Initiation of Antiretroviral Therapy (ART)

Christopher Behrens, MDNorthwest AIDS Education &

Training CenterUniversity of Washington

When Should Patients with HIV be Treated with ART?

• Benefits– reduced morbidity &

mortality

– immune system recovery

• Drawbacks– toxicities

– lifestyle changes

– potential for developing resistance

Initiation of Antiretroviral Therapy: Key Considerations

• Symptoms & Opportunistic Infections

• CD4 count

• Viral Load

• Anticipated Adherence - patient ‘readiness’

Initiation of ART: Case

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 cells/mm³ and her viral load is 88,000 copies/mL.

Would you suggest she start antiretroviral therapy?

What does a CD4 count of 330 cells/mm³ mean?

CD4 cell count

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

CD

4 C

ell C

oun

t (c

ells

/mm

³)

1,000

500

Asymptomatic HIV Infection AIDS

Acute Infection

HIV Infection is characterized by a steady decline in the number of CD4 cells

Time

200

high risk of opportunistic infections

mm³

Mellors et al. Ann Intern Med 1997;126:946.

(cells/mm³)

When Should ART be Initiated?An analysis of prospective studies

• 13 cohort studies from Europe & North America

• 12,574 patients initiating ART– Median age 38; mostly men– Median baseline CD4 count 250; VL 74,000– Median month of ART initiation: 12/1997– Mostly PI-based regimens– 24,310 person-years of followup

Egger et al. Lancet 2002; 360:119-30.

Analysis of 13 cohort studies: effect of baseline CD4 count on response to initial ART

Egger et al. Lancet 2002; 360:119-30.

Years from starting HAART

Findings: effects of clinical stage on clinical progression

Egger et al. Lancet 2002; 360:119-30.

Years after starting HAART

Findings: effect of baseline HIV Viral Load on response to ART

Egger et al. Lancet 2002; 360:119-30.

Years from starting HAART

• Initiation of ART after HIV-related symptoms had developed was associated with a less durable response to ART

• For the asymptomatic patient, CD4 count at initiation of ART carried strongest prognostic significance, corroborating findings from other studies1-4

• Age, infection via IDU, history of AIDS-related illness also appeared to affect durability of clinical response to ART

Cohort studies: conclusions

1. Chen RY et al. 8th CROI, Chicago 20012. Hogg RS et al. JAMA. 2001;286:2568-2577

3. Sterling et al, 9th CROI, Seattle 20024. Palella et al, 9th CROI, Seattle 2002

Caveats

• High VL (>100,000 copies/mL) also carried prognostic significance, but– few patients initiated on efavirenz or ritonavir-boosted

regimens– other recent studies have not demonstrated a clear

correlation between baseline viral load and efficacy of ART1,2

• Observational study: other potential confounding factors (e.g., adherence, hemoglobin) could have affected results

1. Philips AN et al. JAMA 2001;286:2560-2567.2. Hogg RS et al. JAMA 2001;286:2568-2577.

Implications for Clinical Practice

• Ideally, initiate ART before CD4 count drops below 200 cells/mm³ and before clinical symptoms develop

• A benefit for treatment before CD4 count falls below 350 may exist, but the small risk of clinical progression if therapy is deferred must be balanced against drawbacks of ART

• If CD4 already less than 200 or clinical progression has occurred, ART is clearly indicated as soon as patient is ready to start

Implications for Clinical Practice: Significance of Baseline Viral Load

• Initiation of ART before VL >100,000 copies/mL may allow for more therapeutic options and greater clinical success

• However, highly potent efavirenz- or boosted PI-based regimens may be equally effective in patients with high baseline viral loads1-3

• VL is a marker for rate of CD4 decline: more frequent monitoring in patients with high VL?

1. XIV International AIDS Conference, July 2002. Abstract TuOrB11892. Arribas JR et al. AIDS 2002;16(11):1554-6.3. Walmsley S et al. NEJM 2002 346(26):2039-46.

