Slide #1 Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the International Antiviral Society USA Panel Melanie A. Thompson,

Slide #1

Antiretroviral Treatment of Adult HIV Infection:2012 Recommendations of the

International Antiviral SocietyUSA Panel

Melanie A. Thompson, MD; Judith A. Aberg, MD; Jennifer F. Hoy, MBBS, FRACP; Amalio Telenti, MD, PhD; Constance Benson, MD;

Pedro Cahn, MD, PhD; Joseph J. Eron Jr, MD; Huldrych F. Günthard, MD; Scott M. Hammer, MD; Peter Reiss, MD, PhD;

Douglas D. Richman, MD; Giuliano Rizzardini, MD; David L. Thomas, MD; Donna M. Jacobsen, BS; Paul A. Volberding, MD

The International Antiviral Society–USAThompson et al, JAMA, 2012.

Slide #2

Available Antiretroviral Agents

Nucleoside RTIs• Zidovudine (ZDV)• Didanosine (ddI)• Zalcitabine (ddC)• Stavudine (d4T)• Lamivudine (3TC)• Abacavir (ABC)• Emtricitabine (FTC)

Nonnucleos(t)ide RTIs• Nevirapine (NVP)• Delavirdine (DLV)• Efavirenz (EFV)• Etravirine (ETR)• Tenofovir DF (TDF)

Protease Inhibitors• Saquinavir (SQV)• Ritonavir (RTV)• Indinavir (IDV)• Nelfinavir (NFV)• Amprenavir (APV)• Lopinavir/r (LPV/r)• Atazanavir (ATV)• Fosamprenavir (Fos-APV)• Tipranavir (TPV)• Darunavir (DRV)Boosters

• Ritonavir (RTV)• Cobicistat* (cobi) Fusion Inhibitor

• Enfuvirtide (T-20)

CCR5 Antagonist• Maraviroc (MVC)

Integrase Inhibitors• Raltegravir (RAL)• Dolutegravir*• Elvitegravir*

* In expanded access or submitted for regulatory approval

July 20, 2012

Slide #3

Fixed-Dose Combination Antiretrovirals

• Abacavir/lamivudine

• Elvitegravir/cobicistat/emtricitabine/tenofovir*

• Lopinavir/ritonavir

• Tenofovir/emtricitabine

• Tenofovir/emtricitabine/efavirenz

• Tenofovir/emtricitabine/rilpivirine

* In expanded access or submitted for regulatory approval

July 20, 2012

Slide #4

Antiretroviral Drugs Available in Generic Forms

• Abacavir

• Didanosine

• Lamivudine

• Nevirapine

• Stavudine

• Zidovudine

July 20, 2012

Slide #5

IASUSA Antiretroviral Guidelines1996 – 2012

Slide #6

2012 IASUSA Antiretroviral Guidelines Authors

Melanie A. Thompson, MD

Judith A. Aberg, MD

Jennifer F. Hoy, MBBS, FRACP

Amalio Telenti, MD, PhD

Constance Benson, MD

Pedro Cahn, MD, PhD

Joseph J. Eron Jr, MD

Huldrych F. Günthard, MD

Scott M. Hammer, MD

Peter Reiss, MD, PhD

Douglas D. Richman, MD

Giuliano Rizzardini, MD

David L. Thomas, MD

Donna M. Jacobsen, BS

Paul A. Volberding, MD

Slide #7

IASUSA Antiretroviral Guidelines

• Authored by 15-member, international (6 countries) panel

– Members receive no compensation and do not participate in industry promotional activities while on the panel

• Based upon pathogenesis- and evidence-based individualization of therapy

• Primarily for clinicians in highly resourced settings; however, principles are universally applicable

• Reviewed data published or presented 7/10 – 5/12

• Rated on strength of recommendations and quality of evidence

• Focused on when to start therapy; pre-exposure prophylaxis; what to start; patient monitoring; treatment-experienced patients

Thompson et al, JAMA, 2012.

