Overview of

Antiretrovirals (ARVs) for

treatment and prevention
Dr Shailendra Sawleshwarkar
Senior Lecturer
Program Director
Postgraduate Program in Sexual and
Reproductive Health
Western Sydney Sexual Health Centre
Westmead Clinical School, Faculty of Medicine
and Health, University of Sydney

The University of Sydney Page 1

 Natural History of HIV Infection

Primary Death
1200 Infection + Acute HIV syndrome 107

1100
Opportunistic
Diseases

HIV/RNA Copies per ml Plasma

1000 106

900
Clinical latency
CD4 + T Lymphocyte Count (cells/mmm3)

800
Constitutional 105
700
Symptoms
600

500 104

400

300
103
200

100

0 102
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11
Weeks Years
The University of Sydney Page 2
Source: Fauci, A., Pantaleo, D., Stanley S., Weismann, D. Annals of Internal Medicine 124: 654-663, 1996
 Progression from HIV disease: untreated

2-6 weeks 10 years 2 years

Risk HIV AIDS Death

behaviour infected

The University of Sydney Page 3

 Antiretroviral therapy coverage and number of
AIDS-related deaths, global, 2000–2015

The University
Sources: GARPRof Sydney
2016; UNAIDS 2016 estimates. Page 4
 Goals of specific therapy of HIV
for the individual

• Control viral replication

– Reduce viral load by > 3 – 4 logs to below level of detection
• Normalise T-cell homeostasis
– Allow CD4 and CD8 T-cell recovery
– Minimise immune reconstitution disease
• Minimise direct side effects in general
• Minimise long term indirect effects on vascular, metabolic
and osteoporosis risk factors
• Maintain future options of ARV therapy if possible

The University of Sydney Page 5

 When to treat ? – guidelines based on
benefit to individual
• Treat as soon as possible after diagnosis
• Good evidence for Rx at all CD4 levels ( START Trial data 2015 )
• WHO guidelines for Rx at all levels of CD4 (since 2016)
• Very Strong evidence for clinical benefit initiating Rx at CD4 of
350/uL- 500/uL / high Viral Load
• Overwhelming evidence for Rx if CD4 T-cells < 350/uL
• Strong evidence for Rx if
– clinical immunodeficiency
– Malignancy needing Rx
– Opportunistic infection ( timing issues are complex )

The University of Sydney Page 6

 When to start – ART Trends from 2012 to 2016 status
Estimated millions of people eligible for
ART in lower & middle-income countries in 2012 onwards

11 17 21 26 37

1 2 3 4 5
“Test and treat”
CD4 ≤ 200 CD4 ≤ 350 CD4 ≤ 350 CD4 ≤ 500 All HIV+
+ + +
TB/HIV TB/HIV TB/HIV HBV/HIV
HBV/HIV HBV/HIV SD couples
Recommended Recommended + Pregnant
until 2010 since 2010 Children < 5

ART regardless of
CD4 count for:
The University of Sydney  HIV-SD couples Page 7
 Pregnant women
 Antiretroviral therapy 2019

2 NRTI + INSTI
OR
2 NRTIs + PI (boosted with Ritonavir)
OR
2NRTI + NNRTI

The University of Sydney Page 8

 ARV Development: US Regulatory processes

HAART era ---------------------------------------

DTG
RAL
DLV ELV
NVP TDF ETR
ddC ABC
ZDV d4T
ddI 3TC EFV FTC

’87 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03’04 ’05’06 ’07’08’09

NRTI SQR NFV LPV/r ATV

NNRTI FPV DRV
PI RTV APV TPV
Entry T-20 MVC
inhibitor IDV
Triple active Combinations
Integrase Atripla;
Inhibitor
Eviplera
The University of Sydney
Stribild Page 9
Triumeq
 Current Antiretrovirals (ARVs)
Nucleoside reverse transcriptase Protease inhibitors (PI)
inhibitors (NRTI) • Saquinavir SQV
• Zidovudine ZDV • Indinavir IDV
• Lamivudine 3TC • Nelfinavir NFV
• Lopinavir/r LPV/r
• Stavudine D4T
• Amprenavir APV
• Didanosine DDI
• Atazanavir ATV
• Abacavir ABC
• Fosamprenavir FPV
• Tenofovir TDF/TAF • Tipranavir TPV
• Emtricitabine FTC • Darunavir/r DRV/r
Non-nucleoside reverse
transcriptase inhibitors (NNRTI)
Entry Inhibitor
• Nevirapine NVP
• Enfuvirtide T-20
• Efavirenz EFV
• Etravirine ETR Integrase Inhibitors (INSTI)
• Rilpivirine RPV • Raltegravir RAL
• Elvitegravir EVG
• Dolutegravir DTG
CCR5 Inhibitors
• Maraviroc MVC
The University of Sydney Page 10
 “ERAS” of Therapy
• Monotherapy 1987 – early 1990s
• Dual Therapy - mainly dual nucleosides
• Triple therapy … HAART since mid 1990s
– Generally two NRTI plus NNRTI or PI
• Boosted HAART late 1990s
• Other co-formulations and cocktails
• Intensification … raltegravir / new integrase
inhibitors - since 2007
• Single “pill” once or twice daily triple active drug
therapy
– Trizivir , Atripla , Eviplera , Stribild, Triumeq
– New coformulations
The University of Sydney Page 11
 What was learned from monotherapy

