hiv updates abdi mohamed, pharm.d assistant professor o pharmacy practice husson university school...

HIV Updates

Abdi Mohamed, Pharm.DAssistant Professor o Pharmacy

PracticeHusson University School of

Pharmacy

Objectives

• Review of the history and epidemiology of HIV/AIDS

• Diagnosis of HIV infection• When to initiate therapy• Overview of antiretroviral

medications• New DHHS adult and adolescent

antiretroviral treatment guidelines.• Importance of adherence

What is HIV?

• HIV is a lentivirus• HIV = Human

Immunodeficiency Virus

• It destroys CD4 cells (T-cells and macrophage)

• AIDS = Acquired immunodeficiency Syndrome– CD4 count <

200/mm3 or– CD4 % < 14%

History of HIV• First cases of AIDS were identified in 1981 in Los

Angeles, CA• Believed to be a zoonosis (transmitted from

animal)• HIV is a descendant of a Simian

Immunodeficiency Virus (SIV)• SIVs bear a very close resemblance to HIV-1 and

HIV-2 (two types of HIV).• HIV-2 is similar to SIVsm, a strain of SIV found in

the sooty mangabey (also known as the White-collared monkey), which is indigenous to western Africa.

• HIV-1, was recently discovered to relate to SIVcpz, the SIV strain found in chimpanzees Chen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol. 1996

Jun;70(6):3617-27

Etiology

• HIV was identified as the etiologic agent of AIDS until 1983

• Two types– HIV-1 – HIV-2

• Both them cause similar condition• They differ in transmission and

progression– HIV-1 more virulent and more easily

transmissible 5

Barre-Sinoussi F, Chermann JC, et al. Science. 1983 May 20;220(4599):868-71.

Transmission

Epidemiology

• 2012 US HIV data–Annually HIV infection 60,000–People living with HIV 1.62 million–HIV patients not in care ~55%–1 in 5 (20%) are unaware of their

infection–By race, blacks/African Americans

face the most severe burden of HIV

7

G.J. Stine. AIDS update 2012. Mc Graw Hill p152

2007 The Hopkins HIV guide

Viral transmission

Progression of HIV

Acute retroviral syndrome Recovery + seroconversion

Asymptomatic chronic HIV inf Symptomatic HIV/AIDS Death

2-3 wks 2-3 wks 2-4 wks

Avg. 8 yrs Avg. 1.5yrs

Viral transmission

Diagnosis & Testing

• HIV antibody testing is performed by using an enzyme-linked immunosorbent assay (ELISA)

• If positive repeat the test• Use Western blot (WB) to confirm• Rapid immunoassy (e.g OraQuick)• Resistance test

– genotype (detects mutations that confers HIV drug resistance)

– Phenotype (culture based on viral replication assays in the absence or presence of drugs)

Use of CD4 Cell Levels to Guide Therapy Decisions

• CD4 count– The major indicator of immune function – Most recent CD4 count is best predictor of

disease progression– A key factor in determining urgency of ART or need for OI

prophylaxis– Important in determining response to ART

• Adequate response: CD4 increase 50-150 cells/µL per year

• CD4 monitoring– Check at baseline (x 2) and at least every 3-6 months*

* May consider every 6-12 months in clinically stable patients on ART with sustained HIV RNA suppression and CD4 status well above threshold for opportunistic infection risk.

February 2013www.aidsetc.

org

Use of HIV RNA Levels to Guide Therapy Decisions

• HIV RNA– May influence decision to start ART

and help determine frequency of CD4 monitoring

– Critical in determining response to ART• Goal of ART: HIV RNA below limit of

detection (ie, <20-75 copies/mL, depending on assay)

– Commercially available assays do not detect HIV-2February 2013 www.aidsetc.org

Other Test• HLA-B*5701 Screening

– Recommended before starting any regiment containing abacavir, to reduce risk of hypersensitivity reaction (HSR)

– Positive patient should not receive ABC and ABC allergy should be recorded in file

• Coreceptor tropism assay– Should be performed to detect whether HIV-1

isolates use CCR5 or CXR4 or both.– Requires plasma HIV RNA ≥ 1000 copies/mL– Maraviroc is considered for patient with

virologic failure

CD4+ Count, cells/mm3

1998 2001 2006 2008 2009 2012

> 500 Offer if VL > 20,000

Offer if VL

> 55,000

Consider if VL

≥ 100,000

Consider in certaingroups

Consider Treat

350-500 Offer if VL > 20,000

Consider if VL

> 55,000

Consider if VL

≥ 100,000

Consider in certain groups

Treat Treat

200-350 Offer if VL > 20,000

Offer, but controversy

exists

Offer after discussion with patient

Treat Treat Treat

< 200 or symptomatic disease

Treat Treat Treat Treat Treat Treat

DHHS: Changing Criteria for Initiating ART

clinicaloptions.com/hiv

Guideline Symptomatic/AIDS

CD4+ Count

< 200

CD4+ Count 200-350

CD4+ Count 350-500

CD4+ Count >

500

DHHS (2/2012) 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.

