

irreversible immune system depletion

Possibly greater difficulty in suppressing viral replication

Easier to transmit HIV to others

Risks and Benefits of Early Therapy

BENEFITS Control of viral

replication easier to achieve and maintain

Delay or prevention of immune system compromise

Lower risk of resistance with complete viral suppression

Decreased risk of HIV transmission

RISKS Drug-related reduction in

quality of life Greater cumulative drug-

related adverse events Earlier development of

drug resistance, if viral suppression is sub optimal

Limitation of future antiretroviral treatment options

Risk of Progression to an AIDS- Defining Illness in 3 Years by

Baseline HIV RNA and CD4

>5

5,0

00

20

K-5

5K

7K

-20

K

1.5

K-7

K

<1

50

0CD4 >350

CD4 201-350

CD4 < 200

0%

20%

40%

60%

80%

100%

HIV-1 RNA (copies/mL)by RT-PCR

Ris

k o

f D

isea

se P

rog

ress

ion

CD

4 (c

ells

/mm

3 )

Mellors J, et al. Science, 1996; 272:1167-1170.

Risk of Progression to an AIDS- Defining Illness in 3 Years by

Baseline HIV RNA and CD4

>5

5,0

00

20

K-5

5K

7K

-20

K

1.5

K-7

K

<1

50

0CD4 >350

CD4 201-350

CD4 < 200

0%

20%

40%

60%

80%

100%

HIV-1 RNA (copies/mL)by RT-PCR

Ris

k o

f D

isea

se

Pro

gre

ssio

n

CD

4 (c

ells

/mm

3 )

Mellors J, et al. Science, 1996; 272:1167-1170.

Guidelines recommendtreatment

Guidelines recommendobservation

Testing

Viral load CD4+ T cells Resistance testing

Decision Making Initiating and Changing Therapy

Plasma HIV RNA (viral load) CD4+ T cell count Clinical condition of the patient

Measuring Plasma HIV RNA and CD4+ T Cells

At the time of diagnosis Every 3-4 months in the untreated

patient Immediately prior to initiating therapy 2-8 weeks after initiating therapy Every 3-4 months in patients on

therapy As indicated in the opinion of the

provider

Factors Affecting the Rate of Plasma HIV RNA Decline

Baseline CD4+ T cell count Initial viral load Potency of the regimen Adherence to the regimen Prior exposure to antiretroviral agents Resistance Presence or history of opportunistic

infections

III - Initiation of Therapy

III. Initiation of Therapy:Contents

Goals of Therapy and Tools to Achieve Them

ART in the chronically HIV infected Treatment options Adherence Drug interactions Toxicities

Goals of Therapy

Eradication of HIV? Not yet…

“…in spite of plasma RNA below detection there is evidence of genetic evolution in reservoirs.”

Goals of Therapy and Tools To Achieve Goals

Maximal and durable suppression of viral load

Restoration and/or preservation of immunologic function

Improvement of quality of life

Reduction of HIV-related morbidity and mortality

Maximize adherence Rational sequencing

of therapy Preservation of future

treatment options Use of resistance

testing in selected clinical settings

Before Initiating Therapy...

Confirm HIV results Complete H&P CBC, chemistry profile CD4 and T lymphocyte count Plasma HIV RNA measurement Assess “readiness” for rx & adherence Additional tests

Before Initiating TherapyAdditional Tests

VDRL PPD Chest x-ray Hepatitis A,B,C

serology

Gynecology exam with pap smear

Ophthalmology exam (CD4+ T cell <100)

Toxoplasma titer CMV serology (if

indicated by history)

Considerations in Initiating Therapy HIV Asymptomatic

Theoretical benefit No proven long-term clinical benefit for

CD4 >200 cells/ml3 Expert opinion advises initiation of

therapy for CD4 <350 cells/ml3 at any viral load— Consider the viral load when > 350 cells/ml3

CD4+ T cell The “downside” of antiretroviral regimens

Considerations in Initiating Therapy HIV Asymptomatic

Willingness of patient to begin and the likelihood of adherence

Degree of immunodeficiency Plasma HIV RNA Risk of disease progression Potential risks and benefits