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

Primary Infection

Sero-conversion

CD4 Count, Viral Load, and Clinical Course

When Should ART be Initiated? DHHS Guidelines

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 < 350 Any value Treatment should be offered

following full discussion of pros and cons with each patient

Asymptomatic > 350/mm3 > 100,000 copies/mL

Most clinicians recommend deferring therapy, but some would treat

Asymptomatic > 350/mm3 < 100,000 copies/mL

Defer therapy

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, October 6, 2005.

When Should ART be Initiated? IAS-USA Guidelines

Yeni et al. JAMA. 2004;292:251-265.

Recent Advances in Antiretroviral Therapy

incremental gains in convenience, tolerability, and insights into toxicity have added up to significant improvements in

management of HIV disease

Advances in Antiretroviral Therapy: Easier Regimens

• Lower pill burden– Fixed dose combinations

• TDF/FTC (Truvada)• ABC/3TC (Epzicom)• AZT/3TC (Combivir)• AZT3TC/ABC (Trizivir)

– Fewer pills for same effect • efavirenz• nelfinavir • fosamprenavir• lopinavir/ritonavir• saquinavir

• Once-daily dosing• tenofovir

• 3TC, FTC

• abacavir

• ddI

• efavirenz

• atazanavir

• fosamprenavir (w/ ritonavir)

• saquinavir (w/ ritonavir)

• lopinavir/ritonavir

• Fewer food restrictions with newer agents and with ritonavir boosting of protease inhibitors

Advances in Antiretroviral Therapy: Improvements in Toxicity

• New drugs with less toxicity– Tenofovir: no dyslipidemia compared with d4T– Atazanavir: no dyslipidemia compared with other PIs

• Improved Understanding of Toxicities– Nevirapine toxicity: identification of high-risk groups

• women CD4 >250 cells/mm³• men CD4 >400 cells/mm³

– Mitochondrial toxicity as basis for many long-term toxicities

– Clarification of which NRTIs are most likely to cause mitochondrial toxicity (d4T, ddI, ddC)

– Partial clarification of lipodystrophy

Timing of Initiation of ART

Is the Pendulum

Swinging Back to

Earlier Treatment?

Before you start…

Resistance Testing

Adherence Issues

Resistance in treatment-naïve individuals is becoming more common

Little SJ, Holte S, Routy JP, et al. N Engl J Med. 2002;347:385-94

Recently Infected, ART Naïve, United States

Persistence of Resistant Strains Following Primary HIV Infection

• 11 subjects with primary HIV infection who deferred ART and who had at least one major drug resistance mutation identified at presentation, followed with serial resistance assays.

– 7 subjects with NNRTI resistance

– 2 with NRTI and PI resistance

– 1 with NNRTI and PI resistance

– 1 with resistance to all three classes of drugs

• NNRTI resistance was lost slowly: the average time to reversion of 103N variants to mixed 103N/K populations was 196 days following the estimated date of infection (153 to 238 days, 95%CI).

• PI resistance was not lost at all: In the 4 patients with protease resistance mutations, no reversion was detected at 64, 191, 327, and 342 days after infection.

• Complete reversion of genotypic resistance was observed in only one patient, at 1019 days after infection.

Little SJ. 11th CROI, February 2004, Abstract 36LB

Antiretroviral Resistance Testing: Guidelines for Implementation

Clinical Setting/ Recommendation

Rationale

Recommended:

•Virologic failure during ART

•Suboptimal suppression of viral load (VL) after initiation of ART

•Acute (primary) HIV infection

•Chronic HIV infection before starting ART

Determine role of resistance in drug failure and maximize the number of active drugs in the new regimen

Determine the role of resistance in drug failure and maximize the number of active drugs in the new regimen

Determine if resistant virus was transmitted; select regimen accordingly

Assays may not detect minor resistant species, but some resistance mutations may persist for years. Consider testing early after diagnosis of HIV infection.

Usually not recommended:

•After discontinuation of drugs

•Plasma VL <1,000 copies/mL

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

Resistance assays unreliable if VL is low

Adapted from DHHS, Antiretroviral Guidelines, October 6, 2005

Initiation of Antiretroviral Therapy: Key Considerations

• Symptoms & Opportunistic Infections

• CD4 count

• Viral Load

• Anticipated Adherence - patient ‘readiness’

Adherence: Case 1

• A 23 year old single woman with HIV infection diagnosed two years ago.

