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

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 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 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 2

3. Sources and acronyms Presentation includes summaries of recent changes in recommendations on ART (antiretroviral therapy) of two key advisory groups sponsored by: 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 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 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 CDC and NIAID (the part of NIH dealing with infectious diseases) are sources of further information 3

4. Evolution of guidelines on when to start treatment for HIV/AIDS 1996-2000 hit early, hit hard often advocated 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 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 4

5. 2012 ART guidelines introduced a radical change, not fully adopted 2012 guidelines expanded offering of treatment to anyone with HIV 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 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 Early and continuous treatment can reduce morbidity and mortality and also can be the key to controlling the U.S. HIV epidemic 5

6. 6

7. Treatment as prevention Meanwhile, research has proven that ART can reduce HIV transmission by up to 96% 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/WillNewMedicationsReduceInfec tiousnessofHIV-1997.pdf http://www.beyondaids.org/articles/1996MA~1.PDF http://www.beyondaids.org/articles/WillNewMedicationsReduceInfec tiousnessofHIV-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 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

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

9. Potential to expand treatment Study based on CDCs 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

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% 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 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 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 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

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 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 (R 0, 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 Actual rate reduction depends on achieving virological control before most transmission occurs Prevalence drop depends on life expectancy Prevalence drop depends on life expectancy 11

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: 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 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 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

13. Categories of evidence used in DHHS guidelines Ratings of recommendations Ratings of recommendations A = Strong B = Moderate C = Optional Ratings of evidence 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

14. 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) Recommended initial regimens should include 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs: tenofovir/emtricitabine or abacavir/lamivudine) Also include one of the following: 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: 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

15. 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. 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 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 Confirmed treatment failure should be addressed promptly and multiple factors considered Comment: Psychological and cultural factors need to be addressed, affect adherence Comment: Psychological and cultural factors need to be addressed, affect adherence 15

16. 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 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 Clinical benefit is unknown for Elite controllers (viral load undetectable without treatment) 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 500/μL and HIV-1 RNA <1000 copies/mL while not taking ART) –DHHS 2/13: Consider treatment if VL >200 16

17. DHHS Guidelines 1/10/11 http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf Benefits to patient of earlier treatment: 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 (risk ratio: 1.94, 95% CI: 1.37 to 2.79) NA-ACCORD study observed…adjusted mortality rates significantly higher among the 6,935 patients who deferred therapy until CD4 count fell to 500 (risk ratio: 1.94, 95% CI: 1.37 to 2.79) 17

18. Evolution of DHHS recommenda- tions on when to start In 1/10/11 guidelines, half of panel recommended treating everyone regardless of CD4 count 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: 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

19. When to start treatment, DHHS 3/27/12 guidelines http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf ART is recommended for all HIV-infected individuals. ART is recommended for all HIV-infected individuals. Strength of this recommendation varies with pretreatment CD4 cell count: Strength of this recommendation varies with pretreatment CD4 cell count: –CD4 count <350 cells/mm 3 (AI) –CD4 count 350 to 500 cells/mm 3 (AII) –CD4 count >500 cells/mm 3 (BIII) Regardless of CD4 count, initiation of ART strongly recommended for: 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

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) 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 Chronic hepatitis B virus (HBV) coinfection: AII –Both HBV and HIV respond to tenofovir combined with either lamivudine or emtricitabine Age older than 60 years: BII Age older than 60 years: BII During acute phase of primary HIV infection, regardless of symptoms: BIII 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) ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with most opportunistic infections (AI) 20

21. 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 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 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 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

22. Drug selection and initiation of treatment in special situations HIV-2 (not covered by this presentation) may not respond to same drugs 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) 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 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

