What’s New in 2011 and What’s New in 2011 and 2012 Guidelines for 2012 Guidelines for Antiviral Treatment of Antiviral Treatment of Adults and Adolescents Adults and Adolescents with HIVwith HIV(and a little extra on what else is new and current)(and a little extra on what else is new and current)

• Ronald P. Hattis, MD, MPHRonald P. Hattis, MD, MPH– Associate Clinical Prof. of Preventive Associate Clinical Prof. of Preventive

Medicine, Loma Linda UniversityMedicine, Loma Linda University– HIV/AIDS Provider, Desert AIDS ProjectHIV/AIDS Provider, Desert AIDS Project– President, Beyond AIDSPresident, Beyond AIDS

• November 17, 2012 (rev. 2/13)November 17, 2012 (rev. 2/13)11

ObjectivesObjectives

• The participant will be able to apply The participant will be able to apply 2012 treatment guidelines for HIV in the 2012 treatment guidelines for HIV in the care of HIV/AIDS, and will be aware of care of HIV/AIDS, and will be aware of other recent developments in HIV careother recent developments in HIV care

• The participant will be able to explain to The participant will be able to explain to patients the importance of viral load patients the importance of viral load suppression to help prevent suppression to help prevent transmitting the virus to partners, and transmitting the virus to partners, and the advantages of early onset of the advantages of early onset of antiretroviral treatmentantiretroviral treatment

22

Sources and acronymsSources and acronyms• Presentation includes summaries of recent Presentation includes summaries of recent

changes in recommendations on changes in recommendations on ART ART (antiretroviral therapy) (antiretroviral therapy) of two key advisory of two key advisory groups sponsored by:groups sponsored by:– IAS-USA: International Antiviral Society – USA IAS-USA: International Antiviral Society – USA

divisiondivision•Published in JAMA 7/25/12, hereafter referred to as Published in JAMA 7/25/12, hereafter referred to as

IAS or IAS or IAS-USA guidelines IAS-USA guidelines

– NIH/HHS: U.S. Dept. Health and Human NIH/HHS: U.S. Dept. Health and Human Services, which includes National Institutes of Services, which includes National Institutes of HealthHealth•Published on NIH Website 1/10/11 and 3/27/12, Published on NIH Website 1/10/11 and 3/27/12,

hereafter referred to as hereafter referred to as NIH guidelinesNIH guidelines

•NIAID, the part of NIH dealing with infectious NIAID, the part of NIH dealing with infectious diseases, is a source of further informationdiseases, is a source of further information

33

Evolution of guidelines on Evolution of guidelines on when to start treatment for when to start treatment for HIV/AIDSHIV/AIDS• 1996-2000 “hit early, hit hard” often advocated1996-2000 “hit early, hit hard” often advocated

• 2001-2012 treatment guidelines advised delaying 2001-2012 treatment guidelines advised delaying antiretroviral therapy (ART) until CD4antiretroviral therapy (ART) until CD4** cell counts cell counts <200, then <350, more recently <500/ml<200, then <350, more recently <500/ml– Delayed due to concerns about toxicity, resistanceDelayed due to concerns about toxicity, resistance– Cell count drop usually took 5-10 years to occurCell count drop usually took 5-10 years to occur– Most of HIV transmission occurred before treatmentMost of HIV transmission occurred before treatment

* CD4 cell = type of white blood cell critical to immune system, and * CD4 cell = type of white blood cell critical to immune system, and preferentially attacked by HIVpreferentially attacked by HIV

44

2012 ART guidelines 2012 ART guidelines introduce a radical change, introduce a radical change, not widely knownnot widely known• 2012 guidelines expand offering of 2012 guidelines expand offering of

treatment to anyone with HIVtreatment to anyone with HIV

• This major change has been poorly This major change has been poorly publicized so far to providers and publicized so far to providers and patientspatients

• Early and continuous treatment can Early and continuous treatment can reduce morbidity and mortality and also reduce morbidity and mortality and also can be the key to controlling the U.S. HIV can be the key to controlling the U.S. HIV epidemicepidemic

55

66

““Treatment as prevention”Treatment as prevention”• Meanwhile, research has proven that ART Meanwhile, research has proven that ART

can reduce HIV transmission by up to 96%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 HPTN 052 clinical trial showed reduction of transmission to sexual partners of 96% in transmission to sexual partners of 96% in combination with prevention counselingcombination with prevention counseling– Cohen, M. S.; McCauley, M.; Sugarman, J. (2012), Cohen, M. S.; McCauley, M.; Sugarman, J. (2012),

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200068/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200068/

77

““Treatment as Prevention”: Treatment as Prevention”: 2011 “Science Breakthrough of 2011 “Science Breakthrough of the Year” the Year”

(also featured at (also featured at International International AIDS Conference,AIDS Conference,7/12, Washington,7/12, Washington,DC)DC)

88

Potential to expand Potential to expand treatmenttreatment

Study based on CDC’s National HIV Study based on CDC’s National HIV Surveillance system Surveillance system (Hall, I 7/27/12 using 2009 data) (Hall, I 7/27/12 using 2009 data)

– 83% of est. 1.15 million infected persons in U.S. have 83% of est. 1.15 million infected persons in U.S. have been testedbeen tested

– 66% are linked to care (lower if black, young)66% are linked to care (lower if black, young)– Only 33% have received ART (1/2 of those in care)Only 33% have received ART (1/2 of those in care)– Only 25% have very low viral loads (VL, copies of virus Only 25% have very low viral loads (VL, copies of virus

per ml) (3/4 of those receiving ART)per ml) (3/4 of those receiving ART)– Separate study by CDC in 2011 came up with similar Separate study by CDC in 2011 came up with similar

figures: 80% of infected tested, 62% in care, 36% on ART, figures: 80% of infected tested, 62% in care, 36% on ART, 28% virologically controlled28% virologically controlled

– http://blog.aids.gov/2012/07/hivaids-treatment-cascade-helps-identify-gaps-in-care-http://blog.aids.gov/2012/07/hivaids-treatment-cascade-helps-identify-gaps-in-care-retention.htmlretention.html

