Huldrych F. Günthard, MD; Judith A. Aberg, MD; Joseph J. Eron, MD; Jennifer F. Hoy, MBBS, FRACP; Amalio Telenti, MD, PhD; Constance A. Benson, MD; David M. Burger, PharmD, PhD; Pedro Cahn, MD, PhD; Joel E. Gallant, MD, MPH; Marshall J. Glesby, MD, PhD; Peter Reiss, MD, PhD; Michael S. Saag, MD; David L. Thomas, MD, MPH; Donna M. Jacobsen, BS; Paul A. Volberding, MD Antiretroviral Treatment of Adult HIV Infection: 2014 Recommendations of the International Antiviral Society  USA Panel Günthard et al, JAMA, 2014.

Slide 2 of 41 IAS  USA Antiretroviral Guidelines 1996 – 2014 Günthard et al, JAMA, 2014.

Slide 3 of IAS  USA Antiretroviral Guidelines Authors Huldrych F. Günthard, MD Judith A. Aberg, MD Joseph J. Eron, MD Jennifer F. Hoy, MBBS, FRACP Amalio Telenti, MD, PhD Constance A. Benson, MD David M. Burger, PharmD, PhD Pedro Cahn, MD, PhD Joel E. Gallant, MD, MPH Marshall J. Glesby, MD, PhD Peter Reiss, MD, PhD Michael S. Saag, MD David L. Thomas, MD, MPH Donna M. Jacobsen, BS Paul A. Volberding, MD Günthard et al, JAMA, 2014.

Slide 4 of 41 IAS  USA Antiretroviral Guidelines Günthard et al, JAMA, Authored by 14-member, international (5 countries) panel o 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 7/12 – 6/14 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

Slide 5 of 41 Rationale for Issuing Revised Guidelines Günthard et al, JAMA, 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 6 of 41 Methods Günthard et al, JAMA, Systematic Literature Review of PubMed and EMBASE Hand searches for newly published reports and scientific abstracts, safety reports ARV manufacturers submitted lists of recent publications or abstracts meeting established criteria Data not published or presented in a peer-reviewed setting were not considered Drugs, formulations, combinations considered: o Approved by regulatory agencies (eg, FDA) o Available in expanded access program o Submitted for regulatory approval (ie, in late development stages)

IAS-USA RECOMMENDATIONS 2014 Günthard et al, JAMA, When to Start

Slide 8 of 41 When to Start ART: IAS-USA Recommendations 2014 ART is recommended for treatment of HIV infection and prevention of transmission of HIV regardless of CD4 cell count (AIa-BIII) Lack of demonstrated harm with early initiation, cost effective, clinically beneficial ART is cost-effective in resource-rich and –poor countries In next 4 years, more than 20 drugs are expected to become available as generics Günthard et al, JAMA, 2014.

Slide 9 of 41 When to Start ART: IAS-USA Recommendations 2014 Offer ART to all patients with acute or early infection; start as soon as possible to maximize benefit Reduced proviral DNA and plasma viral load, lower viral set point, robust immune reconstitution, and CD4 cell counts greater than 900/µL Planned discontinuation after specific duration is not recommended except in research settings Günthard et al, JAMA, 2014.

Slide 10 of 41 When to Start ART: IAS-USA Recommendations 2014 ART is recommended regardless of CD4 cell count The patient must be willing and ready to initiate therapy; patients not ready to start ART should remain in clinical care, with regular monitoring and ongoing discussion about need for ART The strength of recommendations and evidence increase as CD4 cell counts decrease and in the presence of certain conditions Günthard et al, JAMA, 2014.

Slide 11 of 41 When to Start ART: IAS-USA Recommendations 2014 Strength of recommendation and quality of evidence varies According to CD4 cell count:  CD4 cell counts <500 µL(AIa)  CD4 cell counts of >500 µL (BIII) According to clinical condition with CD4 cell counts of >500 µL:  Pregnancy (AIa)  Chronic HBV co-infection (AIIa)  HIV-associated nephropathy (AIIa) Günthard et al, JAMA, 2014.

Slide 12 of 41 When to Start ART: IAS-USA Recommendations 2014 According to clinical condition (cont’d):  Acute phase of primary HIV infection, regardless of symptoms (BIII)  Preferably within first 2 weeks of diagnosis of opportunistic infections (AIa)  Early in treatment for cryptococcal meningitis, when expert management of both HIV and cryptococcal infection is available (BIII) Günthard et al, JAMA, 2014.

IAS-USA RECOMMENDATIONS 2014 Günthard et al, JAMA, What Treatment to Start

Slide 14 of 41 What Treatment to Start: IAS-USA Recommendations 2014 ART is considered lifelong; sustained viral suppression is foundation for immune recovery, optimal health, and prevention of resistance and transmission. Maximize adherence and minimize toxicity: Goal is to treat with effective, well-tolerated therapy, with limited drug interactions and effects on comorbid conditions. Base selection on baseline resistance testing and patient characteristics and preferences Günthard et al, JAMA, 2014.

