HIV Medication Overview
John J. Faragon, PharmD, BCPS, AAHIV-P
Albany Medical Center Hospital
NY/NJ AIDS Education and Training Center
When to Start
DHHS: Changing Criteria for
Initiating ART
CD4+
Count,
cells/mm3
> 500
350-500
200-350
< 200 or
symptomatic
disease
1998
2001
2006
Offer if
Consider if
VL
VL
> 55,000
≥ 100,000
Consider if Consider if
Offer if
VL
VL
VL > 20,000
> 55,000
≥ 100,000
Offer, but
Offer after
Offer if
controversy discussion
VL > 20,000
exists
with patient
Offer if
VL > 20,000
Treat
Treat
Treat
2008
2009
Consider in
certain
Consider
groups
Consider in
certain
Treat
groups
2012-2014
Treat
Treat
Treat
Treat
Treat
Treat
Treat
Treat
Current Guidelines for Initiating
ART – Other Guidelines
Guideline
Symptomatic/
AIDS
CD4+ Count
< 200
CD4+ Count
200-350
CD4+ Count
350-500
CD4+ Count >
500
DHHS (5/2014)
Yes
Yes
Yes
Yes
Yes
IAS-USA (7/2012)
Yes
Yes
Yes
Yes
Yes
British HIV
Association
(9/2012)
Yes
Yes
Yes
Defer*
Defer*
European AIDS
Clinical Society
(11/2012)
Yes
Yes
Yes
Consider
Defer
WHO (7/2010)
Yes
Yes
Yes
No†
Not addressed
*If a patient with CD4+ count > 350 cells/mm³ wishes to start ART to reduce the risk of transmission to partners,
that wish should be respected and ART started.
†With the exception of an HIV-positive partner in a serodiscordant relationship, who should be offered
antiretroviral therapy at CD4+ count > 350 cells/mm³ to prevent transmission to the uninfected partner.
Potential Benefits of Early
Therapy: Supporting Data (2)
 CD4 count >500 cells/µL
 Cohort study data are not consistent; some show
survival benefit if ART initiated early
 Other considerations (eg, potential benefit of
ART on non-AIDS complications, HIV
transmission risk) support recommendation for
ART
 Data not entirely conclusive, especially for
patients with very high CD4 counts…
www.aidsetc.org
Why treat at CD4 >500 cells/mm3?
 Untreated HIV infection and ongoing
viremia associated with development of
non-AIDS defining diseases such as





Cardiovascular Disease
Renal disease
Liver disease
Neurologic complications
Malignancy
www.aidsetc.org
Community Viral Load Mirrors Reduced
Rate of New HIV Cases in San Francisco
Retrospective analysis of relationship between community viral load (CVL; mean
of summed individual HIV-1 RNA results per yr) and new HIV diagnoses
30,000
P = .005 for
association*
Mean CVL
Newly diagnosed and
reported HIV cases
25,000
20,000
15,000
1000
800
798
600
642
523
10,000
518
434
5000
0
1200
400
200
2004
2005
2006
2007
2008
Yr
*Data insufficient to prove significant association with reduced HIV incidence.
Das-Douglas M, et al. CROI 2010. Abstract 33. Reproduced with permission.
0
Number of Newly
Diagnosed HIV Cases
Mean Community Viral Load
(copies/mL)

