New Antiretrovirals for the Treatment
of HIV
New & Investigational Agents
Convenience, tolerability, simplicity
“Quad” Pill- Stribild
Released by FDA 08-27-12
Tenofovir + Emtricitabine + Cobicistat + Elvitegravir
“Booster”
INSTI
Elvitegravir
ANTIRETROVIRAL THERAPY
Elvitegravir
• Class: integrase strand transfer inhibitor
• Approval Status: Filed for NDA October 2011
• Dose (Requires Boosting)
- Standard Dosing: 150 mg once daily with food
- With Atazanavir-Ritonavir or Lopinavir-Ritonavir: 85 mg once daily
• Fixed Dose “Quad Pill”: Elvitegravir-Cobicistat-Tenofovir-Emtricitabine
• Metabolism: via cytochrome P450 (CYP) 3A4
• Pregnancy: category unknown
• Adverse Events:
- Well tolerated
-diarrhea reported more frequently with elvitegravir than raltegravir
U.S. Food and Drug Administration website. Accessed May 15, 2013.
Elvitegravir
• Multicenter, Randomized, Double-Blind, Double-Dummy,
Phase 3 Study of the Safety and Efficacy of RitonavirBoosted Elvitegravir (EVG/r) Versus Raltegravir (RAL)
Ritonavir-boosted elvitegravir 150 mg (or a 85-mg dose if
co-administered with atazanavir/ritonavir or
lopinavir/ritonavir) versus raltegravir 400 mg twice daily,
each in combination with a background regimen.
• Additionally, elvitegravir is part of the investigational FDC
tablet containing elvitegravir, cobicistat, emtricitabine, and
tenofovir alafenamide
Molina JM, Lamarca A, Andrade-Villanueva J, et al.
ANTIRETROVIRAL THERAPY
Dolutegravir
Dolutegravir, (brand name: Tivicay). formerly S/GSK-572
• Class: integrase strand transfer inhibitor
• Approval Staus: FDA Approved; August 13, 2013
• Dose (with or without food):
- Treatment Naive: 50 mg once daily
- Treatment Experienced, ISTI-Naive: 50 mg once daily
- ISTI Resistant: 50 mg twice daily
• Fixed Dose Combination: Abacavir-Lamivudine-Dolutegravir (572-Trii)
• Pregnancy: category unknown
• Adverse Events:
- Small increases in serum creatinine (inhibition of creatinine secretion)
ANTIRETROVIRAL THERAPY
Dolutegravir (“572”)
10-Day Monotherapy Study: Results
Source: Min S, et al. AIDS. 2011;25:1737-45.
Dolutegravir (“572”)
10-Day Monotherapy Study: Conclusions
Conclusions: “Dolutegravir demonstrated potent antiviral activity, good
short-term tolerability, low pharmacokinetic variability, and a predictable
pharmacokinetics/pharmacodynamics relationship, which support once
daily dosing without a pharmacokinetic booster in integrase-naive
patients in future studies.”
Source: Min S, et al. AIDS. 2011;25:1737-45.
ANTIRETROVIRAL THERAPY
Dolutegravir (“572”) vs. Efavirenz in ARV-Naive
SPRING-1: Study Results
48 Week Data: Virologic Response (TLOVR)
All regimens included 2 NRTIs: Tenofovir-Emtricitabine or Abacavir-Lamivudine
Source: van Lunzen J, et al. Lancet Infect Dis 2011;12:111-8.
Dolutegravir (“572”) vs. Efavirenz in ARV-Naive
SPRING-1: Adverse Events
Adverse Effect
DTG
10mg
DTG
25mg
DTG
50mg
DTG
Subtotal
EFV
600mg
Serious Adverse Events
3 (6%)
1 (2%)
4 (8%)
8 (5%)
4 (8%)
Nausea
7 (13%)
6 (12%)
6 (12%)
19 (12%)
3 (6%)
Diarrhea
4 (8%)
3 (6%)
5 (10%)
12 (8%)
3 (6%)
Dizziness
2 (4%)
0
3 (6%)
5 (3%)
9 (18%)
Headache
2 (4%)
4 (8%)
4 (8%)
10 (6%)
1 (2%)
Fatigue
1 (2%)
3 (6%)
1 (2%)
5 (3%)
4 (8%)
0
0
3 (6%)
3 (2%)
4 (8%)
Abnormal Dreams
1 (2%)
0
0
1 (<1%)
3 (6%)
Rash
2 (4%)
0
0
2 (1%)
4 (8%)
Insomnia
Source: van Lunzen J, et al. Lancet Infect Dis 2011;12:111-8.
