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Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the

Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the International Antiviral Society  USA Panel.

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Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the

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  1. Antiretroviral Treatment of Adult HIV Infection:2012 Recommendations of the International Antiviral SocietyUSA 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–USA Thompson et al, JAMA, 2012.

  2. Available Antiretroviral Agents • 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) • Nonnucleos(t)ide RTIs • Nevirapine (NVP) • Delavirdine (DLV) • Efavirenz (EFV) • Etravirine (ETR) • Tenofovir DF (TDF) • Nucleoside RTIs • Zidovudine (ZDV) • Didanosine (ddI) • Zalcitabine (ddC) • Stavudine (d4T) • Lamivudine (3TC) • Abacavir (ABC) • Emtricitabine (FTC) • Integrase Inhibitors • Raltegravir (RAL) • Dolutegravir* • Elvitegravir* • Boosters • Ritonavir (RTV) • Cobicistat* (cobi) • Fusion Inhibitor • Enfuvirtide (T-20) • CCR5 Antagonist • Maraviroc (MVC) * In expanded access or submitted for regulatory approval July 20, 2012

  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

  4. Antiretroviral Drugs Available in Generic Forms • Abacavir • Didanosine • Lamivudine • Nevirapine • Stavudine • Zidovudine July 20, 2012

  5. IASUSA Antiretroviral Guidelines 1996 – 2012

  6. 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 2012 IASUSA Antiretroviral Guidelines Authors

  7. IASUSA 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.

  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 Thompson et al, JAMA, 2012.

  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.

  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) Thompson et al, JAMA, 2012.

  11. When to Start

  12. Risks and Benefits of Earlier Initiation of ART Benefits Prevention 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 Risks Reduced 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

  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 Thompson et al, JAMA, 2012.

  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 Thompson et al, JAMA, 2012.

  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)

  16. Initial Regimens in the Treatment-Naive Patient

  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 Thompson et al, JAMA, 2012.

  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 Thompson et al, JAMA, 2012.

  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) Thompson et al, JAMA, 2012.

  20. Recommendations for When to Initiate ART (cont’d) • 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) Thompson et al, JAMA, 2012.

  21. Recommendations for When to Initiate ART (cont’d) • 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). Thompson et al, JAMA, 2012.

  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.

  23. Recommended Initial Antiretroviral Regimens* Thompson et al, JAMA, 2012. * See comments

  24. Alternative Initial Antiretroviral Regimens* * See comment**Submitted for regulatory approval Thompson et al, JAMA, 2012.

  25. Initial Antiretroviral Regimens: Comments Thompson et al, JAMA, 2012.

  26. CCR5 AntagonistBased and nRTI-Sparing Initial Regimens in Special Circumstances Only Thompson et al, JAMA, 2012. * See comments

  27. CCR5 AntagonistBased and nRTI-Sparing Initial Regimens in Special Circumstances Only Thompson et al, JAMA, 2012.

  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) Thompson et al, JAMA, 2012.

  29. Recommendations for Initial Treatment in the Settings of Specific Conditions (cont’d) • The recommended initial ART regimen in the setting of rifampinbased 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 HBVcoinfected persons should include tenofovir and emtricitabine or lamivudine as the nRTI background (AIIa) Thompson et al, JAMA, 2012.

  30. Patient Monitoring

  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). Thompson et al, JAMA, 2012.

  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) Thompson et al, JAMA, 2012.

  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) Thompson et al, JAMA, 2012.

  34. Changing Therapy: When and What

  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 Thompson et al, JAMA, 2012.

  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 Thompson et al, JAMA, 2012.

  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). Thompson et al, JAMA, 2012.

  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). Thompson et al, JAMA, 2012.

  39. Recommendations for Management of Treatment-Experienced Patients (cont’d) • 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). Thompson et al, JAMA, 2012.

  40. Recommendations for Management of Treatment-Experienced Patients (cont’d) • PI/r monotherapy is associated with an increased risk of virologic failure and is not recommended when other options are available (AIa). Thompson et al, JAMA, 2012.

  41. Conclusions

  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 Thompson et al, JAMA, 2012.

  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). Thompson et al, JAMA, 2012.

  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). Thompson et al, JAMA, 2012.

  45. Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (cont’d) • 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). Thompson et al, JAMA, 2012.

  46. Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (cont’d) • 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). Thompson et al, JAMA, 2012.

  47. Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (cont’d) • 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). Thompson et al, JAMA, 2012.

  48. Summary of Selected New Recommendations and Those for Which Strength or Quality of Evidence Has Changed Substantially in 2012 (cont’d) • 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). Thompson et al, JAMA, 2012.

  49. Earlier ART Associated with Decreased Mortality and Disease Progression: Observational Studies

  50. CASCADESeroconvertor 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 $$$Add reference$$$

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