99

Potential to control Potential to control epidemic: additional epidemic: additional opportunities opportunities (assuming about 5% uncooperative) (assuming about 5% uncooperative) • Percentage of infected persons tested diagnosis could Percentage of infected persons tested diagnosis could be increased about 15%, from 83% to 95%be increased about 15%, from 83% to 95%

• 95% of the 95% knowing diagnosis could be linked to 95% of the 95% knowing diagnosis could be linked to care, increasing care by 36%, from 66% to 90% of totalcare, increasing care by 36%, from 66% to 90% of total

• 95% of the 90% in care could get ART, increasing 95% of the 90% in care could get ART, increasing treatment 58%, from 33% to 85% of totaltreatment 58%, from 33% to 85% of total

• If virological control rate could be increased from 75% If virological control rate could be increased from 75% to 80% of those treated, patients who are almost non-to 80% of those treated, patients who are almost non-infectious could be increased by 2.76 times, from infectious could be increased by 2.76 times, from current 25% to 69% of totalcurrent 25% to 69% of total

1010

Potential to control Potential to control epidemic: additional epidemic: additional opportunities, contd.opportunities, contd.• 44% more of currently infected persons (69%-25%) 44% more of currently infected persons (69%-25%) would be only 4% as likely to transmit HIV, once VL would be only 4% as likely to transmit HIV, once VL controlledcontrolled– A theoretical potential of A theoretical potential of 42% decrease 42% decrease in infectious in infectious

persons, with similar incidence drop, just to start withpersons, with similar incidence drop, just to start with– As fewer new infected people gradually replace greater As fewer new infected people gradually replace greater

numbers now alive (Rnumbers now alive (R00, viral reproductive rate <1) , , viral reproductive rate <1) , incidence rate of HIV infections will exponentially incidence rate of HIV infections will exponentially drop to lower and lower levelsdrop to lower and lower levels•Actual rate reduction depends on achieving virological Actual rate reduction depends on achieving virological

control before most transmission occurscontrol before most transmission occurs

•Prevalence drop depends on life expectancyPrevalence drop depends on life expectancy

1111

Potential to control Potential to control epidemic: additional epidemic: additional opportunities, contd.opportunities, contd.• However: just applying new guidelines, to offer However: just applying new guidelines, to offer

ART treatment to all already in care, even ART treatment to all already in care, even without increasing testing, linkage to care, or without increasing testing, linkage to care, or % of patients with low VL, could achieve:% of patients with low VL, could achieve:• Using low estimate of 62% in care, and only 90% Using low estimate of 62% in care, and only 90%

acceptance, could treat another 23% of all infected acceptance, could treat another 23% of all infected persons, and control viral load in ¾ of thempersons, and control viral load in ¾ of them

• This would mean 17% more of total infected persons This would mean 17% more of total infected persons would become non-infectious (a 2/3 increase from would become non-infectious (a 2/3 increase from current number) and incidence rates would drop current number) and incidence rates would drop accordinglyaccordingly

1212

Categories of evidence used Categories of evidence used in NIH guidelinesin NIH guidelines• Ratings of recommendationsRatings of recommendations

A = A = StrongStrong

B = B = ModerateModerate

C = C = OptionalOptional

• Ratings of evidenceRatings of evidenceI = I = data from randomized controlled trialsdata from randomized controlled trials

II = data from well-designed nonrandomized trials II = data from well-designed nonrandomized trials or observational cohort studies with long-term or observational cohort studies with long-term clinical outcomesclinical outcomes

III = expert opinionIII = expert opinion

1313

Concise summary of Concise summary of Changes, from IAS-USA Changes, from IAS-USA Guidelines Guidelines 7/25/12 7/25/12 IAS, published in JAMA (Journal of the American Medical Association) IAS, published in JAMA (Journal of the American Medical Association) http://jama.jamanetwork.com/article.aspx?articleid=1221704 http://jama.jamanetwork.com/article.aspx?articleid=1221704 • Treatment now recommended for all adults with Treatment now recommended for all adults with HIV infection; strength of recommendation and HIV infection; strength of recommendation and quality of evidence increase with decreasing CD4 quality of evidence increase with decreasing CD4 cell count and presence of certain concurrent cell count and presence of certain concurrent conditionsconditions

• Clinical benefit is unknown for Clinical benefit is unknown for •Elite controllers (viral load undetectable without Elite controllers (viral load undetectable without

treatment)treatment)– ((CommentComment: Unless CD4 counts begin to steadily decrease): Unless CD4 counts begin to steadily decrease)

•Long-term nonprogressors (stable CD4 cell counts Long-term nonprogressors (stable CD4 cell counts >500/μL and HIV-1 RNA <1000 copies/mL while not >500/μL and HIV-1 RNA <1000 copies/mL while not taking ART)taking ART) 1414

Concise summary of Concise summary of Changes, from IAS-USA Changes, from IAS-USA Guidelines, contd.Guidelines, contd.• Recommended initial regimens should include 2 nucleos(t)ide Recommended initial regimens should include 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs: tenofovir/emtricitabine or reverse transcriptase inhibitors (NRTIs: tenofovir/emtricitabine or abacavir/lamivudine) abacavir/lamivudine)

• Also include one of the following:Also include one of the following:– a nonnucleoside reverse transcriptase inhibitor (NNRTI: efavirenz)a nonnucleoside reverse transcriptase inhibitor (NNRTI: efavirenz)– a ritonavir-boosted protease inhibitor (PI: atazanavir or darunavir), or a ritonavir-boosted protease inhibitor (PI: atazanavir or darunavir), or – an integrase strand transfer inhibitor (INSTI: raltegravir)an integrase strand transfer inhibitor (INSTI: raltegravir)

• Alternatives: Alternatives: – For the NRTI: zidovudine (with lamivudine) (esp. in pregnancy)For the NRTI: zidovudine (with lamivudine) (esp. in pregnancy)– For the NNRTI: nevirapine or rilpivirineFor the NNRTI: nevirapine or rilpivirine– For the PI: ritonavir-boosted lopinavir, fosamprenavir, or saquinavirFor the PI: ritonavir-boosted lopinavir, fosamprenavir, or saquinavir– For the INSTI: cobicistat-boosted elvitegravirFor the INSTI: cobicistat-boosted elvitegravir– Rarely, a CCR5 attachment inhibitor: maraviroc.Rarely, a CCR5 attachment inhibitor: maraviroc.