23. 23 When to Start Treatment: Lack of International Consensus (courtesy of E. Daar, UCLA, 11/21/13) Clinical Category CD4 Count (cells/mm 3 ) DHHS 2013 IAS-USA 2012 EACS 2012 BHIV 2012 WHO 2013 AIDS/Severe SxAny valueRRRRR Asymptomatic350RRRRR 350 to 500RRCDR >500RRDDD Pregnant women Any valueRRRRR HIV-associated nephropathy Any valueRRRRR HIV/HBVAny valueRRRRR HIV-neg partnerAny valueRRCCR DHHS Mar 2013: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf;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;http://www.eacsociety.org/Portals/0/files/pdf%20files/EacsGuidelines-v6.1-2edition.pdf BHIV 2012: http://www.bhiva.org/TreatmentofHIV1_2012.aspx;http://www.bhiva.org/TreatmentofHIV1_2012.aspx WHO June 2013: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdfhttp://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf

24. Treating HIV/HCV coinfection in DHHS guidelines (3/27/12) Hepatitis C section includes bocepravir and telaprevir, add one as 3 rd drug (with interferon and ribavirin) for patients with genotype 1 hepatitis C Hepatitis C section includes bocepravir and telaprevir, add one as 3 rd 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 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 Note: Expect major changes as new oral drugs are approved, starting with simepravir 11/22/13, sofosbuvir pending

25. What else was added in 3/27/12 DHHS guidelines? New section on HIV and the older patient, including comorbidities and their treatment 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 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 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

26. Whats new in 2/12/13 and 10/30/13 DHHS Guidelines? 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 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 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 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 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 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 http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0

27. Whats new in 2/12/13 DHHS Guidelines, contd. Early HIV, or having a seronegative partner, are special indications for urgent initiation of ART 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) Genotypic tropism assay (cheaper) now available as alternate to favored but expensive phenotypic assay, before starting maraviroc (CCR5 antagonist) Genotype for INSTIs (integrase inhibitors) is recommended if failure of a regimen containing one Genotype for INSTIs (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 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

28. Whats new in 2/12/13 DHHS Guidelines, contd. Treatment should be discussed starting at first clinical contact Treatment should be discussed starting at first clinical contact If ARV treatment is started before receiving a genotype, use a PI-based regimen If ARV treatment is started before receiving a genotype, use a PI-based regimen More drug interactions listed, incl. with INSTIs More drug interactions listed, incl. with INSTIs Additional measures needed in labor and delivery Additional measures needed in labor and delivery –Intravenous ZDV if viral load 400 or greater 28

29. 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 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 NNRTIs (Non-nucleoside reverse transcriptase inhibitors): 5 available, 3 used PIs (protease inhibitors): 9 available, 4 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 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 Fusion or attachment inhibitors: 2 available, 1 used 29

30. How the 5 main classes of HIV antiretroviral drugs work 30 Source: http://i-base.info/guides/starting/hiv-lifecycle For more technical explanation see http://www.touchbriefings.com/pdf/3024/biswas.pdf

31. 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 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 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 Those available as generics (5 early NRTIs and one early NNRTI) have asterisks (*) after brand names below 31

32. NRTIs (nukes, block reverse transcriptase, an enzyme HIV needs to make DNA copies of its RNA for reproduction) Abbreviation Generic name Brand name Food restrictions and dosage Date of FDA approval 3TClamivudineEpivir* Take with or without food 1x300 mg tab qd 17-Nov-95 ABCabacavirZiagen* Take with or without food 2x300 mg tabs qd 17-Dec-98 AZT or ZDVzidovudineRetrovir* Take with or without food 1x300 mg tab bid 19-Mar-87 d4TstavudineZerit* Take with or without food 1x30-40 mg cap bid 24-Jun-94 ddIdidanosine Videx EC* Take on an empty stomach 30 mins before, or 2 hours after meal 1x250-400 mg cap qd 31-Oct-00 FTCemtricitabineEmtriva Take with or without food 1x200 mg cap qd 02-Jul-03 TDFtenofovirViread Take with or without food 1x300 mg tab qd 26-Oct-01 32

