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Ronald P. Hattis, MD, MPH Associate Clinical Prof. of Preventive Medicine, Loma Linda University

What’s New in 2011-2013 Guidelines for Antiviral Treatment of Adults and Adolescents with HIV-1 (and a little extra on what else is new and current). Ronald P. Hattis, MD, MPH Associate Clinical Prof. of Preventive Medicine, Loma Linda University AAHIVM HIV Specialist President, Beyond AIDS

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Ronald P. Hattis, MD, MPH Associate Clinical Prof. of Preventive Medicine, Loma Linda University

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  1. What’s New in 2011-2013 Guidelines for Antiviral Treatment of Adults and Adolescents with HIV-1(and a little extra on what else is new and current) • Ronald P. Hattis, MD, MPH • Associate Clinical Prof. of Preventive Medicine, Loma Linda University • AAHIVM HIV Specialist • President, Beyond AIDS • December 5, 2012 On behalf of Beyond AIDS Foundation

  2. Objectives • The participant will be able to apply recent treatment guidelines for HIV in the care of HIV/AIDS, and will be aware of other recent developments in HIV care • The participant will be able to explain to patients the importance of viral load suppression to help prevent transmitting the virus to partners, and the advantages of early onset of antiretroviral treatment

  3. Sources and acronyms • Presentation includes summaries of recent changes in recommendations on ART (antiretroviral therapy) of two key advisory groups sponsored by: • IAS-USA: International Antiviral Society – USA division • Published in JAMA 7/25/12, hereafter referred to as IAS or IAS-USA guidelines • DHHS: U.S. Dept. Health and Human Services, which includes National Institutes of Health • Published on NIH Website 1/10/11, 3/27/12, and 2/12/13, hereafter referred to as DHHS guidelines • CDC and NIAID (the part of NIH dealing with infectious diseases) are sources of further information

  4. Evolution of guidelines on when to start treatment for HIV/AIDS • 1996-2000 “hit early, hit hard” often advocated • 2001-2012 treatment guidelines advised delaying antiretroviral therapy (ART) until CD4* cell counts <200, then <350, more recently <500/ml • Delayed due to concerns about toxicity, resistance • Cell count drop usually took 5-10 years to occur • Most of HIV transmission occurred before treatment * CD4 cell = type of white blood cell critical to immune system, and preferentially attacked by HIV

  5. 2012 ART guidelines introduced a radical change, not fully adopted • 2012 guidelines expanded offering of treatment to anyone with HIV • This major change has been incompletely adopted so far by providers or publicized to patients • Early and continuous treatment can reduce morbidity and mortality and also can be the key to controlling the U.S. HIV epidemic

  6. “Treatment as prevention” • Meanwhile, research has proven that ART can reduce HIV transmission by up to 96% • Concept first proposed 1996 by Hattis and Jason http://www.beyondaids.org/articles/1996MA~1.PDF, http://www.beyondaids.org/articles/WillNewMedicationsReduceInfectiousnessofHIV-1997.pdf • Confirmed effective in series of studies 2010-2011 • HPTN 052 clinical trial showed reduction of transmission to sexual partners of 96% in combination with prevention counseling • Cohen, M. S.; McCauley, M.; Sugarman, J. (2012), http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200068/

  7. “Treatment as Prevention”: 2011 “Science Breakthrough of the Year” (also featured at International AIDS Conference,7/12, Washington,DC)

  8. Potential to expand treatment Study based on CDC’s National HIV Surveillance system (Hall, I 7/27/12 using 2009 data) • 83% of est. 1.15 million infected persons in U.S. have been tested • 66% are linked to care (lower if black, young) • Only 33% have received ART (1/2 of those in care) • Only 25% have very low viral loads (VL, copies of virus per ml) (3/4 of those receiving ART) • Separate study by CDC in 2011 came up with similar figures: 80% of infected tested, 62% in care, 36% on ART, 28%virologically controlled • http://blog.aids.gov/2012/07/hivaids-treatment-cascade-helps-identify-gaps-in-care-retention.html

