IAS  USA Antiretroviral Guidelines 1996 – 2014

1. Antiretroviral Treatment of Adult HIV Infection:2014 Recommendations of the International Antiviral SocietyUSA Panel 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.

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

3. 2014 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.

4. IASUSA Antiretroviral Guidelines • Authored by 14-member, international (5 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 7/12 – 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 Günthard et al, JAMA, 2014.

5. 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 Günthard et al, JAMA, 2014.

6. Methods • 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: • Approved by regulatory agencies (eg, FDA) • Available in expanded access program • Submitted for regulatory approval (ie, in late development stages) Günthard et al, JAMA, 2014.

7. When to Start IAS-USA Recommendations 2014 Günthard et al, JAMA, 2014.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. What Treatment to Start IAS-USA Recommendations 2014 Günthard et al, JAMA, 2014.

14. 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.

15. Recommended Initial ART Regimens:INSTI plus 2 nRTIs Günthard et al, JAMA, 2014.

16. Recommended Initial ART Regimens:NNRTI plus 2 nRTIs Günthard et al, JAMA, 2014.

17. Recommended Initial ART Regimens: RTV-boosted PI plus 2 nRTIs Günthard et al, JAMA, 2014.

18. Alternatives to Recommended Initial Regimens Günthard et al, JAMA, 2014.

19. Alternatives to Recommended Initial Regimens, cont’d Günthard et al, JAMA, 2014.

20. Alternatives to Recommended Initial Regimens, cont’d Günthard et al, JAMA, 2014.

21. Alternatives to Recommended Initial Regimens, cont’d Günthard et al, JAMA, 2014.

22. 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.

23. 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.

24. 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.

25. 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.

26. Monitoring IAS-USA Recommendations 2014 Günthard et al, JAMA, 2014.

27. 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.

28. 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.

29. 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.

30. Changing ART Regimens IAS-USA Recommendations 2014 Günthard et al, JAMA, 2014.

31. 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.

32. 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.

33. Summary of Selected New Recommendations And Those for Which the Strength or Quality of Evidence has changed Substantially IAS-USA Recommendations 2014 Günthard et al, JAMA, 2014.

34. 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.

35. 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/cobiplus 2 NRTIs was added as an alternative initial regimen (BIa). Günthard et al, JAMA, 2014.

36. 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/cobiplus 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.

37. 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.

38. 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.

39. 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.

40. Conclusions IAS-USA Recommendations 2014 Günthard et al, JAMA, 2014.

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.