hiv treatment update - dcpa · 2020-03-02 · 12/22/2015 1 hiv treatment update monique calil,...

12/22/2015

1

HIV Treatment

Update

Monique Calil, Pharm.D.

PGY-1 Resident

Broward Health Medical Center

Objectives

� Review antiretroviral therapy (ART) medications used for the

treatment of HIV, including new combination products

� Outline the “recommended”, “alternative”, and “other” HIV

regimens in treatment-naïve patients according to the updated 2015

Department of Health and Human Services (DHHS) Panel on

Antiretroviral Guidelines for Adults and Adolescents

� Summarize the updates on the treatment and prevention of

opportunistic infections in HIV-infected individuals according to the

latest 2015 DHHS Guidelines

Epidemiology

• >1.2 million

people in the

U.S. are living

with HIV

• 1 in 8 people

are unaware

• 13,712

people with

an AIDS

diagnosis

died in 2012

12/22/2015

2

Who to treat with ART?

� Older recommendations:

� Based on CD4 count

� More recently, recommended everyone be treated with ART, but

level of evidence depended on CD4 count

• CD4 350 to 500 cells/mm3 (AII) and >500 cells/mm3 (BIII)

� New recommendations:

� Results from START and TEMPRANO clinical trials published in

2015

� Large, randomized, controlled trials

� Provided significant evidence of the benefit of early ART

� Strength of recommendation for all patients to be started

regardless of CD4 count: (AI)

INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. Jul 20 2015

Temprano ANRS 12136 Study Group. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. Jul 20 2015

Human Immunodeficiency Virus:

Treatment

� Goals of therapy

� Prevent disease progression

� Decrease viral transmission

� Surrogate markers:

� Viral Load-

• Surrogate for treatment response

• Takes 8-24 weeks to achieve viral suppression in most

patients

• Sub-optimal response versus virologic failure

� CD4-

• Immune response

• Should increase ~150 cells/mm3 after first year of ART

therapy, then 50-100 cells/mm3 in subsequent years

• 15-20% patients with low CD4 count� remain low

Panel on Clinical Practices for Treatment of HIV Infection. "Department of Health and Human Services (DHHS). Guidelines for the

use of antiretroviral agents in HIV-1-infected adults and adolescents. April 2015”. Accessed October 2015

ART Drug Classes Drug class Examples Comment

1) Entry Inhibitor: CCR5 antagonist

Maraviroc (Selzentry) CCR5 Tropic HIV-1

2) Entry Inhibitor: Fusion Inhibitor

Enfuvirtide (Fuzeon) Subcutaneous injection

3) Reverse Transcriptase Inhibitors

Nucleoside reverse transcriptase inhibitors (NRTI) _________________Non-nucleoside reverse

transcriptase inhibitors (NNRTI)

NRTI – “back-bone”•Abacavir+lamivudine•Tenofovir+emtricitabine____________________NNRTI -

Efavirenz, nevirapine, rilpivirine, etravirine

4) Integrase Strand Transfer Inhibitor

INSTI End in “-tegravir”

5) Protease Inhibitors PI End in “-navir”Darunavir, atazanavir, ritonavir (booster), fosamprenavir



12/22/2015

3

ART for HIV Infection

� Initial therapy generally consists of:

Two NRTI’s

Tenofovir/

Emtricitabine

Or Abacavir/

Lamivudine

+

One ARV from either of

the following classes:

INSTI

NNRTI

Boosted PI



https://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle

1) HIV Cell Entry

2) Cell Membrane Fusion

3) Reverse transcriptase

converts viral RNA � DNA

4) Viral DNA

integrated

into host

DNA

5) Immature HIV strands

cleaved � infectious

virus

Recommended Regimens before

April, 2015

NNRTI-Based

� Efavirenz + tenofovir/emtricitabine

Integrase Inhibitor-Based

� Raltegravir + tenofovir/emtricitabine

� Elvitegravir/cobicistat/tenofovir/emtricitabine

� Dolutegravir + tenofovir/emtricitabine

� Dolutegravir + abacavir/lamivudine

Protease Inhibitor-Based

� Darunavir/ritonavir + tenofovir/emtricitabine

� Atazanavir/ritonavir + tenofovir/emtricitabine

Only if baseline viral load

< 100,000 copies/mL

NNRTI-Based:

� Rilpivirine +

tenofovir/emtricitabine

(only if CD4 > 200 cells/mm3)

� Efavirenz + abacavir/lamivudine


� Atazanavir/ritonavir + abacavir

lamivudine



12/22/2015

4

Literature Update

� ACTG A5257- A large randomized controlled trial (2014)

� Atazanavir/ritonavir (n=605) versus darunavir/ritonavir (n=601) or

raltegravir (n=603), each with tenofovir/emtricitabine

� At week 96, all 3 regimens had similar virologic efficacy

Lennox, Jeffrey L., et al. "Efficacy and Tolerability of 3 Nonnucleoside Reverse Transcriptase Inhibitor–Sparing Antiretroviral Regimens for Treatment-

Naive Volunteers Infected With HIV-1: A Randomized, Controlled Equivalence Trial."Annals of internal medicine 161.7 (2014): 461-471.

Literature Update

� 2014 Analysis of 4 AIDS Clinical Trial

Groups studies of efavirenz containing

regimens (n=3241) and efavirenz-free

regimens (n=2091)

� Conclusion

• Initial treatment with efavirenz

was associated with a 2-fold

increased hazard of suicidality

compared with an initial regimen

without efavirenz

Mollan, Katie R., et al. "Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal

ideation or attempted or completed suicide: an analysis of trial data." Annals of internal medicine 161.1 (2014): 1-10.

Literature Update

� However?.

� D:A:D (Data collection on Adverse events of Anti- HIV Drugs)

study (2014)

• Retrospective analysis of the Food and Drug Administration

Adverse Event Reporting System (FAERS)

• Found no association between efavirenz use and suicidality

Napoli, Andrew A., et al. "No evident association between efavirenz use and suicidality was identified from a disproportionality

analysis using the FAERS database." Journal of the International AIDS Society 17.1 (2014).

12/22/2015

5

Literature Update � Cobicistat (Tybost)

� Pharmacokinetic booster that inhibits CYP3A4

� Dose:

� 150 mg daily with Atazanavir 300 mg (Combination product

Evotaz)

� 150 mg daily with Darunavir 800 mg (Combination product

Prezcobix)

� 150 mg daily in combination product

Elvitegravir/cobicistat/tenofovir DF/emtricitabine (Stribild)

� 150 mg daily in combination product

Elvitegravir/cobicistat/tenofovir AF/emtricitabine (Genvoya)

� Misconception: Renal dose adjustments

� No adjustments necessary

� If used with tenofovir, CrCl < 70 mL/min, coadministration not

recommended Tenofovir DF= disoproxil fumarate

Tenofovir AF= alafenamide

Literature Update

� Pharmacokinetic enhancer: Cobicistat

� The 2013 Gilead Study 114 enrolled 692 treatment-native patients

� Atazanavir + tenofovir/emtricitabine boosted with ritonavir or

cobicistat

The two regimens

had similar

percentages of

adverse events,

changes in serum

creatinine, and

changes in bilirubin

levels

Gallant, Joel E., et al. "Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-

naive HIV type 1–infected patients: week 48 results." Journal of Infectious Diseases208.1 (2013): 32-39.

Literature Update

Pharmacokinetic enhancer: Cobicistat

• 2014 Open-label, single-arm trial of

darunavir/cobicistat

• N=313

• Evaluated in combination with

NRTIs (99% given

tenofovir/emtricitabine)

• Week 48 � 81% of participants

achieved HIV RNA < 50

copies/mL

• 5% discontinued due to

adverse effects

Tashima, Karen, et al. "Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected

treatment-nave adults." Journal of the International AIDS Society 17.4Suppl 3 (2014).