Current Guidelines for Initiating ART


Recommendations for Initiating ART

ART is recommended for treatment• “ART is recommended for all HIV-

infected individuals to reduce the risk of disease progression.”– The strength of this recommendation varies on

the basis of pretreatment CD4 count (stronger at lower CD4 levels)

February 2013 15www.aidsetc.org

Recommendations for Initiating ART: CD4

Count or Clinical Category

Recommended for all CD4 counts:CD4 count <350 cells/µL (AI)CD4 count 350-500 cells/µL (AII)CD4 count >500 cells/µL (BIII)

February 2013 www.aidsetc.org 16

Recommendations for Initiating ART:

Prevention Perinatal transmission

Recommended for all HIV-infected pregnant women (AI)

Sexual transmission Recommended for all who are at risk

of transmitting HIV to sexual partners (AI for heterosexuals, AIII for other transmission risk groups)


Potential Benefits of Early Therapy (2)

• Potential decrease in risk of many complications, including:– HIV-associated nephropathy– Liver disease progression from hepatitis B

or C– Cardiovascular disease– Malignancies (AIDS defining and non-

AIDS defining)– Neurocognitive decline– Blunted immunological response owing to

ART initiation at older age– Persistent T-cell activation and

inflammation


When to Start Therapy

Drug toxicity Preservation of

limited Rx options Risk of resistance

(and transmission of resistant virus)

Delayed ART

When to Start Therapy: Balance Now Favors Earlier ART

Drug toxicity Preservation of

limited Rx options Risk of resistance

(and transmission of resistant virus)

↑ potency, durability, simplicity, safety of current regimens

↓ emergence of resistance ↓ toxicity with earlier

therapy ↑ subsequent treatment

options Risk of uncontrolled viremia

at allCD4+ cell count levels

↓ transmissionEarly ARTDelayed ART


ANTIRETROVIRAL THERAPY

History of ART

22

Current ARV Classes

HAART

Protease inhibitors (PI)

Reverse Transcriptase inhibitors (RTI)

Entry Inhibitors

Nucleotide/Nucleoside Reverse

Transcriptase Inhibitors (NRTI)

Non-Nucleoside Reverse

Transcriptase Inhibitors (NNRTI)

Integrase Inhibitor

Current ARV Medications

NRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV)

NNRTI Delavirdine (DLV) Efavirenz (EFV) Nevirapine (NVP)Etravirine (ETR)Rilpivirine (RPV)

PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV)

Integrase Inhibitor (II) Raltegravir (RAL) Elvitegravir* (EVG)

Fusion Inhibitor Enfuvirtide (ENF, T-20)

CCR5 Antagonist Maraviroc (MVC)


* EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC

Nucleoside Reverse Transcriptase Inhibitors

(NRTI)• Backbone of HIV combination

therapy• HIV-1&2• Minimal drug interactions• Renal excreted except ABC• Minimal cross resistance patterns

Abacavir(ABC, Ziagen)• ABC 300mg PO twice day

or 600mg PO daily• Part of Epzicom and Trizivir• HLA-B*5701-positive

patients should not receive ABC– Positive status should be recorded

as an ABC allergy• Life threatening if re-

challenged• Toxicity

– Hypersensitivity (HSR) ≈ 4%• Fever, rash, fatigue, malaise• Occur within 6 weeks• Don’t rechallenge• HLA-B*5701

300mg tablet or 20mg/ml solution

27

Zidovudine (AZT, Retrovir)

• ZDV 300mg BID• Part of Combivir and

Trizivir• First-line regimen for

pregnant women • Toxicity

– Nausea, malaise, headache, insomnia, lipoatrophy

– Anemia and neutropenia are the most frequent dose-limiting adverse effects

100mg tab, 300mg cap, 10mg/ml IV and 10mg/ml solution

28

Twin Drugs

Lamivudine (3TC)/ EpivirEmtricitabine (FTC)/ Emtriva

• FDA approved for treatment of HIV and HBV

• Dose– 300mg PO daily

• Toxicity– Minimal ≈ placebo

• headache– Hepatitis flare (BB)