Slide #8

Rationale for Issuing Revised Guidelines

• Evaluate new data showing all patients may benefit from ART

• Evaluate new data that ART reduces likelihood of HIV transmission

• Consider issues of relevance to persons with hepatic, renal, or cardiovascular comorbidities; opportunistic infections; or at high risk for HIV transmission


Slide #9

Methods

• Systematic Literature Review of PubMed and EMBASE Search terms: HIV and antiretroviral and treatment (or

prevention or toxicity or monitoring). Filters: English, dates (July 2012-May 2012), humans,

adults, clinical trial OR meta-analysis OR guidelines OR editorials OR review OR full text OR free text OR abstracts

• Hand searches for newly published reports and scientific abstracts, safety reports

• ARV manufacturers provided product efficacy or safety data

• Data not published or presented in a peer-reviewed setting were not considered Thompson et al, JAMA, 2012.

Slide #10

Methods

• Drugs, formulations, combinations considered: Approved by regulatory agencies (eg, FDA) Available in expanded access program Submitted for regulatory approval (ie, in late

development stages)


Slide #11

When to Start

Slide #12

Risks and Benefits of Earlier Initiation of ART

BenefitsPrevention of progressive immune dysfunction (reduced immune activation)

Delayed progression to AIDS and prolonged survival

Decreased risk of non-AIDS/HIV-related morbidity (HIVAN, malignancies, neurocognitive dysfunction, cardiovascular disease, etc)

Decreased drug resistance

Decreased risk for some ARV toxicities

Decreased HIV transmission

RisksReduced quality of life

Development of drug resistance if adherence is suboptimal

Limitation in future choices of ART if drug resistance occurs

Uncertain long-term toxicities and duration of effectiveness for some drugs/regimens

Possible transmitted drug resistance

Slide #13

Rationale for Recommending ART for All HIV-Infected Adults

• Uncontrolled HIV replication, immune activation and inflammation associated with ‘non-AIDS’ illnesses– Cardiovascular, hepatic, renal, malignancies – ART and high CD4 associated with decreased disease

incidence

• Patients starting ART when CD4 counts are < 350/μL have greater morbidity and mortality than those starting when CD4 counts are < 500/μL

• Increasing evidence of detrimental effects of uncontrolled viremia at CD4 cell counts > 500/µL


Slide #14

Rationale for Recommending ART for All HIV-Infected Adults

• Strength and quality of evidence are highest with– CD4 count < 500 cells/µL– Pregnancy– HBV or HCV coinfection– HIV-associated nephropathy– Active or high risk for cardiovascular disease– Opportunistic infections, including tuberculosis and meningitis– Age older than 60 years– Primary HIV infection– High risk for HIV transmission


Slide #15

When to Start ART: IAS–USA Recommendations 2012

• Patient readiness should be considered when deciding to initiate antiretroviral therapy (ART)

• ART should be offered regardless of CD4 cell count (increasing strength of the recommendation as CD4 decreases)

– CD4 < 500 cells/µL (AIa)

– CD4 > 500 cells/µL (BIII)

– Pregnancy (AIa)

– Chronic HBV (AIIa)

– HCV (may delay until after HCV treatment if CD4 > 500) (CIII)

– Age older than 60 (BIIa)

– HIV-associated nephropathy (AIIa)

– Acute phase of primary HIV infection, regardless of symptoms (BIII)

Slide #16

Initial Regimens in the Treatment-Naive Patient

Slide #17

Initial Regimen Considerations

• Patient readiness to begin lifelong therapy

• Baseline assessment–Evaluate for HBV or HCV coinfection, diabetes

mellitus, hyperlipidemia, cardiovascular disease, smoking, renal disease, other comorbid conditions

–Consider drug interactions

–Perform resistance testing

–Assess for pregnancy or risk thereof


Slide #18

Recommendations for When to Initiate ART

• Patient readiness for treatment should be considered when deciding to initiate ART. Clinicians should engage supportive services as needed to assist with ART education and to address barriers to adherence (AIII)

• ART is recommended and should be offered regardless of CD4 cell count (AIa-CIII). The strength of the recommendation increases as CD4 cell count decreases and in the presence of certain conditions, with the following grades:– For CD4 cell count of 500/µL and below: AIa– For CD4 cell count above 500/µL: BIII