12/22/2015

6

Literature Update

� Tenofovir and renal dysfunction

� Tenofovir disoproxil fumerate

� Readily converts to tenofovir in

plasma after absorption

� Risk factors:

� Advanced HIV disease

� Longer treatment history

� Low body weight, especially in

females

� Pre-existing renal impairment

� Renal impairment

� Proximal renal tubulopathy

� Fanconi Syndrome

� Osteomalacia http://www.nature.com/ki/journal/v78/n11/full/ki2010344a.html

Literature Update

� New salt form of tenofovir: Tenofovir alafenamide

� Oral prodrug of tenofovir

� Converted to tenofovir and then to tenofovir-diphosphate

intracellularly

� Remains stable in plasma resulting in ↓plasma and higher

intracellular tenofovir concentration ↑

� Potential for adverse kidney and bone effects :

tenofovir alafenamide < tenofovir disoproxil fumurate

Literature Update

� Clinical trials

� 2 double-blinded, phase 3, RCTs: Safety and efficacy

• Elvitegravir/cobicistat/emtricitabine/TDF (Stribild) versus

Elvitegravir/cobicistat/emtricitabine/TAF (Genvoya)

• At 48 weeks, 800 of 866 (92%) in TAF arm and 784 of 867

(90%) in TDF arm:

� HIV RNA < 50 copies/mL

� Both regimens well-tolerated

• TAF arm: smaller decline in eGFR (significant)

� Less proteinuria, less bone mineral density reduction in

spine and hip

Tenofovir DF= disoproxil fumarate

Tenofovir AF= alafenamide

Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir,

cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority

trials. Lancet. Jun 27 2015;385(9987):2606-2615

12/22/2015

7

Recommended Regimens after

April, 2015 NNRTI-Based

� Efavirenz + tenofovir/emtricitabine








� Atazanavir/ritonavir + tenofovir/emtricitabine

Only if baseline viral load < 100,000

copies/mL

NNRTI-Based:

� Rilpivirine/tenofovir/emtricitabine

(only if CD4 > 200 cells/mm3)

� Efavirenz +abacavir/lamivudine


� Atazanavir/ritonavir + abacavir

lamivudine

Panel on Clinical Practices for Treatment of HIV Infection. "Department of Health and Human Services (DHHS). Guidelines for the use of

antiretroviral agents in HIV-1-infected adults and adolescents. April 2015”. Accessed October 2015

Recommended Regimens after

April, 2015








Alternative regimens

NNRTI-Based

�Efavirenz/tenofovir/emtricitabine

�Rilpivarine/tenofovir/emtricitabine

� (Only with pre-treatment HIV RNA < 100,000 copies/mL & CD4 <200

cells/mm3)


�Atazanavir/cobicistat + tenofovir/emtricitabine

�Atazanavir/ritonavir + tenofovir/emtricitabine

�Darunavir/cobicistat or Darunavir/ritonavir + abacavir/lamivudine

�Darunavir/cobicistat + tenofovir/emtricitabine

12/22/2015

8

Other regimens

NNRTI-Based

� Efavirenz plus abacavir/lamivudine

� (Only with pre-treatment HIV RNA < 100,000 copes/mL)


� Atazanavir/cobicistat or Atazanavir/ritonavir + abacavir/lamivudine

� (Only with pre-treatment HIV RNA < 100,000 copes/mL)

� Lopinavir/ritonavir + abacavir/lamivudine

� Lopinavir/ritonavir + tenofovir/emtricitabine

When Tenofovir or Abacavir cannot be used

� Darunavir/ritonavir + raltegravir (HIV RNA <100,000 copies/mL and CD4

>200 cells/mm3)

� Lopinavir/ritonavir + lamivudine

Drug Name Brand Name

FDA Approval date

Picture Guidelines

NNRTI-Based

Efavirenz, emtricitabine, and tenofovir disoproxil fumarate

Atripla July 12, 2006 Alternative

Rilpivirine, tenofovir disoproxil fumarate,

and emtricitabine

Complera August 10, 2011 Alternative

INSTI-Based

Elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate

Stribild August 27, 2012Recommended

Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate

Genvoya November 5, 2015

Recommended

Dolutegravir, abacavir, and lamivudine

Triumeq August 22, 2014 Recommended

Once Daily Combination Pills

https://aidsinfo.nih.gov/education-materials/fact-sheets/21/58/fda-approved-hiv-medicines

More Combination Pills

Drug Name Brand Name FDA Approval date

Lamivudine and zidovudine Combivir September 27, 1997

Lopinavir and ritonavir Kaletra September 15, 2000

Abacavir, lamivudine, and zidovudine

Trizivir November 14, 2000

Emtricitabine and tenofovir

Truvada August 2, 2000

Abacavir and lamivudine

Epzicom August 2, 2000

Atazanavir and cobicistat

Evotaz January 29, 2015

Darunavir and cobicistat Prezcobix January 29, 2015

Bold: Recommended by the DHHS Guidellines https://aidsinfo.nih.gov/education-materials/fact-sheets/21/58/fda-approved-hiv-medicines