• Approved for HIV but also used to treat HBV

• Dose– 200mg PO daily

• Toxicity– Minimal ≈ placebo

• headache– Hepatitis flare (BB)

29

Tenofovir (TDF, Viread)

• FDA approved for HIV and HBV• In 2012, Truvada was approved by

the FDA for pre-exposure prophylaxis (PrEP)

• Usually dose– 300 mg daily

• Toxicity– Well tolerated but rarely can lead to

acute renal failure, Fanconi’s syndrome, proteinuria,

– May contribute to decrease in bone mineral density

30

NRTI Co-formulated Regimen

• Truvada – 1 tablet once a daily

• TDF 300mg + FTC 200mg

• Combivir– 1 tablet twice a day

• 3TC 150mg + AZT 300 mg

• Epzicom– 1 tablet once daily

• 3TC 300mg + ABC 600mg

• Trizivir– 1 tablet twice a day

• 3TC 150mg + AZT 300mg + ABC 300 mg

31

Adverse Effects: NRTIs

• All NRTIs: – Lactic acidosis and hepatic steatosis

(highest incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC)

– Lipodystrophy(higher incidence with d4T)


Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• First Generation– Delavirdine [DLV, RESCRIPTOR®]– Efavirenz [EFV, SUSTIVA®]– Nevirapine [NVP, VIRAMUNE®]

• Second Generation– Etravirine [ETR, INTELENCE®]– Rilpivirine [RPV, EDURANT]

33

Non-Nucleoside Reverse Transcription Inhibitors

(NNRTI)• HIV-2 is resistant• Limitation of first generation NNRTI

– Low genetic barrier to resistance• Long half-lives

Efavirenz (EFV, Sustiva)

• Dosing recommendation– 600mg PO once daily at or before bedtime– Take on empty stomach to reduce side effects– Co-formulated with TDF/FTC (Atripla)– No hepatic (caution) or renal dose adjustment

• Toxicities– CNS side effects (4 weeks)

• drowsiness, insomnia, vivid dreams, and impaired concentration

– Rash– Hyperlipidemia– Potentially teratogenicity to humans

• Pregnancy category D

35

Nevirapine (NVP, Viramune)

• Extended release formulation was approved in 2011

• Dose recommendation– 200mg PO QD x 2 weeks; 200mg PO BID

• Toxicity– Rash including SJ syndrome– Hepatotoxicity (BB)

• Female with CD4 > 250 or male with CD4> 400• Liver disease (HBV, HCV or alcoholics)

– Child Pugh class B or C is contraindicated

36

Rilpivirine (RPV, Edurant)

• Approval: FDA-approved May 20, 2011for treatment-naïve adults

• 25 mg tablet daily– Take with 400 Kcal food

• Fixed dose– Tenofovir-Emtricitabine-Rilpivirine

(Complera)• Toxicity (low): depression, insomnia,

headache, and rash • Pregnancy : category B

37

Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive

ECHO and THRIVE: Study Design


Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

Rilpivirine: 25 mg qd + TDF/FTC(n = 346)

Efavirenz: 600 mg qd + TDF/FTC(n = 344)

Study Features

Protocol - Randomized, double-blind trial- Phase 3- N = 690 (ECHO) and 678 (THRIVE)- Age > 18- ARV-naïve- HIV RNA > 5,000 copies/ml- No baseline NNRTI mutations- Randomized to one of 2 arms - All given 2 NRTIs*

*2 NRTIs: ECHO: Tenofovir + Emtricitabine (TDF/FTC)THRIVE: Tenofovir + Emtricitabine; Zidovudine + Lamivudine; Abacavir + Lamivudine

Rilpivirine: 25 mg qd + 2NRTIs*(n = 340)

Efavirenz: 600 mg qd + 2NRTIs*(n = 338)

ECHO

THRIVE

1x

1x


ECHO and THRIVE: Week 48 Results


Pooled ECHO and THRIVE: Virologic Response ( ITT-TLOVR)


84.3%82.3%

2NRTIs+ Rilpivirine (n = 686)

2NRTIs+ Efavirenz (n = 682)


ECHO and THRIVE: Results


48 Week Data: Virologic Failure


All regimens included 2 NRTIs




48 Week Data: Discontinuation Due to Adverse Effects


All regimens included 2 NRTIs





Conclusions:

• Rilpivirine demonstrated high response rate

• Rilpivirine virologic failure rate higher than efavirenz (9.0% vs 4.8%)

