ANTIRETROVIRAL

THERAPY

AWLACHEW FIRDE (S.PHARMACIST)

 Objectives
• Upon completion of this topic you will be able to
• Explain the routes of transmission for HIV, and its
natural disease progression
• Explain the WHO staging of HIV/AIDS
• Understand criteria to initiate antiretroviral therapy
• Recommend appropriate first and second-line & third
line antiretroviral regimen for pts with HIV infection
• Describe the components of a monitoring plan to
assess effectiveness and adverse effects of 2

antiretroviral regimen
 INTRODUCTION

• Antiretroviral therapy (ART) ART is an abbreviation for Anti-Retroviral Therapy,

• The treatment of HIV infected individuals with anti-retroviral drugs.

• It is also called HAART (Highly Active Antiretroviral Treatment) to explain the use of
at least three anti-retroviral drugs with different mechanism of actions for the
treatment of HIV infection to have effective viral suppression.

• The virus can never be eradicated completely from the body; hence the person
should take the drugs lifelong.

• The goal of ART is

• To suppress the replication and reduce the number of virus in the blood

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And increase the number of CD4 as much as possible and finally improve the general
 Benefits of ART:
Significantly decreases morbidity and mortality
Improves quality of life
Decreased number of orphans
Reduces mother-to-child transmission of HIV
Increased awareness in the community: Increased number of
people who accept HIV testing, hence increase in enrolment int
treatment.
Decreased stigma surrounding HIV infection,
Increased motivation of health workers, they feel they can do
more for HIV patients,
 Improve the productivity of PLWHIV. 4
How HIV Infects Cells?
• Viruses are simple in structure and cannot replicate alone and
thus they require the components of other cells to replicate.
• Main mode of transmission
HIV can be passed from one person to another through:
 Sexual contact (vaginal, anal and oral intercourse), vaginal
secretions, semen
 Blood and body fluids
 Mother to child (>90%) the source of the child’s HIV infection is the
mother. )
Blood transfusion
• Needle prick; sharing of sharp materials; 5

• Mucosal exposure to infected blood & some body fluids

 Etiology and Virology
• HIV has two major types & several subtypes/strains:

• HIV 1- Pandemic:

• HIV 2 – mainly in West Africa

• In sub-Saharan Africa, the majority of infections are caused by

subtype C.

• Subtype B viruses are predominant in Americas, Western Europe & 6

Australia accounting for 12–13% of global infections.

 Etiology and Virology

• HIV is an RNA virus whose hallmark is the reverse

transcription of its genomic RNA to DNA by the
enzyme reverse transcriptase.
• The greatest variability in strains of HIV occurs in the viral
envelope.
• HIV-2 has same genetic organization as HIV-1, but with
significant differences in the envelope glycoproteins.
• HIV-2 variant may be less pathogenic or have a longer
period of latency preceding disease. 7
 Pathophysiology HIV

• Viruses need a receptor on the cell surface in order to attach

themselves and get inside.
• The CD4 molecule is found predominantly on T- helper
lymphocytes.
• The replication cycle of HIV begins with the high-affinity
binding of the gp120 protein to its receptor on the CD4
molecule.
• Once gp120 binds to CD4, the gp120 undergoes a
conformational change that facilitates binding to one of
two major co-receptors of HIV- 1 [CCR5 & CXCR4]. 8
 HIV Life Cycle:
Sites for Therapeutic Intervention.

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Summary: Six steps in life cycle of HIV in the body

1. Attachment/Binding: HIV attaches to the CD4 cell.

2. Fusion: the virion penetrates the plasma membrane of
the CD4+ cells.
3. Reverse Transcription: the enzyme reverse
transcriptase makes DNA copy of the viral RNA.
4. Integration: new viral DNA is then integrated into CD4
cell nucleus using the enzyme integrase.
5. Assembly: the newly formed viral components are
assembled together using the enzyme protease.
6. Budding and release: the new mature virus gets its
envelop proteins and is released in to the circulation
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through budding to continue the cycle.

 WHO Staging of HIV/AIDS

 Primary HIV Infection /Acute retroviral syndrome

 Stage I - asymptomatic
 Stage II - mild disease
 Stage III - moderate disease
 Stage IV - advanced immunosuppression

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 WHO Clinical Stage I

 Asymptomatic
or
 Persistent generalized lymphadenopathy (PGL):
 Bilaterally swollen lymph nodes in the cervical area, under
the arm, or groin.
 Usually not painful
 Performance scale 1: able to carry on normal activity

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 WHO Clinical Stage II
 Moderate unexplained weight loss (<10% of presumed or
measured body weight)
 Recurrent upper respiratory tract infections

 Herpes zoster

 Angular cheilitis

 Recurrent oral ulcerations

 Papular pruritic eruptions

 Seborrheic dermatitis

 Fungal fingernail infections

And/or performance scale 2(normal activity with effort,

but unable to do active work) 13
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 WHO Stage III

 Severe weight loss (>10% of presumed or measured body weight)

 Unexplained chronic diarrhea for > one month
 Unexplained persistent fever (intermittent or constant for

> one month)