Slide #19

Recommendations for When to Initiate ART (cont’d)

– Ratings for specific conditions are as follows: Pregnancy: AIa Chronic HBV coinfection when HBV treatment is indicated: (AIIa) HCV coinfection: CIII (however, coinfection with CD4 cell count >500/µL

may delay ART until after completion of HCV treatment) Age older than 60 years: BIIa HlV-associated nephropathy: AIIa

• ART is recommended and should be offered to persons during the acute phase of primary HIV infection, regardless of symptoms (BIII)


Slide #20


• ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with opportunistic infections (AIa)

• The optimal timing for patients with cryptococcal meningitis is less certain, but initiating ART early during cryptococcal treatment may be associated with higher mortality; therefore, ART initiation in these patients should be managed in consultation with experts (BIII)


Slide #21


• ART is recommended in all HlV-infected persons with tuberculosis (TB) and should be started within 2 weeks of TB treatment when the CD4 cell count is below 50/µL and by 8 to 12 weeks for those with higher CD4 cell counts (Ala).

• The optimal timing for patients with TB meningitis is less certain, but ART should be started within the first 2 to 8 weeks of diagnosis and managed in consultation with experts (BIII).


Slide #22

Choice of Initial Regimen

Tenofovir/emtricitabine (TDF/FTC) OR Abacavir/lamivudine (ABC/3TC)

WITH

Third agent (NNRTI, boosted PI, or InSTI):

• Efavirenz OR

• Atazanavir/r OR

• Darunavir/r OR

• Raltegravir Thompson et al, JAMA, 2012.

Slide #23

Recommended Initial Antiretroviral Regimens*

Component Recommended RegimensNNRTI plus nRTIs • Efavirenz/tenofovir/emtricitabine (AIa)

• Efavirenz plus abacavir/lamivudine (AIa) in HLA-B*5701-negative patients with baseline plasma HIV-1 RNA <100,000 copies/mL

PI/r plus nRTIs • Darunavir/r plus tenofovir/emtricitabine (AIa)• Atazanavir/r plus tenofovir/emtricitabine (AIa)• Atazanavir/r plus abacavir/lamivudine (AIa) in

patients with plasma HIV-1 RNA <100,000 copies/mL

InSTI plus nRTIs • Raltegravir plus tenofovir/emtricitabine (AIa)

Thompson et al, JAMA, 2012.* See comments

Slide #24

Alternative Initial Antiretroviral Regimens*

Component Alternative RegimensNNRTI plus nRTIs • Nevirapine plus tenofovir/emtricitabine or

abacavir/lamivudine (BIa) • Rilpivirine/tenofovir/emtricitabine (or rilpivirine

plus abacavir/lamivudine) with baseline plasma HIV-1 RNA < 100,000 copies/mL (BIa)

PI/r plus nRTIs • Darunavir/r plus abacavir/lamivudine (BIII)• Lopinavir/r plus tenofovir (BIa) (or

abacavir/lamivudine) (BIa)

InSTI plus nRTIs • Raltegravir plus abacavir/lamivudine (BIIa) • Elvitegravir/cobicistat/tenofovir/emtricitabine**

(BIb)

* See comment**Submitted for regulatory approval Thompson et al, JAMA, 2012.

Slide #25

Initial Antiretroviral Regimens: Comments

Component Comments

NNRTI plus nRTIs • Severe hepatotoxicity and rash with nevirapine are more common in initial therapy when CD4 cell count is >250/µL in women and >400/µL in men.

PI/r plus nRTI • Other alternative PIs include fosamprenavir/r and saquinavir/r but indications to use these options for initial treatment are rare.

InSTI plus nRTIs • Raltegravir is given twice daily; experience with elvitegravir/cobicistat/tenofovir/emtricitabine is limited to 48-week data.