• Rilpivirine had significant tolerability advantage over efavirenz

NRTI+NNRTI Co-formulated Regimen

• Atripla – EFT 600mg + FTC 200mg + TDF

300mg• FTC+TDF= Truvada

– 1 tablet once daily at or before bedtime• Complera

– RPV 25mg + FTC 200mg + TDF 300mg• FTC+TDF= Truvada• 1 tablet once daily with a meal

– Avoid antacids– PPI is contraindicated 43

Adverse Effects: NNRTIs

• All NNRTIs:– Rash, including Stevens-Johnson

syndrome– Hepatotoxicity (especially NVP)– Drug-drug interactions

44

Protease Inhibitors• Atazanavir [ATV, REYATAZ®]• Darunavir [DRV, PREZISTA®]• Fosamprenavir [FPV, LEXIVA®]• Indinavir [IDV, CRIXIVAN®]• Lopinavir/Ritonavir [LPV/r,

KALETRA®]• Nelfinavir [NFV, VIRACEPT®]• Ritonavir [RTV, NORVIR®]• Saquinavir [SQV, INVIRASE®]• Tipranavir [TPV, APTIVUS®] 45

ARV Components in Initial Therapy: PIs

ADVANTAGES• Higher genetic

barrier to resistance• PI resistance

uncommon with failure (boosted PI)

• NNRTIs and II preserved for future use

DISADVANTAGES• Metabolic

complications (fat maldistribution, dyslipidemia, insulin resistance)

• GI intolerance

• Potential for drug interactions (CYP450), especially with RTV


Atazanavir (ATV, Reyataz)

• Recommended dose– Naïve patient

• 400 mg once daily or• 300 mg + 100mg RTV once daily

– Take with food – Avoid acid suppressing agents

• Toxicity– Hyperbilirubinemia– PR prolongation– Nephrolithiasis, cholelithiasis

47

Darunavir (DRV, Prezita)

• Dose– ARV naïve or experienced patients with no mutation

• 800mg + 100 mg RTV once daily– ARV experienced patient with at least one mutation– DRV must be boosted with RTN– Take with food

• Toxicity– DRV contains a sulfonamide moiety,

• Avoid patients with a sulfa allergy→ Rash– GI (N/V/D)– Hyperlipidemia

48

Lopinavir/Ritonavir (LPV/r, Keletra)

• The only boosted PI that is coformulated with low-dose ritonavir– LPV 200mg + RTV 50mg or LPV 100mg

+ RTV 25mg• preferred regimen for pregnant

women• Toxicities

– GI (N/V/D)– Hyperlipidemia (especially

↑triglycerides)– Potential increased MI risk

49

Ritonavir (RTV, Norvir)

• Booster for other PI– 100-400mg per day in 1-2 divided doses

• Formulation– 100mg soft gel capsules, 100mg tablet– 80mg/mL solution

• 43% alcohol

• Toxicities– GI (N/V/D)– Hyperlipidemia– Hyperglycemia 50

Integrase Inhibitors

• Raltegravir• Elvitegravir* (EVG)• Currently being studied in phase III

clinical trials– Dolutegravir (S/GSK1249572)

51

* EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC

Integrase Inhibitors

• Virologic response noninferior to EFV• appears to be active against HIV2• Fewer adverse events than with EFV• RAL has fewer drug-drug interactions

than with PIs or NNRTIs (not true of EVG/COBI)

• NNRTIs and PIs preserved for future use


Raltegravir (RAL, Isentress)

• Indicated for both naïve and experienced pt

• Dose recommendation– 400mg po twice a day with or without

food– When combined with other ART dose

stays same• Toxicities

– Diarrhea, Nausea– Fatigue– Myalgia– Abnormal liver function

53

Stribild (Quad Pill)

• Approved August 2012• Elvitegravir 150mg + cobicistat 150mg +

emtricitabine 200mg + tenofovir 300mg • Stribild PO daily with food• Cobicistat is used to increase the levels of

elvitegravir• AE

– Decreased CrCl– Nausea, diarrhea

• EVG/COBI/TDF/FTC recommended as “alternative” regimen in treatment-naive patients with ClCr > 70 mL/min (BI)[1]

• Benefits– Noninferior to EFV/TDF/FTC,[2] ATV/RTV + TDF/FTC[3]

– 1-tablet, once-daily dosing• Limitations

– Potential for drug–drug interactions– Limited safety data; limited data in advanced disease,

women– Possible increased risk proximal renal tubulopathy– Food requirement

1. DHHS Panel Statement. September 18, 2012. 2. Sax PE, et al. Lancet. 2012;379:2439-2448.3. DeJesus E, et al. Lancet. 2010;379:2429-2438.

