D1 Highly Active Antiretroviral Treatment (HAART) DHHS Guidelines 2009 Duffus

Highly Active Antiretroviral Treatment (HAART) DHHS Guidelines 2009 Wayne Duffus, MD, PhD May 25 th 2010

When to Start: Evolution of DHHS Treatment Initiation Guidelines Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 1998-2009. Factor Recommendation 1998 2001 2002 2004 2007 2009 AIDS Treat Treat Treat Treat Treat Treat CD4 count (cells/mm 3 )
Treat <500
Treat <200
Offer <350
Indiv. >350
Treat <200
Offer <350
Indiv. >350
Treat <200
Offer <350
Indiv. >350
Treat <350
Risks/benefits if >350
Treat <350
Recommended between 350 and 500
>500 optional
Viral load (copies/mL) >20,000 >55,000 > 100,000 No specific viral load No specific viral load Other factors
Pregnant women
HBV coinfected
HIVAN
Pregnant women
HBV coinfected
HIVAN

CASCADE: Time Until CD4 Cell Count Declines to ≤500 Cells/mm 3 After Seroconversion
Time from seroconversion to first CD4 cell count ≤500 cells/mm 3 analyzed from CASCADE cohort (N=11,702)
56.6% (n=6626) of subjects declined to CD4 cell count ≤500 cells/mm 3 after a median of 20 months
Predictors of more rapid CD4 cell count decline
Older age (HR 1.06, 1.03-1.09 per 10-years)
More recent seroconversion by calendar year (HR 1.07, 1.06-1.08 per year)
Percent of subjects who have a CD4 cell count ≤500 cells/mm 3 Percent of subjects, % Time after seroconversion, months Lodi S, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOPEB050. 6 12 24 36

Likelihood of Achieving a Normal CD4 Cell Count Depends on When You Start
Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count normalization with earlier therapy
1 Moore R, et al. Clin Infect Dis . 2007;44(3):441-446. 2 Gras L, et al. J Acquir Immune Defic Syndr . 2007;45(2):183-192. Years on ART Johns Hopkins HIV Clinical Cohort 1 Mean CD4 Cell Count (cells/mm 3 ) ATHENA National Cohort 2 Weeks From Starting ART <200 201-350 >350 <50 50-200 200-350 350-500 ≥ 500 1000 800 600 400 200 0 0 48 96 144 192 240 288 336 0 1 2 3 4 5 200 400 600 800 0 1000

ART in Patients >50 Years Old: ATHENA National Cohort Mean CD4 Count (cells/mm 3 ) Gras L, et al. J Acquir Immune Defic Syndr . 2007;45(2):183-192. Median CD4 Response in Patients ≥50 Years of Age at the Start of ART a a Solid lines represent control patient group (male patients <50 years of age at the start of ART); dashed lines represent patients ≥50 year of age at the start of ART. Years from Starting ART <50 cells/mm 3 50-200 cells/mm 3 200-350 cells/mm 3 350-500 cells/mm 3 ≥ 500 cells/mm 3 0 1 2 3 4 6 5 7 1100 1000 900 800 700 600 500 400 300 200 100 0

ART in Patients >50 Years Old: ATHENA National Cohort Gras L, et al. J Acquir Immune Defic Syndr . 2007;45(2):183-192. Median CD4 Response in Patients ≥50 Years of Age at the Start of ART a a Solid lines represent control patient group (male patients <50 years of age at the start of ART); dashed lines represent patients ≥50 year of age at the start of ART. Years from Starting ART 0 1 2 3 4 6 5 7 1100 1000 900 800 700 600 500 400 300 200 100 0 Mean CD4 Count (cells/mm 3 ) <50 cells/mm 3 50-200 cells/mm 3 200-350 cells/mm 3 350-500 cells/mm 3 ≥ 500 cells/mm 3

D:A:D Study: Lower CD4 Count and Detectable Viral Load Associated With Increased Risk of Death Smith C and D:A:D Study Group. 16 th CROI; 2009; Montreal. Abstract 145. HIV-RNA (log copies/mL) and ART Status Adjusted Rate Ratio (95% Cl) CD4 CD4 and HIV-RNA Status Overall AIDS Liver CVD Non-AIDS Malignancies Per 100 <2.6 on >2.6 on <4 off 4-5 off >5 off 0.1 0.5 1 5 10