Slide 15 of 41 Recommended Initial ART Regimens: INSTI plus 2 nRTIs Günthard et al, JAMA, INSTI plus 2 nRTI Combinations RatingComments DTG plus TDF/FTCAIa DTG is dosed once daily. Associated with modest increases in creatinine level due to inhibition of creatinine secretion DTG plus ABC/3TCAIa No evidence that ABC/3TC performs less well at HIV-1 RNA levels > copies/mL when given with DTG. A fixed-dose combination is in late-stage development. EVG/cobi/TDF/FTCAIa Once-daily fixed-dose combination. Cobi is associated with modest increases in creatinine level; has drug interactions similar to RTV. RAL plus TDF/FTCAIaRAL is taken twice daily.

Slide 16 of 41 Recommended Initial ART Regimens: NNRTI plus 2 nRTIs Günthard et al, JAMA, NNRTI plus 2 nRTI Combinations RatingComments EFV/TDF/FTCAIa EFV central nervous symptoms may persist beyond 2-4 weeks, but is no longer contraindicated for use in pregnant women EFV plus ABC/3TCAIa EFV central nervous symptoms may persist beyond 2-4 weeks, but is no longer contraindicated for use in pregnant women RPV/TDF/FTCAIaOnce-daily fixed-dose combination. RPV-based therapy is not recommended in patients with baseline HIV-1 RNA levels > copies/mL

Slide 17 of 41 Recommended Initial ART Regimens: RTV-boosted PI plus 2 nRTIs Günthard et al, JAMA, RTV-boosted PI plus 2 NRTI Combinations RatingComments ATV plus TDF/FTCAIa ATV is associated with nephrolithiasis, cholelithiasis, and chronic kidney injury. ATV plus ABC/3TCAIa ATV is associated with nephrolithiasis, cholelithiasis, and chronic kidney injury. DRV plus TDF/FTCAIaDuring initial therapy, 800 mg of DRV is given once daily with 100 mg of RTV given once daily

Slide 18 of 41 Alternatives to Recommended Initial Regimens Günthard et al, JAMA, Type of Regimen Alternative ARV Drug Combinations RatingComments ISTI plus 2 nRTIsRAL plus ABC/3TCBI1 No evidence that ABC/3TC performs less well at HIV-1 RNA levels > copies/mL when taken with RAL. NNRTI plus 2 nRTIsNVP plus 2 nRTIsBIa Severe hepatotoxicity may occur in initial therapy when CD4 cell count is >250 µ/L in women and >400 µ/L in men. Severe rash is more common than with other NNRTIs. RPV plus ABC/3TCAIaRPV-based therapy is not recommended in patients with baseline HIV-1 RNA levels > copies m/L.

Slide 19 of 41 Alternatives to Recommended Initial Regimens, cont’d Günthard et al, JAMA, Type of Regimen Alternative ARV Drug Combinations RatingComments PI plus 2 nRTIsATV/cobi with 2 nRTIsBIaATV plus cobi as a fixed-dose combination achieves ATV levels similar to those with RTV boosting. As separate agents, they were noninferior to RTV-boosted ATV, both in combination with TDF /FTC.

Slide 20 of 41 Alternatives to Recommended Initial Regimens, cont’d Günthard et al, JAMA, Protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors, cont’d. DRV/cobi with 2 nRTIsBIII DRV plus cobi as a fixed-dose combination achieves DRV levels similar to those with RTV boosting. DRV plus ABC/3TCBIb Comparative clinical data from a subset of patients from a single randomized study. LPV fixed-dose combination with 2 nRTIs BIaMain advantage is fixed-dose combination. May have increased cardiovascular risk and be less tolerable than recommended options.

Slide 21 of 41 Alternatives to Recommended Initial Regimens, cont’d Günthard et al, JAMA, Type of Regimen Alternative ARV Drug Combinations RatingComments nRTIsDRV plus RALBIb RAL taken twice daily, RTV-boosted DRV taken once daily. Less effective at CD4 cell counts of copies/mL. LPV plus 3TCBIa Single study; comparator nRTIs included ZDV (53.9%), TDF (36.6%), and ABC (9.4%), each with 3TC. LPV plus RALBIaBoth medications taken twice daily; single study with relatively small sample size and low baseline plasma HIV-1 RNA level.