EVG/COBI/TDF/FTC: “Alternative”

First-line Regimen

DISADVANTAGES II

• Twice-daily dosing• Lower genetic barrier to resistance

than PIs• COBI has many drug-drug

interactions• COBI may cause or worsen renal

impairment• Myopathy, rhabdomyolysis, skin

reactions reported with RAL (rare)February 2013 www.aidsetc.org 56

Entry InhibitorsEnfuvirtide (T-20, Fuzion)• Use for experienced

patients • 90mg subcutaneous

injection twice a day– Reconstitute with 1.1ml

sterile water• Adverse effects

– Injection-site reactions– HSR– Increased risk of

bacterial pneumonia

Maraviroc (MVC, Selzentry)• Block the binding of

gp120 to the chemokine receptor (CCR5)

• Coreceptor tropism assay– CCR5 or CXCR4

• Adverse Effects– Drug-drug interactions– Rash– Abdominal pain– Upper respiratory

tract infections

New DHHS Treatment guidelines

Feb, 2013

Initial Treatment: Choosing Regimens

• 3 main categories:– 1 NNRTI + 2 NRTIs– 1 PI + 2 NRTIs– 1 II + 2 NRTIs

• Combination of NNRTI, PI, or II + 2 NRTIs preferred for most patients

• Fusion inhibitor, CCR5 antagonist not recommended in initial ART

• Few clinical end points to guide choices• Advantages and disadvantages to each type of

regimen• Individualize regimen choice

DHHS guideline; February 2013 www.aidsetc.org 59

Initial Regimen: Recommended/Preferred

Agents

DHHS Guidelines . Feb 2013; Thompson MA, et al. JAMA. 2010;304;321-333.

EFV ATV/RTV

DRV/RTV RAL

TDF/FTC +

Initial Regimen: Recommended/Alternativ

e

RPV LPV/RTV

FPV/RTVEVG/COBI/TDF/

FTC

TDF/FTC or ABC/3T +

9. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012.10. DHHS Panel Statement. September 18, 2012.

CYP450 and Drug Metabolism

CYP1A2

CYP2E1

CY

P3A

4

CYP2C

CYP2D6

Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9 th ed.

Key points• Majority of drugs metabolized by CYP3A4 and CYP2D6• CYP3A4 and CYP2D6 extensively involved with PI/NNRTI metabolism• Enzymes can be induced or inhibited

3A4

2C19 2D6 2C9

1A2 2E1 2A6 2B6 2C8

Induced by: RTV, NFV, TPVEFV, NVP

Inhibited by: RTV, NFV, IDV, SQV, DLV

Induced by: RTV, NFV

Inhibited by: DLV

Induced by: EFV, NVP

Inhibited by: RTV

Induced by: RTV, NFV

Inhibited by: EFV, DLV

Induced by: RTV, NFV ?

Effect of ARV on Drug Metabolism

From Fichtenbaum CJ. Clin Pharmacokinet 2002:41(14):1195-1211.

Recommendations for Initiating ART: Considerations

“Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence.”

Patients may choose to postpone ART Providers may elect to defer ART, based

on an individual patient’s clinical or psychosocial factors


Immunization

MMWR / February 4, 2011 / Vol. 60 / No. 4 65

ART Approved & Unapproved Drugs

66

References• Chen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol. 1996

Jun;70(6):3617-27• G.J. Stine. AIDS update 2012. Mc Graw Hill 2012• Thompson MA, et al. JAMA. 2012;308:387-402.• Williams I, et al. HIV Med. 2012;13(suppl 2):1-85.• EACS Guidelines for the Treatment of HIV Infected Adults in Europe. November

2012.• WHO Guidelines for Antiretroviral Therapy for HIV Infection in Adults and

Adolescents. July 2010.• DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012.• DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012.• DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. Feb 2013• Cohen M, et al. N Engl J Med. 2011;365:493-505.• DHHS Panel Statement. September 18, 2012. • Sax PE, et al. Lancet. 2012;379:2439-2448.• DeJesus E, et al. Lancet. 2010;379:2429-2438• ww.hivinsite.com• www.clinicaloptions.com • www.hivguidelines.org• www.hopkins-aids.edu

http://www.hivinsite.com/

http://www.clinicaloptions.com/

http://www.hivguidelines.org/

http://www.hopkins-aids.edu/

hiv updates abdi mohamed, pharm.d assistant professor o pharmacy practice husson university school...

Documents

history of hiv

types of hiv

progression hiv

lentivirus hiv

animal hiv

hiv patients

etiology hiv

typestwo types hiv