HOPS Cohort: CD4 Count <350 Increases CVD Risk
CD4 <350 cells/mm 3 independently raised risk of new CVD a 80% in this analysis of 1697 patients 1
HOPS finding corroborated by the FIRST 2 study
Patients with higher on-treatment CD4 cell count had lower risk of non-AIDS events, including CVD 2
1 Lichtenstein KA. 17 th IAC; Mexico City, 2008. THPE0236. 2 Baker JV. AIDS. 2008;22:841-848. a CVD tracked as MI, CAD, PVD, TIA, angina, aortic aneurysm, coronary artery bypass, angioplasty. HOPS Cohort 1 Risk Factor Hazard Ratio for CVD a Age  42 yr 2.5 Male sex 2.0 Smoking 2.0 Baseline CD4 count <350 cells/mm 3 1.8

SMART: Study Design and Findings CD4 cell count >350 cells/mm³ N=5472
Study was stopped January 2006 due to increased risk of progression of disease during the first 2 years of the trial for the DC versus the VS group
Increased risk included progression of disease (the primary endpoint), and progression of major non-HIV/AIDS-related diseases
El-Sadr et al. New Engl J M ed. 355(22): 2283-2296. Virologic Suppression (VS) Strategy Continuous use of ART to maintain viral load as low as possible (n=2752) Drug Conservation (DC) Strategy Defer ART until CD4 count is <250; then episodic ART based on CD4 count to increase counts to >350 (n=2720)

SMART: Non-AIDS Event Rates With Continuous vs Deferred/Intermittent ART
Significantly more individuals in DC arm developed major CV, renal, or hepatic disease than those in VS arm
Significantly more individuals in DC arm experienced grade 4 event or death from any cause than individuals in VS arm
El-Sadr WM et al. N Engl J Med. 2006;355:2283-2296. Endpoint VS (n=2752) DC (n=2720) HR (95% CI) P Value Grade 4 event or death from any cause 164 205 1.3 (1.0-1.6) .03 Death by any cause 30 55 1.8 (1.2-2.9) .007 Major CV, renal, or hepatic disease 39 65 1.7 (1.1-2.5) .009
Fatal/nonfatal CV disease
31 48 1.6 (1.0-2.5) .05
Fatal/nonfatal renal disease
2 9 4.5 (1.0-20.9) .05
Fatal/nonfatal liver disease
7 10 1.4 (0.6-3.8) .46

SMART: Cumulative Probability of OI/Death With Continuous vs Deferred/Intermittent ART
In January 2006, the study was modified to restart ART in DS group following the recommendations by the DSMB, and follow-up continued through July 2007
Cumulative Probability of OI/death From Any Cause Before Study Modification Cumulative Probability of OI/death From Any Cause Following Study Modification SMART Study Group. Ann Intern Med . 2008;149(5):289-299. Cumulative Probability of Opportunistic Disease or Death* Participants in the risk set, n DC group 1892 1297 957 VS group 1914 1305 978 Time from Randomization (mo) DC group 2508 2446 2414 VS group 2617 2567 2528 Participants in the risk set, n Time from Study Modification (mo) Overall HR, 2.9 (Cl, 1.9-4.5); P <.001 Change in HRs (log-time term); P = .23 Overall HR, 1.4 (Cl, 1.0-2.0); P = .04 Change in HRs (log-time term); P = .29 DC Group VS Group HR, 3.7 (Cl, 1.6-8.4); P =.003 HR, 3.9 (Cl, 1.8-8.5); P <.001 HR, 2.1 (Cl, 1.1-4.2); P =.04 HR, 1.2 (Cl, 0.7-2.2); P =.55 HR, 1.3 (Cl, 0.8-2.3); P= .32 HR, 2.2 (Cl, 1.1-4.3); P =.034 0.06 0.04 0.02 0 0 6 12 18 0.06 0.04 0.02 0 0 6 12 18

Association Between Current CD4 Cell Count and Non-AIDS Complications Phillips A et al. 15 th CROI; 2008; Boston. Abstract 8. Is Lower Current CD4 Cell Count Significantly Associated With Increased Risk of non-AIDS Events? Study Non-AIDS malignancies Renal disease/death CVD events/death Liver disease/ death FIRST Yes Yes Trend, NS No D:A:D Yes Yes Trend, NS Yes CASCADE Yes NA Yes Yes SMART Trend, NS Trend, NS Trend, NS Yes

