1

Joel E. Gallant, MD, MPHJohns Hopkins University, School of Medicine

Jean R. Anderson, MDJohns Hopkins HIV Women’s Health Program

John G. Bartlett, MD Johns Hopkins University, School of Medicine

Care of Women with HIV Living in Limited-Resource Settings

Antiretroviral Therapy

2

Objectives

Review the natural history of HIV Discuss the benefits of antiretroviral (ARV) therapy and

general principles regarding their use Discuss considerations in starting ARV therapy Review possible adverse effects and drug interactions

with ARV use Discuss the limitations and barriers to success with the

use of ARV therapy

3

Natural History of HIV Infection Without the Use of Antiretroviral Therapy

Source: Fauci et al 1996.

Weeks Years

CD

4 +

T L

ymp

ho

cyte

Co

un

t (c

ells

/mm

m3)

HIV

/RN

A C

op

ies per m

l Plasm

a

107

106

105

104

103

102

0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11

1200

1100

1000

900

800

700

600

500

400

300

200

100

0

Primary Infection + Acute HIV syndrome

Wide dissemination of virusSeeding of lymphoid organs

Clinical latency

Constitutional Symptoms

OpportunisticDiseases

Death

4

Natural History of HIV Infection Without the Use of Antiretroviral Therapy

Source: Fauci et al 1996.

Weeks Years

CD

4 +

T L

ymp

ho

cyte

Co

un

t (c

ells

/mm

m3)

HIV

/RN

A C

op

ies per m

l Plasm

a

107

106

105

104

103

102

0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11

1200

1100

1000

900

800

700

600

500

400

300

200

100

0

Primary Infection + Acute HIV syndrome

Wide dissemination of virusSeeding of lymphoid organs

Clinical latency

Constitutional Symptoms

OpportunisticDiseases

Death

5

Natural History of HIV Infection Without the Use of Antiretroviral Therapy

Source: Fauci et al 1996.

Weeks Years

CD

4 +

T L

ymp

ho

cyte

Co

un

t (c

ells

/mm

m3)

HIV

/RN

A C

op

ies per m

l Plasm

a

107

106

105

104

103

102

0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11

1200

1100

1000

900

800

700

600

500

400

300

200

100

0

Primary Infection + Acute HIV syndrome

Wide dissemination of virusSeeding of lymphoid organs

Clinical latency

Constitutional Symptoms

OpportunisticDiseases

Death

6

0%

20%

40%

60%

80%

100%

>55,000 20-55,000 7-20,000 1500-7,000 <1500

HIV RNA (copies/ml)

>750

501-750

351-500

201-350

<200

Likelihood of Developing AIDS Within Three Years without ARV

CD4+ T cells/mm3

Source: Mellors et al 1996.

7

Benefits of ARV Therapy

Prevents opportunistic infections Alters/reverses course of existing opportunistic infections Decreases hospitalizations Increases survival Improves quality of life Restores hope Reduces HIV transmission Benefits both adults and children

8

Antiretroviral Drugs*

Zidovudine (ZDV, AZT) Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T)

Lamivudine (3TC) Abacavir (ABC) NRTI combinations

ZDV+3TC ZDV+3TC+ABC

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

*Food and Drug Administration (FDA)-approved drugs as of March 2002

Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)

Tenofovir (DF)

9

Antiretroviral Drugs* continued

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):

*FDA-approved drugs as of March 2002

Nevirapine (NVP) Delavirdine (DLV)

Efavirenz (EFV)

10

Antiretroviral Drugs* continued

Protease Inhibitors (PIs)

*FDA-approved drugs as of March 2002

Indinavir (IDV) Ritonavir (RTV) Nelfinavir (NFV)

Saquinavir (SQV) Amprenavir (APV) Lopinavir (LPV) + Ritonavir

(RTV)

11

General Principles for the Use of ARV Therapy

The goal of therapy is to reduce viral load as much as possible and sustain that reduction as well as restore and/or preserve immune function

ARV agents, usually from different classes, must be used in combination Several effective ARV combination regimens are available Adherence to prescribed regimen is more important as a

predictor of successful ARV treatment than the specific drug combination used

12

General Principles for the Use of ARV Therapy continued

Continued HIV replication in the presence of ARV drugs promotes development of drug resistance Development of resistance to a specific ARV agent may

confer resistance to other drugs within the same class and can significantly limit future treatment options

Measurement of CD4+ cells and HIV RNA level reflects immunologic and virologic response to ARV treatment; these measurements are repeated at intervals and are indicators of the success or failure of therapy

Once therapy is started, long-term or generally life-long treatment may be needed

13

When to Start ARV Therapy in HIV-Infected Adults and Adolescents in Limited-Resource Settings

If CD4 testing available: WHO Stage IV disease (clinical AIDS) irrespective of CD4

cell count WHO Stage I, II, III1 with CD4 cell counts 200/mm3 or lower

If CD4 testing unavailable: WHO Stage IV disease (clinical AIDS) irrespective of total

lymphocyte count WHO Stage II or III disease with a total lymphocyte count

1200/mm3 or lower

Source: WHO 2002.