• No history of antiretroviral therapy.• Current CD4 count is 230 cells/mm³.• Her physical exam is remarkable only for oral

candidiasis (thrush). • Review of her past medical history includes

depression, which she admits has been worse lately. • Current medications include nortriptyline and oral

contraceptives.

• Which of the following factors in her situation suggests that adherence may be problematic for her?

A. her depressionB. she is already symptomatic with HIV infectionC. her age (less than 30 years old)D. all of the above factors are associated with

reduced adherence to antiretrovirals.

Adherence

• Which of the following factors in her situation suggests that adherence may be problematic for her?

A. her depressionB. she is already symptomatic with HIV infectionC. her age (less than 30 years old)D. all of the above factors are associated with

reduced adherence to antiretrovirals.

Adherence

Adherence

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

- C. Everett Koop

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

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

Predictors of Poor Adherence

• active alcohol1 or substance2 abuse

• work outside the home for pay1

• depressed mood1

• lack of perceived efficacy of ART3

• lack of advanced disease4

• concern over side effects4

• regimen complexity5

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 CROI, 1999, Abstract 98. 5. Stone VE, et al. JAIDS 2001; 28:124-131

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

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.

How good are clinicians at predicting their patients’ adherence?

A. 95%

B. 85%

C. 75%

D. Not much better than flipping a coin

Clinicians’ Estimates of Adherence Not Much Better Than Random

Bangsberg 2001 JAIDS ARTPaterson 2000 Annals Int Med ARTHaubrich1999 AIDS ARTSteiner 1995 Arch Int Med AZTBosely 1995 Eur Resp J Inhaled terbutalineCharney 1967 Pediatrics PenicillinCaron 1978 Clin Pharmacol AntacidsGilbert 1980 Can Med Assoc J DigoxinBlowey 1997 Ped Nephrology CyclosporinMushlin 1977 Arch Int Med Hypertensive

Improving Adherence: Before Initiation of Therapy

Assess patient's understanding and acceptance of the regimen: negotiated plan

Investigate and manage medical barriers to adherence

• Try to use simple regimens– Twice-daily or better– Without food requirements if possible

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

Improving Adherence: After Initiation of Therapy

• Close follow-up

• Ask patient to verbalize treatment regimen

• Education about adherence

• Consider cues, alarms to remind patients of dosing

• Referral to community support groups

• Involve other members of the health care team

Back to Case 1

• You confirm her viral load and CD4 count; she keeps her follow-up appointments and appears to understand the importance of adherence. You start her on an antidepressant medication and refer her for counseling. 3 months later her depression is significantly improved and she feels ready to initiate ART.

• What regimen would you recommend?

Selecting the Initial ART Regimen

Combination Antiretroviral Therapy (ART)

• 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

HIV Life Cycle and Classes of ARVs

RNA DNA

HIV

Nucleus

Host Cell

Nucleoside Analogues (NRTIs)

Non-Nucleosides (NNRTIs) Protease Inhibitors (PIs)

Reverse Transcriptase

Fusion Inhibitors

FDA-Approved ARVS: NRTIs

FDA-Approved ARVS: NNRTIs and PIs

FDA-Approved ARVS: PIs (cont.) and Fusion Inhibitor

Ritonavir intensification of other Protease Inhibitors (PIs)

• PIs, 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 PIs

• Low doses of ritonavir can be used to increase the potency and simplify the dosing of PI-based regimens

Time after dose (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.

Preferred Initial ART Regimens:DHHS Guidelines

• NNRTI-based:

• PI-based:

Efavirenz*+

3TC or FTC+

AZT or tenofovir

Lopinavir/ritonavir (Kaletra)+

3TC or FTC+

AZT

* except during first trimester of pregnancy or women with high pregnancy potential

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, October 6, 2005.

• 2 pills once daily• Not associated with

dyslipidemia1 and hyperglycemia2, unlike other PIs

• Case reports of reversal of lipodystrophy when PI switched to ATV

Atazanavir: favorable dosing and toxicity profile

1. Piliero P et al. 9th CROI, Seattle, February 2002. Abstract 706-T.2. Sension M et al, 4th Intl Lipodystrophy Workshop, San Diego, 2002. Abstract 36.