 Oral candidiasis

 Oral hairy leukoplakia

 Pulmonary tuberculosis (TB) diagnosed in last two years

 Severe presumed bacterial infections (e.g. pneumonia,

empyema, pyomyositis, bone or joint infection, meningitis,

bacteremia)
 Acute necrotizing ulcerative stomatitis, gingivitis or
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periodontitis
WHO Stage III

 Conditions where confirmatory diagnostic testing is

necessary:
 Unexplained anemia (<8 g/dl), and or
 neutropenia (<500/mm3) and or
 thrombocytopenia (<50 000/ mm3) for more than one
month
 Performance Scale 3 (bedridden <50% of the day for
the past month)

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 WHO Stage IV

 HIV wasting syndrome

 Pneumocystis pneumonia
 Recurrent severe or radiological bacterial pneumonia
 Chronic herpes simplex infection (orolabial, genital or
anorectal of more than one month’s duration)
 Oesophageal candidiasis
 Extrapulmonary TB
 Kaposi’s sarcoma
 Central nervous system (CNS) toxoplasmosis
 HIV encephalopathy, or
 Performance Scale 4 (bedridden >50% of the day for
the past month)
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 HIV Wasting Syndrome

• Wt loss >10% body wt

plus
• Unexplained chronic diarrhea (>1
mo) or
• Unexplained fever (>1 mo) plus
chronic weakness

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 Investigation and Diagonisis

• Demonstration of antibodies to HIV by Rapid test using

the National HIV test algorism using rapid diagnostic
tests (RDTs)
• HIV antigen detection
• Direct detection of the virus using PCR
Algorithm for HIV Testing
 Management

• Objective
• Suppress viral replication to undetectable levels durably;
• Restore and preserve immunologic function;
• Prevent HIV transmission;
• Prevent opportunistic infections;
• Rehabilitate the patient and allow full function and
survival.
 Preparing patients for ART
• Before people start ART, it is important to have a detailed discussion with
them about their willingness and readiness to initiate ART.
• The following issues should be addressed during the preparation: -
• The benefits of ART, advantage of Rapid initiation over delayed initiation,
• Possible adverse effects of ARVs & OI medications,
• Information regarding lifelong treatment,
• The required follow-up and monitoring visits,
• Detailed examination and treatment of OIs,
• Proper adherence counseling and support,
• Counseling on effective FP planning choices,
• Counseling on disclosure and screening of family members,
• Education on safer sex
 Non pharmacologic

• Counseling and psychological support

• Nutritional support

• Socio-economic support
 Pharmacology

1. Prevention:
A. Primary Prevention:
• Vaccine development is on trial;
• Effective prevention of transmission through universal precautions of
IP is vital.
• PMTCT
B. Secondary Prevention:
• HAART and prophylactic regimens can prevent OIs and improve
survival.
• Prophylaxis for common OIs should be given to pts per the national
guideline. 23

• Secondary prophylaxis includes PEP.

 Pharmacology

2. HAART:
• HAART is one component of the comprehensive care and
treatment of PLWHA.
• Treatment regimens for HIV infection are constantly
changing.
• People are still doing well over 25 years with good
adherence to HAART.

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 Goals of ART

• Clinical goal: Prolong & improve quality of life

• Virologic goal: Reduce viral load
• HIV RNA < 50 copies/ml or “undetectable” within 4-6 months of ART
initiation is good achievement.

• Immunologic goal: Immune reconstitution

• Therapeutic goals: Maintain future treatment options,
minimizes toxicity & maximizes benefit.
• Preventive goals: Reduce HIV transmission:
• PMTCT
• PEP 25
 Classes of Antiretrovirals

1. Reverse transcriptase (RT) inhibitors

Nucleoside RT inhibitors (NRTI)
Nucleotide RT inhibitors (NtNRI)
Non-nucleoside RT inhibitors (NNRTI)
2. Protease inhibitors (PI)
3. Fusion inhibitor
4. Integrase inhibitors
5. CCR5 Inhibitor
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• Combination of at least 3 drugs:
• 2 NRTIs
• 1 Integrase inhibitor or NNRTI, 1-2 PIs;

• Therapy with only one or two agents allows HIV to overcome

therapy through resistance mutations.
• Regular follow up is mandatory with clinical and laboratory
evaluation.
• CD4 counts every 3-6 months
• Viral load tests every 3-6 months and 1 month following a change in
therapy; and
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•
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Other tests should be done regularly based on national guideline.
What ART regimen to start with (First-line
ART)
• First line ART for Adults and adolescents including pregnant and breast feeding
women
• It is recommended to use simplified, less toxic, and more effective with rapid onset of
viral suppression and convenient regimens as fixed-dose combinations (FDC) for ART.
• The preferred first-line regimen for adults and adolescents (>10 years of age or >30 kg
body weight) including pregnant and breast-feeding women is TDF+ 3TC+DTG as a
once-daily dose
• NB; Current evidence-based guidelines do not recommend NNRTI (e.g., EFV) based
regimen as firs line options due to the availability of more tolerable and efficacies INSTI
(DTG, RAL) containing regimens.
• Previous guideline does not recommend DTG containing regimens for pregnant and
breast feeding and women of childbearing age due to preliminary NTD report of 0.9%
from Botswana. Based on this evidence DTG can be used as the alternative preferred
agent for women of childbearing potential after discussing the potential risk with the
mother.
• For HIV/TB co-infected adults and adolescents, the recommended dose of DTG is 50
mg twice daily
 Treatment Regimen