1Treatment is also recommended for patients with advanced WHO Stage III disease including recurrent or persistent oral thrush and recurrent invasive bacterial infections irrespective of CD4 cell or total lymphocyte count.

14

Clinical Evaluation Before Start of ARV Therapy

Assess stage of infection Identify past and current HIV-related illnesses that may

require treatment (e.g., TB) Identify other co-existing medical conditions (e.g., chronic

hepatitis) List current medications Assess sexual and drug-using behaviors

Condom and contraceptive access and use Menstrual history Assess possibility of pregnancy and plans/risk for pregnancy

Assess readiness to start therapy

15

ARV Factors in Choice of Initial Regimen

Strength of data on effectiveness Potential for serious adverse effects and toxicity Possible side effects Convenience

Pill burden Dosing frequency Food/refrigeration requirements

Potential interaction with other drugs Potential for alternative treatment options should initial

combination fail Cost and accessibility

16

Patient Factors in Choice of Initial Regimen

Stage of disease Likelihood of adherence Pregnancy or risk of pregnancy Concurrent TB and other illnesses (e.g., hepatitis B, C) Opportunity for reliable followup

17

Recommended Initial ARV Regimens

Regimen Pregnancy Considerations

ZDV/3TC plus EFZ or NVP

Substitute NVP for EFV in pregnant women or women for whom effective contraception cannot be assured

ZDV/3TC/ABC Limited safety data on ABC

ZDV/3TC plus RTV enhanced PI (IDV/r, LPV/r, SQV/r)* or NFV

Limited safety data on LPV/r

Most supportive safety data on NFV

* r = ritonavir

Adapted from WHO 2002.

18

Advantages and Disadvantages of Regimens with 2 NRTIs Only

Advantages Low cost Low pill burden Better tolerability Easier to monitor

Disadvantages Lower antiviral potency

Partially suppressive Decreased durability

Emergence of NRTI resistance inevitable

19

Monitoring ARV Therapy: Effectiveness of Regimen

Clinical signs/symptoms Weight gain Resolution of oral thrush Resolution or reduced frequency of other infections

CD4 count or total lymphocyte count increase Viral load reduction (preferably to undetectable levels)

20

Monitoring ARV Therapy: Adverse Effects and Toxicity of Regimen

Clinical signs/symptoms Rash Jaundice Abdominal pain Numbness or pain in extremities

Laboratory abnormalities

21

Laboratory Monitoring for Toxicity and Effectiveness of ARV Therapy

Minimum Tests

Basic Tests

Desirable Tests

Optional Tests

HIV antibody testHemoglobin or

hematocrit

White blood cell count/ differential

Liver enzymesSerum creatinine

and/ or blood urea nitrogen

Serum glucosePregnancy test

CD4 cell countBilirubinAmylaseSerum lipids

(triglycerides cholesterol)

HIV-1 RNA

Adapted from WHO 2002.

22

Serious Adverse Effects of NRTIs

*Lactic acidosis/fatty liver All NRTIs

Loss of subcutaneous fat All NRTIs

Anemia ZDV

Myopathy ZDV

*Pancreatitis ddI, ddC

Neuropathy ddI ddC d4T

Ascending motor weakness d4T

*Hypersensitivity reaction ABC

Oral ulcers ddC

*Potentially life-threatening

23

Serious Adverse Effects of NNRTIs

*Hepatitis All NNRTIs

Skin rash All NNRTIs

Central nervous system symptoms Efavirenz

*Stevens-Johnson syndrome Nevirapine

*Potentially life-threatening

24

Serious Adverse Effects of PIs

Hyperglycemia and diabetes All PIs

Elevated serum lipids All PIs

Changes in body fat distribution All PIs

*Liver toxicity All PIs

Kidney stones Indinavir

Hypersensitivity rash Amprenavir

Pancreatitis Lopinavir/ritonavir

*Potentially life-threatening

25

Antiretroviral Drug Interactions

These are of clinical importance if they: Increase likelihood of drug toxicity Decrease therapeutic effectiveness of an administered

drug Important interactions may be seen between ARV

agents and: Other ARV agents Prescribed or non-prescription drugs (e.g., rifampin) Herbal or traditional remedies Certain foods Certain illicit drugs

26

Some Important ARV Drug Interactions for Limited-Resource Settings

Rifampin – PIs (except SQV/r), NNRTIs (except efavirenz) Should not be used together

Oral contraceptives – ritonavir, nelfinavir, amprenavir, lopinavir, nevirapine, efavirenz May decrease effectiveness of oral contraceptives Use additional or alternative method

Anticonvulsants – PIs, NNRTIs May decrease ARV levels

Cotrimoxazole, hydroxyurea, isoniazid, dapsone May have overlapping toxicities with ARV agents

27

Indications of Treatment Failure

Clinical – Clinical progression of disease (weight loss, oral thrush, etc.)

