1. HIV Updates Abdi Mohamed, Pharm.D
Assistant Professor o Pharmacy Practice
Husson University School of Pharmacy

2. 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

3. 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%

4. 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 Jun;70(6):

5. 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
Barre-Sinoussi F, Chermann JC, et al. Science May 20;220(4599):

6. Transmission

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

8. Progression of HIV Death 2007 The Hopkins HIV guide 2-3 wks 2-3 wks
Viral transmission
Viral transmission
Acute retroviral syndrome
Recovery + seroconversion
Avg. 1.5yrs
Death
Avg. 8 yrs
Asymptomatic chronic HIV inf
Symptomatic HIV/AIDS
2007 The Hopkins HIV guide

9. 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)

10. 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 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 2013

11. Use of HIV RNA Levels to Guide Therapy Decisions
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, < copies/mL, depending on assay)
Commercially available assays do not detect HIV-2
February 2013

12. Other Test HLA-B*5701 Screening Coreceptor tropism assay
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

13. DHHS: Changing Criteria for Initiating ART
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 certain groups
Consider
Treat
Consider if VL > 55,000
Offer, but controversy exists
Offer after discussion with patient
< 200 or symptomatic disease
clinicaloptions.com/hiv

14. Current Guidelines for Initiating ART
Symptomatic/ AIDS
CD4+ Count < 200
CD4+ Count
CD4+ Count
CD4+ Count > 500
DHHS (2/2012)
Yes
IAS-USA (7/2012)
British HIV Association (9/2012)
Defer*
European AIDS Clinical Society (11/2012)
Consider
Defer
WHO (7/2010)
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.
clinicaloptions.com/hiv

15. 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

16. Recommendations for Initiating ART: CD4 Count or Clinical Category
Recommended for all CD4 counts:
CD4 count <350 cells/µL (AI)
CD4 count cells/µL (AII)
CD4 count >500 cells/µL (BIII)
February 2013

17. 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)
February 2013

18. 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
February 2013

19. When to Start Therapy Delayed ART Drug toxicity
Preservation of limited Rx options
Risk of resistance (and transmission of resistant virus)
Delayed ART

20. 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 all CD4+ cell count levels
↓ transmission
Delayed ART
Early ART
clinicaloptions.com/hiv

21. Antiretroviral therapy

22. History of ART
Got is from CCO inPractice

23. 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

25. 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
February 2013

26. Nucleoside Reverse Transcriptase Inhibitors (NRTI)
Backbone of HIV combination therapy
HIV-1&2
Minimal drug interactions
Renal excreted except ABC
Minimal cross resistance patterns

27. 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

28. 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

29. Twin Drugs Lamivudine (3TC)/ Epivir
Emtricitabine (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)

30. 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

31. 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
3TC 150mg + AZT 300mg + ABC 300 mg

32. 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)
February 2013

33. 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]

34. Non-Nucleoside Reverse Transcription Inhibitors (NNRTI)
HIV-2 is resistant
Limitation of first generation NNRTI
Low genetic barrier to resistance
Long half-lives

35. 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
Administration with food especially high fat meal may increase CNS side effects. False positive reported with cannabinoid and benzodiazepine screening

36. 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

37. 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

38. ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Study Design
Rilpivirine: 25 mg qd + TDF/FTC (n = 346)
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*
ECHO 1x
Efavirenz: 600 mg qd + TDF/FTC (n = 344)
Rilpivirine: 25 mg qd + 2NRTIs* (n = 340)
THRIVE 1x
Efavirenz: 600 mg qd + 2NRTIs* (n = 338)
*2 NRTIs: ECHO: Tenofovir + Emtricitabine (TDF/FTC) THRIVE: Tenofovir + Emtricitabine; Zidovudine + Lamivudine; Abacavir + Lamivudine
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

39. Pooled ECHO and THRIVE: Virologic Response ( ITT-TLOVR)
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive 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)
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

40. 48 Week Data: Virologic Failure
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results
48 Week Data: Virologic Failure
All regimens included 2 NRTIs
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

41. 48 Week Data: Discontinuation Due to Adverse Effects
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results
48 Week Data: Discontinuation Due to Adverse Effects
All regimens included 2 NRTIs
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

42. ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results
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
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

43. 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
1 tablet once daily with a meal
Avoid antacids
PPI is contraindicated

44. Adverse Effects: NNRTIs
All NNRTIs:
Rash, including Stevens-Johnson syndrome
Hepatotoxicity (especially NVP)
Drug-drug interactions

45. 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®]

46. 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
February 2013

47. 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

48. Darunavir (DRV, Prezita)
Dose
ARV naïve or experienced patients with no mutation
800mg 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

49. 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

50. Ritonavir (RTV, Norvir)
Booster for other PI
mg 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

51. Integrase Inhibitors Raltegravir Elvitegravir* (EVG)
Currently being studied in phase III clinical trials
Dolutegravir (S/GSK )
* EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC

52. 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
February 2013

53. 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
Low genetic barrier to resistance

54. 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

55. EVG/COBI/TDF/FTC: “Alternative” First-line Regimen
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, Sax PE, et al. Lancet. 2012;379:
3. DeJesus E, et al. Lancet. 2010;379:

56. 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

57. Entry Inhibitors Enfuvirtide (T-20, Fuzion) Maraviroc (MVC, Selzentry)
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
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

58. New DHHS Treatment guidelines
Feb, 2013

59. 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

60. Initial Regimen: Recommended/Preferred Agents
TDF/FTC +
EFV
ATV/RTV
DRV/RTV
RAL
DHHS Guidelines . Feb 2013; Thompson MA, et al. JAMA. 2010;304;

61. Initial Regimen: Recommended/Alternative
TDF/FTC or ABC/3T +
RPV
LPV/RTV
FPV/RTV
EVG/COBI/TDF/FTC
9. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012.
10. DHHS Panel Statement. September 18, 2012.

62. CYP450 and Drug Metabolism
CYP2E1
CYP3A4
CYP2C
CYP2D6
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
Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. 62

63. Effect of ARV on Drug Metabolism
Induced by: RTV, NFV, TPV EFV, NVP
Inhibited by: RTV, NFV, IDV, SQV, DLV
3A4
Inhibited by: RTV
Induced by: RTV, NFV
Inhibited by: EFV, DLV
Induced by: RTV, NFV
Inhibited by: DLV
2C19
2D6
2C9
Induced by: RTV, NFV ?
Induced by: EFV, NVP
1A2
2E1
2A6
2B6
2C8
From Fichtenbaum CJ. Clin Pharmacokinet 2002:41(14): 63

64. 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
February 2013

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

66. ART Approved & Unapproved Drugs

67. References
Chen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol Jun;70(6):
G.J. Stine. AIDS update Mc Graw Hill 2012
Thompson MA, et al. JAMA. 2012;308:
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. Feb 2013
Cohen M, et al. N Engl J Med. 2011;365:
DHHS Panel Statement. September 18, 2012.
Sax PE, et al. Lancet. 2012;379:
DeJesus E, et al. Lancet. 2010;379:
ww.hivinsite.com 67