33. NNRTIs (non-nukes, bind to reverse transcriptase, an enzyme HIV needs to make DNA copies of its RNA in cell) Abbreviation Generic name Brand name Food restrictions and dosage Date of FDA approval DLVdelavirdineRescriptor Take with or without food 2x200 mg tabs tid 04-Apr-97 EFVefavirenz Sustiva (US) Take on an empty stomach 600 mg 1x 600 mg tab qd (pref. qhs) 17-Sep-98 Stocrin (Europe) ETR etravirine (IAS: occas. salvage use) Intelence Take following a meal 2x100 mg tabs bid 18-Jan-08 NVPnevirapineViramune* Take with or without food 1x200 mg tab qd x 14d then bid 21-Jun-96 RPVrilpivirineEdurant Take with food 1x 25 mg tab qd 20-May-11 33

34. PIs (block protease, an enzyme HIV needs to assemble new viral components into complete copies of itself) AbbreviationGeneric nameBrand name Food restrictions and dosage Date of FDA approval FPVfosamprenavir Lexiva (US) Take with or without food, 4x 700 mg tabs /r qd or 2 bid (or 1 bid /r PI Tx exp) 20-Oct-03 Telzir (Europe) ATVatazanavirReyataz Take with food 1x300 mg tab /r qd 20-Jun-03 DRVdarunavirPrezista Take with food 1x800 mg /r tab qd (new; or 2x400 mg /r or 1x600 mg /r bid Tx experienced) 23-Jun-06 IDVindinavirCrixivan Take on empty stomach w fluids 1 hour before, or 2 hours after, a meal, 2x400 mg caps q8h (or bid /r, non- FDA) 13-Mar-96 34

35. PIs, contd. AbbreviationGeneric nameBrand name Food restrictions and dosage Date of FDA approval LPV/RTV lopinavir + ritonavir (favored in pregnancy) Kaletra 9 Take with or without food 4x250/50 mg tabs qd, or 2 bid (Tx exp or preg.) Swallow whole 15-Sep-00 Aluvia (developing world) NFVnelfinavirViracept Take with food 2x625 mg tabs bid 14-Mar-97 RTV ritonavir (used only as booster) Norvir Take with food if possible /r means 100 mg, /rr means 200 mg 01-Mar-96 SQV saquinavir (occasionally used) Invirase (hard gel capsule) Take within two hours of food 2x500 mg caps bid/r 06-Dec-95 TPVtipranavirAptivus Take with or without food 2x250 mg caps bid /rr 22-Jun-05 35

36. Entry/fusion /attachment inhibitors (block entry of virus into cells) INSTIs (inhibit enzyme integrase, block integration of HIV copy into DNA) 36 Abbreviation Generic name Brand Name Food restrictions and dosage Date of FDA approval T-20enfuvirtideFuzeon Prepared from powder, injected into thigh, arm, abdomen 90 mg (1 ml) bid 13-Mar-03 MVCmaraviroc Celsentri (Europe) Take with or without food 1-4x150 mg tab bid 18-Sep-07 Selzentry (US) Abbreviation Generic name Brand Name Food restrictions and dosage Date of FDA approval RALraltegravirIsentress Take with or without food 1x400 mg tab bid 12-Oct-07 EVGelvitegravirComponent of Stribild (Stribild taken with food) 1 daily 27-Aug-12 only as component DTGdolutegravirTivicay Take with or without food 50 mg, 1 tab daily 12-Aug-13

37. Combination pills (not incl. LPV/RTV) Multi-class 1/day Combinations Brand name Food restrictions and dosage Date of FDA approval EFV + TDF + FTCAtripla Take on an empty stomach 1 qd 12-Jul-06 RPV + TDF + FTCCompleraTake with food 1 qd10-Aug-11 EVG + cobicistat + TDF + FTC StribildTake with food 1 qd27-Aug-12 37 NRTI Combinations Brand name Food restrictions and notes Date of FDA approval ABC + 3TC Epzicom (US) Take with or without food 1 qd 02-Aug-04 Kivexa (Europe) ABC + AZT + 3TC Trizivir (no longer recommended) Take with or without food 1 bid 14-Nov-00 AZT + 3TCCombivir Take with or without food 1 bid 27-Sep-97 TDF + FTC Truvada (also for PrEP) Take with or without food 1 qd 02-Aug-04

