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

1. What’s New in 2011 and 2012 Guidelines for Antiviral Treatment of Adults and Adolescents with HIV(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 • HIV/AIDS Provider, Desert AIDS Project • President, Beyond AIDS • November 17, 2012 (rev. 2/13)

2. Objectives • The participant will be able to apply 2012 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 • NIH/HHS: U.S. Dept. Health and Human Services, which includes National Institutes of Health • Published on NIH Website 1/10/11 and 3/27/12, hereafter referred to as NIH guidelines • NIAID, the part of NIH dealing with infectious diseases, is a source 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 introduce a radical change, not widely known • 2012 guidelines expand offering of treatment to anyone with HIV • This major change has been poorly publicized so far to providers and patients • Early and continuous treatment can reduce morbidity and mortality and also can be the key to controlling the U.S. HIV epidemic

7. “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/

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

9. 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

10. 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

11. 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

12. 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

13. Categories of evidence used in NIH 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

14. 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) • (Comment: Unless CD4 counts begin to steadily decrease) • Long-term nonprogressors (stable CD4 cell counts >500/μL and HIV-1 RNA <1000 copies/mL while not taking ART)

15. 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.

16. 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

17. NIH/HHS 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)

18. Evolution of NIH recommendations 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

19. When to start treatment, NIH 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)

20. 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)

21. When to start treatment, NIH 3/27/12 guidelines, contd. • Patients who are at risk of transmitting HIV to 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

22. Timing of initiation of treatment in special situations (IAS-USA 7/25/12) • Timing and choice of ART may be modified with cryptococcal disease and tuberculosis. • For Cryptococcus, death rates were lower when ART delayed till after 10 weeks of antifungal treatment • For TB, adverse events were 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

23. Treating HIV/HCV coinfection in NIH guidelines(3/27/12) • 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 is new in 3/27/12 NIH guidelines? • New section on HIV and the older patient, including comorbidities and their treatment • Non-AIDS morbidities; inflammation speeds chronic diseases • (Comment: HIV itself and some ART drugs can lower HDL, raise triglycerides, or cause neuropathy, nephropathy, lipodystrophy; some ARV drugs increase metabolic risks) • Wholesale cost table included • 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. 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): 2 available and used, one only in a combination and needs “booster” • Fusion or attachment inhibitors: 2 available, 1 used

26. 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

27. Review of currently available antiretroviral drugs (following tables adapted with edits from http://aidsinfo.nih.gov/contentfiles/ApprovedMedstoTreatHIV_FS_en.pdf) • Of 25 drugs on market, 15 are in recommended regimens, and only 8 are in first-line regimens • 1 of these, and 1 new agent, are used only to increase blood levels of PIs or an INSTI by inhibiting CYP3A • Combination pills (5 recommended, 1 new) 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

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

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

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

31. PIs, contd. (none on this slide more than twice/day)

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

33. Combination pills

34. 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

35. What to start, commentary on NIH recommendations (no changes in either 2011 or 2012) • 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 • RAL + DAR/r is a 2-drug regimen (plus ritonavir) that has had good initial results but increased virological failures • “Warmline” (11/7/12) recommends it, but advises adding 3TC or FTC if possible • 3TC or FTC may add beneficial results even if mutations present

36. 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 • 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, elvitegravir (combos only) • Entry inhibitor: maraviroc • Must be pre-ordered, requires special eligibility

37. 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” (NIH 3/27/12) • Cultural competence is important • Patient must be approached with sensitivity when recommending onset of therapy

38. What to start, per NIH recommendations (no changes in either 2011 or 2012)

39. What to start, per NIH, contd.

40. What to start, per NIH, contd.

41. 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) • More virological failures if baseline VL >100,000 (similar to abacavir)

42. Newest ARV drugs, contd. • Stribild: combination of 4 drugs, sometimes referred to as “quad” • Approved 8/27/12, after both NIH and IAS-USA guidelines issued • Formulated as tablet with 2 old drugs (FTC/TDF) and 2 new ones • Elvitegravir (EVG), a new INSTI not used separately • Requires boosting, but low-dose RTV without another PI was considered a risk for PI resistance • Cobicistat, a new CYP3A booster without ART effect • Would probably be classified as “alternate” or possibly as “acceptable” regimen • Faster VL suppression than ATV/r regimen, slightly superior to EFV regimen with same NRTIs