Slide #26

CCR5 AntagonistBased and nRTI-Sparing Initial Regimens in Special Circumstances Only

Component RegimensCCR5 antagonist plus nRTIs, (NNRTI-, PI-, and InSTI-sparing)

• Maraviroc plus tenofovir/emtricitabine or abacavir/lamivudine (CIII)

PI/r plus InSTI (nRTI-sparing) • Darunavir/r plus raltegravir (BIIa)• Lopinavir/r plus raltegravir (BIa)

Thompson et al, JAMA, 2012.* See comments

Slide #27

CCR5 AntagonistBased and nRTI-Sparing Initial Regimens in Special Circumstances Only

Component CommentsCCR5 antagonist plus nRTIs

(NNRTI-, PI-, and InSTI-sparing)

• Tropism assay to confirm R5 virus should be done before prescribing maraviroc. Maraviroc is not effective in persons who have X4 or dual/mixed X4/R5 virus infection. Few data are available for maraviroc with tenofovir/emtricitabine or abacavir/lamivudine

PI/r plus InSTI (nRTI-sparing) • Data emerging for these regimens. Clinical trial evidence needed before formal recommendation can be made.


Slide #28

Recommendations for Initial Treatment in the Settings of Specific Conditions

• In patients with or at high risk of cardiovascular disease, avoiding use of abacavir, lopinavir/r, or fosamprenavir/r might be considered (BIIa)

• In patients with reduced renal function, tenofovir should be avoided, or if treatment for HBV coinfection is needed, dosing should be adjusted according to the prescribing information (AIIa)

• Given the increased risk of fragility fractures, it may be prudent to avoid tenofovir as part of initial therapy in postmenopausal women (BIIa)


Slide #29

Recommendations for Initial Treatment in the Settings of Specific Conditions (cont’d)

• The recommended initial ART regimen in the setting of rifampinbased tuberculosis treatment is efavirenz plus 2 nRTls (AIa)

• The recent recommendation for use of a 3-month, once-weekly regimen of isoniazid with rifapentine for treatment of latent TB infection is not recommended for HlV-infected patients receiving ART (BIII).

• The ART regimen for HIV- and HBVcoinfected persons should include tenofovir and emtricitabine or lamivudine as the nRTI background (AIIa)


Slide #30

Patient Monitoring

Slide #31

Recommendations for Monitoring

• Plasma HIV-1 RNA levels should be monitored at least every 3 months after treatment is initiated or changed for virologic failure to confirm suppression of viremia below 50 copies/mL (AIa).

• CD4 cell count should be monitored at least every 3 months after initiation of therapy, especially among patients with less than 200/µL, to determine the need for primary opportunistic infection prophylaxis (BIII).

• Once viral load is suppressed for 1 year and CD4 cell count is stable at 350/µL or greater, HIV-1 RNA and CD4 cell count can be monitored at intervals of up to 6 months in patients with dependable adherence (CIII).


Slide #32

Recommendations for Monitoring (cont’d)

• Detectable HIV-1 RNA (>50 copies/mL) during therapy should be confirmed in a subsequent sample between 2 and 4 weeks afterward and prior to making management decisions (BIII)

• Sustained elevation of HIV-1 RNA between 50 and 200 copies/mL should prompt evaluation of factors leading to failure and consideration of switching of ART (BIII)

• Baseline genotypic testing for resistance should be performed in all treatment-naive patients (AIIa) and in cases of confirmed virologic failure (AIa)


Slide #33

Recommendations for Monitoring (cont’d)

• Therapeutic drug monitoring is not recommended in routine care; however, selected patients (eg, pregnant women, children, and patients with renal or liver impairment) might benefit from this intervention (BIII)

• Health care practitioners and health systems should initiate strategies to monitor and improve entry into and retention in care and ART adherence and to incorporate and analyze quality-of-care indicators (CIII)


Slide #34

Changing Therapy: When and What

Slide #35

When and What to Change: Principles

• Assess possible causes for virologic failure

–Nonadherence to drug regimen

–Drug interactions

–Intercurrent infections

–Recent vaccinations

• Repeat to exclude measurement error or self-resolving transient viremia


Slide #36

When and What to Change: Principles

• Regimen intolerance, inconvenience, or toxicity

–Single agent substitutions acceptable if virus is suppressed

–Monotherapy with boosted PI not recommended

• Treatment failure

–Treatment goal is virologic suppression to < 50 copies/mL in both initial and multiple failures

–Ideally 3, but at least 2, fully active agents


Slide #37

Recommendations for Management of Treatment-Experienced Patients

• In the setting of confirmed virologic failure, changing to a new regimen should occur promptly, with consideration of potential contributory factors to prevent further evolution of drug resistance (AIIa).