Slide 22 of 41 Recommendations for Initial Treatment in the Settings of Specific Conditions Pregnancy: ART should be initiated in all HIV-infected women who become pregnant; ZDV/3TC plus either RTV-boosted LPV or RTV-boosted ATV are preferred. Comorbid diseases: Choice of regimen is influenced by chronic and acute comorbidities; assess for exacerbation of comorbid conditions, negative clinical outcomes, increased ARV toxicity, drug interactions with ARV agents. Günthard et al, JAMA, 2014.

Slide 23 of 41 Recommendations for Initial Treatment in the Settings of Specific Conditions, cont’d. In patients with or at high risk of cardiovascular disease, avoiding use of ABC, RTV-boosted LPV, or RTV- boosted Fos-APV might be considered. In patients with reduced renal function, TDF should be avoided, especially in combination with a boosted PI. Given the increased risk of fragility fractures, it may be prudent to avoid TDF as part of initial therapy in postmenopausal women. Günthard et al, JAMA, 2014.

Slide 24 of 41 Recommendations for Initial Treatment in the Settings of Specific Conditions, cont’d. The recommended initial ART regimen in the setting of rifampin  based TB treatment is 600 mg EFV plus 2 NRTIs; if EFV cannot be used, rifabutin-based therapy with a boosted PI plus 2 NRTIs is an alternative. A 3-month, once-weekly regimen of isoniazid with rifapentine for treatment of latent TB infection is as effective as 9 months of isoniazid alone and is equally effective in HIV-infected individuals. No data yet on use of bedaquiline for treatment of multidrug- resistant TB in HIV-infected patients receiving ART; expert consultation is recommended. Günthard et al, JAMA, 2014.

Slide 25 of 41 Recommendations for Initial Treatment in the Settings of Specific Conditions, cont’d. The ART regimen for HIV- and HBV  coinfected persons should include TDF and FTC or 3TC as the NRTI background. DTG- or RAL-based regimens are recommended for patients receiving anticancer or immunosuppressive drugs. In the setting of HCV and HIV co-infection, consult guidance from the AASLD, IDSA, or IAS-USA. Günthard et al, JAMA, 2014.

IAS-USA RECOMMENDATIONS 2014 Günthard et al, JAMA, Monitoring

Slide 27 of 41 Recommendations for Monitoring Upon Initiation of or Change in ART HIV-1 RNA levels: Monitor at approximately 4 weeks after treatment initiation or change; Monitor every 3 months to confirm suppression of viremia to below the limitation of quantification of sensitive commercial assays (AIa). CD4 cell count: Monitor every 3 months after initiation of ART, especially for patients with cell counts of <200 µL; results will determine need to initiate or discontinue primary opportunistic infection prophylaxis (BIII) Günthard et al, JAMA, 2014.

Slide 28 of 41 Recommendations for Ongoing Monitoring Monitor at intervals of ≤6 months if viral load is suppressed for 1 year, CD4 cell count is stable at ≥350 µL, and patient’s adherence is dependable (CIII). Monitoring is optional if viral load is suppressed consistently for more than 2 years, CD4 cell counts are persistently >500/µL, except in setting of virologic failure or immunosuppressive treatments or conditions (CIII). If HIV-1 RNA level is detectable (>50 copies/mL) during therapy, confirm within 4 weeks before making changes (BIII). If HIV-1 RNA level is greater than 200 copies/mL during therapy, evaluate factors leading to failure and consider switch in ART (AIIa). Günthard et al, JAMA, 2014.

Slide 29 of 41 Recommendations for Ongoing Monitoring, cont’d. Perform baseline genotypic testing for resistance in all treatment-naive patients (AIIa) and in cases of confirmed virologic failure (AIa). Routine therapeutic drug monitoring is not recommended, though selected patients may benefit (BIII). Laboratory monitoring for ART toxicity is recommended, guided by presence or absence of comorbidities and by components of the regimen. Günthard et al, JAMA, 2014.

IAS-USA RECOMMENDATIONS 2014 Günthard et al, JAMA, Changing ART Regimens

Slide 31 of 41 Recommendations for Changing the ART Regimen in Treatment-Experienced Patients Design of a new regimen should consider previous ART exposure, previous resistance profile, and history of intolerance or toxic effects (AIIa). Depending on the resistance profile, viral tropism, and options available for patients with multidrug resistance, inclusion of a boosted PI and agents from newer drug classes (eg, an INSTI or maraviroc) should be considered (AIa). Monotherapy with a boosted PI is not recommended when other options are available (AIa). Günthard et al, JAMA, 2014.

Slide 32 of 41 Recommendations for Changing the ART Regimen in Treatment-Experienced Patients, cont’d. Maintenance of virologic suppression is paramount when switching the regimen to improve tolerability, reduce toxicity, and improve convenience (AIa). Switching or regimen simplification in virologically suppressed individuals is generally safe if prior treatment and resistance profile are considered. Full activity of the NRTIs is important when switching from a RTV-boosted to a drug with a lower barrier to resistance (AIa). Günthard et al, JAMA, 2014.