38. How do I keep all these straight? Common complaints by clinicians Too many –virs Too many –virs –Names of 12 drugs from 3 classes end with vir 3-digit acronyms dont help 3-digit acronyms dont help –Not always easy to associate generic names and acronyms with brand names Suggestions: 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

39. 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) 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 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 Warmline suggests can add FTC or 3TC even if mutations found 39

40. 40 NRTI-sparing options Courtesy of E. Daar, UCLA, 11/21/13 StrengthsWeaknesses LPV/r + EFV (A5142)Good efficacy High pill count Large study Poor tolerability Lipid elevation LPV/r monotherapySimplicity Tolerability Concerns regarding efficacy DRV/r monotherapySimplicity Tolerability Mixed results for efficacy LPV/r + 3TCDecrease toxicity Efficacy No data with preferred PI/r DRV/r + RALGood tolerabilityTwice daily Concerns regarding efficacy in naive Large study nearly complete ATV bid + RALNo boosterPoor tolerability Poor efficacy PI/r + MVC (R5 only pts)INSTI-sparingConcerns regarding efficacy Study recently stopped

41. The ART-ful Restaurant Some selections will be served together as one combo dish. This menu not available if fewer than 3 selections ordered. Chefs recommendations in orange. Select two items from list A (the NRTIs) 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 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: 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 This group will be garnished with a little ritonavir for enhancement –Integrase inhibitors: raltegravir, dolutegravir, elvitegravir Latter in combo only, the Stribild Special Latter in combo only, the Stribild Special –Entry inhibitor: maraviroc ( pre-ordered, requires special eligibility) 41

42. 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) 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) Patient should be committed to adherence to treatment before starting (DHHS 2/12/13) Cultural competence is important Cultural competence is important –Patient must be approached with sensitivity when recommending onset of therapy 42

43. What to start, per DHHS recommendations Preferred Regimens (Regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use) TDF/FTC backbone or EFV/TDF/FTC can be one pill (Truvada or Atripla) NNRTI-Based Regimen EFV/TDF/FTC (AI) EFV should not be used during first trimester of pregnancy or in women trying to conceive or not using effective contraception. 1 tablet once/day PI-Based Regimens (in alphabetical order) ATV/r + TDF/FTC (AI) DRV/r (once daily) + TDF/FTC (AI) /r means boosted with ritonavir. Both regimens require 3 pills once/day ATV/r should not be used in patients who require >20 mg omeprazole equivalent per day ATV/r associated with cholelithiasis Start with PI if no genotype first (2/12/13 DHHS recommendation) PI-Based Preferred Regimen for Pregnant Women LPV/r (twice daily) + ZDV/3TC (AI) Based on long experience of safety Kaletra 2 tabs and Combivir 1 tab, both taken twice/day in pregnancy 43

44. 44 What to start, per DHHS recommendations, contd. Preferred Regimens, contd. (Regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use) TDF/FTC backbone or EFV/TDF/FTC can be one pill (Truvada or Atripla) ABC/3TC backbone can also be one pill (Epzicom) INSTI-Based Regimens RAL + TDF/FTC (AI) DTG + TDF/FTC DTG + ABC/3TC EVG/COBI/TDF/FTC RAL is taken twice/day, Truvada once/day DTG and EVG were approved as preferred initial therapy components 10/30/13, both in once/day tablets EVG/COBI/TDF/FTC is available as a single pill containing entire regimen, once daily DTG + ABC/3TC is only preferred starting regimen containing abacavir, which is otherwise an alternative NRTI 44