• A new regimen should be constructed using resistance testing (both past and present), treatment history and consideration of tolerability and adherence issues (AIa).


Slide #38

Recommendations for Management of Treatment-Experienced Patients (cont’d)

• Initial failed regimen should be changed to regimens including a minimum of 2 and ideally 3 fully active drugs (AIa).

• Management of multidrug resistance is complex and expert advice should be sought (BIII).

• In virologically suppressed patients, switching single agents for toxicity or prevention of anticipated adverse reactions or drug interactions is generally safe and effective (AIa).


Slide #39


• Intensification of or switching therapy has not been successful in improving suboptimal CD4 cell count responses in the setting of durable virologic suppression and is not recommended (AIa).

• Treatment interruptions (outside of clinical trial) should be avoided because of increased risk of death, AIDS, and serious non-AIDS morbidity associated with untreated HIV infection (AIa).


Slide #40


• PI/r monotherapy is associated with an increased risk of virologic failure and is not recommended when other options are available (AIa).


Slide #41

Conclusions

Slide #42

Conclusions I

• Recommendation to begin therapy earlier in asymptomatic persons is informed by

–Increased evidence of the harmful effects of uncontrolled viremia and its associated immune activation and inflammation, even at higher CD4 cell counts

–Evidence that all HIV-infected adults may benefit from ART

–Data showing ART reduces likelihood of transmission


Slide #43

Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012

• ART is recommended and should be offered regardless of CD4 cell count (A1a-CIII depending on CD4 cell count and existing conditions).

• ART is recommended and should be offered to persons during the acute phase of primary HIV infection, regardless of symptoms (BIII).


Slide #44

Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (cont’d)

• ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with opportunistic infections (other than cryptococcal and tuberculous meningitis),with attention to drug interactions and the potential for immune reconstitution inflammatory syndrome (IRIS) (AIa).

• The optimal timing of ART initiation in patients with cryptococcal meningitis is less certain, but initiating ART early during cryptococcal treatment may be associated with higher mortality; therefore, ART initiation in patients with cryptococcal meningitis should be managed in consultation with experts (BIII).


Slide #45


• ART is recommended in all HlV-infected persons with TB and should be started within weeks of TB treatment when CD4 cell count is below 50/µL and by 8 to 12 weeks for those with higher CD4 cell counts (AIa).The optimal timing for patients with TB meningitis is less certain, but ART should be started within the first 2 to 8 weeks of TB treatment and managed in consultation with experts (BIII).

• Abacavir/lamivudine (in patients with HIV-1 RNA levels < 100,000 copies/mL) is now a recommended rather than alternative dual nRTI component of initial ART (AIa).


Slide #46


• Rilpivirine has been added as an alternative NNRTI component of the initial regimen (BIa).

• Coformulated elvitegravir/cobicistat/tenofovir/emtricitabine has been added as an initial regimen component, pending regulatory approval (BIb). Elvitegravir is an investigational InSTI and cobicistat is an investigational pharmocokinetic booster.

• Given increased risk of fragility fractures in postmenopausal women, it may be prudent to consider avoiding tenofovir as part of initial therapy in this group (BIIa).


Slide #47


• The recommended initial ART regimen in the setting of rifampin-based TB therapy is efavirenz plus 2 nRTIs (AIa).

• The recent recommendation for use of a 3-month, once-weekly regimen of isoniazid with rifapentine for treatment of latent TB infection is not recommended for HlV-infected patients receiving ART (BIII).

• Sustained elevation of plasma HIV-1 RNA between 50 and 200 copies/mL should prompt evaluation of factors leading to failure and consideration for switching of ART (BIII).


Slide #48


• Health care practitioners and health systems should initiate strategies to monitor and improve entry into and retention in care and ART adherence and to incorporate and analyze quality-of-care indicators (CIII).

• Management of multidrug resistance is complex and expert advice should be sought (BII).


