M01 S04 L07 ART Roxas &w=1170&h=500]

1. SHIP Telehealth
Antiretroviral Agents
Evalyn A. Roxas, MD, MPH ©, FPCP, FPSMID
Infectious Diseases Specialist
Cllinical Associate Professor,Sectionof InfectiousDiseases,UP-PGH
AssistantProfessor,DepartmentofMedicalMicrobiology,UP-CPH
September 13, 2018

2. Module 1- Lecture 7:
ART Dosing and Side Effects

3. At the end of this session, the participants should be able…
1. To appreciate the importance of discovery of antiretroviral drugs
2. To understand the different types of antiretroviral drugs
a. mechanism of action
b. side effects
c. dosing
3. To know the 2016 WHO guidelines on the use of antiretroviral
drugs for treating and preventing HIV infection
a. when to start
b. what to start
Objectives

4. Timeline of ARV Approvals
1987: Zidovudine1987: 1st NRTI Approved
1995: 1st PI
1996: 1st NNRTI
2003: 1st Fusion Inhibitor
Entry inhibitors, Integrase
inhibitors
1995: Lamivudine, Invirase®
1996: Nevirapine, Ritonavir, Indinavir
2003: T-20, Atazanavir, Emtricitabine,
Fosamprenavir
2005: Tipranavir
2006: Darunavir
2007: Maraviroc
1991: Didanosine
1992: Zalcitabine
1994: Stavudine
1997: Delavirdine, Nelfinavir, Fortovase®
1998: Abacavir, Efavirenz
1999: Amprenavir
2000: Lopinavir/ritonavir
2001: Tenofovir

5. Currently, 51 DOH-designated treatment facilities
offering anti-retroviral drugs in the Philippines.
As of August 2017, a total of 22,413 PLHIV are
currently enrolled on ART – 33% of the
estimated total number of PLHIV (67,000) by the
end of 2017.
By 2022, the goal is to provide ART to 90% of
PLHIV.
www.doh.gov.ph

6. 1200
1000
800
600
400
200
0
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11+
0
1/2
1/4
1/8
1/16
1/32
1/64
1/128
1/256
1/512
CD4+T-cells,cells/mL
PlasmaViremia(DilutionalTiter)
Clinical latency
Opportunistic
diseases
Constitutional
symptoms
Death Acute HIV syndrome
wide dissemination of virus
seeding of lymphoid organs
Primary
infection
Weeks Years
Natural History of HIV Disease

7. HAART Improves Outcomes1
1Palella FJ et al. N Engl J Med 1998 March; 338:853-60.

8. What is the Goal of Treatment?
Maximize Viral Suppression
Restore and Preserve Immunological Function
Improve Quality of Life
Reduce HIV-related Morbidity and Mortality

9. Antiretroviral Drugs

10. Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors (NRTIs)
◼Abacavir
◼Didanosine
◼Emtricitabine
◼Lamivudine
◼Stavudine
◼Tenofovir
◼Zalcitabine
◼Zidovudine

11. NRTI Mechanism of Action
◼NRTIs mimic other nucleosides and are
incorporated into the DNA strand
◼They prevent the addition of the natural
nucleosides into the DNA strand
◼NRTIs inhibit the viral reverse transcriptase
enzyme
◼Enzyme responsible for transcribing viral RNA
into double stranded DNA
◼This halts the production of new virions
Clinical Pharmacology 2007. Gold Standard, Inc.

12. 1
2
3
4

13. Zidovudine (AZT)
• Zidovudine (ZDV), also known as azidothymidine (AZT)
• Oldest ARV (1987)
• Thymidine analogue
• SE: headaches, fever, and nausea
• Toxicities: rash, anemia, neutropenia, lactic acidosis,
hepatotoxicity, cardiomyopathy, and myopathy
• These conditions were found to be reversible upon
reduction of AZT dosages
• For lactic acidosis: usual symptoms are nonspecific –
tired, muscle pain, abdominal pain
• Lactic acidosis – medical emergency, stop meds, admit,
check ABG and (if available) lactate level
NRTIs

14. Lamivudine (3TC)
• Originally developed for hepatitis B
• Good activity against HIV at higher doses than that for
Hepatitis B
• Cytidine analogue
• Well tolerated, allergies rare
• Potential for lactic acidosis, but usually the last suspect
• SE: nausea, diarrhea, headaches, feeling tired, and cough
• Toxicities: liver disease, lactic acidosis, and worsening
hepatitis B among those already infected
• Can be taken with or without food
• High level resistance is associated with the M184V/I mutation
• Long-term use of lamivudine can trigger a resistant hepatitis B
virus (YMDD) mutant.
NRTIs