1515

Concise summary of Concise summary of Changes, from IAS-USA Changes, from IAS-USA Guidelines, contd.Guidelines, contd.• ““CD4 cell count and HIV-1 RNA level should be CD4 cell count and HIV-1 RNA level should be

monitored, as should engagement in care, ART monitored, as should engagement in care, ART adherence, HIV drug resistance, and quality-of-care adherence, HIV drug resistance, and quality-of-care indicators.” indicators.”

• Reasons for regimen switching include virologic, Reasons for regimen switching include virologic, immunologic, or clinical failure and drug toxicity or immunologic, or clinical failure and drug toxicity or intoleranceintolerance

• Confirmed treatment failure should be addressed Confirmed treatment failure should be addressed promptly and multiple factors consideredpromptly and multiple factors considered

• CommentComment: Psychological and cultural factors need to : Psychological and cultural factors need to be addressed, affect adherencebe addressed, affect adherence

1616

NIH/HHS Guidelines NIH/HHS Guidelines 1/10/111/10/11http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescenhttp://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdftgl.pdf• Benefits to patient of earlier treatment:Benefits to patient of earlier treatment:– Increasing evidence demonstrates benefits of viral Increasing evidence demonstrates benefits of viral

suppression and immunologic responses on reducing suppression and immunologic responses on reducing mortality and non-AIDS-related complications in mortality and non-AIDS-related complications in patients with higher pretreatment CD4 counts. patients with higher pretreatment CD4 counts. •NA-ACCORD study observed…adjusted mortality rates NA-ACCORD study observed…adjusted mortality rates

significantly higher among the 6,935 patients who deferred significantly higher among the 6,935 patients who deferred therapy until CD4 count fell to <500 compared with rates therapy until CD4 count fell to <500 compared with rates in the 2,200 patients who started therapy while CD4 count in the 2,200 patients who started therapy while CD4 count was > 500 (risk ratio: 1.94, 95% CI: 1.37 to 2.79) was > 500 (risk ratio: 1.94, 95% CI: 1.37 to 2.79)

1717

Evolution of NIH Evolution of NIH recommendations on when to recommendations on when to startstart• In 1/10/11 guidelines, half of panel In 1/10/11 guidelines, half of panel

recommended treating everyone regardless recommended treating everyone regardless of CD4 countof CD4 count

• In 3/27/12 guidelines, entire panel In 3/27/12 guidelines, entire panel recommended treatment at any CD4 count recommended treatment at any CD4 count based on emerging evidence:based on emerging evidence:– Harmful impact of ongoing HIV replication on Harmful impact of ongoing HIV replication on

AIDS and non-AIDS disease progression AIDS and non-AIDS disease progression – Benefit of effective ART in preventing secondary Benefit of effective ART in preventing secondary

transmission of HIVtransmission of HIV

1818

When to start treatment, NIH When to start treatment, NIH 3/27/12 guidelines3/27/12 guidelineshttp://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.phttp://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfdf

• ART is recommended for all HIV-infected individuals. ART is recommended for all HIV-infected individuals.

• Strength of this recommendation varies with Strength of this recommendation varies with pretreatment CD4 cell count:pretreatment CD4 cell count:– CD4 count <350 cells/mmCD4 count <350 cells/mm33 (AI) (AI)– CD4 count 350 to 500 cells/mmCD4 count 350 to 500 cells/mm33 (AII) (AII)– CD4 count >500 cells/mmCD4 count >500 cells/mm33 (BIII) (BIII)

• Regardless of CD4 count, initiation of ART strongly Regardless of CD4 count, initiation of ART strongly recommended for:recommended for:– Pregnancy (AI)Pregnancy (AI)– History of an AIDS-defining illness (AI)History of an AIDS-defining illness (AI)– HIV-associated nephropathy (HIVAN) (AII)HIV-associated nephropathy (HIVAN) (AII)

1919

Additional priority Additional priority indications for treatment indications for treatment (IAS-USA 7/25/12)(IAS-USA 7/25/12)• Hepatitis C virus (HCV) coinfection: CIII (however, if Hepatitis C virus (HCV) coinfection: CIII (however, if

CD4 cell count >500/μL may delay ART until after CD4 cell count >500/μL may delay ART until after completion of HCV treatment)completion of HCV treatment)

• Chronic hepatitis B virus (HBV) coinfection: AIIChronic hepatitis B virus (HBV) coinfection: AII– Both HBV and HIV respond to tenofovir Both HBV and HIV respond to tenofovir combinedcombined with either with either

lamivudine or emtricitabinelamivudine or emtricitabine

• Age older than 60 years: BIIAge older than 60 years: BII

• During acute phase of primary HIV infection, regardless During acute phase of primary HIV infection, regardless of symptoms: BIIIof symptoms: BIII

• ART should be started as soon as possible, preferably ART should be started as soon as possible, preferably within the first 2 weeks of diagnosis, in patients with within the first 2 weeks of diagnosis, in patients with most opportunistic infections (AI)most opportunistic infections (AI)

2020

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

partners (AI [heterosexuals] or AIII [other partners (AI [heterosexuals] or AIII [other transmission risk groups])transmission risk groups])

• Patients starting ART should be willing and able to Patients starting ART should be willing and able to commit to treatment and should understand the commit to treatment and should understand the benefits and risks of therapy and the importance of benefits and risks of therapy and the importance of adherence (AIII)adherence (AIII)

• Patients may choose to postpone therapy, and Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or defer therapy on the basis of clinical and/or psychosocial factorspsychosocial factors– However, ART should be offered and discussed with all However, ART should be offered and discussed with all

patientspatients2121

Timing of initiation of Timing of initiation of treatment in special treatment in special situations situations (IAS-USA 7/25/12)(IAS-USA 7/25/12)• Timing and choice of ART may be modified Timing and choice of ART may be modified

with cryptococcal disease and tuberculosis.with cryptococcal disease and tuberculosis.– For Cryptococcus, death rates were lower when For Cryptococcus, death rates were lower when

ART delayed till after 10 weeks of antifungal ART delayed till after 10 weeks of antifungal treatmenttreatment