Indications for ART in the Chronically HIV-Infected Patient

TREAT ALL(regardless of viral load)

Symptomatic (AIDS, severe symptoms) Asymptomatic, CD4+ <200 cells/mm3

Asymptomatic, CD4+ >200/mm3 but <350 cells/ mm3 *

* Treatment should generally be offered, though controversy

exists

Indications for ART in the Chronically HIV-Infected Patient

TREAT

Asymptomatic CD4+ >350/mm3

HIV RNA>30,000(bDNA)/55,000(RT-PCR)*

* Some experts would recommend initiating therapy, recognizing that the 3 year risk of developing AIDS in untreated patients is >30%. In the absence of very high levels of plasma HIV RNA, some would defer therapy and monitor the CD4+ and level of plasma HIV RNA more frequently. Clinical

outcomes data after initiating therapy are lacking.

Indications for ART in the Chronically HIV-Infected Patient

DEFER TREATMENT

Asymptomatic CD4+ cells > 350/mm3

HIV RNA <30,000(bDNA)/55,000(RT-PCR)*

* Many experts would defer therapy and observe, recognizing that the 3 year risk of developing AIDS in untreated patients is <15%.

Indications for ART in the Chronically HIV-Infected Patient

Clinical benefit has been demonstrated for patients w/ CD4 <200 mm3. However, most experts would offer therapy at a CD4 threshold <350 mm3.

All decisions should be based on prognosis for disease-free survival in the absence of treatment, as determined by the CD4 count and viral load (Table V), the potential benefits and risks of therapy (Table IV), and the willingness of the patient to accept therapy. For further information, see text.

WHO HIV Staging System

WHO HIV Staging System

Scaling Up Antiretroviral Therapy In Resource-limited Settings Guidelines For APublic Health Approach- WHO 2002

WHO Guidelines for ARV Therapy in Resource Limited Settings

Scaling Up Antiretroviral Therapy In Resource-limited Settings Guidelines For A Public Health Approach- WHO 2002

WHO Guidelines for ARV Therapy in Resource Limited Settings

Current Antiretroviral MedicationsNRTI Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine ZDV Zalcitabine DDC Tenofovir TDF

NNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP

PI Amprenavir APV Atazamavir ATV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV

— soft gel SGC— hard gel HGC

Fusion Inhibitor Enfuvirtide T-20

Antiretroviral Activity:An Historical PerspectiveH

IV R

NA

ch

ang

e (l

og

10 c

/mL

)

1994:Two-Drug Therapy

1997: HAART

1987: AZTMonotherapy

24-week response

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

Fischl, NEJM, 1987Katzenstein, NEJM, 1996

Eron, NEJM, 1995;Hammer, NEJM, 1996

Gulick, NEJM, 1997;Cameron, Lancet, 1998

24-week response 24-week response

Goal of ARV Therapy: Prolonged Virologic Suppression

% W

ith

VL

BL

Q

Past (Two-Drug Therapy) Future

Present(Three-Drug Therapy)

Weeks MonthsYears Decades

100

0

20

40

60

80

100

0

20

40

60

80

100

0

20

40

60

80

Antiretroviral Components in Initial Therapy: NNRTIs

ADVANTAGES Less fat

maldistribution and dyslipidemia than PI-based regimens

PI options preserved for future use

DISADVANTAGES Resistance - single

mutation Cross resistance

among NNRTIs Rash Potential drug

interactions (CYP450)

Antiretroviral Components in Initial Therapy: PIs

ADVANTAGES NNRTI options

preserved for future use

Longest prospective data

DISADVANTAGES Metabolic

complications (fat maldistribution, dyslipidemia, insulin resistance)

Greater potential for drug interactions (CYP3A4)

Antiretroviral Components in Initial Therapy: NRTIs

ADVANTAGES Established backbone of

combination therapy Limited cross resistance

within the class Minimal drug interactions Triple NRTI regimen of

abacavir + lamivudine + zidovudine (or stavudine)* spares PI and NNRTI for future options