START Study
 INSIGHT Network: multinational
 Study population: adults with CD4 >500
 Study treatment:
 Immediate ART
 CD4 <350
 Study endpoints:
 Serious AIDS-defining illness, non-AIDS illness, death
 Sample size:
 N=900 (pilot for feasibility; enrollment completed)
 N=3100 (definitive)
 Duration: ~6 yrs.
http://insight.ccbr.umn.edu- START Protocol Synopsis
What to Start
Current ARV Medications
NRTI
PI
Integrase Inhibitor
 Abacavir (ABC)
 Didanosine (ddI)
 Emtricitabine (FTC)
 Lamivudine (3TC)
 Stavudine (d4T)
 Tenofovir (TDF)
 Zidovudine (AZT)
 Atazanavir (ATV)
 Darunavir (DRV)
 Fosamprenavir (FPV)
 Indinavir (IDV)
 Lopinavir (LPV)
 Nelfinavir (NFV)
 Ritonavir (RTV)
 Saquinavir (SQV)
 Tipranavir (TPV)
 Raltegravir (RAL)
 Elvitegravir (EVG)
 Dolutegravir (DTG)
NNRTI
 Delavirdine (DLV)
 Efavirenz (EFV)
 Etravirine (ETR)
 Nevirapine (NVP)
 Rilpivirine (RPV)
Fusion Inhibitor
 Enfuvirtide (ENF, T-20)
CCR5 Antagonist
 Maraviroc (MVC)
26 medications, but we use only
about ½ of them usually
www.aidsetc.org
3-Drug Combination ART 1996:
Crixivan/Retrovir/Epivir
8AM
4PM
12 MID
Fasting (1 hour before/2 hours after meals)1.5 liters of hydration/day
HIV Lifecycle And Drug Targets
Fusion
Entry Inhibitors
Nukes and Non Nukes
Budding
Reverse
transcription
Uncoating
Viral DNA
Assembly
3’-processing
Viral proteins
Pre-Integration
Complex
Integrase Inhibitors
Protein chains
Viral RNA
Nucleus
Integration
(strand transfer)
Human Genomic DNA
Transcription
Translation
Viral DNA
RNA
Protease Inhibitors
DHHS Guidelines Update 2014: Recommended
Regimens in ARV Naives Regardless of Baseline
CD4 and Viral Load
NNRTI – Based Regimen
Efavirenz/tenofovir/emtricitabine (AI)
PI – Based Regimens:
Atazanavir/ritonavir + tenofovir/emtrictiabine (AI)
Darunavir/ritonavir + tenofovir/emtricitabine (AI)
INSTI – Based Regimens:
Dolutegravir plus abacavir/lamivudine – ONLY if patient HLA-B*5701 negative (AI)
Dolutegravir plus tenofovir/emtricitabine (AI)
Elvitegravir/cobicistat/tenofovir/emtricitabine – ONLY if pre-ART CrCl >70ml/min (AI)
Raltegravir plus tenofovir/emtricitabine (AI)
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV1-infected adults and adolescents. Department of Health and Human Services. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14
DHHS Guidelines Initial
Recommended Regimens - 2014
Atripla
1/day
Reyataz/Norvir/Truvada
3/day
Prezista/Norvir/Truvada
3/day
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. Department of Health and Human Services. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14.
DHHS Guidelines Initial
Recommended Regimens - 2014
Isentress (BID)/Truvada
3/day
Tivicay/Truvada OR Epzicom
OR
2/day
Stribild
1/day
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. Department of Health and Human Services. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14.
Atripla Key Points






3 drugs in one tablet
Efavirenz/tenofovir/emtricitabine
AKA Sustiva+Truvada
Dosed at bedtime usually
Pregnancy Category D
CNS side effects common in first few
weeks
 Renal side effects possible with tenofovir
Reyataz Norvir Truvada
Key Points







3 pills daily
“Boosted” PI regimen
Dosed once a day with food
GI side effects, minimal effect on lipids
Hyperbilirubinemia, nephrolithiasis
Proton Pump Inhibitor interaction
Renal side effects possible with tenofovir
Prezista Norvir Truvada
Key Points







3 tablets daily
“Boosted” PI regimen
Dosed once a day with food
GI side effects, minimal effect on lipids
Sulfa moeity
Renal side effects possible with tenofovir
400mg off market now!
Ritonavir (Norvir®, RTV, r)
 Dosing / Administration
 For PI-boosting: 100-200mg PO BID or daily
 Full dose - 600mg PO Q12H (usually wrong)
 Take with food to improve tolerability
 Refrigerate capsules
 Adverse effects
 GI effects, taste perversion, circumoral tingling
  [cholesterol] &  [triglycerides]
 Drug interactions
 Potent CYP3A4 inhibitor and inducer
Single-Dose Pharmacokinetics of
Lopinavir With and Without Ritonavir
Lopinavir Concentration (mg/mL)
10
Lopinavir/ritonavir
1
0.1
IC50 wt HIV
0.01
Lopinavir alone
0.001
0
6
12
18
24
30
36
42
Time After Dosing (hr)
Sham HL, et al. Antimicrob Agents Chemother. 1998;42(12):3218-3224; Lal R, et al., 37th ICAAC, 1997, # I-194
48
Why Norvir Boosted Protease Inhibitors
 Less resistance – nearly no resistance
reported in naïve trials with all boosted PI
regimens currently on guidelines
 Lower pill burdens
 Reduced frequency – now all are once
daily, versus 2-3 times daily for unboosted
protease inhibitors
 “Ritonaphobia” is the REAL downside
Isentress Truvada Key Points
 3 tablets
 Isentress dosed twice a day
 Once daily dosing possible, but inferior to BID
 Well tolerated, no effect on lipids
 Renal side effects possible with tenofovir
Stribild Key Points
 4 drugs in one tablet
 Elvitegravir – a new integrase inhibitor
 Cobicistat – a new booster (does the same thing as
RTV)
 Tenofovir – preferred NRTI
 Emtricitiabine – preferred NRTI
 Head to head data with Atripla and
Reyataz/Norvir/Truvada showed similar results (noninferior at 48 weeks)
Sax P, et al. CROI 2012. Abstract 101.
DeJesus E, et al. CROI 2012. Abstract 627.
Stribild – Additional Information
 Contains cobicistat
 Booster for the elvitegravir
 Similar to Norvir for drug interactions
 Increased creatinine levels due to
inhibition of tubular secretion of creatinine
back into bloodstream in the kidney
 Similar to cimetidine
Tubular Reabsorption
Substances reabsorbed back into
blood from the renal tubule
Tubular Secretion
Substances secreted from the
blood back into renal tubule for
elimination
X
Blocking Tubular Secretion
Cobicistat BLOCKS tubular
secretion of creatinine, causing an
increase in blood levels of
creatinine
Tivicay Key Points
OR
 FDA-approved August 12, 2013
 Approved for wide range of HIV populations, adults
and children aged 12 and above and at least 40kg
 New integrase inhibitor dosed as a 50 mg tablet
 Once daily for treatment-naïve patients
 Twice daily for integrase treatment-experienced patients