15. Tenofovir (TDF)
• Tenofovir disoproxil fumarate (tenofovir DF)
• Nucleotide analog reverse transcriptase
• High barrier to resistance
• Very good activity, drug of choice especially for HBV coinfection
(with 3TC)
• SE: nausea; occasional dizziness, diarrhea, headache
• Toxicities: Lactic acidosis, liver toxicity, decreased bone
mineral density
• Potential to cause Fanconi-like syndrome – monitor creatinine;
Avoid in renal failure
• Low allergy potential
• Can be taken with or without food.
• Pregnancy category B drug
• Passed through breast milk and could have serious side effects
on a child who is breastfed.
NRTIs

16. Emtricitabine (FTC)
• Fixed-dose combination with tenofovir disoproxil
(Truvada) or triple combination of emtricitabine,
tenofovir and efavirenz (Sustiva)
• Cytidine analogue
• SE: unusual; diarrhea, headache, nausea, and
rash.
• More severe side effects: hepatotoxicity or a lactic
acidosis.
NRTIs

17. Stavudine (D4T)
• Avoid as much as possible
• Metabolic side effects, wasting
• High potential for lactic acidosis
NRTIs

18. ◼Adverse Effect
▪ Mitochondrial toxicity
▪ Increase the risk of lactic acidosis with hepatic steatosis
▪ Increase transaminases
▪ Lipid metabolism disorders
▪ Lipodystrophy
NRTI

19. 2-NRTI as part of Combination Regimen
◼ Most dual nucleoside regimens included one
thymidine based drug, specifically zidovudine or
stavudine. These drugs, when used along with
lamivudine as two-NRTI backbones of potent
combination regimens, have durable virologic
potency for over five years
◼ Side effects of these agents however, may make it
necessary to closely monitor for toxicities or to
prescribe alternative NRTIs for selected patients.

20. Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
◼Delavirdine
◼Efavirenz
◼Nevirapine

21. Mechanism of Action
◼NNRTIs also inhibit the viral reverse
transcriptase enzyme but have a different
mechanism of action compared to NRTIs
◼NNRTIs bind directly to the reverse
transcriptase enzyme
Viral RNA double stranded DNA

22. 1
2
3
4

23. Nevirapine
• Older NNRTI
• High hepatotoxicity risk for Male with CD4<400 or Female
CD4<250
• SE: rash, headache, nausea, feeling tired, and liver
problems
• Toxicities: severe skin rash to Steven Johnsons
Syndrome
• DO NOT USE with Anti-tuberculous drugs (levels become
subtherapeutic)
• Low barrier for resistance (K103N)
• Safe for use during pregnancy
NNRTI

24. Efavirenz
• Newer NNRTI
• Generally well tolerated
• Can cause vivid dreams, avoid in patients
with suicidal ideation
• Low potential to cause rash and SJS
• Can be used with Anti-Koch’s
• TERATOGENIC, do not use in pregnant
women
NNRTI

25. NNRTI
◼HIV-2 is intrinsically resistant to most NNRTIs
◼AE
▪ GI
▪ Skin rash – rarely, Stevens -Johnson syndrome
▪ Numerous interactions with other drugs due to
their metabolism by the CYP450 system

26. Protease Inhibitors (PIs)
◼Amprenavir
◼Atazanavir
◼Fosemprenavir
◼Indinavir
◼Lopinavir
◼Ritonavir*
◼Nelfinavir
◼Saquinavir
◼Tipranavir

27. PI Mechanism of Action
◼Protease - enzyme is responsible for cleaving
(cutting up) larger polyproteins into structural
proteins and reverse transcriptase enzyme
◼Protease is needed to form a fully mature,
functional virus that is able to replicate and
produce more virus
◼Protease inhibitors prevent this enzyme from
doing its job in the later steps of the viral life
cycle
Clinical Pharmacology 2007. Gold Standard, Inc.

28. ENTRY
UNCOATING
REVERSE
TRANSCRIPTION
INTEGRATION
PROTEIN
PROCESSING
ASSEMBLY
BUDDING
APOBEC3G
CD4
CCR5
FUSION
ATTACHMENT
P
RT

29. Lopinavir-ritonavir
• Combination PI (ritonavir for boosting)
• Common side effects: diarrhea (improves
with time), metabolic (lipid abnormalities,
wasting)
• Serious: pancreatitis
• High barrier to mutation
• Expensive
• Lots of drug interactions: rifampicin, PPI’s,
statins
• Safe for pregnant
• Special precaution: structural heart
disease,IHD, or cardiomyopathies

30. ◼AE
▪ Redistribution and accumulation of body fat
▪ Central obesity
▪ Dorsocervical fat enlargement
▪ Facial and peripheralwasting
▪ Breast enlargement
▪ Cushingoid appearance
▪ Inc in triglycerides and LDL
▪ Glucose intolerance, insulin resistance