DISADVANTAGES Lactic acidosis

reported with most NRTIs

Triple NRTI regimens show inferior virologic response compared to efavirenz-based and indinavir-based regimens

*This is the only triple NRTI regimen considered acceptable (as an “alternative” regimen)

Initial Treatment: NNRTI-Based Regimens

*Avoid in pregnant women or women with pregnancy potential

Preferred Regimen

Efavirenz +lamivudine + (zidovudine or tenofovir or stavudine)*

3-5

#pills/day

Initial Treatment: NNRTI-Based Regimens

*Avoid in pregnant women or women with pregnancy potential

Alternative Regimens

Efavirenz + emtricitabine + (zidovudine or tenofovir or stavudine)*

Efavirenz + (lamivudine or emtricitabine) + didanosine*

Nevirapine + (lamivudine or emtricitabine) + (zidovudine or stavudine or didanosine)

3-4

3-5

4-6

#pills/day

Initial Treatment: PI-Based Regimens

Preferred Regimen

Lopinavir/ritonavir (Kaletra) + lamivudine + (zidovudine or stavudine)

8-10

#pills/day

Initial Treatment: PI-Based Regimens #pills

/day

Alternative Regimens (1)

Amprenavir/ritonavir + (lamivudine or emtricitabine) + (zidovudine or stavudine)

Atazanavir + (lamivudine or emtricitabine) + (zidovudine or stavudine)

Indinavir + (lamivudine or emtricitabine) + (zidovudine or stavudine)

Indinavir/ritonavir + (lamivudine or emtricitabine) + (zidovudine or stavudine)

12-14

4-6

8-10

8-12

Initial Treatment: PI-Based Regimens

#pills/day

Alternative Regimens (2)

Lopinavir/ritonavir (Kaletra) + emtricitabine + (zidovudine or stavudine)

Nelfinavir + (lamivudine or emtricitabine) + (zidovudine or stavudine)

Saquinavir (hard or soft gel capsule)/ritonavir + (lamivudine or emtricitabine) + (zidovudine or stavudine)

8-9

6-14

14-16

Initial Treatment: NRTI-Based Regimens*

Alternative to NNRTI- or PI-based regimen

Abacavir + lamivudine + zidovudine (or stavudine)

2-6

#pills/day

* To be used only when an NNRTI- or PI-based regimen cannot or should not be used as first line therapy

Antiretroviral Medications: Not Recommended in Initial

TreatmentModest antiviral activity

DelavirdineZidovudine + zalcitabine

High pill burden AmprenavirSaquinavir soft gel capsuleNelfinavir + saquinavir

High incidence of toxicities

Stavudine + didanosineRitonavir used as sole PI

Antiretroviral Medications: Should not be offered

Regimens not recommended:—Monotherapy (except in prevention of perinatal

HIV transmission)

—Dual NRTI therapy—3-NRTI regimen with abacavir + tenofovir +

lamivudine —3-NRTI regimen with didanosine +

tenofovir + lamivudine

Antiretroviral Medications: Should not be offered

Antiretroviral components not recommended:—Stavudine + didanosine —Efavirenz in pregnancy—Saquinavir hard gel capsule (Invirase) as single PI—Stavudine + zidovudine—Zalcitabine + stavudine; zalcitabine + didanosine—Atazanavir + indinavir—Emtricitabine + lamivudine—Amprenavir oral solution in pregnancy, in children

<4 years, in renal or hepatic failure, or in patients treated with metronidazole or disulfiram

—Hydroxyurea

Staszewski S, et al. NEJM, 1999;341:1865-1873.

3TC and ZDV Plus Efavirenz or Indinavir in Naïve Patients: DMP 006

302 HIV-infected patients

Open-label study

Efavirenz 600 mg QD

Indinavir 800 mg q8h

Data presented at 48 weeks as % of patients with viral load <50 c/ml

0102030405060708090

100

% <

50 c

/mL

AT ITT

EFV

IDV

EFV+IDV arm omitted

Podzamczer D, et al. 1st IAS, 2001: Abst. 7.