Can be taken with or without food
Pregnancy category B
Adverse events > 2% were insomnia and headache
Contra-indicated to be given with dofetilide, an antiarrhythmic
 Submitted to FDA STR of Epzicom/dolutegravir
Tivicay Dosing
 Treatment naïve or treatment experienced,
integrase inhibitor naïve
 50mg once daily
 Treatment naïve or treatment experienced, with
UGT1A/CYP3A4 inducers: Efavirenz,
fosamprenavir/ritonavir, tipranavir, or rifampin
 50mg twice daily
 Integrase inhibitor with II resistance
 50mg twice daily
 No food restrictions
 Separate from cations – ie Magnesium, Calcium,
Iron
DHHS Guidelines Update 2014: Recommended
Regimens, ARV Naives, ONLY if Pre ART Viral
Load <100,000 copies/ml
NNRTI – Based Regimen
Efavirenz + abacavir/lamivudine – ONLY if patient HLA-B*5701 negative (AI)
Rilpivirine/tenofovir/emtricitabine – ONLY if patient has CD4 count>200 cells/mm3 (AI)
PI – Based Regimens:
Atazanavir/ritonavir + abacavir/lamivudine (AI) – ONLY if patient is HLA-B*5701 negative
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV1-infected adults and adolescents. Department of Health and Human Services. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14
28
Complera
Rilpivirine/tenofovir/emtricitabine
 STR once daily
 Food required
 Take antacids at least 2 hours before or at
least 4 hours after
 Take H-2 blockers at least 12 hours before
or at least 4 hours after
 PPIs are contraindicated
DHHS Guidelines Update 2014
Alternative Regimens in ARV Naives
PI – Based Regimen
Darunavir/ritonavir + abacavir/lamivudine – ONLY for patients who are HLA-B*5701
negative (BII)
Lopinavir/ritonavir (once or twice daily) plus abacavir/lamivudine – ONLY for
patients who are HLA-B*5701 negative (BI)
Lopinavir/ritonavir (once or twice daily) plus tenofovir/emtricitabine (BI)
INSTI – Based Regimens:
Raltegravir + abacavir/lamivudine – ONLY for patients who are HLA-B*5701 negative
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV1-infected adults and adolescents. Department of Health and Human Services. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14
30
Preferred NRTI Backbones in Pregnancy –
DHHS Perinatal Guidelines, March 2014
Preferred NRTI Backbones
Abacavir/lamivudine
Available as fixed dose combination, once
daily dosing. Do NOT use in patients
testing positive for HLAB*5701
Tenofovir/emtricitabine or lamivudine
Available as fixed dose combination, once
daily dosing. Tenofovir may cause renal
impairment
Zidovudine/lamivudine
Available as fixed dose combination.
Most experience in pregnancy to date,
but twice daily adminstration, and
potential for hematologic toxicity
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of
Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission
in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 5/2/14
31
Preferred PI, NNRTI Regimens in Pregnancy –
DHHS Perinatal Guidelines, March 2014
Preferred PI Regimens
Atazanavir/ritonavir + preferred dual
NRTI backbone
Once daily administration
Lopinavir/ritonavir + preferred dual NRTI
backbone
Twice daily administration. Once daily
dosing not recommended in pregnancy.
May need to increase dosage in 3rd
trimester
Preferred NNRTI Regimens
Efavirenz + preferred dual NRTI backbone Teratogenicity in primates.
initiated AFTER first 8 weeks of pregnancy
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of
Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV
Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 5/2/14
32
What to Avoid
ARV Medications: Should NOT
Be Offered at ANY Time
 ARV regimens not recommended:




Monotherapy with NRTI*
Monotherapy with boosted PI
Dual-NRTI therapy
3-NRTI regimen (except ABC + 3TC + ZDV or possibly
TDF + 3TC + ZDV)
* ZDV monotherapy is not recommended for prevention of perinatal HIV
transmission but might be considered in certain circumstances; see Public
Health Service Task Force Recommendations for the Use of Antiretroviral Drugs
in Pregnant HIV-Infected Women for Maternal Health and Interventions to
Reduce Perinatal HIV Transmission in the United States.
www.aidsetc.org
ARV Medications: Should NOT
Be Offered at ANY Time
 ARV components not recommended:





Didanosine + stavudine
Didanosine + tenofovir
Emtricitabine + lamivudine
Stavudine + zidovudine
Darunavir, saquinavir, or tipranavir as single,
unboosted PIs
 Atazanavir + Indinavir
www.aidsetc.org
ARV Medications: Should NOT
Be Offered at ANY Time
 ARV components not recommended:
 Efavirenz during first trimester of pregnancy and in
women with significant potential for pregnancy
 Nevirapine initiation in women with CD4 counts of
>250 cells/µL or in men with CD4 counts of >400
cells/µL
 Etravirine + unboosted PI
 Etravirine + boosted Atazanavir, fosamprenavir or
tipranavir
 Any combination of 2 NNRTIs
www.aidsetc.org
PrEP Guidelines
2014 CDC PrEP Guidelines
 Guidelines for PrEP were released in May 2014
 Addresses the role of PrEP in the following adult
populations




