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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.