31. NNRTI vs. PI Based Regimens
Pro Con
NNRTI-
based
•Low pill
burden
•Spare PI class
•Low barrier for
developing drug
resistance (K103N)
PI-
based
•Potency
•High barrier to
developing
resistance
•Long-term metabolic
consequences:
dyslipidemia, insulin
resistance, abnormal
lipoaccumulation

32. Fusion Inhibitors
Enfuvirtide - N/A;
MOA: disrupts the HIV-1 molecular machinery
at the final stage of fusion with the target cell,
preventing uninfected cells from becoming
infected
◼AE
▪ Local injection site reactions
▪ Hypersensitivity reactions
▪ Eosinophilia

33. ENTRY
UNCOATING
REVERSE
TRANSCRIPTION
INTEGRATION
PROTEIN
PROCESSING
ASSEMBLY
BUDDING
APOBEC3G
CD4
CCR5
FUSION
ATTACHMENT
P
RT

34. CCR5 inhibitors
Maraviroc -N/A
◼ First in new class of agents
◼ binds to the CCR5 receptor on the membrane of
human cells such as CD4 cells. This binding prevents
the interaction of HIV-1 gp120 and human CCR5
which is necessary for entry into the cell.
◼ does not prevent HIV-1 entry into CXCR4-tropic or
dual-tropic cells.

36. Antiretroviral Drugs Slow
HIV Replication
Integrase Inhibitors
Block the action of integrase, a viral enzyme that inserts the viral
genome into the DNA of the host cell.

37. Integrase Inhibitors
◼Raltegravir
◼Elvitegravir
◼Useful in salvage therapy for patients whose
virus has mutated and acquired resistance to
other drugs

38. Highly Active Antiretroviral Therapy
(HAART)

40. Selecting a Regimen
• Potency
• Tolerability
• Drug-drug interactions
• Co-morbidities
• Lifestyle (dosing convenience, etc)
• Adherence
• Pre-treatment CD4 cell count
• Gender

44. 2002- WHO first published guidelines on the use of antiretroviral therapy (ART)
for HIV infection among adults and adolescents
2006 -updates of the guidelines introduced the concept of a public health
approach, with simplified and harmonized ART regimens
2013 - first revision by WHO into consolidated guidelines that address the use of
ARV drugs for HIV treatment and prevention across all age groups and
populations, based on the HIV service continuum.
2016- updates the 2013 consolidated guidelines on the use of antiretroviral drugs
following an extensive review of evidence and consultations in mid-2015
• strong evidence has emerged to show that using ART earlier results in
better clinical outcomes for people living with HIV compared with delayed
treatment.
• newer class of drugs – integrase inhibitors – is becoming more affordable
for low- and middle-income countries.
• Most countries have moved or are moving to provide lifelong ART
regardless of CD4 cell count to all pregnant and breastfeeding women, and
many are moving to implement viral load testing as the preferred means of
monitoring people who are taking ART.

45. New recommendations
• Provide lifelong ART to all children, adolescents and
adults, including all pregnant and breastfeeding women
living with HIV, regardless of CD4 cell count.
• WHO has also expanded earlier recommendations to offer
PrEP to selected people at substantial risk of acquiring
HIV.
• Alternative first-line treatment regimens are
recommended, including an integrase inhibitor as an
option in resource-limited settings and reduced dosage of
a key recommended first-line drug, efavirenz, to improve
tolerability and reduce costs.

50. 1. HAART improves outcomes (death)
The goals of treatment are
a. maximize viral suppression
b. restore and preserve immunologic function
c. reduce HIV related morbidity and mortality
d. improve quality of life
2. Different types of antiretroviral drugs
a. NRTI
b. NNRTI
c. PI
d. Fusion inhibitor
e. CCR5 inhibitors
f. Integrase inhibitors
Summary

51. 3. 2016 WHO guidelines on ART
Strong evidence has emerged to show that using ART
earlier results in better clinical outcomes for people
living with HIV compared with delayed treatment.
Newer class of drugs – integrase inhibitors – is
becoming more affordable for low- and middle-income
countries.
Most countries have moved or are moving to provide
lifelong ART regardless of CD4 cell count to all
pregnant and breastfeeding women, and many are
moving to implement viral load testing as the preferred
means of monitoring people who are taking ART.
Summary

52. 3. 2016 WHO guidelines on ART
Most countries have moved or are moving to provide
lifelong ART regardless of CD4 cell count to all
pregnant and breastfeeding women, and many are
moving to implement viral load testing as the preferred
means of monitoring people who are taking ART.
Summary

53. End