AI424-034: Atazanavir vs Efavirenz

• N=810 treatment-naïve patients randomized to AZT/3TC plus either efavirenz or atazanavir

• Mean baseline viral load 4.85 log copies/mL

• Mean baseline CD4 count 320 cells/mm³

0

10

20

30

40

50

60

70

80

90

100

4 8 12 16 24 32 40 48

Efavirenz Atazanavir

Line 4

Week

Squires KE et al. 42nd ICAAC, September 2002. Abstract 1076.

% R

espo

nder

s VL <400 copies/mL

VL <50 copies/mL

p = NS

Initial ART: Practice

• NNRTI-based:

• PI-based:

efavirenz+

3TC or FTC+

AZT or tenofovir

lopinavir/ritonavir (Kaletra) or atazanavir/ritonavir

+3TC or FTC

+AZT or tenofovir

* except during first trimester of pregnancy or women with high pregnancy potential

Initial ART: Practice

Anchor Drug NRTI backbone Dosing Daily pill burden

Efavirenz AZT + 3TC bid 3

TDF + FTC qd 2

Lopinavir/ ritonavir

AZT + 3TC bid 6

TDF + FTC bid 5

Atazanavir/ ritonavir

AZT + 3TC bid 5

TDF + FTC qd 4

Initial HAART: Future?

Anchor Drug NRTI backbone Dosing Daily pill burden

Efavirenz

AZT + 3TC bid 3

TDF + FTC qd 2

ABC + 3TC qd 2

Lopinavir/ ritonavir

AZT + 3TC bid 6

TDF + FTC bid 5

ABC + 3TC bid 5

Atazanavir/ ritonavir

AZT + 3TC bid 5

TDF + FTC qd 4

ABC + 3TC qd 4

ABC hypersensitivity may be more severe with qd versus bid dosing

• CNA30021: n = 770 treatment naïve patients randomized to ABC 300mg bid versus ABC 600mg qd

• Combined with 3TC plus efavirenz (each once daily)

• Equivalent treatment efficacy

• ? More severe hypersensitivity with qd dosing

9%

5%

2%

7%

2%

0%0%

2%

4%

6%

8%

10%

hyper-sensitivity

severehyper-

sensitivity

severediarrhea

ABC 600mg qd

ABC 300mg bid

% o

f pa

tien

t wit

h re

acti

on

Epzicom package labeling, August 2004

Which ART regimen performs best in clinical trials?

Results from Comparable Trials:ITT analysis of VL <400 c/mL at Week 48

Based on: Bartlett. Presented at: 7th CROI; 2000; San Francisco, Calif. Poster 519.

d4T + 3TC + LPV/RTV (M98-863)

Reg

imen

(tr

ial)

d4T + 3TC + EFV (GS-903)

TDF + 3TC + EFV (GS-903)

0 10 20 30 40 50 60 70 80 90 100

AZT + 3TC + EFV (AI424-034)

AZT + 3TC + IDV (DMP-006)

AZT + 3TC + ABC (CNA3005)d4T + ddI + IDV (START II)

AZT + 3TC + IDV (AVANTI 2)AZT + ddI + NVP (INCAS)

AZT + 3TC + NFV (AVANTI 3)AZT + 3TC + IDV (CNA3005)AZT + 3TC + IDV (START I)

d4T + ddI + 3TC (Atlantic)d4T + 3TC + IDV (START I)

d4T + ddI + NVP (Atlantic)

2 NRTIs + SQV-SGC (NV-15355)

AZT + 3TC + ABC (CNAB3003)

d4T + ddI + IDV (Atlantic)

AZT + 3TC + EFV (DMP-006)

TDF + 3TC + EFV (GS-903)

d4T + 3TC + NFV (M98-863)

% with HIV RNA<50 copies/mL

at 48 Weeks (ITT)

AZT + 3TC + ATV (AI424-034)

d4T + 3TC + EFV (GS-903)

AZT + 3TC + EFV (EPV20001)

AZT + 3TC + IDV (START II)

Selection of the Initial ART regimen: Summary

• Regimen potency• Patients’ preference regarding pill burden, dosing

frequency, and food and fluid considerations• Potential adverse effects• Baseline antiretroviral resistance profile• Co-morbidity or conditions such as tuberculosis, liver

disease, depression or mental illness, cardiovascular disease, chemical dependency, pregnancy, and family planning status

• Potential drug interactions with other medications

DHHS Antiretroviral Therapy Guidelines, July 2003, p. 14.