45. What to start, per DHHS, contd. Alternative Regimens (Regimens that are effective and tolerable but have potential disadvantages compared with preferred regimens. An alternative regimen may be the preferred regimen for some patients.) NNRTI-Based Regimens (in alphabetical order) EFV + ABC/3TC (BI) RPV/TDF/FTC (BI) RPV + ABC/3TC (BIII) PI-Based Regimens (in alphabetical order) ATV/r + ABC/3TC (BI) DRV/r + ABC/3TC (BIII) FPV/r (once or twice daily) + ABC/3TC or TDF/FTC (BI) LPV/r (once or twice daily) + ABC/3TC or TDF/FTC (BI) 45

46. What to start, per DHHS, contd. Acceptable Regimens (CI) (Regimens that may be selected for some patients but are less satisfactory than preferred or alternative regimens) and Regimens that may be acceptable but more definitive data are needed (CIII) NNRTI-Based Regimen EFV + ZDV/3TC (CI) NVP + (TDF/FTC or ZDV/3TC) (CI) NVP + ABC/3TC (CIII) RPV + ZDV/3TC (CIII) Comments: NVP should not be used in patients with moderate to severe hepatic impairment, in women with pre-ART CD4 count >250 or men with pre-ART CD4 count >400. RPV virologic failure more common if baseline VL >100,000. Dont use with PPIs. Use NVP and ABC together with caution, both can cause HSRs within the first weeks after initiation of therapy. ZDV can cause bone marrow suppression, lipoatrophy, and rarely lactic acidosis with hepatic steatosis. Unboosted ATV may be used but only when RTV boosting is not possible. MVC requires prior tropism testing; patient must have only CCR5-tropic virus. (Added 1/10/11 by NIH) PI-Based Regimens ATV + (ABC or ZDV)/3TC (unboosted, CI) ATV/r + ZDV/3TC (CI) DRV/r + ZDV/3TC (CIII) FPV/r + ZDV/3TC (CI) LPV/r + ZDV/3TC (CIII) (non-pregnant) INSTI-Based Regimen RAL + ZDV/3TC (CIII) CCR5 Antagonist-Based Regimens MVC + ZDV/3TC (CI) MVC + TDF/FTC or ABC/3TC (CIII) 46

47. Preferred Regimens EFV/TDF/FTC ATV/r + TDF/FTC DRV/r (once daily) + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + TDF/FTC DTG + ABC/3TC [Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC] Alternative Regimens EFV + ABC/3TC RPV + (TDF or ABC)/(FTC or 3TC) ATV/r or DRV/r + ABC/3TC FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC RAL + ABC/3TC Acceptable Regimens EFV or RPV + ZDV/3TC NVP + TDF/FTC or ZDV/3TC or ABC/3TC ATV + (ABC or ZDV)/3TC ATV/r, DRV/r, LPV/r, FPV/r, RAL + ZDV/3TC MVC + ZDV or ABC/3TC SQV/r + TDF/FTC or ABC/3TC or ZDV/3TC (with caution) Summary of what to start per DHHS courtesy of E. Daar, UCLA, 11/21/13 October 30, 2013

48. Individualizing First-line Therapy: Specific Circumstances courtesy of E. Daar, UCLA, 11/21/13 CircumstanceAgents No genotype Use boosted PI High HIV-1 RNA Caution with ABC, RPV Renal disease Caution with TDF, ATV/RTV; monitoring complicated with COBI and DTG Dyslipidemia RAL, DTG, RPV most lipid neutral CV risk factors Possible association with ABC, ddI, LPV/RTV No data for DRV/RTV, INSTIs, MVC Pregnancy Preferred: ZDV/3TC + NVP, LPV/RTV, or ATV/RTV EFV can be used after first 5-6 wks Chronic HBV Preferred TDF + 3TC or FTC Alternative is entecavir Decreased BMD Caution with TDF CNS effects Caution with EFV for at least first month