Combivir Plus Nelfinavir or Nevirapine in Naïve Patients: COMBINE

142 antiretroviral-naïve patients

Open-label study

Nelfinavir 1250 mg BID

Nevirapine 200 mg BID

Data presented at 12 months as % of patients with viral load <20 c/ml

0102030405060708090

100

% <

20 c

/mL

AT ITT

NVP arm

NFV arm

ABC/COM is Comparable to IDV/COM in HIV-1 Infected Antiretroviral-Naïve

Adults: CNA3014 342 antiretroviral-naïve

patients

Open label study

Median baseline viral load: 54,000 c/mL

48 week data presented as % of patients with viral load <50 c/mL (ITT: Missing/Switch = Failure)

60

50

0

10

20

30

40

50

60

% <

50 c

/mL

ABC IDV

Vibhagool A, et al. 1st IAS, 2001: Abst. 63.

Ruane P, et al. 1st IAS, 2001: Abst. 6.

Lopinavir/r vs Nelfinavir in Antiretroviral- Naïve Subjects: M98-863

Randomized, double-blind trial

Patients nearly ART- naïve (n=653)

d4T/3TC plus either lopinavir/ritonavir BID or nelfinavir TID

Data analyzed at 60 weeks, ITT, % of patients with viral load <20 c/ml

63

51

0

10

20

30

40

50

60

70

% <

20 c

/mL

LPV/RTV NFV

p=0.001

Predicting Long-Term Suppression in ARV-Naïve Patients: Evidence-Based Data

Note: Randomized comparative trials with 100 subjects/arm; populations’ entry criteria and adherence differ for each trial.

ITT Analysis of VL <400 c/mL at Week 48

0 10 20 30 40 50 60 70 80

Abbott 863: LPV/r + d4T + 3TC

Dupont 006: EFV + ZDV + 3TC

Abbott 863: NFV + d4T + 3TC

Agouron 542: NFV BID + d4T + 3TC

Atlantic: IDV + d4T + ddI

Agouron 542: NFV TID + d4T + 3TC

BMS Start I: IDV + d4T + 3TC

BMS Start I: IDV + ZDV + 3TC

Dupont 006: IDV + ZDV + 3TC

Percent:

The Advantage of Sequencing Drugs

To extend the overall long-term effectiveness of the available therapy options

Delay the risk of certain side effects uniquely associated with a single class of drugs

Anticipates up to 50% of failure rate and preserves future treatment options

Adherence

Adherence

“The achilles heel of HAART”— G. Friedland

“Drugs don’t work if people don’t take them.”— C. Everett Koop

Adherence

The “rule” of thirds…— 1/3 take medication as prescribed— 1/3 are intermittently adherent— 1/3 take little or no medication

Correlation Between Optimal Therapeutic Response and Adherence to Protease Inhibitor Therapy

Prospective, observational study, n = 81

Subjects’ adherence to PIs assessed electronically using Medication Event Monitoring System (MEMS)— Median follow-up: 6 months (range 3 - 15 months)

Baseline demographics— CD4 count ranged from <50 cells/mm3 (14% of subjects) to

>500 cells/mm3 (27% of subjects)— HIV RNA ranged from <400 c/mL (30% of subjects) to

>100,000 c/mL (11% of subjects)

Paterson D, et al. Ann Intern Med. 2000;133:21-30.

Adherence to a PI-Containing Regimen CorrelatesWith HIV RNA Response at Median 6 Months

Pat

ien

ts W

ith

Vir

olog

ic F

ailu

re (

%)

0

20

40

60

80

100

<70 70-80 80-90 90-95 >95

Adherence (%)

Paterson. Ann Intern Med 2000;133:21.

What Degree of AdherenceIs Needed?

82.1

71.466.7

54.6

21.7

Adherence Declines Over Time (Treatment Fatigue)

Pat

ien

ts (

%)

What Happensto Adherence Over Time?