12/22/2015

9

Updates to the Treatment and

Prevention of Opportunistic

Infections in HIV-Infected

Adults and Adolescents

Pyrimethamine (Daraprim)

� Antiparasitic agent:

� Inhibits parasitic dihydrofolate reductase, inhibiting vital

tetrahydrofolic acid synthesis

� Recommended for:

� Treatment and prophylaxis of Toxoplasma encephalitis and

Isopora infection

� Prophylaxis of Pneumocystis pneumonia

� June 2015, no longer available in retail pharmacies

� Sold only through special pharmacy program

� Can no longer order from general wholesaler

� Be familiar with alternative agents for specific

pathogens

� Use until pyrimethamine available

http://money.cnn.com/2015/11/25/news/companies/turing-pharmaceuticals

daraprim-price-drop/

Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents:

recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV

Medicine Association of the Infectious Diseases Society of America

Toxoplasmosis

Encephalitis

� Toxoplasmic encephalitis (TE) is caused by the protozoan

Toxoplasma gondii.

� Prevalence is 11% in the US

� Patients with CD4 counts < 50 cells/µL are at greatest risk

� Primary prophylaxis indications:

� Toxoplasma IgG (+) patients with CD4 count <100 cells/mm3 (AII)

� Toxoplasma seronegative patients receiving a PCP prophylaxis

regimen not active against toxoplasmosis should have toxoplasma

� serology retested if CD4 count declines to <100 cells/mm3 (CIII)

� Prophylaxis against toxoplasmosis should be initiated if

seroconversion occurred (AII)

Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for

Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America

12/22/2015

10

Toxoplasmosis

Encephalitis

Treatment:

�Preferred Regimen (AI):

� Pyrimethamine 200 mg PO once, then dose based on body weight:

� Body Weight ≤60 kg:

• Pyrimethamine 50 mg PO daily plus sulfadiazine 1000 mg PO q6h

plus leucovorin 10–25 mg PO daily (can increase to 50 mg daily or

BID)

� Body Weight >60 kg:



BID)



Toxoplasmosis

Encephalitis

Treatment:

�Preferred Regimen (AI):

� Pyrimethamine 200 mg PO once, then dose based on body weight:

� Body Weight ≤60 kg:



BID)

� Body Weight >60 kg:



BID)



Toxoplasmosis

Treatment:

�Alternative Regimens:

� Pyrimethamine (leucovorin) plus clindamycin 600 mg IV or PO q6h (AI

� TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) (IV or PO) BID (BI)

� Atovaquoneb 1500 mg PO BID plus pyrimethamine (leucovorin) (BII)

� Atovaquoneb 1500 mg PO BID plus sulfadiazine (BII)

� Atovaquoneb 1500 mg PO BID (BII)

� Pyrimethamine (leucovorin) plus azithromycin 900–1200 mg PO daily (CII)

�Note:

� If pyrimethamine is unavailable or there is a delay in obtaining it, TMP-SMX

should be utilized in place of pyrimethaminesulfadiazine (BI).

� History of sulfa allergy, sulfa desensitization should be attempted using one of

several published strategies (BI).

� Atovaquone should be administered until therapeutic doses of TMP-SMX are

achieved (CIII).`



12/22/2015

11

Toxoplasmosis

Encephalitis Treatment:

� TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) (IV or PO) BID

(BI)

� Small, Randomized trial (n=77) comparing trimethoprim-

sulfamethoxazole versus pyrimethamine-sulfadiazine

� 40 patients treated with TMP-SMX and 37 were treated with

pyrimethamine-sulfadiazine

� There was no statistically significant difference in clinical

efficacy during acute therapy

Torre, Donato, et al. "Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with

AIDS." Antimicrobial agents and chemotherapy 42.6 (1998): 1346-1349.