ART-CC: Prognosis Based on CD4 Count at Initiation of ART Sterne J et al. CROI 2009. Abstract 72LB. Graphic reproduced with permission for educational use only. Sterne J et al. Lancet . 2009;373(9672):1352-63. CD4 Threshold a Adjusted for lead-time and unobserved events. 0.5 1.0 2.0 4.0 500 400 300 100 HR for AIDS or Death a 200 0 Comparison (CD4 cells/mm 3 ) HR a (95% CI) 1-100 vs 101-200 3.35 (2.99-3.75) 101-200 vs 201-300 2.21 (1.91-2.56) 201-300 vs 301-400 1.34 (1.12-1.61) 251-350 vs 351-450 1.28 (1.04-1.57) 351-450 vs 451-550 0.99 (0.76-1.29)

Guidelines Outline
Overview
Initiation of Therapy
Management of the Treatment-Experienced Patient
Special Issues

What the Guidelines Address
Baseline evaluation
Laboratory testing (HIV RNA, CD4 cell count, resistance)
When to initiate therapy
When to change therapy
Therapeutic options
Adherence
ART-associated adverse effects

What the Guidelines Address (2)
Treatment of acute HIV infection
Special considerations in adolescents, pregnant women, injection drug users, HIV-2 infection, and patients coinfected with HIV and HBV, HCV, or TB
Preventing secondary transmission

Goals of Treatment
Improve quality of life
Reduce HIV-related morbidity and mortality
Restore and/or preserve immunologic function
Maximally and durably suppress HIV viral load
Prevent HIV transmission

Tools to Achieve Treatment Goals
Selection of ARV regimen
Maximizing adherence
Pretreatment resistance testing

Predicting Adherence: Individual and Psychosocial Factors Not Predictive Negative Effect Positive Effect
Race
Gender
Disease stage
History of substance abuse
Active IDU
Active alcohol abuse (>14 drinks/week)
Untreated psychiatric disease
Patient belief in HAART
Physician expertise
Social supports
Adherence to office visits

Most Common Reasons for Nonadherence
Vacations/away from home
Forgetting to take a dose (timing)
Fatigue
Conflict with eating
Ran out of medications
Side-effects
Doubts about efficacy

Improving Adherence
Support and reinforcement
Simplified dosing strategies
Reminders, alarms, timers, and pillboxes
Ongoing patient education
Trust in primary care provider

Use of CD4 Cell Levels to Guide Therapy Decisions
CD4 count
The major indicator of immune function
Most recent CD4 count is best predictor of disease progression
A key factor in decision to start ART or OI prophylaxis
Important in determining response to ART
Adequate response: CD4 increase 50-150 cells/µL per year
CD4 monitoring
Check at baseline (x2) and at least every 3-6 months

Use of HIV RNA Levels to Guide Therapy Decisions
HIV RNA
May influence decision to start ART and help determine frequency of CD4 monitoring
Critical in determining response to ART
Goal of ART: HIV RNA below limit of detection (ie, <40-75 copies/mL, depending on assay)
RNA monitoring
Check at baseline (x2)
Immediately before initiating ART
2-8 weeks after start or change of ART
Every 3-6 months with stable patients

Testing for Drug Resistance
Before initiation of ART:
Transmitted resistance in 6-16% of HIV-infected patients
In absence of therapy, resistance mutations may decline over time and become undetectable by current assays, but may persist and cause treatment failure when ART is started
Identification of resistance mutations may optimize treatment outcomes
Resistance testing (genotype) recommended for all at entry to care
Recommended for all pregnant women

Testing for Drug Resistance
Patients with virologic failure:
Perform while patient is taking ART, or ≤4 weeks after discontinuing therapy
Interpret in combination with history of ARV exposure and ARV adherence

Drug Resistance Testing: Recommendations To assist in selecting active drugs for a new regimen. Suboptimal suppression of viral load after starting ART Transmitted drug-resistant virus is common in some areas; is more likely to be detected earlier in the course of HIV infection. If treatment is deferred, consider repeat testing at time of ART initiation. Genotype preferred. Chronic HIV infection, at entry into care COMMENT RECOMMENDED To determine if resistant virus was transmitted; guide treatment decisions. If treatment is deferred, consider repeat testing at time of ART initiation. Genotype preferred. Acute HIV infection, regardless of whether treatment is to be started