• Efficacy in short early trials of AZT in advanced patients

… reduced progression to AIDS
• Development of resistance was a rapid problem with
monotherapy
• Intracellular pharmacology more important than plasma
level of Nucleoside Reverse Transcriptase Inhibitor
• Post marketing revealed toxicities reduced as doses
reduced
• Many trials continued including use in pregnancy ….
Important findings for preventing MTC transmission.

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 The “original” Zidovudine .. A
prototypic thymidine analogue

• Initial dosing was 200 mg q 4 hours round the

clock = 1200 mg/day
• 1200mg - High rates of anaemia and
neutropaenia and Bone marrow toxicity
• Now 500- 600mg still results in Mitochondrial
toxicity - interference with gamma polymerases
• Myopathy, muscle toxicity / wasting common at
initial doses
• BUT even one drug reduced mortality in short
term
• Became a component of many HAART regimens
The University of Sydney Page 13
 Dual therapy
• Randomised DBPCT demonstrated benefit from use of
dual therapy eg AZT + ddC or AZT + ddI
– “Two drugs are better than one” = DELTA TRIAL
• Brief period of dual Rx use before availability of
NNRTI and PI based HAART (triple therapy) followed
in mid 1990s
• New coformulations of Rilpivirine (NNRTI) and
Integrase inhibitor (Dolutegravir) for controlled
parients

The University of Sydney Page 14

 HAART/cART
• Term refers to Highly Active AntiRetroviral
Therapy or combination ART
• Involves at least 3 drugs
• Usually at least 2 classes
• Commonly 2 NRTIs and either an integrase
inhibitor (usually) or NNRTI or Protease
Inhibitor ( usually boosted by ritonavir or
another agent – but losing favour )
The University of Sydney Page 15
 Guidelines continue to be in rapid evolution

– ASHM Australian commentary on DHHS

– ashm.org.au
– DHHS ( USA) aidsinfo.nih.gov/guidelines
– Adults
– Paediatric
– others
– European Guidelines
– WHO

The University of Sydney Page 16

 Principles of ARV Rx in 2019
• Long term Rx
• Avoid interruptions
• If have to interrupt avoid long-acting drug “tail”
• Avoid drug interactions
• Consider absorption and Blood brain barrier issues
& Seek brain protective formulations
• Pay attention to Timing during the day– it is
important
• Many formulations only oral – ( issues if Nil By
Mouth NBM )
• Avoid predictable side effects
The University of Sydney Page 17
 ARV ratings explained

Rating of Recommendations:
– A = Strong;
– B = Moderate;
– C = Optional
Rating of Evidence:
– I = Data from randomized controlled trials;
– II = Data from well-designed nonrandomized trials,
observational cohort studies with long-term clinical outcomes,
relative bioavailability/bioequivalence studies, or regimen
comparisons from randomized switch studies;
– III = Expert opinion

The University of Sydney Page 18

 ASHM ARV guidelines

– Bictegravir/tenofovir alafenamide/emtricitabine (AI)

– Dolutegravir/abacavir/lamivudinea—only for patients who
are HLA-B*5701 negative (AI)
– Dolutegravir (DTG) plus tenofovirb/emtricitabinea (AI)
– Raltegravir plus tenofovirb/emtricitabinea (BI for tenofovir
disoproxil fumerate, BII for tenofovir alafenamide)