  9. Potential to control epidemic: additional opportunities (assuming about 5% uncooperative) • Percentage of infected persons tested diagnosis could be increased about 15%, from 83% to 95% • 95% of the 95% knowing diagnosis could be linked to care, increasing care by 36%, from 66% to 90% of total • 95% of the 90% in care could get ART, increasing treatment 58%, from 33% to 85% of total • If virological control rate could be increased from 75% to 80% of those treated, patients who are almost non-infectious could be increased by 2.76 times, from current 25% to 69% of total

  10. Potential to control epidemic: additional opportunities, contd. • 44% more of currently infected persons (69%-25%) would be only 4% as likely to transmit HIV, once VL controlled • A theoretical potential of 42% decrease in infectious persons, with similar incidence drop, just to start with • As fewer new infected people gradually replace greater numbers now alive (R0, viral reproductive rate <1) , incidence rate of HIV infections will exponentially drop to lower and lower levels • Actual rate reduction depends on achieving virological control before most transmission occurs • Prevalence drop depends on life expectancy

  11. Potential to control epidemic: additional opportunities, contd. • However: just applying new guidelines, to offer ART treatment to all already in care, even without increasing testing, linkage to care, or % of patients with low VL, could achieve: • Using low estimate of 62% in care, and only 90% acceptance, could treat another 23% of all infected persons, and control viral load in ¾ of them • This would mean 17% more of total infected persons would become non-infectious (a 2/3 increase from current number) and incidence rates would drop accordingly

  12. Categories of evidence used in DHHS guidelines • Ratings of recommendations A = Strong B = Moderate C = Optional • Ratings of evidence I = data from randomized controlled trials II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes III = expert opinion

  13. Concise summary of Changes, from IAS-USA Guidelines, contd. • Recommended initial regimens should include 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs: tenofovir/emtricitabine or abacavir/lamivudine) • Also include one of the following: • a nonnucleoside reverse transcriptase inhibitor (NNRTI: efavirenz) • a ritonavir-boosted protease inhibitor (PI: atazanavir or darunavir), or • an integrase strand transfer inhibitor (INSTI: raltegravir) • Alternatives: • For the NRTI: zidovudine (with lamivudine) (esp. in pregnancy) • For the NNRTI: nevirapine or rilpivirine • For the PI: ritonavir-boosted lopinavir, fosamprenavir, or saquinavir • For the INSTI: cobicistat-boosted elvitegravir • Rarely, a CCR5 attachment inhibitor: maraviroc.

  14. Concise summary of Changes, from IAS-USA Guidelines, contd. • “CD4 cell count and HIV-1 RNA level should be monitored, as should engagement in care, ART adherence, HIV drug resistance, and quality-of-care indicators.” • Reasons for regimen switching include virologic, immunologic, or clinical failure and drug toxicity or intolerance • Confirmed treatment failure should be addressed promptly and multiple factors considered • Comment: Psychological and cultural factors need to be addressed, affect adherence

  15. Concise summary of Changes, from IAS-USA Guidelines 7/25/12 IAS, published in JAMA (Journal of the American Medical Association) http://jama.jamanetwork.com/article.aspx?articleid=1221704 • Treatment now recommended for all adults with HIV infection; strength of recommendation and quality of evidence increase with decreasing CD4 cell count and presence of certain concurrent conditions • Clinical benefit is unknown for • Elite controllers (viral load undetectable without treatment) • DHHS 2/13: Treat if CD4 counts decrease, or symptoms • Long-term nonprogressors (stable CD4 cell counts >500/μL and HIV-1 RNA <1000 copies/mL while not taking ART) • DHHS 2/13: Consider treatment if VL >200

  16. DHHS Guidelines 1/10/11http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf • Benefits to patient of earlier treatment: • Increasing evidence demonstrates benefits of viral suppression and immunologic responses on reducing mortality and non-AIDS-related complications in patients with higher pretreatment CD4 counts. • NA-ACCORD study observed…adjusted mortality rates significantly higher among the 6,935 patients who deferred therapy until CD4 count fell to <500 compared with rates in the 2,200 patients who started therapy while CD4 count was > 500 (risk ratio: 1.94, 95% CI: 1.37 to 2.79)