Drug Resistance Testing: Recommendations (2) To assist in selecting active drugs for a new regimen. Genotype preferred if patient on 1st or 2nd regimen; add phenotype if known or suspected complex drug resistance pattern. If virologic failure on integrase inhibitor or fusion inhibitor, consider testing for resistance to these to determine whether to continue them. Coreceptor tropism assay if considering use of CCR5 antagonist. Virologic failure during ART COMMENT RECOMMENDED

Drug Resistance Testing: Recommendations (3) COMMENT RECOMMENDED Recommended before initiation of ART or prophylaxis. Recommended for all on ART with detectable HIV RNA levels. Genotype usually preferred; add phenotype if complex drug resistance mutation pattern. Pregnancy

Drug Resistance Testing: Recommendations (4) Resistance assays cannot consistently be performed if HIV RNA is low Plasma HIV RNA <500 copies/mL Resistance mutations may become minor species in the absence of selective drug pressure After discontinuation (>4 weeks) of ARVs NOT USUALLY RECOMMENDED COMMENT

Other Assessment and Monitoring Studies
HLA-B*5701 screening
Recommended before starting abacavir, to reduce risk of hypersensitivity reaction (HSR)
HLA-B*5701-positive patients should not receive ABC
Positive status should be recorded as an ABC allergy
If HLA-B*5701 testing is not available, ABC may be initiated after counseling and with appropriate monitoring for HSR
Coreceptor tropism assay
Should be performed when a CCR5 antagonist is being considered
Requires plasma HIV RNA ≥1,000 copies/mL
Consider in patients with virologic failure on a CCR5 antagonist

When to Start ART
Potent ART may improve and preserve immune function in most patients with virologic suppression, regardless of baseline CD4 count
ART indicated for all with low CD4 count or symptoms
Earlier ART may result in better immunologic responses and better clinical outcomes
Reduction in AIDS- and non-AIDS-associated morbidity and mortality
Reduction in HIV-associated inflammation and associated complications
Reduction in HIV transmission
Recommended ARV combinations are considered to be durable and tolerable

When to Start ART
Exact CD4 count at which to initiate therapy not known, but evidence points to starting at higher counts
Current recommendation: ART for all patients with CD4 <500 cells/µL
For patients with CD4 >500 cells/µL, 50% of the panel recommend ART, 50% consider ART to be optional
Randomized control trial (RTC) data support benefit of ART if CD4  350
No RTC data on benefit of ART at CD4 >350, but observational cohort data
Currently available ARVs are effective and well tolerated

Potential Benefits of Early Therapy (CD4 count >500 cells/µL)
Cohort study data show survival benefit if ART initiated at CD4 count >500 cells/µL
Earlier ART may prevent HIV-related end organ damage; deferred ART may not reliably repair damage acquired earlier
Increasing evidence of direct HIV effects on various end organs and indirect effects via HIV-associated inflammation
End organ damage occurs at all stages of infection

Potential Benefits of Early Therapy (CD4 count >500 cells/µL) (2)
Potential decrease in risk of many complications, including:
HIV-associated nephropathy
Liver disease progression from hepatitis B or hepatitis C
Cardiovascular disease
Malignancies (AIDS defining and non-AIDS defining)
Neurocognitive decline
Blunted immunological response due to ART initiation at older age
Persistent T-cell activation and inflammation

Potential Benefits of Early Therapy (CD4 count >500 cells/µL) (3)
Prevention of sexual and bloodborne transmission of HIV
Prevention of mother-to-child transmission of HIV

Potential Limitations of Early Therapy (CD4 count >500 cells/µL)
ARV-related toxicities
Drug resistance
Nonadherence to ART
Cost

Recommendations for Initiating ART * Treatment with fully suppressive drugs active against both HIV and HBV is recommended. Initiate ART
History of AIDS-defining illness
CD4 count <350 cells/µL
CD4 count 350-500 cells/µL
Pregnant women
HIV-associated nephropathy (HIVAN)
Hepatitis B (HBV) coinfection, when HBV treatment is indicated*
Recommendation Clinical Category or CD4 Count