49. Newest ARV drugs Rilpivirine: NNRTI with fewer CNS side effects than efavirenz 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 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

50. Newest ARV drugs, contd. Dolutegravir (DTG, 50 mg/day) 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 Walmsley et al., ICAAC 2012 50

51. Newest ARV drugs, contd. Stribild: combination of 4 drugs, sometimes referred to as quad Stribild: combination of 4 drugs, sometimes referred to as quad –Approved 8/27/12, after both NIH and IAS-USA guidelines issued –Recommended 10/30/13 by HHS as a preferred initial regimen for treatment-naïve patients Faster VL suppression than ATV/r regimen, slightly superior to EFV regimen with same NRTIs Faster VL suppression than ATV/r regimen, slightly superior to EFV regimen with same NRTIs –Formulated as tablet with 2 old drugs (FTC/TDF) and 2 new ones Elvitegravir (EVG), a new INSTI not used separately 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 Cobicistat, a new CYP3A booster without ART effect 51

52. Lab monitoring schedule (DHHS 1/10/11) Care entry f/u before ART ART start or change 2-8 wks after start or change Every 3-6 mos. Every 6-12 mos. (IAS: 6 mos) Treat- ment failure CD4 countYEvery 3-6 months YYStable w VL suppr. Y Viral load (VL) YEvery 3-6 months YYYY GenotypeYYY HLA- B*5701 If considering abacavir CCR5 tropism If considering maraviroc If maraviroc considered or is failing 52

53. Less frequent CD4 counts needed if VL undetectable (DHHS 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 patients clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents (CIII). 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 patients 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 IAS-USA goes along with this up to every 6 months, not 12 Comments: 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 53

54. Virologic definitions (DHHS 1/10/11) Virologic suppression: A confirmed HIV RNA level below the limit of assay detection 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) 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 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) 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 Change 2-3 drugs (never only 1) if failing regimen 54

55. Treatment-experienced patients, salvage regimens Give DRV, LPV, FPV bid; increase ritonavir dose with DRV, FPV for experienced patients Give DRV, LPV, FPV bid; increase ritonavir dose with DRV, FPV for experienced patients Consider third-line drugs not on the starter list Consider third-line drugs not on the starter list If cant find 3 drugs without resistance, use 4-5 If cant find 3 drugs without resistance, use 4-5 If expert consultation not locally available, or for rapid advice, nationally-funded services at UCSF: 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 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 55

56. HIV and Chronic Disease HIV care includes chronic disease prevention and management HIV care includes chronic disease prevention and management –Not emphasized in the presentation in proportion to importance in overall treatment Body is in a state of chronic inflammatory response Body is in a state of chronic inflammatory response –Increased rates of diabetes, hyperlipidemia, renal disease, and other chronic diseases –Many non-AIDS-defining conditions due to HIV infection HIV itself and some ART drugs can increase metabolic risks HIV itself and some ART drugs can increase metabolic risks –Lower HDL, raise triglycerides, or cause neuropathy, nephropathy, lipodystrophy Common co-morbidities including psychiatric, substance abuse, hepatitis C, etc. complicate therapy Common co-morbidities including psychiatric, substance abuse, hepatitis C, etc. complicate therapy 56

57. Prevention of opportunistic infections (OIs) Last updated by CDC 4/10/09 http://www.aidsinfo.nih.gov/contentfiles/Adult_OI.pdf http://www.aidsinfo.nih.gov/contentfiles/Adult_OI.pdf 57 Prophylaxis to prevent first episode of opportunistic disease DISEASE TO PREVENT PROPHYLAXIS INDICATION DRUGS OF FIRST CHOICE ALTERNATE REGIMENS Pneumocystis (now reclassi- fied as a fungus, Pneumocystis jirovecii) CD4 <200 (or oro-pharyngeal Candida) Trimethoprim- sulfamethoxazole (TMP-SMX), 1 DS PO daily (AI); or 1 SS daily (AI) TMP-SMX 1 DS PO tiw (BI); or Dapsone 100 mg PO daily or 50 mg PO bid (BI); or Dapsone 50 mg PO daily + pyrimethamine 50 mg PO weekly + leucovorin 25 mg PO weekly (BI); or Aerosolized pentamidine 300 mg via Respigard II nebulizer every month (BI); or Atovaquone 1,500 mg PO daily (BI); or Atovaquone 1,500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily (CIII)