Slide #49

Earlier ART Associated with Decreased Mortality and Disease Progression:

Observational StudiesStudy Published N Endpoint Relative Hazard P or 95% CI

NA-ACCORD NEJM, 2009 8,362 Death 1.69 CD4 <350 vs 350-500

< 0.001

NA-ACCORD NEJM, 2009 9,155 Death 1.94 CD4 <500 vs > 500

< 0.001

When to Start Consortium

Lancet, 2009 24,444 AIDS or Death

1.28CD4 251-350 vs 351-400

HIV-CAUSAL Ann Int Med, 2011

AIDS or Death

1.38CD4 <350 vs <500

CASCADE Arch Int Med, 2011

9,455 Death 0.51 (HR)*CD4 350-499 vs deferred

0.33-0.80

COHERE Plos Med, 2012

75,336 AIDS or Death

0.74 (HR)*CD4 350-<500 on ART

0.96 (HR)*CD4 > 500 on ART

0.58-0.80

0.92-0.99

Slide #50

• CASCADE Seroconvertor Cohort– Compared with

deferred ART in any given month, starting ART was associated with slowed disease progression in all CD4 strata except 500-799 cells/µL

$$$Add reference$$$

Slide #51

HPTN 052• 1,750 heterosexual serodiscordant couples in resource-

constrained countries randomized to receive ART early (CD4 350-550 cells/µL) or defer until CD4 < 250 cells/µL (Cohen M, et al. NEJM 2011)

Event Rates Early ART Deferred ART HR P-value

Transmission Rate per 100 pt-years

(95% CI)

0.3 (0.1-0.6)

2.2 (1.6-3.1)

0.11(0.04-0.32)

< 0.001

Clinical Event Rate per 100 pt-years

(95% CI)

2.4(1.7-3.3)

4.0(3.5-5.0)

0.59(0.40-0.88)

<0.001

Cohen et al, NEJM, 2011Cohen et al, NEJM, 2011

Slide #52

Effect of ART Timing on TB Death (CAMELIA) or Death/AIDS Progression (STRIDE, SAPIT)

34% ↓ p=0.004

19% ↓ p=0.45

11% ↓ p=0.73

Blanc NEJM 2011, Havlir NEJM 2011, Abdool Karim NEJM 2011

Earlier: 2-4 weeks after TB treatment

started

Later: 8-12 weeks after TB treatment

started

Slide #53

Significant Reduction in Death/AIDS Among Those with TB and CD4 < 50 Cells/µL

34% ↓ p=0.004

42% ↓ p=0.02

68% ↓ p=0.06


Earlier: 2-4 wks after TB

treatment started

Later: 8-12 wks after TB

treatment started

Slide #54

Greater Reduction in Mortality at Lower CD4

P = 0.004

P = 0.45

P = 0.73


Slide #55

Cryptococcal Meningitis and Antiretroviral Therapy

• Randomized clinical trial in Zimbabwe; ART started within 72 hours vs. 8 weeks after initiation of fluconazole alone for treatment of CM (Makadzange C, et al. Clin Infect Dis 2010)

– Trial stopped by the DSMB due to increased HR for death (HR 2.85) in the early ART arm

• Randomized clinical trial in Uganda, South Africa (COATS) in patients with CM – After 7-11 days of treatment with amphotericin B +

fluconazole, patients were randomized to start ART within 48 hours or > 4 weeks

– Trial stopped by the DSMB due to increased mortality in the early ART arm

Slide #56

When to Start ART During Acute Opportunistic Infections: IAS–USA

Recommendations 2012• Start ART as soon as possible, preferably within the

first two weeks (AIa) except for TB and cryptococcal meningitis as indicated below:– Patients with cryptococcal meningitis should be managed

in consultation with experts (BIII)– Patients with TB should start TB treatment first; start ART

as soon as possible but within the first 2 weeks for those with CD4 < 50 cells/µL

– Within the first 2-8 weeks of TB treatment for those with TB meningitis

– Within the first 8-12 weeks of TB treatment for others

Slide #1 Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the International Antiviral Society USA Panel Melanie A. Thompson,

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