Case 1, continued

You decide to start her on AZT (zidovudine) plus 3TC (lamivudine) plus efavirenz.

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

Antiretroviral Therapy: Optimal Response

10

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100000

1000000

0 1 2 3 4 5 6 7 8

Viral Load

ART Initiated

50 50

Time (months)

CD

4 co

unt (

cell

s/m

m3 )

Vir

al L

oad

(cop

ies/

mL

)

10

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1000

10000

100000

1000000

0 1 2 3 4 5 6 7 8

0

50

100

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200

Viral Load

CD4 Count

ART Initiated

50 50

Time (months)

CD

4 co

unt (

cell

s/m

m3 )

Vir

al L

oad

(cop

ies/

mL

)

Antiretroviral Therapy: Optimal Response

Follow-up Laboratory Testing

• Viral load & CD4 counts, initially once monthly after starting therapy; can space out to every 3 months if doing well

• Goals are undetectable viral load (<50 or 75 copies/mL) and rise in CD4 count

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

Case 2

• A 33 year old woman with a CD4 count of 30 cells/mm³ initiates antiretroviral therapy with a regimen of AZT + 3TC + nevirapine (NVP)

• Initially she feels better, but 3 weeks later she returns complaining of fevers, night sweats, and swollen lymph nodes

• Physical examination is remarkable for:– Fever of 38.7 C

– Bilateral axillary enlarged, tender lymph nodes

– Weight 120 lbs (unchanged from when she initiated ART)

What is likely responsible for her symptoms?

A. She is having a toxic reaction to her ART medications

B. Her ART regimen is not working, as evidenced by development of a new opportunistic infection

C. Her ART regimen is working so well that her newly strengthened immune system is reacting against a previously unrecognized infection

D. I have no idea what is going on with her

Case continued

• You order diagnostic tests including blood cultures and a biopsy and culture of her enlarged lymph nodes

Gram stain of lymph node: acid-fast bacilli in macrophages.

www.med.sc.edu:85/fox/mycobacteria.htm

Immune Reconstitution Syndrome

• Reflects newly invigorated immune system mounting an inflammatory response against an infection that was previously clinically silent in the face of severe immunodeficiency

• Common among patients with robust rise in CD4 count (e.g., over 100 cells/mm³) in the first several weeks following initiation of ART

• Typically managed by continuing ART and administering anti-inflammatory medications to control symptoms, such as NSAIDS and/or steroids

• Occasionally discontinuation of antiretrovirals is necessary

IRD Clinical Manifestations Onset Typical Course

MAC Lymphadenitis, high fever, infiltrates on chest x-ray

1 - 12 wk

Resolves with continued ART and anti-MAC therapy; may require corticosteroid therapy

CMV Retinitis and vitreitis 1 - 2 mo Resolves with continued ART and anti-CMV therapy

Uveitis 2 mo - 2y

Macular edema, epiretinal membrane formation, cataracts

Herpeszoster

Localized 1 - 4 mo Resolves with acyclovir therapy

TB Fever, worsening infiltrates/effusion on chest film, mediastinal and peripheral lymphadenopathy

1 - 6 wk Resolves with continued ART and antituberculous therapy; may require corticosteroid therapy

Cryptococcal

meningitis

New headache, meningismus, increased number of white blood cells in cerebrospinal fluid

1 wk - 8 mo

Resolves with continued ART and antifungal therapy

IRD, immune restoration disease; MAC, Mycobacterium avium complex; CMV, cytomegalovirus.

Clinical Presentation & Course of Common Immune Reconstitution Syndromes

Qazi NA et al. AIDS Reader 12(10):452-457, 2002.

Initial Antiretroviral Therapy: Summary

• ART has made HIV a treatable and manageable chronic disease for many patients

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

• When to initiate therapy remains controversial, but probably best to start before CD4 falls below 200 cells/mm³

• 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