AND THOSE FOR WHICH THE STRENGTH OR QUALITY OF EVIDENCE HAS CHANGED SUBSTANTIALLY IAS-USA RECOMMENDATIONS 2014 Günthard et al, JAMA, Summary of Selected New Recommendations

Slide 34 of 41 Summary of Selected New Recommendations and Those for Which the Strength or Quality of Evidence Has Changed Substantially Changes in Recommendations for When to Start ART: ART is recommended for the treatment of HIV infection and prevention of transmission regardless of CD4 cell count (AIa- BIII). ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with opportunistic infections (AIa) and other opportunistic diseases and AIDS-defining illnesses (AIa-BIII). Optimal timing of ART initiation in patients with cryptococcal meningitis is less certain, but early start should be considered where expert management for both cryptococcal and HIV-1 infection is available (BIII). Günthard et al, JAMA, 2014.

Slide 35 of 41 Summary of Selected New Recommendations and Those for Which the Strength or Quality of Evidence Has Changed Substantially, cont’d. Changes in Recommendations for What Treatment to Start: DTG-based regimens and co-formulated EVG/cobi/TDF/FTC have been added to the list of recommended initial regimens (AIa). Co-formulated RPV/TDF/FTC has been added as an initial recommended regimen in patients with HIV-1 RNA levels <100,000 copies/mL (AIa). RAL plus ABC/3TC has been added as an alternative initial regimen (BIa). ATV/cobi plus 2 NRTIs was added as an alternative initial regimen (BIa). Günthard et al, JAMA, 2014.

Slide 36 of 41 Summary of Selected New Recommendations and Those for Which the Strength or Quality of Evidence Has Changed Substantially, cont’d. Changes in Recommendations for What Treatment to Start, cont’d: DRV/cobi plus 2 NRTIs was added as an alternative initial regimen (BIII). RTV-boosted DRV plus ABC/3TC was added as an alternative initial regimen (BIb). RTV-boosted DRV plus RAL has been added as NRTI-sparing alternative regimen only to be used in certain circumstances (BIb) RTV-boosted LPV plus 3TC has been added as an NRTI-limiting alternative regimen only to be used in certain circumstances (BIb). Günthard et al, JAMA, 2014.

Slide 37 of 41 Summary of Selected New Recommendations and Those for Which the Strength or Quality of Evidence Has Changed Substantially, cont’d. Changes in Recommendations for Monitoring: HIV-1 RNA level should be monitored approximately 4 weeks after treatment is initiated or changed, and then every 3 months to confirm suppression of viremia below the limit of quantification of sensitive commercial assays (AIa). Once viral load has been suppressed consistently for >2 years and CD4 cell counts are consistently >500/µL, monitoring CD4 cell counts is optional unless virologic failure occurs or there are intercurrent immunosuppressive treatments or conditions (CIII). Günthard et al, JAMA, 2014.

Slide 38 of 41 Summary of Selected New Recommendations and Those for Which the Strength or Quality of Evidence Has Changed Substantially, cont’d. HIV-1 RNA level >200 copies/mL should prompt evaluation of factors leading to failure and consideration of switching ART (AIIa). Laboratory monitoring for ART toxicity is recommended. In the absence of new abnormalities after week 16 of treatment, the frequency of monitoring—generally between 3–6 months—should be guided by the presence or absence of comorbidities and by the components of the regimen (CIII). Günthard et al, JAMA, 2014.

Slide 39 of 41 Summary of Selected New Recommendations and Those for Which the Strength or Quality of Evidence Has Changed Substantially, cont’d. Changes in Recommendations for Treatment-Experienced Patients Depending on resistance, viral tropism, and available options, inclusion of a boosted PI and agents from newer drug classes should be considered in patients with multidrug resistance (AIa). Maintenance of virologic suppression is paramount when switching a regimen to improve tolerability, reduce toxicity, and improve convenience (AIa). Switching or regimen simplification in virologically suppressed individuals is generally safe if prior treatment and resistance profile are considered. Full activity of the NRTIs is important when switching from a RTV-boosted to a drug with a lower barrier to resistance (AIa). Günthard et al, JAMA, 2014.

IAS-USA RECOMMENDATIONS 2014 Günthard et al, JAMA, Conclusions

Slide 41 of 41 Conclusions Early, intensified, widespread, and uninterrupted treatment is best option for controlling the epidemic. To exploit full potential of ART, greater efforts are needed to diagnose and treat infection as early as possible, and particularly acute and recent infection, which is a major driver of the epidemic. New, less toxic drugs with convenient dosing facilitates widespread acceptance of early ART. New strategies are needed to reduce stigmatization and discrimination that delay care. Günthard et al, JAMA, 2014.