The University of Sydney Page 19

 2019 WHO ARV Guidelines

The University of Sydney Page 20

 Dolutegravir and Pregnancy

– Preliminary data have raised concerns about an increased risk

of neural tube defects in infants born to people who were
receiving DTG at the time of conception.
– Effective contraception should be offered to adult women and
adolescent girls of childbearing age or potential.
– DTG can be prescribed for adult women and adolescent girls
of childbearing age or potential who wish to become pregnant
or who are not otherwise using or accessing consistent and
effective contraception if they have been fully informed of the
potential increase in the risk of neural tube defects (at
conception and until the end of the first trimester).
– If women identify pregnancy after the first trimester, DTG
should be initiated or continued for the duration of the
pregnancy.
The University of Sydney Page 21
 2019 WHO ARV Guidelines

The University of Sydney Page 22

 Transition to Dolutegravir

The University of Sydney Page 23

 Transition to Dolutegravir

The University of Sydney Page 24

 Transition to Dolutegravir

The University of Sydney Page 25

 Future of ART – oral and injectable 2 drug regimens

The University of Sydney Page 26

 Success in HIV Management
• Multidimensional
• Multidisciplinary
• Clear goals
• Long term approach
• Optimisation of timing of interventions
• Clear expectations of patient’s participation
• Prepare for the unexpected !

The University of Sydney Page 27

 STEPS in MANAGEMENT
• Understanding of person (patient) and the infection
• Education of patient
• Assessing patient by physical examination / Investigation
• Preparing for /and introducing interventions
– Prophylactic agents against OI
– Antiviral therapy
• Developing an Adherance strategy
• Monitoring plan
– Efficacy
– Adverse effects
– Other comorbid conditions
• Dealing with side effects
• Adjusting or changing regimens

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 Assess Key social, behavioural and demographic
information -

• Educational level
• Health literacy and Capacity to Access quality information

• Identification within “communities” – sometimes hidden

• Family and close/ trusted relationships
• Sexual relationships and practices
• Workplace circumstances
• Financial situation

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 Key laboratory information to guide management

• Proof of HIV infection by serology /virology -

attempt to identify duration of infection

• CD4 T-cell level in % of mononuclear cells

(%PBMC) and absolute levels

• HIV viral load (copies /ml units)

• HIV resistance to antivirals – asses by genotype in

countries with high background primary resistance or
where surveillance policy is to assess resistance before
therapy
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 Other laboratory data
• Urinalysis for HIV nephropathy,
(albumin:creatinine ratio and protein:creatinine
ratio)
• Full Blood Count (FBC)
• Liver function tests;
• Renal (kidney) function tests
• Blood glucose
• Blood cholesterol and triglycerides
• Chest X Ray;
• ECG (EKG) “cardiogram”
The University of Sydney Page 31
 Typical monitoring of Rx

– Clinical
– Baseline FBC, biochemistry (creatinine, glucose, lipids ),
CD4-Tcells as % and absolute, VL c/ml
– Week 2 - safety blood tests FBC, LFT, Creat, CPK
– Week 6 - FBC, LFT, Creat, CD4
– Week 12 – Viral load , CD4, FBC, biochemistry
– Thence 3 – 4 monthly
– In Australia can dispense 6 months at one visit

The University of Sydney Page 32

 Clinical indicators of response

– Weight recovery
– Skin rashes often clear
– Resolution of superficial fungal infections
– Kaposi’s sarcoma may regress
– Neurological disease may improve ( brain function
plasticity effect)
– Fewer new OI ( but may be confused by immune
reconstitution syndrome)
– Resolution of existing OI

The University of Sydney Page 33

 What to expect from an effective
regimen given to ARV naïve patient
– Approximately 1 log reduction per drug
– 3-4 logs reduction in viral load at 10-12 weeks of Rx
with cART ( 3- 4 drugs)
– Sustained reduction to <50 c/ml viral load, mostly to
<20 copies/ml ; usually by 16 weeks
– Gradual recovery of CD4 T-cells over years
– Clinical trial experience usually better than “real-life”
– New trials will generally have data generated from
adding the new drug on top of existing pattern .

The University of Sydney Page 34

 Barbour JD. AIDS. 20(16):2123-5, 2006 Oct 24.

Note

Slopes approx
parallel

CD 4 T-
cell Rise
with
HAART
approx
60-70 /uL
/year

The University of Sydney Page 35

 Strategy for
Adherance
• Good understanding of
– Need
– Duration
– How to mitigate side effects
– Impact of interruptions eg resistance
– Strategies for ensuring adherance
• INDIVIDUAL
• GENERAL
• Planned monitoring and feedback to
patient
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 Failure to control virus – WHY?