Immunologic – Decrease in CD4 cell count Virologic – Lack of sustained decrease in viral load to

below limits of detection

Indicates need for change in therapy

28

Factors Contributing to ARV Failure

Suboptimal ARV regimen Mono/dual NRTI

Suboptimal drug level Suboptimal dose Bio-equivalence of generic drugs Drug interactions Malabsorption (e.g., intestinal parasites, nausea and

vomiting) Lack of proper adherence to therapy

29

Factors Contributing to ARV Failure continued

Interruptions in treatment Cost Drug stockouts Side effects/toxicity Lack of proper adherence to therapy

30

0

10

20

30

40

50

60

70

80

90

100

>95% 90–95 80–90 70–80 <70

Adherence (%)

Pro

po

rtio

n w

ith

vir

olo

gic

fa

ilu

re (

%)

Correlation Between Lack of Adherence

and Virologic Failure

P = 0.00001, r = –0.554

Source: Paterson 1999.

31

Ensuring Adherence to Therapy

Provide initial and ongoing counseling about importance of adherence

Educate patient about possible drug side effects and toxicity Signs and symptoms Management

Assess readiness and commitment of patient to start and to maintain therapy before beginning treatment

32

Ensuring Adherence to Therapy continued

Assess adherence and barriers to adherence at each followup visit

Develop concrete plan for specific regimen with relation to meals and daily schedule

Encourage support for treatment from family and friends

Provide ongoing support for adherence at each clinical visit

Assure continued supply of ARV medications

33

Reasons to Change ARV Therapy

Intolerance Drug toxicity Occurrence of active TB Pregnancy ARV treatment failure

34

Recommended ARV Therapy After Treatment Failure with Initial Regimen

InitialRegimen

Second-LineRegimen

Alternative Second-Line

RegimenZDV/3TC/EFV

or ZDV/3TC/NVP

RTV-enhanced PI + d4T/ddI

RTV-enhanced PI* + ABC/ddI

NFV + ABC/ddI

NFV + d4T/ddI

ZDV/3TC/ABC NNRTI** + LPV/r +/- d4T or ddI

RTV-enhanced PI* + d4T/ddI

ZDV/3TC/RTV-enhanced PI*

or ZDV/3TC/NFV

NNRTI** + d4T/ddI NNRTI** + ABC/ddI

* IDV/r, LPV/r, or SQV/r** EFV or NVP

35

Tuberculosis and ARV Therapy

Status When to Start ARV Therapy

Pulmonary TB and CD4 less than 50/mm3 or extrapulmonary TB

Start TB Therapy

Start ARV as soon as TB therapy can be tolerated

Pulmonary TB and CD4 between

50 and 200/mm3 or total lymphocyte count less than 1000-1200/mm3

Start TB therapy

Start ARV therapy after 2 mo. Of TB therapy

Pulmonary TB and CD4 greater

than 200/mm3 or total lymphocyte count greater than 1000-1200/mm3

Treat TB, start ARV therapy according to general indications

36

Special Considerations

Condition Drug Considerations

Chronic liver disease Use caution with PIs (esp. RTV) and NNRTIs (esp. NVP)

Chronic diarrhea Use caution with NFV, RTV, LPV/RTV,

ddI (nonenteric-coated)

Renal insufficiency Avoid IDV

Dose adjust ZDV, 3TC, d4T, ddI

Anemia Use ZDV with caution

37

Important Reminders

ARV therapy is not a cure for HIV/AIDS – elimination of HIV from the body has not been achieved using the most powerful antiretroviral therapies available

HIV can still be transmitted, even when an individual is on ARV therapy and even when HIV RNA levels are below the limits of detection

38

Summary

ARV therapy can significantly reduce morbidity and mortality related to HIV.

For therapy to be effective, ARV agents must be used in combination and must achieve a sustained decrease in HIV viral load to below detectable levels.

Decisions about ARV therapy are complex and require consideration of potential adverse effects, drug interactions, resistance issues and the need for proper adherence.