New Guidelines, Strategies, and Drugs for Initiation of Antiretroviral Therapy 2013
Antiretroviral Therapy DHHS Guidelines. Guidelines for the Use of Antiretroviral Agents in Adults...
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Transcript of Antiretroviral Therapy DHHS Guidelines. Guidelines for the Use of Antiretroviral Agents in Adults...
Antiretroviral Therapy
DHHS Guidelines
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