Toxoplasmosis

Encephalitis

� Sulfa Desensitization Protocol

example:

� After each dose, patients drank 6

oz. of water

� No pre-medication given

� Mild toxic effects: macular rash,

fever, nausea= symptomatic

treatment

� Anaphylactoid reactions: urticaria,

dyspnea, severe vomiting,

hypotension= stopped

Gluckstein,Ruskin. "Rapid oral desensitization to trimethoprim-sulfamethoxazole (TMP-SMZ): use in prophylaxis for Pneumocystis carinii

pneumonia in patients with AIDS who were previously intolerant to TMP-SMZ." Clinical infectious diseases 20.4 (1995)

Assessment Questions

True/False:

�Efavirenz/tenofovir/emtricitabine (Atripla) remains a preferred

regimen for treatment naïve HIV-infected individuals

�False

�The two protease inhibitors darunavir and atazanavir that may

require boosting with ritonavir can now be boosted with cobicistat

and are included as Alternative regimens

�True

�Patients who are in need of a pyrimethamine-containing regimen

for the treatment of an indicated opportunistic infection should have

treatment withheld until pyrimethamine is available

�False

12/22/2015

12

Conclusion

� New, emerging information from clinical trials are continually

coming out

� It is important to keep up with the DHHS Guidelines on the

treatment of HIV and opportunistic infections

� Pharmacists can serve as pivotal team members in both

outpatient and inpatient settings by having the latest information

accessible

� The Aids Info website (https://aidsinfo.nih.gov/ ) provides the

guidelines from DHHS and the CDC and has pop-up

announcements for updated information

Questions?

References

� Panel on Clinical Practices for Treatment of HIV Infection. "Department

of Health and Human Services (DHHS). Guidelines for the use of

antiretroviral agents in HIV-1-infected adults and adolescents. April

2015”. Accessed October 2015.

� Panel on Opportunistic Infections in HIV-Infected Adults and

Adolescents. Guidelines for the prevention and treatment of

opportunistic infections in HIV-infected adults and adolescents:

recommendations from the Centers for Disease Control and

Prevention, the National Institutes of Health, and the HIV Medicine

Association of the Infectious Diseases Society of America. Available at

http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed

October 2015.

� Lennox, Jeffrey L., et al. "Efficacy and Tolerability of 3 Nonnucleoside

Reverse Transcriptase Inhibitor–Sparing Antiretroviral Regimens for

Treatment-Naive Volunteers Infected With HIV-1: A Randomized,

Controlled Equivalence Trial."Annals of internal medicine 161.7 (2014):

461-471

12/22/2015

13

References

� Napoli, Andrew A., et al. "No evident association between efavirenz use

and suicidality was identified from a disproportionality analysis using

the FAERS database." Journal of the International AIDS Society 17.1

(2014).

� Mollan, Katie R., et al. "Association between efavirenz as initial therapy

for HIV-1 infection and increased risk for suicidal ideation or attempted

or completed suicide: an analysis of trial data." Annals of internal

medicine 161.1 (2014): 1-10.

� Gallant, Joel E., et al. "Cobicistat versus ritonavir as a

pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil

fumarate in treatment-naive HIV type 1–infected patients: week 48

results." Journal of Infectious Diseases208.1 (2013): 32-39.

� Tashima, Karen, et al. "Phase IIIb, open-label single-arm trial of

darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-

infected treatment-nave adults." Journal of the International AIDS

Society 17.4Suppl 3 (2014).

References

� Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus

tenofovir disoproxil fumarate, coformulated with elvitegravir,

cobicistat, and emtricitabine, for initial treatment of HIV-1

infection: two randomised, double-blind, phase 3, non-

inferiority trials. Lancet. Jun 27 2015;385(9987):2606-2615

� Torre, Donato, et al. "Randomized trial of trimethoprim-

sulfamethoxazole versus pyrimethamine-sulfadiazine for

therapy of toxoplasmic encephalitis in patients with

AIDS." Antimicrobial agents and chemotherapy 42.6 (1998):

1346-1349.

� Gluckstein, Daniel, and Joel Ruskin. "Rapid oral

desensitization to trimethoprim-sulfamethoxazole (TMP-SMZ):

use in prophylaxis for Pneumocystis carinii pneumonia in

patients with AIDS who were previously intolerant to TMP-

SMZ." Clinical infectious diseases 20.4 (1995): 849-853.

hiv treatment update - dcpa · 2020-03-02 · 12/22/2015 1 hiv treatment update monique calil,...

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