Men who have sex with men
Heterosexual men and woman
Injection Drug Users
Sero-discordant couples
 ONLY medication to be used in this setting is
tenofovir/emtricitabine (Turvada)
http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.
38
Results of PrEP Trials, CDC
Results from randomized, placebo-controlled, clinical trials of the efficacy of daily oral antiretroviral preexposure prophylaxis
(PrEP) for preventing human immunodeficiency virus (HIV) infection
Clinical trial
Participants
iPrEx
Fem-PrEP
VOICE
mITT efficacy*
Adherence-adjusted efficacy based
on TDF detection in blood
TDF
%
49
(95% CI)
(10–72)
%
70
(95% CI)
(2–91)
TDF
TDF/FTC
67
75
(44–81)
(55–87)
86
90
(67–94)
(58–98)
Heterosexually
TDF/FTC
active men and
women
Men who have sex TDF/FTC
with men
Heterosexually
TDF/FTC
active women
62
(22–83)
84
NS
42
(18–60)
92
(40–99)
NS
—
NA
—
Heterosexually
active women
NS
NS
—
—
NA
NA
—
—
Bangkok Tenofovir Injecting drug
Study
users
Partners PrEP
HIV discordant
couples
TDF2
Type of
medication
TDF
TDF/FTC
Abbreviations: mITT = modified intent to treat analysis, excluding persons determined to have had HIV infection at enrollment; CI =
confidence interval; TDF = tenofovir disoproxil fumarate; FTC = emtricitabine; NS = not statistically significant; NA = data not
available. * % reduction in acquisition of HIV infection.
Center for Disease Control. MMWR. June 14, 2013 / 62(23);463-465
39
2014 CDC PrEP Guidelines –
Recommended Indications for PrEP
Use in MSM
•
•
•
•
Adult man
Without acute or established HIV infection
Any male sex partners in past 6 months
Not in a monogamous partnership with a recently tested, HIVnegative man
AND at least one of the following
• Any anal sex without condoms (receptive or insertive) in past 6
months
• Any STI diagnosed or reported in past 6 months
• Is in an ongoing sexual relationship with an HIV-positive male
partner
http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.
40
2014 CDC PrEP Guidelines –
Recommended Indications for PrEP Use
in Heterosexual Men and Women
•
•
•
•
Adult person
Without acute or established HIV infection
Any sex with opposite sex partners in past 6 months
Not in a monogamous partnership with a recently tested HIV-negative
partner
AND at least one of the following
• Is a man who has sex with both women and men (behaviorally bisexual)
• Infrequently uses condoms during sex with 1 or more partners of
unknown HIV status who are known to be at substantial risk of HIV
infection (IDU or bisexual male partner)
• Is in an ongoing sexual relationship with an HIV-positive partner
http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.
41
2014 CDC PrEP Guidelines –
Recommended Indications for PrEP Use
Injection Drug Users
• Adult person
• Without acute or established HIV infection
• Any injection of drugs not prescribed by a clinician in past 6 months
AND at least one of the following
• Any sharing of injection or drug preparation equipment in past 6 months
• Been in a methadone, buprenorphine, or suboxone treatment program
in past 6 months
• Risk of sexual acquisition
http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.
42
2014 CDC PrEP Guidelines –
Monitoring
All patients receiving PrEP should be seen as follows:
At least every 3 months to
• Repeat HIV testing and assess for signs or symptoms of acute infection
to document that patients are still HIV negative
• Repeat pregnancy testing for women who may become pregnant
• Provide a prescription or refill authorization of daily TDF/FTC for no
more than 90 days (until the next HIV test)
• Assess side effects, adherence, and HIV acquisition risk behaviors
• Provide support for medication adherence and risk-reduction behaviors
• Respond to new questions and provide any new information about PrEP
use
http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.
43
2014 CDC PrEP Guidelines –
Monitoring
At least every 6 months to
• Monitor eCrCl
• If other threats to renal safety are present renal function may require
more frequent monitoring or may need to include additional tests
• A rise in serum creatinine is not a reason to withhold treatment if eCrCl
remains ≥60 ml/min.
• If eCrCl is declining steadily (but still ≥60 ml/min), consultation with a
nephrologist may be indicated.
• Conduct STI testing recommended for sexually active adolescents and
adults (i.e., syphilis, gonorrhea, chlamydia)
At least every 12 months to
• Evaluate the need to continue PrEP as a component of HIV prevention
http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf. Accessed 5/15/14.
44
PEP Guidelines
HIV Prophylaxis Following
Exposure
 The Medical Care Criteria Committee now
recommends tenofovir + emtricitabine*
plus raltegravir as the preferred initial
PEP regimen
 excellent tolerability, proven potency, and
ease of administration.
 Zidovudine is no longer recommended
 no clear advantage in efficacy over tenofovir
 higher rates of treatment-limiting side effects.
HIV Prophylaxis Following
Occupational Exposure
 Recommendations place emphasis on the
importance of initiating occupational
PEP as soon as possible, ideally within
2 hours of exposure.
 First dose of PEP should be offered while
evaluation is underway.
 PEP should not be delayed while awaiting
source patient or results of the exposed
baseline HIV test.
Updated Public Health Service
Occupational PEP Guidelines, November 2013
Preferred HIV PEP Regimen
Raltegravir (Isentress; RAL) 400 mg PO twice
daily
PLUS
Truvada, 1 PO once daily
(Tenofovir DF [Viread; TDF] 300 mg +
emtricitabine [Emtriva; FTC] 200 mg) Fixed
Dose Combination
Kuhar DT. Infect Control Hosp Epidemiol. 2013;34(9):875-92.
48
Resources
Web Resources of Interest
– DHHS Guideline Tables
– http://www.aidsinfo.nih.gov/guidelines/
– NY/NJ AIDS Education and Training Center
– http://www.nynjaetc.org/
– University of Liverpool
– www.hiv-druginteractions.org
– Toronto HIV Clinic
– http://www.hivclinic.ca/main/home
http://aidsinfo.nih.gov/guidelines/
www.hiv-druginteractions.org
www.hiv-druginteractions.org
Upper Left Corner
New data, reports
Top middle – Charts and
Recommendations
www.hep-druginteractions.org
www.nynjaetc.org
www.nynjaetc.org
CLICK HERE
www.nynjaetc.org
CLICK HERE
NY/NJ AETC – www.nynjaetc.org
NY/NJ AETC – www.nynjaetc.org
NY/NJ AETC – www.nynjaetc.org
NY/NJ AETC – www.nynjaetc.org
www.hivguidelines.org
HIV Medication Overview
John J. Faragon, PharmD, BCPS, AAHIV-P
Albany Medical Center Hospital
NY/NJ AIDS Education and Training Center