  17. Evolution of DHHSrecommenda-tions on when to start • In 1/10/11 guidelines, half of panel recommended treating everyone regardless of CD4 count • In 3/27/12 guidelines, entire panel recommended treatment at any CD4 count based on emerging evidence: • Harmful impact of ongoing HIV replication on AIDS and non-AIDS disease progression • Benefit of effective ART in preventing secondary transmission of HIV

  18. When to start treatment, DHHS 3/27/12 guidelineshttp://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf • ART is recommended for all HIV-infected individuals. • Strength of this recommendation varies with pretreatment CD4 cell count: • CD4 count <350 cells/mm3 (AI) • CD4 count 350 to 500 cells/mm3 (AII) • CD4 count >500 cells/mm3 (BIII) • Regardless of CD4 count, initiation of ART strongly recommended for: • Pregnancy (AI) • History of an AIDS-defining illness (AI) • HIV-associated nephropathy (HIVAN) (AII)

  19. Additional priority indications for treatment (IAS-USA 7/25/12) • Hepatitis C virus (HCV) coinfection: CIII (however, if CD4 cell count >500/μL may delay ART until after completion of HCV treatment) • Chronic hepatitis B virus (HBV) coinfection: AII • Both HBV and HIV respond to tenofovircombined with either lamivudine or emtricitabine • Age older than 60 years: BII • During acute phase of primary HIV infection, regardless of symptoms: BIII • ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with most opportunistic infections (AI)

  20. When to start treatment, DHHS 3/27/12 guidelines, contd. • Patients who are at risk of transmitting HIV to sero-negative sexual partners (AI [heterosexuals] or AIII [other transmission risk groups]) • Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII) • Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors • However, ART should be offered and discussed with all patients

  21. Drug selection and initiation of treatment in special situations • HIV-2 (not covered by this presentation) may not respond to same drugs • Resistant to NNRTIs; darunavir, lopinavir, and saquinavir are most effective PIs http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/24/hiv-2-infection • Timing and choice of ART may be modified with cryptococcal disease and tuberculosis (IAS-USA 7/25/12) • For Cryptococcus, death rates lower when ART delayed till after 10 weeks of antifungal treatment • For TB, adverse events lower for patients with CD4 counts over 50, when ART delayed for 8-12 weeks after starting TB therapy • NIH 3/27/12 recommended delay of only 2 weeks if low BMI, anemia, or severe disease, and for patients with CD4 counts <50

  22. When to Start Treatment: Lack of International Consensus (courtesy of E. Daar, UCLA, 11/21/13) DHHS Mar 2013: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf; IAS-USA: Thompson MA, et al. JAMA. 2012; 308: 387-402; EACS Nov 2012. http://www.eacsociety.org/Portals/0/files/pdf%20files/EacsGuidelines-v6.1-2edition.pdf; BHIV 2012: http://www.bhiva.org/TreatmentofHIV1_2012.aspx; WHO June 2013:http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf

  23. Treating HIV/HCV coinfection in DHHS guidelines(3/27/12) Note: Expect major changes as new oral drugs are approved, starting with simepravir 11/22/13, sofosbuvir pending • Hepatitis C section includes bocepravir and telaprevir, add one as 3rd drug (with interferon and ribavirin) for patients with genotype 1 hepatitis C • Both can be used with raltegravir • Telaprevir but not bocepravir can be used with ATV/r • Telaprevir at increased dose can be used with EFV • Avoid DRV/r, LPV/r, EFV with bocepravir • Avoid DRV/r, FPV/r, or LPV/r with telaprevir • Interferon and ribavirin may be coadministered with ART but drug interactions, hepatotoxicity additive • This is rationale for delay in initiating ART if VL >500 and plan immediate hepatitis C treatment, till it is completed

  24. What else was added in 3/27/12 DHHS guidelines? • New section on HIV and the older patient, including comorbidities and their treatment • Non-AIDS morbidities; inflammation speeds chronic diseases • Wholesale cost table included (and updated 2/12/13) • Wholesale cost of most approved regimens is still over $2,000/mo (AIDS Drug Assistance Plan needed by many) • Section on women has expanded discussion of interactions of hormonal contraceptives with ARVs • Injectable Depo-Provera associated in 1 study with double risk of acquiring or transmitting HIV