43. Lab monitoring schedule (NIH 1/10/11)

44. Less frequent CD4 counts needed if VL undetectable (NIH 1/10/11) • “Poor CD4 response is rarely an indication for modifying a virologically suppressive ARV regimen…for the patient on a suppressive regimen whose CD4 cell count has increased well above the threshold for opportunistic infection risk, the CD4 count can be measured less frequently than the viral load…every 6 to 12 months, unless there are changes in the patient’s clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents (CIII).” • IAS-USA goes along with this up to every 6 months, not 12 • Comments: • Aim for VL and CD4 every 3 months; if CD4 high and stable and VL undetectable, do CD4 every 2 visits • Steadily decreasing CD4 count may be indication for modifying regimen

45. Virologic definitions(NIH 1/10/11) • Virologic suppression: A confirmed HIV RNA level below the limit of assay detection • Virologic failure: The inability to achieve or maintain HIV RNA level <200 copies/mL) • Incomplete virologic response: Two consecutive plasma HIV RNA levels >200 copies/mL after 24 weeks on ARV regimen • Baseline HIV RNA and regimen may affect timing of response • Determine whether failure is do to adherence • Repeat genotype (while on failing regimen, per UCSF) • Dilemma if 200-1000, lab may not be able to do • Change 2-3 drugs (never only 1) if failing regimen

46. Treatment-experienced patients, salvage regimens • Give DRV, LPV, FPV bid; increase ritonavir dose with DRV, FPV for experienced patients • Consider third-line drugs not on the “starter” list • If can’t find 3 drugs without resistance, use 4-5 • If expert consultation not locally available, or for rapid advice, nationally-funded services at UCSF: • “Warmline” (HIV management) (800) 933-3413 • Only number really needed, others go to same staff • “PEPline (occup. exposures) (888) 448-4911 • Perinatal hotline (prevention of transmission to newborn) (888) 448-8765

47. Prevention of opportunistic infections (OIs) Last updated by CDC 4/10/09 • http://www.aidsinfo.nih.gov/contentfiles/Adult_OI.pdf

49. Pediatric NIH guidelines (11/1/12)http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf • Recommend treatment of all infants <12 months old and for all children with symptoms • Generally recommend treatment of children >1 yr without symptoms, with strength of recommendation based on CD4 counts • <1000 for ages 1-3 (AII) • <750 for ages 3-5 (AII) • <500 for age 5 and older (AI) • Some drugs approved only above certain ages • Not all drugs have liquid or chewable versions • Dosages based on weight

50. PrEP (Pre-exposure prophylaxis) http://www.cdc.gov/hiv/prep/pdf/PrEPfactsheet.pdf • 7/16/12: FDA approved Truvada for PrEP, based on 2 studies a year earlier, showing “strong evidence that PrEP is effective and safe among heterosexually-active men and women” • TDF2 study: once-daily tenofovir plus emtricitabine reduced risk of acquiring HIV infection by roughly 62 percent of heterosexually-active men and women. • Partners PrEP study: daily tenofovir plus emtricitabine reduced HIV transmission among heterosexual serodiscordant couples by 75% • Before initiating PrEP (From CDC Interim Guidelines 8/12): • Document negative HIV antibody test immediately before starting PrEP medication. • Test for acute HIV infection if patient has symptoms consistent with acute HIV infection or reports unprotected sex with an HIV-positive person in the preceding month. • Determine if women are planning to become pregnant, are currently pregnant, or are breastfeeding. • Confirm that patient is at ongoing, very high risk for acquiring HIV infection. • If any sexual partner is known to be HIV-infected, determine whether receiving antiretroviral therapy; assist with linkage to care if not in care or not receiving antiretroviral therapy. • Confirm that calculated creatinine clearance is ≥60 mL per minute (Cockcroft-Gault formula).