Dolutegravir (“572”) vs. Efavirenz in ARV-Naive
SPRING-1: Conclusions
Interpretation: “Dolutegravir was effective when given once daily without
a pharmacokinetic booster and was well tolerated at all assessed doses.
Our findings support the assessment of once daily 50 mg dolutegravir in
phase 3 trials.”
Source: van Lunzen J, et al. Lancet Infect Dis 2011;12:111-8.
SINGLE STUDY
• A total of 833 participants received at least one dose of study
drug. Randomized, double-blind, phase 3 study involving adult
participants who had not received previous therapy for HIV-1
infection and who had an HIV-1 RNA level of 1000 copies per
milliliter or more. Participants were randomly assigned to
dolutegravir at a dose of 50 mg plus abacavir–lamivudine once
daily or combination therapy with efavirenz–tenofovir disoproxil
fumarate (DF)–emtricitabine once daily. The primary end point
was the proportion of participants with an HIV-1 RNA level of
less than 50 copies per milliliter at week 48. Secondary end
points included the time to viral suppression, the change from
baseline in CD4+ T-cell count, safety, and viral resistance.
N Engl J Med 2013; 369:1807-1818
SINGLE STUDY
• First trial to show statistical superiority to an
efavirenz/FTC/TDF coformulated regimen for treatment
naive patients. After 48 weeks of treatment, 88% of the
dolutegravir group had HIV RNA levels < 50 copies / mL
versus 81% of the efavirenz group
• Conclusions
Dolutegravir plus abacavir–lamivudine had a better
safety profile and was more effective through 48
weeks than the regimen with efavirenz–tenofovir DF–
emtricitabine.
N Engl J Med 2013; 369:1807-1818
ANTIRETROVIRAL THERAPY
Tenofovir Alafenamide
Tenofovir Alafenamide (TAF)
• Other Names: GS-7340, TAF, prodrug of tenofovir, tenofovir
alafenamide fumarate
• Drug Class: Nucleoside Reverse Transcriptase Inhibitors
• Chemical Class: Purine Nucleotides
• Company: Gilead Sciences
• Phase of Development: Phase II and III (as part of fixed-dose
combination [FDC] tablets; one FDC tablet is in Phase II testing,
and another one is in Phase III testing)
Tenofovir Alafenamide (TAF)
• Tenofovir alafenamide is a prodrug, which means that it is
an inactive drug. Once taken, a prodrug does not work until
the body converts it into an active form. In the body,
tenofovir alafenamide is converted to tenofovir diphosphate
(TFV-DP).
• Tenofovir alafenamide is currently being studied as a
component of two investigational fixed-dose combination
(FDC) drugs for the treatment of HIV infection. Tenofovir
alafenamide is being studied in the following combinations:
 elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
 darunavir/cobicistat/emtricitabine/tenofovir alafenamide
Edurant and Complera
Rilpivirine
&
Co-formulated Rilpivirine + Tenofovir + Emtricitabine
Rilpivirine (Edurant)
• NNRTI compound with potent activity
Rilpivirine-3D Structure
• Once daily dose: 25 mg
• Decreased potency with VL > 100,000 (do not use)
• Co-formulated with Tenofovir-Emtricitabine (Complera)
• Less CNS disturbances than efavirenz and nonteratogenic
• Active against most efavirenz-resistant clinical isolates
• Unfavorable interactions with acid suppressant
medications
From: Garvey L, et al. Expert Opin Investig Drugs. 2009;18:103-41.
From: Azijn H, et al.
AAC. 2010:54;718-27.
South Dakota sees most syphilis cases in 44
years
• SIOUX FALLS | South Dakota Department of Health officials say
the number of syphilis cases reported last year was the most in
44 years.
• An annual summary of infectious diseases in the state shows that
48 syphilis cases were reported in 2013.
• The most reports of the sexually transmitted disease were in the
Sioux Falls area, the largest population area in the state, with 23
cases, and Corson County, where the Standing Rock
Reservation is located. Standing Rock reported 14 cases.
• The Argus Leader reports that the Sioux Falls cases involve
mostly men, and the Corson County cases both men and
women.
January 20, 2014 7:47 am • Associated Press, Rapid City Journal
Questions?