  25. What’s new in 2/12/13 and 10/30/13 DHHS Guidelines? http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0 • Stribild (Elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COBI/TDF/FTC) as a fixed-dose combination product) is recommended as an alternative regimen for ART-naive patients, then 10/30/13 as a preferred initial complete regimen for treatment-naïve patients • Should have pre-treatment creatinine clearance >70 mL/min (BI). • Dolutegravir (alternative INSTI to raltegravir) recommended 10/30/13 as a preferred initial drug for treatment-naïve patients • http://aidsinfo.nih.gov/news/1392/hhs-panel-on-antiretroviral-guidelines-for-adults-and-adolescents-updates-recommendations-on-insti-based-regimens-for-art-naive-individuals

  26. What’s new in 2/12/13 DHHS Guidelines, contd. • Early HIV, or having a seronegative partner, are special indications for urgent initiation of ART • Genotypic tropism assay (cheaper) now available as alternate to favored but expensive phenotypic assay, before starting maraviroc (CCR5 antagonist) • Genotype for INSTI’s (integrase inhibitors) is recommended if failure of a regimen containing one • Not part of standard genotype panels • Not a requirement before initial treatment • Efavirenz does not need to be discontinued in pregnancy if it is maintaining undetectable VL • Avoid in females if pregnancy is planned or risk (no contraception) • By 5-6 wks., 2-3x estimated risk of neural tube defects is over

  27. What’s new in 2/12/13 DHHS Guidelines, contd. • Treatment should be discussed starting at first clinical contact • If ARV treatment is started before receiving a genotype, use a PI-based regimen • More drug interactions listed, incl. with INSTIs • Additional measures needed in labor and delivery • Intravenous ZDV if viral load 400 or greater

  28. ARV drug classes and how they are combined (adapted from multiple sources) • NRTIs (Nucleoside or nucleotide reverse transcriptase inhibitors): 2 used together as “backbone” of standard regimens; 7 available, 5 used • These are typically combined with one additional drug from any of following classes: • NNRTIs (Non-nucleoside reverse transcriptase inhibitors): 5 available, 3 used • PIs (protease inhibitors): 9 available, 4 used • Typically need to be “boosted” by a small dose of ritonavir, a fifth member of same drug class • INSTIs (Integrase strand transfer inhibitors): 3 available and used, one only in a combination and needs “booster” • Fusion or attachment inhibitors: 2 available, 1 used

  29. How the 5 main classes of HIV antiretroviral drugs work Source: http://i-base.info/guides/starting/hiv-lifecycle For more technical explanation see http://www.touchbriefings.com/pdf/3024/biswas.pdf

  30. Review of currently available antiretroviral drugs (following tables adapted with edits from http://aidsinfo.nih.gov/contentfiles/ApprovedMedstoTreatHIV_FS_en.pdf) • Of 27 drugs on market, only 18 are in recommended and 11 are in first-line regimens • 2 of these are used only to increase blood levels of PIs, or of an INSTI, by inhibiting CYP3A (ritonavir, cobicistat) • 2 only available in a combination product (Stribild) • Combination pills provide convenience, reduce pill burden • Drugs still currently recommended as primary, alternative, or booster drugs highlighted in bold below • Those available as generics (5 early NRTIs and one early NNRTI) have asterisks (*) after brand names below

  31. NRTIs(“nukes,” block reverse transcriptase, an enzyme HIV needs to make DNA copies of its RNA for reproduction)

  32. NNRTIs(“non-nukes,” bind to reverse transcriptase, an enzyme HIV needs to make DNA copies of its RNA in cell)

  33. PIs (block protease, an enzyme HIV needs to assemble new viral components into complete copies of itself)

  34. PIs, contd.

  35. Entry/fusion /attachment inhibitors (block entry of virus into cells) INSTIs(inhibit enzyme integrase, block integration of HIV copy into DNA)