Recommendations for Initiating ART (2) 50% of the Panel favors starting ART; 50% views ART as optional CD4 count >500 cells/µL , asymptomatic, without conditions listed above Recommendation Clinical Category or CD4 Count

Recommendations for Initiating ART (3)
“ Patients initiating ART should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence.”
Patients may choose to postpone ART
Providers may elect to defer ART, based on patients’ clinical and/or psychosocial factors

Consider More Rapid Initiation of ART
Pregnancy
AIDS-defining condition
Acute opportunistic infection
Lower CD4 count (eg, <200 cells/µL)
Rapid decline in CD4
Higher viral load
HIVAN
HBV coinfection when HBV treatment is indicated

Consider Deferral of ART
Clinical or personal factors may support deferral of ART
If CD4 is low, deferral should be considered only in unusual situations, and with close follow-up
When there are significant barriers to adherence
If comorbidities complicate or prohibit ART
“ Elite controllers” and long-term non-progressors

Current ARV Medications
Integrase Inhibitor (II)
Raltegravir (RAL)
Fusion Inhibitor
Enfuvirtide (ENF, T-20)
CCR5 Antagonist
Maraviroc (MVC)
PI
Atazanavir (ATV)
Darunavir (DRV)
Fosamprenavir (FPV)
Indinavir (IDV)
Lopinavir (LPV)
Nelfinavir (NFV)
Ritonavir (RTV)
Saquinavir (SQV)
Tipranavir (TPV)
NRTI
Abacavir (ABC)
Didanosine (ddI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Tenofovir (TDF)
Zidovudine (AZT, ZDV)
NNRTI
Delavirdine (DLV)
Efavirenz (EFV)
Etravirine (ETR)
Nevirapine (NVP)

Initial ART Regimens: DHHS Categories
Preferred
Randomized controlled trials show optimal efficacy and durability
Favorable tolerability and toxicity profiles
Alternative
Effective but have potential disadvantages
May be the preferred regimen in individual patients
Acceptable
Less virologic efficacy, lack of efficacy data, or greater toxicities
May be acceptable but more definitive data are needed

Initial Treatment: Choosing Regimens
3 main categories:
1 NNRTI + 2 NRTIs
1 PI + 2 NRTIs
3 NRTIs
Combination of NNRTI or PI + 2 NRTIs preferred for most patients
Fusion inhibitor, CCR5 antagonist, integrase inhibitor not recommended in initial ART
Few clinical end points to guide choices
Advantages and disadvantages to each type of regimen
Individualize regimen choice

DHHS Guidelines: Recommended Regimens for Treatment-Naïve Patients Preferred Regimens PI-based ATV + (3TC or FTC) + (AZT, d4T, ABC or ddI) or (TDF+RTV 100 mg/d) LPV/r + (3TC or FTC) + (d4T, ABC, TDF or ddI) FPV or FPV/r or IDV/r or NFV or SQV/r + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI) Alternative Regimens NNRTI-based EFV + (3TC or FTC) + (ABC, ddI or d4T) NVP + (3TC or FTC) + (AZT, d4T, ddI, ABC or TDF) EFV + (3TC or FTC) + (AZT or TDF) LPV/r + (3TC or FTC) + AZT 3 NRTI-based ABC + AZT + 3TC – only when a preferred or an alternative NNRTI- or PI-based regimen cannot or should not be used DHHS Guidelines for the Use of ARV Agents in HIV-1-Infected Adults and Adolescents; May 2006.

Initial Treatment: Preferred
EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception.
2. 3TC can be used in place of FTC and vice versa.
LPV/r (BID) ³ + ZDV/3TC
Pregnant Women
RAL + TDF/FTC²
II based
ATV/r + TDF/FTC²
DRV/r (QD) + TDF/FTC²
PI based
EFV/TDF/FTC 1,2
NNRTI based

Initial Treatment: Alternatives
3. ABC should not be used in patients who test positive for HLA B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease.
4. NVP should not be started if pre-ARV CD4 >250 in women or >400 in men.
ATV/r + (ABC/3TC) or (ZDV/3TC) 2,3
FPV/r (QD or BID) + (ABC/3TC) or (ZDV/3TC) or (TDF/FTC) 2,3
LPV/r (QD or BID) + (ABC/3TC) or (ZDV/3TC) or (TDF/FTC) 2,3
SQV/r + TDF/FTC 2
PI based
EFV¹ + (ABC/3TC) or (ZDV/3TC)²
NVP4 + ZDV/3TC
NNRTI based