– Pre-existing resistance
– Inadequate sustained drug levels
– Drug interactions

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 HIV Resistance

Be alert but not alarmed

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 Changing
regimens
• Carefully consider any changes
• Sequence drugs in view of potential implications
on resistance
• May need to washout some agents
• Generally always introduce at least TWO
effective agents in a new regimen
• Preferably use three drugs to which that virus is
sensitive to
• Avoid overlapping toxicities with previous
regimens
The University of Sydney Page 39
 Changing regimens

– Should only occur if

– Adverse effects
– Lack of efficacy
– Viral escape
– No increase in CD4 levels
– Likely that a switch will improve adherance

NOT for minor short blips of virus which may be artefacts or

transient

The University of Sydney Page 40

HIV Prevention using antiretrovirals:
towards an integrated approach

• Post-exposure prophylaxis (PEP)

• Pre-exposure prophylaxis (PrEP)
• Treatment as prevention (TasP)
• Prevention of mother-to-child transmission
(PMTCT) – (separate session on this topic)

The University of Sydney Page 41

Post exposure prophylaxis (PEP/nPEP)

– A course of ART: 2-3 drugs

– Started within 72 hours

– Taken for 28 days.

– Extensive animal evidence of efficacy

– Used in occupational and non-occupational (sexual

exposure) settings

The University of Sydney Page 42

 Pre-exposure prophylaxis - PrEP

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Pre-exposure prophylaxis (PrEP)

– PrEP – pre-exposure prophylaxis (preventive treatment before

exposure to HIV)
– Two drug regimen for preventing sexual transmission – tenofovir
plus emtricitabine/lamivudine
– Effective, well tolerated, low rates of side effects
– Also the same drugs used in post-exposure prophylaxis (PEP or
NPEP)
– In clinical trials conducted in Africa, Asia, Europe and North
America over the past decade, PrEP has been shown to
significantly reduce the risk of HIV acquisition among
– Men who have sex with men (MSM)
– heterosexual men and women, and
– People who inject drugs (PWID)

The University of Sydney Page 44

 PrEP - Issues

– Maintaining adherence
– Intermittent dosing reduces cost (adherence)
– Available resources, targeting PrEP
– Relative cost-effectiveness of prevention methods
– PrEP cost-effective when used in serodiscordant Ugandan couples
Ying R et al. JIAS 2015;18(Suppl 3):20013
• Uninfected partner starts ART, uninfected partner takes PrEP for the
first 6 months
– Inadvertent Rx during seroconversion
– Risk of developing resistance, but no resistance mutations detected
among newly infected (adherence)
– Transmission of resistant virus – PrEP ineffective
– Long-term safety in HIV-uninfected

The University of Sydney Page 45

 Treatment as prevention – TasP

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ART to prevent HIV transmission
: Treatment as prevention (TasP)
– HPTN 052: RCT to evaluate the effectiveness of ART versus HIV
primary care alone to prevent the sexual transmission of HIV-1
in serodiscordant couples.
– Two study arms: (1) ART at enrollment, or (2) no ART until CD4 <
200, or AIDS.
– Early vs delayed ART 2003-11
• 96% reduction in linked HIV-1 transmission
• 41% reduction in HIV-related disease
– 10 year follow-up
• 93% risk reduction in linked HIV transmissions
• 8 linked infections after infected partner started ART
– 4 before or soon after start, 4 after failure of ART
• No infections occurred while partner stable VL undetectable

The University of Sydney Page 47

Cohen MS et al. NEJM 2011

 Partners studies

– Confirmed that “zero transmissions means

zero risk” for MSM & anal sex as well as
heterosexuals
– Partners 2 study
• 1,000 serodiscordant MSM followed for 8
years
• No linked transmissions
– Partners 1
• 65% heterosexual

Rodger AJ et al. 22nd International AIDS Conference 2018 Abstract

WEAX0104LB; JAMA 2016

The University of Sydney Page 48

 Implementing TasP

– Early diagnosis of primary HIV essential to limit transmission

– Practicality & cost-effectiveness of up-scaling testing &
treatment (coercive testing, stigma)
– Integration with other ARV prevention strategies (PEP, PrEP,
preventing MTCT)

The University of Sydney Page 49

 “The excellent must
not become the enemy
of the good”

The University of Sydney Page 50

Acknowledgements:
Prof Roger Garsia, Head of School, Central Clinical School, Faculty of
Medicine and Health, University of Sydney

Questions?

The University of Sydney Page 51