58. Prophylaxis to prevent first episode of opportunistic disease, contd. DISEASE TO PREVENT PROPHYLAXIS INDICATION DRUGS OF FIRST CHOICE ALTERNATE REGIMENS ToxoplasmosisCD4 <100 Toxoplasma IgG positive (AII) TMP-SMX, 1 DS PO daily (AII) TMP-SMX 1 DS PO tiw (BIII); or TMP-SMX 1 SS PO daily (BIII); Dapsone 50 mg PO daily + pyrimethamine 50 mg PO weekly + leucovorin 25 mg PO weekly (BI); or (Dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) PO weekly (BI); (Atovaquone 1,500 mg +/- pyrimethamine 25 mg + leucovorin 10 mg) PO daily (CIII) TuberculosisPPD or Quantiferon positive Isoniazid (INH) 300 mg PO daily (AII) or 900 mg PO biw (BII) for 9 months – both plus pyridoxine 50 mg PO daily (BIII); or if exposed to drug- resistant TB, consultation with public health (AII) Rifampin (RIF) 600 mg PO daily x 4 months (BIII); or Rifabutin (RFB) (dose adjusted based on concomitant ART) x 4 months (BIII) Mycobacterium avium complex (MAC) CD4 <50Azithromycin 1,200 mg PO once weekly (AI); or Clarithromycin 500 mg PO bid (AI); or Azithromycin 600 mg PO twice weekly (BIII) Rifabutin (RFB) 300 mg PO daily (BI) (dosage adjustment based on drug-drug interactions with ART); rule out active TB before starting RFB 58

59. Pediatric DHHS 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 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 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 Some drugs approved only above certain ages Not all drugs have liquid or chewable versions Not all drugs have liquid or chewable versions Dosages based on weight Dosages based on weight 59

60. 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 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): 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). 60

61. PrEP (pre-exposure prophylaxis) contd. Follow-up while PrEP medication is being taken (CDC 8/12): Follow-up while PrEP medication is being taken (CDC 8/12): –Every 2–3 months, perform an HIV antibody test (or fourth generation antibody/antigen test) and document negative result. –At each follow-up visit for women, conduct a pregnancy test and document results; if pregnant, discuss continued use of PrEP with patient and prenatal-care provider. –Evaluate and support PrEP medication adherence at each follow-up visit, more often if inconsistent adherence is identified. –Every 2–3 months, assess risk behaviors and provide risk-reduction counseling and condoms. Assess STI symptoms and, if present, test and treat for STIs as needed. –Every 6 months, test for bacterial STIs even if asymptomatic, and treat as needed. –Three months after initiation, then every six months while on PrEP medication, check serum creatinine and calculate creatinine clearance. Comments: Comments: –HIV viral load before initiation would confirm patient not already infected. Truvada is not adequate therapy for infected persons, and if infection has already occurred, or occurs during treatment, this could lead to increased population resistance to a backbone drug –FDA and CDC did not clearly limit indications. Three logical ones exist, but first 2 were not included in studies, so unknown how much they add to effectiveness of prevention: Bridging gap till infected partners VL is reduced to very low levels Bridging gap till infected partners VL is reduced to very low levels PrEP for uninfected partner + ART for infected partner, when pregnancy intended PrEP for uninfected partner + ART for infected partner, when pregnancy intended In a marriage or committed relationship, if infected partner refuses to take ART In a marriage or committed relationship, if infected partner refuses to take ART 61