Initial Treatment: Acceptable
3. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease .
ATV + (ABC/3TC) or (ZDV/3TC) 2,3
PI based
EFV¹ + ddI + (3TC or FTC)
NNRTI based

Initial Treatment: May Be Acceptable but More Definitive Data Needed
3TC can be used in place of FTC and vice versa.
2. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease.
3. Tropism testing required before treatment with MVC; use only if only CCR5-tropic virus is present.
RAL + (ABC/3TC) or (ZDV/3TC) 1
II based
MVC + ZDV/3TC 1,3
CCR5 Antagonist based
DRV/r + (ABC/3TC) or (ZDV/3TC) 1,2
SQV/r + (ABC/3TC) or (ZDV/3TC) 1,2
PI based

Initial Treatment: Use with Caution
3TC can be used in place of FTC and vice versa.
2. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease.
3. NVP and ABC both can cause hypersensitivity reaction in first few weeks of treatment.
4. NVP should not be started if pre-ARV CD4 >250 in women or >400 in men.
5. Early virologic failure in some patients; larger studies under way.
6. Virologic failure may select mutations that confer cross-resistance to DRV.
FPV + (ABC/3TC) or (ZDV/3TC) 1,2,3,6
PI based
NVP + ABC/3TC 1,2,3 ,4
NVP + TDF/FTC 1,2,3, 4,5
NNRTI based

ARVs Not Recommended in Initial Treatment
d4T + 3TC
IDV/r
RTV as sole PI
High incidence of toxicities
ddI + TDF
High rate of early virologic failure
ABC + 3TC + ZDV as 3-NRTI regimen
ABC + 3TC + ZDV + TDF as 4-NRTI regimen
DLV
NFV
SQV as sole PI (unboosted)
TPV/r
Inferior virologic efficacy

ARVs Not Recommended in Initial Treatment (2)
ABC+ TDF
ABC + ddI
DRV (unboosted)
ENF (T-20)
ETR
Lack of data in initial treatment
3-class regimens
3 NRTIs + NNRTI
No benefit over standard regimens
IDV (unboosted)
High pill burden/ Dosing inconvenience

ARV Medications: Should Not Be Offered at Any Time
ARV regimens not recommended:
Monotherapy with NRTI*
Dual-NRTI therapy
3-NRTI regimen (except ABC + 3TC + ZDV or possibly TDF + 3TC + ZDV, when other regimens are not desirable)
* If ZDV monotherapy is being considered for prevention of mother-to-child transmission, see Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.

ARV Medications: Should Not Be Offered at Any Time (2)
ARV components not recommended:
ddI + d4T
FTC + 3TC
d4T + ZDV
DRV, SQV, or TPV as single PIs (unboosted)

ARV Medications: Should Not Be Offered at Any Time (3)
ARV components not recommended:
EFV during pregnancy and in women with significant potential for pregnancy
NVP initiation in women with CD4 counts of >250 cells/µL or in men with CD4 counts of >400 cells/µL
ETR + unboosted PI
ETR + RTV-boosted ATV, FPV, or TPV
2-NNRTI combination

ARV Components in Initial Therapy: NNRTIs
ADVANTAGES
Long half-lives
Less metabolic toxicity (dyslipidemia, insulin resistance) than with some PIs
PIs and II preserved for future use
DISADVANTAGES
Low genetic barrier to resistance – single mutation
Cross-resistance among most NNRTIs
Rash; hepatotoxicity
Potential drug interactions (CYP450)
Transmitted resistance to NNRTIs more common than resistance to PIs

ARV Components in Initial Therapy: PIs
ADVANTAGES
Higher genetic barrier to resistance
PI resistance uncommon with failure (boosted PI)
NNRTIs and II preserved for future use
DISADVANTAGES
Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance)
GI intolerance
Potential for drug interactions (CYP450), especially with RTV

ARV Components in Initial Therapy: II (Raltegravir)
ADVANTAGES
Virologic response noninferior to EFV
Fewer adverse events than with EFV
Fewer drug-drug interactions than with PIs or NNRTIs
NNRTIs and PIs preserved for future use
DISADVANTAGES
Less experience with IIs, limited data
Twice-daily dosing
Lower genetic barrier to resistance than PIs
No data with NRTIs other than TDF/FTC in initial therapy