• Second-line ARV combination regimens for adults and adolescents

• Before switching to second (as well as third) line regimen, ensure the following.
• Two consecutive viral load measurements > 1000 copies/ml at least 3 months apart.
• First viral load measurement done at least 6 months after switching to second-line regimen.
• The repeat VL test should be done after 3 months of EAS.
• A new regimen for treatment experienced patients should include at least two, and preferably
three, fully active agents (Fully active agents: have uncompromised activity based on patient’s
ART history and drug-resistance test results, if available or have a novel mechanism of action).
• Provide continuous adherence support to all patients before and after regimen changes.
• Discontinuation or a briefly interruption of therapy will lead to a rapid increase in HIV RNA, a
decrease in CD4 count, and an increase in the risk of clinical progression.
 Second-line ART

Target population Preferred Second line regimen

If AZT was used in first-line ART TDF + 3TC + LPV/r or ATV/r

Adults and adolescents
(≥10 years) If TDF was used in first line ART AZT + 3TC + LPV/r or ATV/r

HIV and HBV co-infection DTG + TDF + 3TC or (ATV/r or LPV/r)

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 PEP

• Indications for PEP

• Occupational exposure (healthcare workers, police)
• Exposure to other people’s blood
• Non occupational
• Discordant couples following barrier protection breakage,
• Rape
• PEP regimens
• TDF+3TC+DTG: 1 tab daily for 28 days
• Given at earliest possible opportunity, within 72 hours of
exposure 33
 Pre exposure prophylaxis

• Oral Pre – Exposure Prophylaxis (PrEP) is the use of ARV drugs by

people who are not infected with HIV but on continuous risk to block
the acquisition of HIV.
• Substantial risk of HIV infection is provisionally defined as an incidence
of HIV higher than 3 per 100 person-years in the absence of pre-
exposure prophylaxis (PrEP).
• The Target population for PrEP service are FCSWs and HIV negative
partners of sero-discordant couples with substantial risk of acquiring
HIV.
• PrEp regimen TDF+3TC
 ARV drug Toxicities

AZT
• Anemia, neutropaenia, myopathy, lipodystrophy
• Lactic acidosis
Mgt:
• Substitute AZT with TDF or ABC if used in 1st -line ART
• Substitute AZT with TDF or ABC if used in 2nd -line ART
TDF
• Tubular renal dysfunction, Fanconi syndrome
• Decreases in bone mineral density
• Lactic acidosis or severe hepatomegaly with steatosis
Mgt :
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• Substitute TDF with AZT or ABC if being used in 1 -line ART
st
 ARV drug toxicities

ABC
• Hypersensitivity reaction
• Electrocardiographic abnormalities (PR interval prolongation)
Mgt :
• Substitute ABC with TDF or AZT if is being used in first-line ART
• Substitute ABC with TDF if ABC is being used in second-line ART

EFV
• Persistent CNS toxicity (such as abnormal dreams, depression or mental confusion)
• Hepatotoxicity
• Hypersensitivity reaction, Stevens-Johnson syndrome
• Male gynaecomastia
Mgt :
• Substitute with boosted PI/DTG
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• If the person cannot tolerate either NNRTI, use boosted PIs

 Adherence

• Make sure patient understands the importance of adherence.

• Remind the patient that ART is life saving and good outcome
depends on taking them every day at the right time.
• Use the medication regimen and discuss which pills need to be taken
at which specific time.
• Advise the patient not to miss any medication or timing.
• If there is missing, the patient can take the missed doze within 6
hours for medications taken on twice per day or 12 hours for
medications taken once per day or 24 hours doses respectively.
• If these times passed, do not take, wait for the next
 Adherence…

• Estimating adherence based on the number of doses/ drugs

missed in a certain period:
• While calculating adherence using number of doses missed,
always take the last one month.
• Example: If you dispensed 60 doses (BID) at the last visit and
the patient missed three doses, the adherence will be 95%.
(3/60) X 100= 5%, as percentage missed adherence.
• If the patient did not miss any dose, then the adherence will be
100%.
 Adherence…

• . Record the percentage or write G, F, or P:

• G (GOOD) - equal to or greater than 95% adherence i.e., missing only 1 out of
30 doses or missing 2 from the 60 doses implies good adherence.
• F (FAIR) - 85-94% adherence, i.e., missing 2-4 doses out of 30 doses or 4 to 9
doses from 60 doses.
• P (POOR) - less than 85% adherence, i.e. missing >5 doses out of 30 doses or
> 10 doses from 60 doses implies poor adherence.
• Fair or poor adherence requires adherence counseling by health worker.
• Toxicity/Side effects , Share with others , Forgot ,Too ill ,Stigma, discloser ,
Drug stock out , Lost/ran out of pills , Delivery/travel problems
END
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