62. PrEP: Concerns of Beyond AIDS http://www.beyondaids.blogspot.com/2012_07_01_archive.html http://www.beyondaids.blogspot.com/2012_07_01_archive.html Toxicity and cost of treatment justified for persons who are actually infected, but more problematic for persons who might merely be exposed. Toxicity and cost of treatment justified for persons who are actually infected, but more problematic for persons who might merely be exposed. –Treatment of a defined population of already-infected persons should logically be much more cost-effective, and should have a higher risk-benefit ratio, than treating a larger, ill-defined population of persons, including many who will not even become exposed. PrEP may be substituted by some people for regular condom use in spite of counseling (motive for PrEP use) PrEP may be substituted by some people for regular condom use in spite of counseling (motive for PrEP use) Episodic use (effectiveness not studied) can lead to acquisition and potential drug resistance due to sub- optimal two-drug treatment Episodic use (effectiveness not studied) can lead to acquisition and potential drug resistance due to sub- optimal two-drug treatment 62

63. What about vaginal microbicides? The Microbicide Pipeline (sources: NIAID, Wikipedia): The Microbicide Pipeline (sources: NIAID, Wikipedia): –A number of active components, including proteins, small molecule inhibitors, and natural products that being developed as microbicide candidates –Surfactants/Detergents to inactivate virus unfortunately damage mucosa Nonoxynol-9, still on some condoms, should not be used) Nonoxynol-9, still on some condoms, should not be used) Most promising: Most promising: –tenofovir (TDF) 1% gel, 39% effective; CAPRISA 004 was 12th microbicide-efficacy study completed, and first to demonstrate a significant reduction in HIV transmission in humans But concern about development of drug resistance to a key backbone drug But concern about development of drug resistance to a key backbone drug –ViraGel, a nanoscale dendrimer to bind to virus and prevent entry into cells, 85% effective in preventing both HIV and HSV in macaque monkeys; human studies pending 63

64. 2003 U.S. and Royal Thai governments jointly initiated RV144, a Phase III trial to evaluate a novel HIV vaccine strategy commonly referred to as "prime-boost." Formation of Global HIV Vaccine Enterprise proposed in Science 2004VaxGen candidate failed in Phase III trials. 2009 Results of Phase III Thai Trial (RV144) show vaccine combination is first to demonstrate modest preventive effect (31%) in humans. Trial enrolled more than 16,000 volunteers. Over six months, volunteers received a prime-boost vaccination including six injections of a vaccine called ALVAC HIV (vCP1521) with the last two of the six injections being a combination of that vaccine and another one called AIDSVAX B/E (gp120). ALVAC HIV (vCP1521) consists of a viral vector (inert form of canarypox) containing genetically engineered versions of three HIV genes (env, gag and pro). AIDSVAX B/E is composed of genetically engineered gp120, a protein on the surface of HIV. 2010 Two potent antibodies that prevent most strains of HIV identified by the VRC (VRC01 and VRC02). Establishment of Pox-Protein Public-Private Partnership (P5) 64 History of HIV Vaccine Research: long, slow slog (NIAID Web site)

65. Summary Almost all HIV-infected patients should be offered ART, which can benefit them and also serve as the most effective strategy for preventing transmission and controlling the epidemic Almost all HIV-infected patients should be offered ART, which can benefit them and also serve as the most effective strategy for preventing transmission and controlling the epidemic Current treatment recommendations cover most aspects of effective care Current treatment recommendations cover most aspects of effective care –15 recommended and 2 new drug components, and 6 combination pills (5 recommended, 1 new) provide a wide range of options for once and twice daily dosing However, all recommended regimens rely on only 4 NRTI combinations, only 1 alt.; insufficient data on NRTI-free regimens However, all recommended regimens rely on only 4 NRTI combinations, only 1 alt.; insufficient data on NRTI-free regimens –No recent changes in antimicrobial prophylaxis –Pre-exposure prophylaxis: concerns, limited indications –Recent modest progress on vaginal microbicides, vaccines 65