– For TB, adverse events were lower for patients For TB, adverse events were lower for patients with CD4 counts over 50, when ART delayed for with CD4 counts over 50, when ART delayed for 8-12 weeks after starting TB therapy8-12 weeks after starting TB therapy• NIH 3/27/12 recommended delay of only 2 weeks if low NIH 3/27/12 recommended delay of only 2 weeks if low

BMI, anemia, or severe disease, and for patients with BMI, anemia, or severe disease, and for patients with CD4 counts <50CD4 counts <50

2222

Treating HIV/HCV coinfection Treating HIV/HCV coinfection in NIH guidelinesin NIH guidelines (3/27/12)(3/27/12)

• Hepatitis C section includes bocepravir and telaprevir, add Hepatitis C section includes bocepravir and telaprevir, add one as 3one as 3rdrd drug (with interferon and ribavirin) for patients drug (with interferon and ribavirin) for patients with genotype 1 hepatitis Cwith genotype 1 hepatitis C– Both can be used with raltegravirBoth can be used with raltegravir– Telaprevir but not bocepravir can be used with ATV/rTelaprevir but not bocepravir can be used with ATV/r– Telaprevir at increased dose can be used with EFVTelaprevir at increased dose can be used with EFV– Avoid Avoid DRV/rDRV/r, LPV/r, EFV with bocepravir, LPV/r, EFV with bocepravir– Avoid Avoid DRV/rDRV/r, FPV/r, or LPV/r with telaprevir, FPV/r, or LPV/r with telaprevir

• Interferon and ribavirin may be coadministered with ART but Interferon and ribavirin may be coadministered with ART but drug interactions, hepatotoxicity additivedrug interactions, hepatotoxicity additive– This is rationale for delay in initiating ART if VL >500 and plan This is rationale for delay in initiating ART if VL >500 and plan

immediate hepatitis C treatment, till it is completedimmediate hepatitis C treatment, till it is completed

2323

What else is new in 3/27/12 What else is new in 3/27/12 NIH guidelines? NIH guidelines?

• New section on HIV and the older patient, including New section on HIV and the older patient, including comorbidities and their treatmentcomorbidities and their treatment– Non-AIDS morbidities; inflammation speeds chronic diseasesNon-AIDS morbidities; inflammation speeds chronic diseases– ((CommentComment: HIV itself : HIV itself andand some ART drugs can lower HDL, raise some ART drugs can lower HDL, raise

triglycerides, or cause neuropathy, nephropathy, lipodystrophy; some triglycerides, or cause neuropathy, nephropathy, lipodystrophy; some ARV drugs increase metabolic risks) ARV drugs increase metabolic risks)

• Wholesale cost table includedWholesale cost table included– Wholesale cost of most approved regimens is still over $2,000/mo Wholesale cost of most approved regimens is still over $2,000/mo

(AIDS Drug Assistance Plan needed by many) (AIDS Drug Assistance Plan needed by many)

• Section on women has expanded discussion of interactions of Section on women has expanded discussion of interactions of hormonal contraceptives with ARVshormonal contraceptives with ARVs– Injectable Depo-Provera associated in 1 study with double risk of Injectable Depo-Provera associated in 1 study with double risk of

acquiring or transmitting HIVacquiring or transmitting HIV

2424

ARV drug classes and how ARV drug classes and how they are combined they are combined (adapted from (adapted from

multiple sources)multiple sources)• NRTIs (Nucleoside or nucleotide reverse transcriptase NRTIs (Nucleoside or nucleotide reverse transcriptase inhibitors): inhibitors): 2 used together as “backbone” of standard regimens; 7 2 used together as “backbone” of standard regimens; 7 available, 5 used available, 5 used – These are typically These are typically combined with one additional drug from any of combined with one additional drug from any of

following classes:following classes:

• NNRTIs (Non-nucleoside reverse transcriptase inhibitors): NNRTIs (Non-nucleoside reverse transcriptase inhibitors): 5 5 available, 3 usedavailable, 3 used

• PIs (protease inhibitors): PIs (protease inhibitors): 9 available, 4 used9 available, 4 used– Typically need to be “boosted” by a small dose of ritonavir, a fifth member of Typically need to be “boosted” by a small dose of ritonavir, a fifth member of

same drug classsame drug class

• INSTIs (Integrase strand transfer inhibitors): INSTIs (Integrase strand transfer inhibitors): 2 available and 2 available and used, one only in a combination and needs “booster”used, one only in a combination and needs “booster”

• Fusion or attachment inhibitors: Fusion or attachment inhibitors: 2 available, 1 used2 available, 1 used

2525

How the 5 main classes of How the 5 main classes of HIV antiretroviral drugs workHIV antiretroviral drugs work

2626

Source: http://i-base.info/guides/starting/hiv-lifecycle

For more technical explanation see http://www.touchbriefings.com/pdf/3024/biswas.pdf

Review of currently available Review of currently available antiretroviral drugs antiretroviral drugs (following tables adapted (following tables adapted

with edits from with edits from http://aidsinfo.nih.gov/contentfiles/ApprovedMedstoTreatHIV_FS_en.pdf)http://aidsinfo.nih.gov/contentfiles/ApprovedMedstoTreatHIV_FS_en.pdf)

• Of 25 drugs on market, 15 are in recommended Of 25 drugs on market, 15 are in recommended regimens, and only 8 are in first-line regimensregimens, and only 8 are in first-line regimens– 1 of these, and 1 new agent, are used only to increase blood 1 of these, and 1 new agent, are used only to increase blood

levels of PIs or an INSTI by inhibiting CYP3Alevels of PIs or an INSTI by inhibiting CYP3A– Combination pills (5 recommended, 1 new) provide Combination pills (5 recommended, 1 new) provide

convenience, reduce pill burden convenience, reduce pill burden

• Drugs still currently recommended as primary, Drugs still currently recommended as primary, alternative, or booster drugs alternative, or booster drugs highlighted in bold highlighted in bold belowbelow

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

2727

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

Abbreviation

Generic name

Brand name

Food restrictions and dosage

Date of FDA approval

3TC lamivudine Epivir*Take with or without food 1x300 mg tab qd

17-Nov-95

ABC abacavir Ziagen* Take with or without food 2x300 mg tabs qd

17-Dec-98

AZT or ZDV

zidovudine Retrovir*

Take with or without food 1x300 mg tab bid

19-Mar-87

d4T stavudine Zerit* Take with or without food 1x30-40 mg cap bid

24-Jun-94

ddI didanosine Videx EC*

Take on an empty stomach 30 mins before, or 2 hours after meal 1x250-400 mg cap qd

31-Oct-00

FTC emtricitabine

Emtriva Take with or without food 1x200 mg cap qd

02-Jul-03

TDF tenofovir Viread Take with or without food 1x300 mg tab qd

26-Oct-01

2828

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

Abbreviation

Generic name

Brand name

Food restrictions and dosage

Date of FDA approval

DLV delavirdine

Rescriptor Take with or without food2x200 mg tabs tid

04-Apr-97

EFV efavirenz

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 meal2x100 mg tabs bid

18-Jan-08

NVP nevirapine

Viramune*

Take with or without food 1x200 mg tab qd x 14d then bid

21-Jun-96

RPV rilpivirine Edurant Take with food1x 25 mg tab qd

20-May-11

2929

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

n Generic name

Brand name Food restrictions and dosage

Date of FDA approval

FPV fosamprenavir

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)

ATV atazanavir Reyataz Take with food 1x300 mg tab /r qd

20-Jun-03

DRV darunavir Prezista

Take with food1x800 mg /r tab qd (new; or 2x400 mg /r or 1x600 mg /r bid Tx experienced)

23-Jun-06

IDV indinavir Crixivan

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

3030

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

Abbreviation

Generic name

Brand name Food restrictions and dosage

Date of FDA approval

LPV/RTV

lopinavir + ritonavir (favored in pregnancy)

Kaletra9 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)

NFV nelfinavir Viracept

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 food2x500 mg caps bid/r

06-Dec-95

TPV tipranavir Aptivus Take with or without food2x250 mg caps bid /rr

22-Jun-05

3131

Entry/fusion /attachment inhibitors Entry/fusion /attachment inhibitors (block entry of virus into cells)(block entry of virus into cells)

INSTIs INSTIs (inhibit enzyme integrase, block integration of HIV copy (inhibit enzyme integrase, block integration of HIV copy into DNA)into DNA)

3232

Abbreviation

Generic name

Brand Name Food restrictions and dosage

Date of FDA approval

T-20 Enfuvirtide

Fuzeon

Prepared from powder, injected into thigh, arm or abdomen90 mg (1 ml) bid

13-Mar-03

MVC maraviroc

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

RAL raltegravir

Isentress Take with or without food 1x400 mg tab bid

12-Oct-07

EVG Elvitegravir

Component of Stribild

(Stribild taken with food)

27-Aug-12 as component only

Combination pillsCombination pillsMulti-class 1/day Combinations

Brand name Food restrictions and dosage

Date of FDA approval

EFV + TDF + FTC

Atripla Take on an empty stomach 1 qd

12-Jul-06

RPV + TDF + FTC

CompleraTake with food 1 qd

10-Aug-11

EVG + cobicistat + TDF + FTC

StribildTake with food 1 qd

27-Aug-12

3333

NRTI Combinations

Brand name Food restrictions and notes

Date of FDA approval

ABC + 3TC Epzicom (US) Take with or

without food 1 qd02-Aug-04

Kivexa (Europe)

ABC + AZT + 3TC TrizivirTake with or without food 1 bid

14-Nov-00

AZT + 3TC Combivir 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

How do I keep all these How do I keep all these straight? straight? Common complaints by Common complaints by cliniciansclinicians• Too many “–virs”Too many “–virs”

– Names of 12 drugs from 3 classes end with “vir”Names of 12 drugs from 3 classes end with “vir”

• 3-digit acronyms don’t help3-digit acronyms don’t help– Not always easy to associate generic names and acronyms Not always easy to associate generic names and acronyms

with brand nameswith brand names

• Suggestions:Suggestions:– Take advantage of lists from pharmaceutical companies, Take advantage of lists from pharmaceutical companies,

some with pictures, dosages, etc.some with pictures, dosages, etc.– Become familiar with 4 (of 7) two/three-drug combination Become familiar with 4 (of 7) two/three-drug combination

pills, plus 4 more: darunavir, atazanavir, raltegravir; and pills, plus 4 more: darunavir, atazanavir, raltegravir; and ritonavir as boosterritonavir as booster

3434

What to start, commentary on What to start, commentary on NIH recommendations NIH recommendations (no changes in (no changes in

either 2011 or 2012)either 2011 or 2012)• All recommended regimens include choice of only 4 All recommended regimens include choice of only 4

NRTIs combos: lamivudine (3TC) or emtricitabine (FTC), NRTIs combos: lamivudine (3TC) or emtricitabine (FTC), combined with either tenofovir (TDF) or abacavir (ABC)combined with either tenofovir (TDF) or abacavir (ABC)– TDF precautions: nephrotoxic, avoid or give alternate days if TDF precautions: nephrotoxic, avoid or give alternate days if

CrCl<50, twice weekly if CrCl 20-29; increased bone lossCrCl<50, twice weekly if CrCl 20-29; increased bone loss– ABC precautions: Pre-screen with HLA-B*5701, must be neg.; M.I. ABC precautions: Pre-screen with HLA-B*5701, must be neg.; M.I.

risk in one study, more virological failure if baseline VL >100,000risk in one study, more virological failure if baseline VL >100,000

• No guidelines are provided (due to lack of data) when No guidelines are provided (due to lack of data) when neither TDF or ABC can be usedneither TDF or ABC can be used– No “Nuke-free” regimens are discussedNo “Nuke-free” regimens are discussed– RAL + DAR/r is a 2-drug regimen (plus ritonavir) that has had RAL + DAR/r is a 2-drug regimen (plus ritonavir) that has had

good initial results but increased virological failuresgood initial results but increased virological failures• ““Warmline” (11/7/12) recommends it, but advises adding 3TC or FTC Warmline” (11/7/12) recommends it, but advises adding 3TC or FTC

if possibleif possible

• 3TC or FTC may add beneficial results even if mutations present3TC or FTC may add beneficial results even if mutations present

3535

The ART-ful RestaurantThe ART-ful RestaurantSome selections will be served together as one combo dish. Some selections will be served together as one combo dish.

This menu not available if fewer than 3 selections ordered. This menu not available if fewer than 3 selections ordered. Chef’s recommendations in Chef’s recommendations in orange.orange.• Select Select twotwo items from list A (the NRTIs) items from list A (the NRTIs)

– One from these 2: One from these 2: emtracitabineemtracitabine, or , or lamivudinelamivudine– One from these 3: One from these 3: tenofovirtenofovir, abacavir, zidovudine (“AZT”), abacavir, zidovudine (“AZT”)

• Warning: must have been tested for allergy to abacavir; AZT recommended only for Warning: must have been tested for allergy to abacavir; AZT recommended only for experienced palates, not for the faint of heartexperienced palates, not for the faint of heart

• Add Add oneone item from any of the following groups: item from any of the following groups:– NNRTIs: NNRTIs: efavirenzefavirenz, rilpivirine, rilpivirine– Protease inhibitors: Protease inhibitors: atazanavir, darunavir,atazanavir, darunavir, fosamprenavir, lopinavir (a fosamprenavir, lopinavir (a

perennial favorite for expecting ladies)perennial favorite for expecting ladies)• This group will be garnished with a little This group will be garnished with a little ritonavirritonavir for enhancement for enhancement

– Integrase inhibitors: Integrase inhibitors: raltegravirraltegravir, elvitegravir (combos only), elvitegravir (combos only)– Entry inhibitor: maravirocEntry inhibitor: maraviroc

• Must be pre-ordered, requires special eligibility Must be pre-ordered, requires special eligibility

3636

What to start, commentary What to start, commentary on individual and cultural on individual and cultural factorsfactors• ““Selection of a regimen should be Selection of a regimen should be

individualized on the basis of virologic individualized on the basis of virologic efficacy, toxicity, pill burden, dosing efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction frequency, drug-drug interaction potential, resistance testing results, and potential, resistance testing results, and comorbid conditions” comorbid conditions” (NIH 3/27/12)(NIH 3/27/12)

• Cultural competence is importantCultural competence is important– Patient must be approached with sensitivity Patient must be approached with sensitivity

when recommending onset of therapywhen recommending onset of therapy

3737

What to start, per NIH What to start, per NIH recommendations recommendations (no changes in either 2011 (no changes in either 2011

or 2012)or 2012)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/dayATV/r should not be used in patients who require >20 mg omeprazole equivalent per day.

INSTI-Based Regimen • RAL + TDF/FTC (AI)

RAL is taken twice/day, Truvada once/day

Preferred Regimen for Pregnant Women • LPV/r (twice daily) + ZDV/3TC (AI)

Based on long experience of safetyKaletra 2 tabs and Combivir 1 tab, both taken twice/day in pregnancy

3838

What to start, per NIH, contd. What to start, per NIH, 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/3TCa (BI)• DRV/r + ABC/3TCa (BIII)• FPV/r (once or twice daily) + ABC/3TCa or TDF/FTCa (BI)• LPV/r (once or twice daily) + ABC/3TCa or TDF/FTCa (BI)

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)

3939

What to start, per NIH, What to start, per NIH, contd.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. Don’t 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)

4040

Newest ARV drugsNewest ARV drugs• Rilpivirine: NNRTI with fewer CNS side Rilpivirine: NNRTI with fewer CNS side

effects than efavirenzeffects than efavirenz– Approved separately as Edurant 5/20/11Approved separately as Edurant 5/20/11– Approved as component of Complera 8/10/11Approved as component of Complera 8/10/11

•Formulated in once-daily tablet with FTC/TDFFormulated in once-daily tablet with FTC/TDF

– Should not be used with proton pump inhibitorsShould not be used with proton pump inhibitors– Pregnancy category B (vs. D for efavirenz)Pregnancy category B (vs. D for efavirenz)– Taken with food (vs. without for efavirenz)Taken with food (vs. without for efavirenz)– More virological failures if baseline VL More virological failures if baseline VL

>100,000 (similar to abacavir)>100,000 (similar to abacavir)

4141

Newest ARV drugs, contd.Newest ARV drugs, contd.• Stribild: combination of 4 drugs, sometimes referred to as Stribild: combination of 4 drugs, sometimes referred to as

“quad”“quad”– Approved 8/27/12, after both NIH and IAS-USA guidelines issuedApproved 8/27/12, after both NIH and IAS-USA guidelines issued– Formulated as tablet with 2 old drugs (FTC/TDF) and 2 new onesFormulated as tablet with 2 old drugs (FTC/TDF) and 2 new ones

•Elvitegravir (EVG), a new INSTI not used separatelyElvitegravir (EVG), a new INSTI not used separately– Requires boosting, but low-dose RTV without another PI was considered a risk for Requires boosting, but low-dose RTV without another PI was considered a risk for

PI resistancePI resistance

•Cobicistat, a new CYP3A booster without ART effectCobicistat, a new CYP3A booster without ART effect

– Would probably be classified as “alternate” or possibly as Would probably be classified as “alternate” or possibly as “acceptable” regimen“acceptable” regimen•Faster VL suppression than ATV/r regimen, slightly superior to EFV Faster VL suppression than ATV/r regimen, slightly superior to EFV

regimen with same NRTIsregimen with same NRTIs

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Lab monitoring schedule Lab monitoring schedule (NIH (NIH 1/10/11)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 count

Y Every 3-6 months

Y Y Stablew VL suppr.

Y

Viral load (VL)

Y Every 3-6 months

Y Y Y Y

Genotype

Y Y Y

HLA-B*5701

If considering abacavir

CCR5 tropism

If considering maraviroc

If maraviroc considered or is failing

4343

Less frequent CD4 counts Less frequent CD4 counts needed if VL undetectable needed if VL undetectable (NIH (NIH

1/10/11) 1/10/11) • ““Poor CD4 response is rarely an indication for modifying a Poor CD4 response is rarely an indication for modifying a virologically suppressive ARV regimen…for the patient on a virologically suppressive ARV regimen…for the patient on a suppressive regimen whose CD4 cell count has increased well above suppressive regimen whose CD4 cell count has increased well above the threshold for opportunistic infection risk, the CD4 count can be the threshold for opportunistic infection risk, the CD4 count can be measured less frequently than the viral load…every 6 to 12 months, 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 unless there are changes in the patient’s clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents (CIII).”interferon, corticosteroids, or anti-neoplastic agents (CIII).”

• IAS-USA goes along with this up to every 6 months, not 12IAS-USA goes along with this up to every 6 months, not 12

• CommentsComments: : – Aim for VL and CD4 every 3 months; if CD4 high and stable and VL Aim for VL and CD4 every 3 months; if CD4 high and stable and VL

undetectable, do CD4 every 2 visitsundetectable, do CD4 every 2 visits– Steadily decreasing CD4 count may be indication for modifying regimenSteadily decreasing CD4 count may be indication for modifying regimen

4444

Virologic definitionsVirologic definitions (NIH 1/10/11) (NIH 1/10/11)

• Virologic suppression: A confirmed HIV RNA level below the Virologic suppression: A confirmed HIV RNA level below the limit of assay detectionlimit of assay detection

• Virologic failure: The inability to achieve or maintain HIV RNA Virologic failure: The inability to achieve or maintain HIV RNA level <200 copies/mL)level <200 copies/mL)

• Incomplete virologic response: Two consecutive plasma HIV Incomplete virologic response: Two consecutive plasma HIV RNA levels >200 copies/mL after 24 weeks on ARV regimen RNA levels >200 copies/mL after 24 weeks on ARV regimen – Baseline HIV RNA and regimen may affect timing of response Baseline HIV RNA and regimen may affect timing of response – Determine whether failure is do to adherence 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 doDilemma if 200-1000, lab may not be able to do

• Change 2-3 drugs (never only 1) if failing regimenChange 2-3 drugs (never only 1) if failing regimen

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Treatment-experienced Treatment-experienced patients, salvage regimenspatients, salvage regimens

• Give DRV, LPV, FPV bid; increase ritonavir dose with Give DRV, LPV, FPV bid; increase ritonavir dose with DRV, FPV for experienced patientsDRV, FPV for experienced patients

• Consider third-line drugs not on the “starter” list Consider third-line drugs not on the “starter” list

• If can’t find 3 drugs without resistance, use 4-5If can’t find 3 drugs without resistance, use 4-5

• If expert consultation not locally available, or for If expert consultation not locally available, or for rapid advice, nationally-funded services at UCSF:rapid advice, nationally-funded services at UCSF:– ““Warmline” (HIV management) Warmline” (HIV management) (800) 933-3413(800) 933-3413

•Only number really needed, others go to same staffOnly number really needed, others go to same staff

– ““PEPline (occup. exposures) (888) 448-4911PEPline (occup. exposures) (888) 448-4911– Perinatal hotline (prevention of transmission to Perinatal hotline (prevention of transmission to

newborn) (888) 448-8765newborn) (888) 448-8765

4646

Prevention of opportunistic Prevention of opportunistic infections (OIs) infections (OIs) Last updated by CDC Last updated by CDC 4/10/094/10/09• http://www.aidsinfo.nih.gov/contentfiles/Adult_OI.pdfhttp://www.aidsinfo.nih.gov/contentfiles/Adult_OI.pdf

4747

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)

Prophylaxis to prevent first episode of opportunistic disease, contd.

DISEASE TO PREVENT

PROPHYLAXIS INDICATION

DRUGS OF FIRST CHOICE

ALTERNATE REGIMENS

Toxoplasmosis

CD4 <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)

Tuberculosis PPD 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 <50 Azithromycin 1,200 mg PO once weekly (AI); or Clarithromycin 500 mg PO bid (AI); orAzithromycin 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

4848

Pediatric NIH guidelines Pediatric NIH guidelines (11/1/12)(11/1/12)http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdfpdf• Recommend treatment of all infants <12 months old Recommend treatment of all infants <12 months old

and for all children with symptoms and for all children with symptoms

• Generally recommend treatment of children Generally recommend treatment of children >>1 yr 1 yr without symptoms, with strength of recommendation without symptoms, with strength of recommendation based on CD4 countsbased on CD4 counts– <<1000 for ages 1-3 (AII)1000 for ages 1-3 (AII)– <<750 for ages 3-5 (AII)750 for ages 3-5 (AII)– <<500 for age 5 and older (AI)500 for age 5 and older (AI)

• Some drugs approved only above certain agesSome drugs approved only above certain ages

• Not all drugs have liquid or chewable versionsNot all drugs have liquid or chewable versions

• Dosages based on weightDosages based on weight

4949

PrEP (Pre-exposure PrEP (Pre-exposure prophylaxis) prophylaxis) http://www.cdc.gov/hiv/prep/pdf/PrEPfactsheet.pdfhttp://www.cdc.gov/hiv/prep/pdf/PrEPfactsheet.pdf• 7/16/12: FDA approved Truvada for PrEP, based on 2 studies 7/16/12: FDA approved Truvada for PrEP, based on 2 studies

a year earlier, showing “strong evidence that PrEP is a year earlier, showing “strong evidence that PrEP is effective and safe among heterosexually-active men and effective and safe among heterosexually-active men and women”women”– TDF2 study: once-daily tenofovir plus emtricitabine reduced risk of acquiring TDF2 study: once-daily tenofovir plus emtricitabine reduced risk of acquiring

HIV infection by roughly 62 percent of heterosexually-active men and women. HIV infection by roughly 62 percent of heterosexually-active men and women. – Partners PrEP study: daily tenofovir plus emtricitabine reduced HIV Partners PrEP study: daily tenofovir plus emtricitabine reduced HIV

transmission among heterosexual serodiscordant couples by 75%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. Document negative HIV antibody test immediately before starting PrEP medication. – Test for acute HIV infection if patient has symptoms consistent with acute HIV infection 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. 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 Determine if women are planning to become pregnant, are currently pregnant, or are

breastfeeding. breastfeeding. – Confirm that patient is at ongoing, very high risk for acquiring HIV infection. 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 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; assist with linkage to care if not in care or not receiving antiretroviral therapy. antiretroviral therapy.

– Confirm that calculated creatinine clearance is ≥60 mL per minute (Cockcroft-Gault Confirm that calculated creatinine clearance is ≥60 mL per minute (Cockcroft-Gault formula).formula). 5050

PrEP PrEP (pre-exposure prophylaxis) contd.(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 Every 2–3 months, perform an HIV antibody test (or fourth generation antibody/antigen test) and document negative result. test) and document negative result.

– At each follow-up visit for women, conduct a pregnancy test and document results; if 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. 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 Evaluate and support PrEP medication adherence at each follow-up visit, more often if inconsistent adherence is identified.inconsistent adherence is identified.

– Every 2–3 months, assess risk behaviors and provide risk-reduction counseling and 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. 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. 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 Three months after initiation, then every six months while on PrEP medication, check

serum creatinine and calculate creatinine clearance. serum creatinine and calculate creatinine clearance.

• CommentsComments::– HIV viral load before initiation would confirm patient not already infected. Truvada is 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 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 occurs during treatment, this could lead to increased population resistance to a “backbone” drug“backbone” drug

– FDA and CDC did not clearly limit indications. Three logical ones exist, but first 2 were 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:not included in studies, so unknown how much they add to effectiveness of prevention:

• Bridging gap till infected partner’s VL is reduced to very low levelsBridging gap till infected partner’s VL is reduced to very low levels

• PrEP for uninfected partner + ART for infected partner, when pregnancy intendedPrEP for uninfected partner + ART for infected partner, when pregnancy intended

• In a marriage or committed relationship, if infected partner refuses to take ARTIn a marriage or committed relationship, if infected partner refuses to take ART5151

PrEP: Concerns of Beyond PrEP: Concerns of Beyond AIDSAIDShttp://www.beyondaids.blogspot.com/2012_07_01_archive.html

• Toxicity and cost of treatment justified for persons who are Toxicity and cost of treatment justified for persons who are actually infected, but more problematic for persons who might actually infected, but more problematic for persons who might merely be exposed. merely be exposed. – Treatment of a defined population of already-infected persons Treatment of a defined population of already-infected persons

should logically be much more cost-effective, and should have a should logically be much more cost-effective, and should have a higher risk-benefit ratio, than treating a larger, ill-defined population higher risk-benefit ratio, than treating a larger, ill-defined population of persons, including many who will not even become exposed.of persons, including many who will not even become exposed.

• PrEP will be substituted by some people for regular condom use PrEP will be substituted by some people for regular condom use in spite of counseling (motive for PrEP use)in spite of counseling (motive for PrEP use)

• Episodic use (effectiveness not studied) can lead to acquisition Episodic use (effectiveness not studied) can lead to acquisition and potential drug resistance due to sub-optimal two-drug and potential drug resistance due to sub-optimal two-drug treatmenttreatment

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What is in the pipeline?What is in the pipeline?• Dolutegravir (DTG, 50 mg/day)Dolutegravir (DTG, 50 mg/day)

– IAS-USA: An INSTI with good activity against RAL and IAS-USA: An INSTI with good activity against RAL and EVG-resistant strainsEVG-resistant strains

– Does not require boostingDoes not require boosting– Faster and superior VL suppression when combined with Faster and superior VL suppression when combined with

ABC + 3TC, compared with Atripla (EFV + FTC + TDF) in ABC + 3TC, compared with Atripla (EFV + FTC + TDF) in one trial, with similar toxicity, less CNS side effects and one trial, with similar toxicity, less CNS side effects and rashrash•Walmsley et al., ICAAC 2012Walmsley et al., ICAAC 2012

– Expanded access for patients who need an INSTI and Expanded access for patients who need an INSTI and have documented resistance to RAL and EVG have documented resistance to RAL and EVG ((www.dolutegravir-eap.com/www.dolutegravir-eap.com/))

5353

What about vaginal What about vaginal microbicides?microbicides?

• The Microbicide PipelineThe Microbicide Pipeline (sources: NIAID, (sources: NIAID, Wikipedia):Wikipedia):– A number of active components, including proteins, small A number of active components, including proteins, small

molecule inhibitors, and natural products that being developed as molecule inhibitors, and natural products that being developed as microbicide candidatesmicrobicide candidates

– Surfactants/Detergents to inactivate virus Surfactants/Detergents to inactivate virus unfortunately damage unfortunately damage mucosamucosa • Nonoxynol-9, still on some condoms, should not be usedNonoxynol-9, still on some condoms, should not be used))

• Most promising: Most promising: – tenofovir (TDF) 1% gel, 39% effective; CAPRISA 004 was 12th tenofovir (TDF) 1% gel, 39% effective; CAPRISA 004 was 12th

microbicide-efficacy study completed, and first to demonstrate a microbicide-efficacy study completed, and first to demonstrate a significant reduction in HIV transmission in humanssignificant reduction in HIV transmission in humans• But concern about development of drug resistance to a key But concern about development of drug resistance to a key

“backbone” drug“backbone” drug

– ViraGel, a nanoscale dendrimer to bind to virus and prevent entry ViraGel, a nanoscale dendrimer to bind to virus and prevent entry into cells, 85% effective in preventing both HIV and HSV in into cells, 85% effective in preventing both HIV and HSV in macaque monkeys; human studies pendingmacaque monkeys; human studies pending

5454

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

2004 VaxGen 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)

5555

History of HIV Vaccine Research: long, slow slog (NIAID Web site)

SummarySummary• Almost all HIV-infected patients should be offered ART, which Almost all HIV-infected patients should be offered ART, which

can benefit them and also serve as the most effective strategy can benefit them and also serve as the most effective strategy for preventing transmission and controlling the epidemicfor preventing transmission and controlling the epidemic

• Current treatment recommendations cover most aspects of Current treatment recommendations cover most aspects of effective careeffective care– 15 recommended and 2 new drug components, and 6 combination 15 recommended and 2 new drug components, and 6 combination

pills (5 recommended, 1 new) provide a wide range of options for pills (5 recommended, 1 new) provide a wide range of options for once and twice daily dosingonce and twice daily dosing• However, all recommended regimens rely on only 4 NRTI combinations, only 1 However, all recommended regimens rely on only 4 NRTI combinations, only 1

alt.; insufficient data on NRTI-free regimensalt.; insufficient data on NRTI-free regimens

– No recent changes in antimicrobial prophylaxisNo recent changes in antimicrobial prophylaxis– Pre-exposure prophylaxis: concerns, limited indicationsPre-exposure prophylaxis: concerns, limited indications– Recent modest progress on vaginal microbicides, vaccinesRecent modest progress on vaginal microbicides, vaccines

5656