  36. Combination pills (not incl. LPV/RTV)

  37. How do I keep all these straight? Common complaints by clinicians • Too many “–virs” • Names of 12 drugs from 3 classes end with “vir” • 3-digit acronyms don’t help • Not always easy to associate generic names and acronyms with brand names • Suggestions: • Take advantage of lists from pharmaceutical companies, some with pictures, dosages, etc. • Become familiar with 4 (of 7) two/three-drug combination pills, plus 4 more: darunavir, atazanavir, raltegravir; and ritonavir as booster

  38. The “nuke” dependence problem • All recommended regimens include choice of only 4 NRTIs combos: lamivudine (3TC) or emtricitabine (FTC), combined with either tenofovir (TDF) or abacavir (ABC) • TDF precautions: nephrotoxic, avoid or give alternate days if CrCl<50, twice weekly if CrCl 20-29; increased bone loss • ABC precautions: Pre-screen with HLA-B*5701, must be neg.; M.I. risk in one study, more virological failure if baseline VL >100,000 • No guidelines are provided (due to lack of data) when neither TDF or ABC can be used • No “Nuke-free” regimens are discussed in DHHS guidelines • See table on next slide for recent studies of such regimens • “Warmline” suggests can add FTC or 3TC even if mutations found

  39. NRTI-sparing options Courtesy of E. Daar, UCLA, 11/21/13

  40. The ART-ful RestaurantSome selections will be served together as one combo dish. This menu not available if fewer than 3 selections ordered. Chef’s recommendations in orange. • Select two items from list A (the NRTIs) • One from these 2: emtracitabine, or lamivudine • One from these 3: tenofovir, abacavir, zidovudine (“AZT”) • Warning: must have been tested for allergy to abacavir; AZT recommended only for experienced palates, not for the faint of heart • Add one item from any of the following groups: • NNRTIs: efavirenz, rilpivirine(latter if baseline VL<100,000) • Protease inhibitors: atazanavir, darunavir,fosamprenavir, lopinavir (a perennial favorite for expecting ladies) • This group will be garnished with a little ritonavir for enhancement • Integrase inhibitors: raltegravir, dolutegravir, elvitegravir • Latter in combo only, the Stribild Special • Entry inhibitor: maraviroc (pre-ordered, requires special eligibility)

  41. What to start, commentary on individual and cultural factors • “Selection of a regimen should be individualized on the basis of virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions” (DHHS 3/27/12) • Patient should be committed to adherence to treatment before starting (DHHS 2/12/13) • Cultural competence is important • Patient must be approached with sensitivity when recommending onset of therapy

  42. What to start, per DHHS recommendations

  43. What to start, per DHHS recommendations, contd. 44

  44. What to start, per DHHS, contd.

  45. What to start, per DHHS, contd.

  46. Summary of what to start per DHHScourtesy of E. Daar, UCLA, 11/21/13 October 30, 2013

  47. Individualizing First-line Therapy: Specific Circumstancescourtesy of E. Daar, UCLA, 11/21/13

  48. Newest ARV drugs • Rilpivirine: NNRTI with fewer CNS side effects than efavirenz • Approved separately as Edurant 5/20/11 • Approved as component of Complera 8/10/11 • Formulated in once-daily tablet with FTC/TDF • Should not be used with proton pump inhibitors • Pregnancy category B (vs. D for efavirenz) • Taken with food (vs. without for efavirenz) • Not recommended due to virological failures if baseline VL >100,000 (similar to abacavir)

  49. Newest ARV drugs, contd. • Dolutegravir (DTG, 50 mg/day) • Approved by FDA 8/12/13, brand name Tivicay • Recommended by HHS 10/30/13 in preferred initial therapy for treatment-naïve patients • IAS-USA: An INSTI with good activity against RAL and EVG-resistant strains • Does not require boosting; one dosage (50 mg/d) • Faster and superior VL suppression when combined with ABC + 3TC, compared with Atripla (EFV + FTC + TDF) in one trial, with similar toxicity, less CNS side effects and rash • Walmsley et al., ICAAC 2012

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