Clinical Pharmacology

of
Anti-Retro Viral drugs

Project Prashiksha - Online Training of ART Medical Officer 2023

 Session Objective

By the end of the session participants will understand:

• Mechanism of drug action in relation to the life cycle of HIV

• Classification of antiretroviral drugs(ARV)

• Clinical pharmacology of ARV drugs used in National Program

• Recognize common adverse reactions

• Understand drug interactions

 HIV Replication & Mechanism of Drug action

• HIV attacks and destroys the CD4 cells of the immune system.
• HIV uses the machinery of the CD4 cells to multiply (i.e. make copies of itself) and spread
throughout the body.
• The stages of the HIV life cycle are:
o Viral attachment and Viral fusion
o Viral Entry
o Reverse transcription in the cellular cytoplasm
o Integration into the cellular genome.
o Viral replication
o Viral assembly and
o Viral budding.
 Mechanism of Action of ARV drugs

HIV cycle video to be played

to explain how ARV drugs act
Fixed Dose Combinations (FDCs) – Definition and Advantages

• Definition of fixed-dose combination (FDC)

is a medicine that includes two or more
active ingredients combined in a single
dosage form
• Fewer tablets to swallow
• Fewer tablets to handle
• Lower risk of drug resistance
Image Source: https://www.google.com/url?sa=i&url=https%3A%2F
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Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

• The first effective class of ARV drugs discovered was the Nucleoside analogues.

• These drugs act by

o Incorporating themselves into the DNA of the virus, thereby stopping the
building process. The resulting DNA is incomplete and cannot replicate.
o Competitive binding with reverse transcriptase enzyme at functionally
essential sites

Note: Nucleotide analogues work similar as nucleosides, but have a nonpeptidic chemical structure
 Tenofovir (TDF)
• Tenofovir is a Nucleotide Reverse Transcriptase Inhibitors (NtRTI)
• Potent drug against HIV-1, HIV-2 and HBV
• Usually well tolerated; Flatulence may bother some

Dose Adverse effects

• Fanconi syndrome-
o Normoglycemic glycosuria
o Proteinuria
Tenofovir
o Hypophosphatemia
300 mg once daily o Hypouricemia
• Bone demineralization and osteopenia
• Azotemia , Rarely Acute Renal Failure
 NRTI: Zidovudine (AZT, ZDV)
• Zidovudine is a thymidine analogue
• Effective against HIV-1 & HIV-2
• Reduces the rate of vertical transmission of HIV
• Available as Fixed Dose Combination (FDC) and single drug as syrup and tablets

Available as Adult Dose Adverse effects

• Bone marrow suppression- Anaemia,
• Tablet and Syrup neutropenia
• Single drug and 300 mg twice • Gastrointestinal intolerance
Fixed Drug daily as a FDC • Headache, insomnia, myopathy
Combinations(FDC) • Lactic acidosis
• Skin and nail hyperpigmentation
Infant ARV Prophylaxis: dosage of Syrup Zidovudine(10 mg/ml)

Source: National Guidelines for HIV Care and Treatment.2021

 NRTI: Lamivudine (3TC, LMV)
• Effective against HIV-1, HIV-2 and HBV
• Excellent drug, well tolerated and least toxic
• Synergistic action with Zidovudine & Stavudine
• Low genetic barrier for resistance
• Lamivudine resistant mutants reduce HIV viral fitness

Available as Adult Dose Adverse effects

150 mg twice • Minimal toxicity

FDC daily or • Rash (though very rare)
300 mg once daily
 NRTI: Abacavir (ABC)
• Abacavir is available along with Lamivudine (3TC) in formulations of 60/30 mg and
600/300 mg
• Can be taken with food
• Hypersensitivity in <5% of adults and children, linked to the presence of the HLA-B
5701 gene
• Hypersensitivity reactions are Potentially fatal. STOP Abacavir and NEVER use it again
Adult Dose Adverse effects
300 mg twice • Hypersensitivity reaction in 3 to 5% (can be fatal)
daily • Fever, rash, fatigue, nausea, vomiting, anorexia
or • Respiratory symptoms (sore throat, cough, shortness of
600 mg once breath)
daily • Re-challenging after reaction can be fatal
 Summary : Commonly used NRTI
Generic Name Dose Adverse effects
Tenofovir
Disoproxil
300 mg once daily Renal toxicity, bone demineralization
Fumarate (TDF)

Zidovudine Anaemia, neutropenia, bone marrow suppression,

300 mg twice daily gastrointestinal intolerance, headache, insomnia, myopathy,
(ZDV, AZT) lactic acidosis, skin, and nail hyperpigmentation
150 mg twice daily
Lamivudine (3TC,
or Minimal toxicity, rash (though very rare)
LMV)
300 mg once daily

Abacavir 300 mg twice daily Hypersensitivity reaction in 3 to 5% (can be fatal), fever, rash,
fatigue, nausea, vomiting, anorexia, respiratory symptoms (sore
(ABC) or
throat, cough, shortness of breath); Re-challenging after
600 mg once daily reaction can be fatal
Source: Table-2.2.3, Chapter 2.2, National Guidelines for HIV Care and Treatment, 2021
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Non-competitively block Reverse Transcriptase by directly binding onto it and

preventing the conversion of RNA to DNA
• Active against HIV-1 replication cycles as NRTIs
• Not active against HIV-2 replication cycles
• Inducers of the hepatic cytochrome P450 enzyme system (CYP3A4 and others) –
leading to many drug interactions
• Primarily excreted via hepatic route
• NNRTIs in Program: Efavirenz and Nevirapine
 NNRTI: Efavirenz (EFV)
• Active against HIV-1; Not active against HIV-2
• Oral bioavailability increased with fatty meal
• Avoid in children: If age is <3 years and Weight is <10 kg

Adult Dose Adverse Effects

600 mg once daily as a • CNS symptoms (dizziness, abnormal dreams/
single drug tablet. nightmares insomnia)
(bed time administration is • Psychiatric symptoms (anxiety, depression, mental
suggested to decrease CNS confusion, hallucinations)
side-effects) • Personality changes
• Rash occurs, Though less common than NVP
 NNRTI: Nevirapine (NVP)

• Active against HIV-1; Not active against HIV-2

• Excellent oral bioavailability, not food dependent
• Tab Nevirapine is no longer used, under the NACO program
• Syrup Nevirapine is used for Infant ARV prophylaxis in baby born to HIV infected mothers
to prevent vertical transmission of HIV
• Adverse Effects to NVP :
• Hepatitis
• Skin rash may progress to Stevens Johnson syndrome (SJS) and Toxic Epidermal
Necrolysis (TEN).
• Patients who develop severe hepatic toxicity or grade 4/5 skin rashes should not be re-
challenged with NNRTI
Infant ARV Prophylaxis: dosage of Syrup Nevirapine(10 mg/ml)

Source: National Guidelines for HIV Care and Treatment 2021

 Summary: Commonly used NNRTIs
Food related
Generic Name Dose Adverse Effects
advice

600 mg once daily

Avoid taking • CNS symptoms (dizziness, somnolence,
(bedtime is suggested insomnia, confusion, hallucinations,
Efavirenz (EFV) after high fat
to decrease CNS side- agitation) and personality change.
meals
effects) • Rash occurs, but less common than NVP

• Hepatitis (usually within 12 weeks);

sometime life-threatening hepatic toxicity.
200 mg once daily for • Skin rash may progress to severe
Nevirapine
14 days, followed by None conditions, SJS and TEN
(NVP)
200 mg twice daily • Patients who develop severe hepatic
toxicity or grade 4 skin rashes should not
be re-challenged

Source: Table-2.2.4, Chapter-2.2, National Guidelines for HIV Care and Treatment 2021
 Integrase Inhibitors
• Block the action of Integrase, a viral enzyme that inserts the viral genome into
the DNA of the host cell.
• Since integration is a vital step in retroviral replication, blocking it can halt further
spread of the virus
• NACO have rolled out Dolutegravir (DTG) based ART regimen. It is the preferred INSTI.
• DTG can be used for HIV 1, HIV 2, HIV 1 & 2, women exposed to single dose Nevirapine
in past and PLHIV coinfected with TB or Hepatitis B & C
• Women in reproductive age group not using/ accessing contraception/want to be
pregnant should be provided informed choice about the risks and benefits for the use
of Dolutegravir (DTG). Linkages to contraceptive services essential
Current DTG Data In Pregnancy & Newborn: Botswana Tsepamo Study
• The Botswana Tsepamo Study conducts birth outcomes surveillance study at government hospitals
throughout Botswana, covering ~70% of all births.
• Prevalence difference of Neural Tube Defects by ARV and HIV Exposure Categories in 2018, interim analysis
was rate of 0.94%. Till April 2020, prevalence in study had declined to 0.19%.
• Results since April 2021 to March 2022 are compiled in table on Prevalence Difference of Neural Tube
Defects by ARV and HIV Exposure Categories
Exposure group vs. comparison group Prevalence difference (%) (95% CI)
DTG at conception vs. non-DTG at conception 0.00 (-0.07, 0.10)
DTG at conception vs. EFV at conception 0.03 (-0.05, 0.12)
DTG at conception vs. DTG started in pregnancy 0.04 (-0.06,0.14)
DTG at conception vs. non-DTG started in pregnancy 0.04 (-0.07,0.13)
DTG at conception vs. women without HIV 0.04 (-0.01, 0.13)
Conclusion: Prevalence of NTDs among infants born to women on DTG at conception has declined to 0.11% and does
not substantially differ from other exposure groups. Data support existing WHO guidelines that recommend DTG as
first-line for use in all adults, regardless of reproductive potential
Source: Update on neural tube defects with antiretroviral exposure in the Tsepamo Study, Botswana
Available at: https://programme.aids2022.org/Abstract/Abstract/?abstractid=12759
 Advantages of Dolutegravir
• Can be used for HIV-1, HIV-2, HIV-1 and HIV-2
• Can be used in PLHIV co-infected with TB or Hepatitis B or Hepatitis C
• Can be used in women exposed to single dose Nevirapine in the past
• Generally well tolerated with fewer side effects
• achieves rapid viral suppression and much sooner, as compared to Efavirenz
• has a high genetic barrier to developing drug resistance
• has minimal drug-drug interactions (except in HIV-TB co-infected patients)
• Very effective in prevention of HIV transmission from the pregnant woman to her
baby
 Integrase Inhibitors: Dolutegravir (DTG)
Generic Name Dose Adverse Effects

• Insomnia – Patient with complaints of sleep disturbances needs to reviewed

and managed accordingly
• Headache – If persistent and affecting daily routine, refer for expert opinion
• Dizziness, Tiredness
50mg once
• Allergic reactions
daily
Dolutegravir • Weight gain – Strict monitoring is needed and info to be given to PLHIV
in PLHIV >6 • Serious, life threatening side effects:
(DTG) years and 20 o hypersensitivity (allergic) reactions
kg weight o liver derangements
• People with a history of
- Hepatitis B or Hepatitis C co-infection or Deranged LFTs ,
have an increased risk of developing new or worsening liver problems while
taking DTG
 Integrase Inhibitor: Raltegravir (RAL)
• Approved for use in both treatment-naïve and treatment-experienced patients
• Primarily used for Alternate Second-line and Third line ART regimens in the Programme

Generic
Adult Dose Adverse Effects
Name
• Rhabdomyolysis, Myopathy, Myalgia
• Diarrhoea, fever
Raltegravir 400 mg twice • Rash, Stevens-Johnson syndrome, Toxic
(RAL) daily Epidermal Necrolysis,
• Hepatitis and Hepatic failure
• Insomnia
 Summary of commonly used INSTI drugs in NACP
Generic Name Dose Adverse Effects

 Insomnia: Patients with h/o sleep disturbances need to be assessed and managed
accordingly. Sedatives should be added after consultation if it is affecting patient’s daily
routine
Dolutegravir  Headache: If headache is persistent and affecting daily routine of activities, the PLHIV should
(DTG) 50 mg be referred for expert opinion.
(Preferred once  Dizziness
INSTI in daily
programme)  Tiredness
 Allergic reactions
 Weight gain: Weight gain is a known side-effect and strict monitoring is required and
information should be given to the PLHIV for the same.

400 mg  Rhabdomyolysis, Myopathy, Myalgia, diarrhoea, fever, Rash, Stevens-Johnson syndrome,

Raltegravir Toxic Epidermal Necrolysis, Hepatitis and Hepatic failure,
twice
(RAL)
daily  Insomnia

Source: Table-2.2.5, Chapter 2.2, National Guidelines for HIV Care and Treatment, 2021
 Protease Inhibitors (PIs)
• Act at the last stage of viral replication cycle.
• Prevents assembly and release of HIV virus from the infected CD4 cell.
• Extensively metabolised by cytochrome enzyme system (CYP3A4 and others)
Ritonavir Boosted PI
• Ritonavir is added to Atazanavir, Lopinavir and Darunavir to enhance the
bioavailability of the PIs. This is achieved by inhibition of CYP3A4
Advantages of PIs boosted with Ritonavir
• Raises the genetic barrier for development of PI resistance
• High levels of viral suppression
• Reduces pill burden
 Common Side-effects of PIs
All PIs can produce following side effects:
• GI intolerance
• Altered taste
• Abnormal liver function test
• Bone disorder
• Metabolic abnormalities-
o hyperglycaemia
o insulin resistance
o increase in triglycerides and cholesterol level
o lipodystrophy
 Ritonavir Boosted PI- Formulations
Ritonavir boosted PIs used in Alternate First Line ART and Second Line ART
• Atazanavir/ritonavir,
• Lopinavir/ritonavir
Ritonavir boosted PIs Used in Third Line ART regimens: Darunavir/ritonavir
Available
as Adult Dose Adverse effects
• Common- Gastrointestinal adverse effects
100 mg twice o diarrhoea
daily o nausea
Ritonavir
(RTV) (used only to o vomiting
boost o abdominal pain
another PI) • Rarely- Neurological disturbances (including
paraesthesia)
 Atazanavir (ATV)
• Active against HIV-1; variable activity against HIV-2
• Administration with food enhances its bioavailability
• Atazanavir is a Category B drug in Pregnancy (FDA)
Adult Dose Adverse Effects

•Unconjugated hyperbilirubinemia
•Skin rash
FDC tablets-ATV/r •Lipid abnormality
300 mg Atazanavir +100 mg •Hyperglycaemia
Ritonavir •Nephrolithiasis
Dose- once daily •Cholelithiasis
•PR prolongation
•Fat maldistribution
 Atazanavir (ATV)
• Atazanavir is NOT recommended for use patients, who weigh <25 kg or age less than 6yrs
• In Renal failure:
• No dosage adjustment required for patients with renal dysfunction not requiring
Haemo-Dialysis (HD)
• ARV-naive patients on HD: ATV 300 mg + RTV 100 mg OD
• Not Recommended in ARV-experienced patients on HD
• ATV/r can only be used in patients with chronic liver disease in Child-Pugh Class A.
• It should not be used in second line patients with Child Pugh class B or C
 Lopinavir (LPV)
• Active against HIV-1 and against HIV-2
• Lopinavir is boosted with Ritonavir in ratio of 4:1
• LPV/r syrup and Pediatric tablet formulations are available for administration in
children; should be given with food
• A high-fat meal increases absorption, especially of the liquid preparation

Adult Dose Adverse Effects

• Gastrointestinal-Diarrhoea, nausea, vomiting
FDC tablets-LPV/r
• Abnormal lipid profiles
200 mg Lopinavir+50 mg
• Glucose intolerance
Ritonavir
• Use with caution in Hepatitis B and C co-infections
2 tablets twice daily
patients
 Darunavir (DRV)
• Darunavir is highly potent against laboratory strains and clinical isolates of wild-type
and multidrug-resistant HIV and has limited cytotoxicity
• Ritonavir boosted Darunavir is reserved for Third line ART regimens

Adult Dose Dose Adverse Effects

• