Guidelines for Antiviral Guidelines for Antiviral Treatment of Adults and Treatment of Adults and Adolescents with HIV-1Adolescents with HIV-1(including 2011-2013 changes, and a little extra on (including 2011-2013 changes, and a little extra on what else is new and current)what else is new and current)

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

Loma Linda UniversityLoma Linda University– AAHIVM HIV SpecialistAAHIVM HIV Specialist– President, Beyond AIDSPresident, Beyond AIDS

• December 5, 2013December 5, 2013 On behalf of Beyond AIDS FoundationOn behalf of Beyond AIDS Foundation

11

ObjectivesObjectives

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

• 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 transmitting suppression to help prevent transmitting the virus to partners, and the the virus to partners, and the advantages of early onset of 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

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

2/12/13, hereafter referred to as 2/12/13, hereafter referred to as DHHS guidelinesDHHS guidelines

•CDC and NIAID (the part of NIH dealing with CDC and NIAID (the part of NIH dealing with infectious diseases) are sources of further infectious diseases) are sources of further informationinformation 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 introduced a radical change, introduced a radical change, not fully adoptednot fully adopted• 2012 guidelines expanded offering of 2012 guidelines expanded offering of

treatment to anyone with HIVtreatment to anyone with HIV

• This major change has been incompletely This major change has been incompletely adopted so far by providers or publicized to adopted so far by providers or publicized to patientspatients

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

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

– 66%66% are linked to care (lower if black, young) are linked to care (lower if black, young)– Only Only 33%33% have received ART (1/2 of those in care) have received ART (1/2 of those in care)– Only Only 25%25% have very low viral loads (VL, copies of virus 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: figures: 80%80% of infected tested, of infected tested, 62%62% in care, in care, 36%36% on ART, on ART, 28%28% virologically controlled 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 DHHS guidelinesin DHHS 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, 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.

1414

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

1515

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 HIV Treatment now recommended for all adults with HIV infection; strength of recommendation and quality infection; strength of recommendation and quality of evidence increase with decreasing CD4 cell count of evidence increase with decreasing CD4 cell count and presence of certain concurrent conditionsand presence of certain concurrent conditions

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

treatment)treatment)– DHHS 2/13: Treat if CD4 counts decrease, or symptomsDHHS 2/13: Treat if CD4 counts decrease, or symptoms

•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)

– DHHS 2/13: Consider treatment if VL >200DHHS 2/13: Consider treatment if VL >200

1616

DHHS Guidelines 1/10/11DHHS Guidelines 1/10/11http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadoleschttp://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdfentgl.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 DHHS Evolution of DHHS recommenda-tions on when recommenda-tions on when to startto start• 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, When to start treatment, DHHS 3/27/12 guidelinesDHHS 3/27/12 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 CD4 cell Hepatitis C virus (HCV) coinfection: CIII (however, if CD4 cell

count >500/μL may delay ART until after completion of HCV count >500/μL may delay ART until after completion of HCV treatment)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 of During acute phase of primary HIV infection, regardless of symptoms: BIIIsymptoms: BIII

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

2020

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

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

Drug selection and initiation Drug selection and initiation of treatment in special of treatment in special situationssituations• HIV-2 (not covered by this presentation) may not respond to HIV-2 (not covered by this presentation) may not respond to

same drugs same drugs – Resistant to NNRTIs; darunavir, lopinavir, and saquinavir are most Resistant to NNRTIs; darunavir, lopinavir, and saquinavir are most

effective PIseffective PIshttp://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/24/hiv-2-infectionhttp://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 Timing and choice of ART may be modified with cryptococcal disease and tuberculosis disease and tuberculosis (IAS-USA 7/25/12)(IAS-USA 7/25/12)

– For Cryptococcus, death rates lower when ART delayed till after 10 For Cryptococcus, death rates lower when ART delayed till after 10 weeks of antifungal treatmentweeks of antifungal treatment

– For TB, adverse events lower for patients with CD4 counts over 50, For TB, adverse events lower for patients with CD4 counts over 50, when ART delayed for 8-12 weeks after starting TB therapywhen 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 NIH 3/27/12 recommended delay of only 2 weeks if low BMI, anemia, or severe

disease, and for patients with CD4 counts <50disease, and for patients with CD4 counts <50

2222

2323

When to Start Treatment: Lack of When to Start Treatment: Lack of International Consensus International Consensus (courtesy of E. Daar, UCLA, 11/21/13)(courtesy of E. Daar, UCLA, 11/21/13)

Clinical Category

CD4 Count (cells/mm3)

DHHS 2013

IAS-USA 2012

EACS 2012

BHIV 2012

WHO 2013

AIDS/Severe Sx Any value R R R R R

Asymptomatic ≤350 R R R R R

350 to ≤500 R R C D R

>500 R R D D D

Pregnant women

Any value R R R R R

HIV-associated nephropathy

Any value R R R R R

HIV/HBV Any value R R R R R

HIV-neg partner

Any value R R C C R

DHHS Mar 2013: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf;IAS-USA: Thompson MA, et al. JAMA. 2012; 308: 387-402;EACS Nov 2012. http://www.eacsociety.org/Portals/0/files/pdf%20files/EacsGuidelines-v6.1-2edition.pdf;BHIV 2012: http://www.bhiva.org/TreatmentofHIV1_2012.aspx;WHO June 2013: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf

Treating HIV/HCV coinfection Treating HIV/HCV coinfection in DHHS guidelinesin DHHS 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

2424

Note: Expect major changes as new oral drugs are approved, starting with Note: Expect major changes as new oral drugs are approved, starting with simepravir 11/22/13, sofosbuvir pendingsimepravir 11/22/13, sofosbuvir pending

What else was added in What else was added in 3/27/12 DHHS guidelines? 3/27/12 DHHS 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 Non-AIDS morbidities; inflammation speeds chronic

diseasesdiseases

• 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 Wholesale cost of most approved regimens is still over

$2,000/mo (AIDS Drug Assistance Plan needed by many) $2,000/mo (AIDS Drug Assistance Plan needed by many)

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

risk of acquiring or transmitting HIVrisk of acquiring or transmitting HIV

2525

What’s new in 2/12/13 and What’s new in 2/12/13 and 10/30/13 DHHS Guidelines? 10/30/13 DHHS Guidelines?

• Stribild (Elvitegravir/cobicistat/tenofovir/emtricitabine Stribild (Elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COBI/TDF/FTC) as a fixed-dose combination (EVG/COBI/TDF/FTC) as a fixed-dose combination product) is recommended as an alternative regimen product) is recommended as an alternative regimen for ART-naive patients, then 10/30/13 as a preferred for ART-naive patients, then 10/30/13 as a preferred initial complete regimen for treatment-naïve patientsinitial complete regimen for treatment-naïve patients– Should have pre-treatment creatinine clearance >70 Should have pre-treatment creatinine clearance >70

mL/min (mL/min (BIBI). ).

• Dolutegravir (alternative INSTI to raltegravir) Dolutegravir (alternative INSTI to raltegravir) recommended 10/30/13 as a preferred initial drug for recommended 10/30/13 as a preferred initial drug for treatment-naïve patientstreatment-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

2626

http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdfhttp://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0

What’s new in 2/12/13 What’s new in 2/12/13 DHHS Guidelines, contd.DHHS Guidelines, contd.

• Early HIV, or having a seronegative partner, are Early HIV, or having a seronegative partner, are special indications for urgent initiation of ARTspecial indications for urgent initiation of ART

• Genotypic tropism assay (cheaper) now available as Genotypic tropism assay (cheaper) now available as alternate to favored but expensive phenotypic alternate to favored but expensive phenotypic assay, before starting maraviroc (CCR5 antagonist)assay, before starting maraviroc (CCR5 antagonist)

• Genotype for INSTI’s (integrase inhibitors) is Genotype for INSTI’s (integrase inhibitors) is recommended if failure of a regimen containing onerecommended if failure of a regimen containing one– Not part of standard genotype panelsNot part of standard genotype panels– Not a requirement before initial treatment Not a requirement before initial treatment

• Efavirenz does not need to be discontinued in Efavirenz does not need to be discontinued in pregnancy if it is maintaining undetectable VLpregnancy if it is maintaining undetectable VL– Avoid in females if pregnancy is planned or risk (no contraception)Avoid in females if pregnancy is planned or risk (no contraception)– By 5-6 wks., 2-3x estimated risk of neural tube defects is overBy 5-6 wks., 2-3x estimated risk of neural tube defects is over

2727

What’s new in 2/12/13 What’s new in 2/12/13 DHHS Guidelines, contd.DHHS Guidelines, contd.

• Treatment should be discussed starting at first Treatment should be discussed starting at first clinical contactclinical contact

• If ARV treatment is started before receiving a If ARV treatment is started before receiving a genotype, use a PI-based regimengenotype, use a PI-based regimen

• More drug interactions listed, incl. with INSTIsMore drug interactions listed, incl. with INSTIs

• Additional measures needed in labor and Additional measures needed in labor and deliverydelivery– Intravenous ZDV if viral load 400 or greaterIntravenous ZDV if viral load 400 or greater

2828

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): 3 available and 3 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

2929

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

3030

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 27 drugs on market, only 18 are in recommended and Of 27 drugs on market, only 18 are in recommended and 11 are in first-line regimens11 are in first-line regimens– 2 of these are used only to increase blood levels of PIs, or of an 2 of these are used only to increase blood levels of PIs, or of an

INSTI, by inhibiting CYP3A (ritonavir, cobicistat)INSTI, by inhibiting CYP3A (ritonavir, cobicistat)– 2 only available in a combination product (Stribild)2 only available in a combination product (Stribild)– Combination pills provide convenience, reduce pill burden Combination pills provide 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

3131

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

3232

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

3333

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)

Abbreviation

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 3434

PIs, contd. PIs, contd. 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

3535

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)

3636

Abbreviation

Generic name

Brand Name Food restrictions and dosage

Date of FDA approval

T-20 enfuvirtide

Fuzeon

Prepared from powder, injected into thigh, arm, 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) 1 daily

27-Aug-12 only as component

DTG dolutegravir

Tivicay Take with or without food 50 mg, 1 tab daily

12-Aug-13

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

Multi-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

3737

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 Trizivir (no longer recommended)

Take 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

3838

The “nuke” dependence The “nuke” dependence problemproblem• All recommended regimens include choice of only 4 All recommended regimens include choice of only 4

NRTIs combos: lamivudine (3TC) or emtricitabine NRTIs combos: lamivudine (3TC) or emtricitabine (FTC), combined with either tenofovir (TDF) or (FTC), combined with either tenofovir (TDF) or abacavir (ABC)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.; ABC precautions: Pre-screen with HLA-B*5701, must be neg.;

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

• No guidelines are provided (due to lack of data) No guidelines are provided (due to lack of data) when neither TDF or ABC can be usedwhen neither TDF or ABC can be used– No “Nuke-free” regimens are discussed in DHHS guidelinesNo “Nuke-free” regimens are discussed in DHHS guidelines– See table on next slide for recent studies of such regimensSee table on next slide for recent studies of such regimens

• ““Warmline” suggests can add FTC or 3TC even if mutations foundWarmline” suggests can add FTC or 3TC even if mutations found

3939

•

4040

NRTI-sparing optionsNRTI-sparing optionsCourtesy of E. Daar, UCLA, 11/21/13Courtesy of E. Daar, UCLA, 11/21/13

Strengths Weaknesses

LPV/r + EFV (A5142) Good efficacyHigh pill countLarge study

Poor tolerabilityLipid elevation

LPV/r monotherapy SimplicityTolerability

Concerns regarding efficacy

DRV/r monotherapy SimplicityTolerability

Mixed results for efficacy

LPV/r + 3TC Decrease toxicityEfficacy

No data with preferred PI/r

DRV/r + RAL Good tolerability Twice dailyConcerns regarding efficacy in naiveLarge study nearly complete

ATV bid + RAL No booster Poor tolerabilityPoor efficacy

PI/r + MVC (R5 only pts)

INSTI-sparing Concerns regarding efficacyStudy recently stopped

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: tenofovir, abacavirtenofovir, abacavir, zidovudine (“AZT”), 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: efavirenz, rilpivirine efavirenz, rilpivirine (latter if baseline VL<100,000)(latter if baseline VL<100,000)– 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: raltegravir, dolutegravir, elvitegravirraltegravir, dolutegravir, elvitegravir• Latter in combo only, the Stribild SpecialLatter in combo only, the Stribild Special

– Entry inhibitor: maraviroc (Entry inhibitor: maraviroc (pre-ordered, requires special eligibility) pre-ordered, requires special eligibility)

4141

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

• Patient should be committed to adherence to Patient should be committed to adherence to treatment before starting treatment before starting (DHHS 2/12/13)(DHHS 2/12/13)

• 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

4242

What to start, per DHHS What to start, per DHHS recommendationsrecommendations

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 dayATV/r associated with cholelithiasisStart 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 safetyKaletra 2 tabs and Combivir 1 tab, both taken twice/day in pregnancy

4343

4444

What to start, per DHHS What to start, per DHHS recommendations, contd.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/dayDTG and EVG were approved as preferred initial therapy components 10/30/13, both in once/day tabletsEVG/COBI/TDF/FTC is available as a single pill containing entire regimen, once dailyDTG + ABC/3TC is only preferred starting regimen containing abacavir, which is otherwise an alternative NRTI

4444

What to start, per DHHS, What to start, per DHHS, contd. 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)

4545

What to start, per DHHS, What to start, per DHHS, 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)

4646

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]

AlternativeRegimens

• 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

AcceptableRegimens

• 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 Summary of what to start per DHHS courtesy of E. Daar, UCLA, 11/21/13courtesy of E. Daar, UCLA, 11/21/13

October 30, 2013

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

Circumstance Agents

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

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)– Not recommended due to virological failures if Not recommended due to virological failures if

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

4949

Newest ARV drugs, contd.Newest ARV drugs, contd.• Dolutegravir (DTG, 50 mg/day)Dolutegravir (DTG, 50 mg/day)

– Approved by FDA 8/12/13, brand name TivicayApproved by FDA 8/12/13, brand name Tivicay– Recommended by HHS 10/30/13 in preferred initial therapy Recommended by HHS 10/30/13 in preferred initial therapy

for treatment-naïve patientsfor treatment-naïve patients– IAS-USA: An INSTI with good activity against RAL and EVG-IAS-USA: An INSTI with good activity against RAL and EVG-

resistant strainsresistant strains– Does not require boosting; one dosage (50 mg/d)Does not require boosting; one dosage (50 mg/d)– 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

5050

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– Recommended 10/30/13 by HHS as a preferred initial regimen Recommended 10/30/13 by HHS as a preferred initial regimen

for treatment-naïve patientsfor treatment-naïve patients•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

– 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 PI Requires boosting, but low-dose RTV without another PI was considered a risk for PI resistanceresistance

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

5151

Lab monitoring schedule Lab monitoring schedule (DHHS (DHHS 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

5252

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

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

5353

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

5454

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

5555

HIV and Chronic DiseaseHIV and Chronic Disease• HIV care includes chronic disease prevention and HIV care includes chronic disease prevention and

managementmanagement– Not emphasized in the presentation in proportion to Not emphasized in the presentation in proportion to

importance in overall treatmentimportance in overall treatment

• Body is in a state of chronic inflammatory responseBody is in a state of chronic inflammatory response– Increased rates of diabetes, hyperlipidemia, renal disease, Increased rates of diabetes, hyperlipidemia, renal disease,

and other chronic diseasesand other chronic diseases– Many non-AIDS-defining conditions due to HIV infectionMany non-AIDS-defining conditions due to HIV infection

• HIV itself HIV itself andand some ART drugs can increase metabolic some ART drugs can increase metabolic risksrisks– Lower HDL, raise triglycerides, or cause neuropathy, Lower HDL, raise triglycerides, or cause neuropathy,

nephropathy, lipodystrophynephropathy, lipodystrophy

• Common co-morbidities including psychiatric, Common co-morbidities including psychiatric, substance abuse, hepatitis C, etc. complicate therapysubstance abuse, hepatitis C, etc. complicate therapy

5656

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

5757

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

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Pediatric DHHS guidelines Pediatric DHHS 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

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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). 6060

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 ART6161

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 may be substituted by some people for regular condom use PrEP may 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 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

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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)

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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

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