ARV Components in Initial Therapy: Dual-NRTI Pairs
ADVANTAGES
Established backbone of combination therapy
Minimal drug interactions
DISADVANTAGES
Lactic acidosis and hepatic steatosis reported with most NRTIs (rare)

Treatment-Experienced Patients
In clinical studies of ART, most patients maintained virologic suppression for at least 3-7 years
Appropriate initial ARV regimens should suppress HIV indefinitely, assuming adequate adherence
In patients with suppressed viremia:
Assess adherence frequently
Simplify ARV regimen as much as possible
Patients with ARV failure: assess and address aggressively

Treatment-Experienced Patients: ART Failure
Causes of treatment failure include:
Patient factors (eg, CD4 nadir, pretreatment HIV RNA, comorbidities)
Drug resistance
Suboptimal adherence
ARV toxicity and intolerance
Pharmacokinetic problems
Suboptimal drug potency
Provider experience

Treatment-Experienced Patients: ART Failure (2)
Virologic failure:
HIV RNA >400 copies/mL after 24 weeks, >50 copies/mL after 48 weeks, or >400 copies/mL after viral suppression
Immunologic failure:
Failure to achieve and maintain adequate CD4 increase despite virologic suppression
Clinical progression:
Occurrence of HIV-related events (after ≥ 3 months on therapy; excludes immune reconstitution syndromes)

Treatment-Experienced Patients: Virologic Failure
Incomplete virologic response:
In patient on initial ART, HIV RNA >400 copies/mL after 24 weeks on therapy or >50 copies/mL by 48 weeks (confirm with second test)
Virologic rebound:
Repeated detection of HIV RNA after virologic suppression (eg, >50 copies/mL)

Treatment-Experienced Patients: Virologic Failure (2)
Assess drug resistance:
Drug resistance test
Prior treatment history
Prior resistance test results
Drug resistance usually is cumulative – consider all previous treatment history and test results

Treatment-Experienced Patients: Virologic Failure (3)
Management:
Clarify goals: aim to reestablish maximal virologic suppression (eg, <50 copies/mL)
Evaluate remaining ARV options
Newer agents have expanded treatment options
Base ARV selection on medication history, resistance testing, expected tolerability, adherence, and future treatment options
Avoid treatment interruption, which may cause viral rebound, immune decompensation, clinical progression

Virologic Failure: Changing an ARV Regimen
General principles:
Add at least 2 (preferably 3) fully active agents to an optimized background ARV regimen
Determined by ARV history and resistance testing
Consider potent RTV-boosted PIs, drugs with new mechanisms of action (eg, integrase inhibitor, CCR5 antagonist, fusion inhibitor, 2nd generation NNRTI) + optimized ARV background
In general, 1 active drug should not be added to a failing regimen (drug resistance is likely to develop quickly)
Consult with experts

Patients Prefer Once-daily With Low Pill Burden 0 10 20 30 40 50 60 70 80 90 100 If you were to take a certain number of pills each day, how would you prefer them to be administered? All at once Divided and taken twice a day % patients preferring >8 pills 8 pills 6 pills 4 pills 3 pills 31% 69% 38% 62% 59% 41% 84% 16% 93% 7% Moyle G et al. Paper presented at: 6th International Congress on Drug Therapy in HIV Infection; Glasgow, Scotland; November 17-21, 2002. Poster 99.

Regimen Simplification
Changing a suppressive ARV regimen to:
Reduce pill burden
Reduce dosing frequency
Enhance tolerability
Decrease food and fluid requirements
Goals: improve patient’s quality of life, improve ART adherence, avoid long-term toxicities, reduce risk of virologic failure

Regimen Simplification (2)
Types of substitution
Within class: substitution of a new agent or co-formulation
Out-of-class: eg, change from PI to NNRTI or agent from another class
Reducing number of active drugs in ARV regimen: simplification to boosted-PI monotherapy is not recommended
After simplification, monitor in 2-6 weeks (laboratory and clinical)

Websites to Access the Guidelines
http://www.aidsetc.org
http://aidsinfo.nih.gov

D1 Highly Active Antiretroviral Treatment (HAART) DHHS Guidelines 2009 Duffus

by DSHS

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