0

10

20

30

40

50

60

70

80

1 Month 4 Months 8 Months

100% 80%-100% 0%-80%

Mannerheimer. 13th IAC; 2000; Durban. Abstract 421.

Duration of Antiretroviral Adherence Predicts Biologic Outcomes

in Clinical Trials Randomized clinical trials (n = 732 subjects)

—Patients had 1 month follow-up—Adherence measured using confidential, self-report, 7-day

recall questionnaires

Results up to 12 months

Adherence HIV RNA % HIV RNA CD4

(log10 c/mL) <50 c/mL (cells/mm3)

0 - 79% -0.65 19% 41

80 - 99% -2.27 46% 175

100% -2.72 70% 152

Friedland GH, et al. 1st IAS, 2001: Abst. 33.

CPCRA 057, 058

Size of symbol is directly proportional to weight of data point in the analysis

Virologic Response by Daily Pill Burden

Bartlett JA, et al. AIDS, 2001; 15:1369-1377.

Who Will Be Adherent?

Age, race, sex, socioeconomic level educational level, socioeconomic status, and a past history of alcoholism or drug use are not reliable predictors of poor adherence

Active drug use or alcoholism, unstable housing, mental illness, and major life crises ARE predictors of poor adherence

Adherence – Predicting Success

The more severe the symptoms or illness the better adherence

Improved adherence if patients believe in efficacy of treatment

Adherence – Keep It Simple

Once daily therapy - 90% adherence Twice daily therapy - 80% adherence Three or more times daily - 65%

adherence

Improving Adherence

A trusting provider-patient relationship

Education Development of treatment plan with

patient Social support network Simple regimen

Adherence in Special Populations

Flexible clinic hours Accessible clinical staff Incentives Bilingual staff Adherence discussion during

support groups Individualized adherence programs Others?

Adherence Strategies

Negotiate a treatment plan Assess patient readiness Educate Reminder devises Social support Others?

Poor Adherence – Now What?

Increase the intensity of clinical follow up

Shorten the follow up interval Recruit additional health team members

— Mental health— Chemical dependency counselor— Others

Involve family and friends Take a break

Initially Amendedrecommended dose (mg) dose (mg)

ddI 200 BID 400 QD(pill, suspension)

AZT 100 five times a day 300 BID

AZT + 3TC AZT 300 BID 1 (300/150) pill BID3TC 150 BID (Combivir)

AZT + 3TC + ABC AZT 300 BID 1 (300/150/300) pill BID 3TC 150 BID (Trizivir)ABC 300 BID

Simplified Dosing Strategies - NRTIs

IV - Changing Therapy

AETC NRC Slide Set

Version 1.0, February 2001

IV. Changing Therapy:Contents

Considerations Patterns of change Criteria for change Alternatives Monitoring Testing for resistance Treatment interruption

Changing Therapy:Considerations

Recent clinical history and physical examination

Two plasma HIV RNA levels CD4+ T cell count Remaining treatment options Assessment of adherence Patient education

Changing Therapy

Drug failure or drug toxicity? Medication adherence Pharmacology & drug interactions Testing for antiretroviral drug

resistance

Changing TherapyThree Different Patients - 1

Individuals who are receiving incompletely suppressive antiretroviral therapy with detectable or undetectable plasma viral load

Changing TherapyThree Different Patients - 2

Individuals who have been on potent combination therapy and whose viremia was initially suppressed to undetectable levels but has again become detectable

Changing TherapyThree Different Patients - 3

Individuals who have been on potent combination therapy and whose viremia was never suppressed to below detectable limits.

Criteria for Changing Therapy

Less than a 0.5-0.75 log reduction in plasma HIV RNA by 4 weeks following initiation of therapy, or less than a 1 log reduction by 8 weeks (CIII)

Criteria for Changing Therapy

Failure of a 1st or 2nd line regimen to suppress plasma HIV RNA to undetectable levels within 4-6 months of initiating therapy (BIII)

Repeated detection of virus in plasma after initial suppression to undetectable levels, suggesting the development of resistance (BIII)

Criteria for Changing Therapy

Any reproducible significant increase, defined as 3-fold or greater, from the nadir of plasma HIV RNA in two or more consecutive viral loads not attributable to intercurrent infection, vaccination, or test methodology except as noted above (BIII)

Criteria for Changing Therapy

Undetectable viremia in the patient receiving double nucleoside therapy (BIII)

Persistently declining CD4+ T cell numbers, as measured on at least two separate occasions (CIII)

Clinical deterioration (DIII)

Changing Therapy Other Considerations

Adherence Results of resistance testing Limited choices Reduction of future choices

Change OptionsPatient With Intolerance to One Drug

Substitute for offending drug Use agent in same class Changing other medications

unnecessary

Change OptionsPatient on Non-preferred Regimen

Viral Load below detection Continue treatment and carefully

monitor* or Add drugs to the current regimen

(intensify) in limited defined setting

*most authorities feel that treatment with regimens not in the strongly recommended category is associated with eventual failure and

recommend the latter tactic.

Change OptionsPatient on Recommended Regimen

Few specific strategies

Theoretical considerations should guide decisions

Broad cross-resistance among drugs within a class

Reinforcement of adherence

Guided by resistance testing

Option to delay changing therapy

Consult an experienced clinician

Evidence of better outcomes with using a new class

Implications of Treatment Failure at 2 Years

25%40%67%3rd HAART

24%30%50%2nd HAART

5%20%40%1st HAART

Clinical events

Immune and clinical failure

Virologic failure (VL > 500 c/mL)

Regimen cohort

Mocroft A, et al. Antivir Ther, 2000.

EuroSIDA Cohort (n = 8507)

Interruption of Antiretroviral Therapy

Intolerable side effects Drug interactions First trimester pregnancy Unavailability of drugs Numerous other possible causes

Interruption of Antiretroviral Therapy

Stop all antiretroviral medications at once

V - Special Issues

V. Special Issues:Contents

Acute HIV infection Advanced HIV infection Adolescents Interruption of therapy Adherence

Early Intervention Theory

Should be limited to the clinical trial setting

Suppress the initial burst of viral replication

Decrease the severity of acute disease Alter the viral “set point” Reduce the rate of mutation Reduce risk of viral transmission Preserve immune function

Risks and Benefits of Delayed Initiation of Therapy

BENEFITS Avoid negative effects

on quality of life Avoid drug-related

adverse events Delay in development

of drug resistance Preserve maximum

number of available and future drug options when HIV disease risk is highest

RISKS Possible risk of

irreversible immune system depletion

Possibly greater difficulty in suppressing viral replication

Easier to transmit HIV to others

Risks and Benefits of Early Therapy

BENEFITS Control of viral

replication easier to achieve and maintain

Delay or prevention of immune system compromise

Lower risk of resistance with complete viral suppression

Decreased risk of HIV transmission

RISKS Drug-related reduction in

quality of life Greater cumulative drug-

related adverse events Earlier development of

drug resistance, if viral suppression is sub optimal

Limitation of future antiretroviral treatment options

The Patient With Advanced Disease

Treatment of the Patient With Advanced HIV Disease

Offer to all with AIDS and patients with symptomatic HIV infection with thrush or unexplained fever

Clinical Issues in the Patient With Advanced HIV Disease

Drug toxicity Ability to adhere Drug interactions Laboratory abnormalities

Advanced HIV Infection

Often complicated drug regimens Wasting and anorexia Co-infection

Treatment of the Patient with Advanced HIV Disease

Recovery of immune function Immune reconstitution syndromes :

Immunologic response to sub-clinical pathogen, e.g.: MAC or CMV

Immune reconstitution syndromes are different from clinical failure

Treat new opportunistic infections

The HIV Infected Adolescent

Timing of infection; perinatal vs. acquired as an adolescent

Early intervention

The HIV Infected Adolescent

Normal adolescent development Drug pharmacology in puberty Dosing based on Tanner stages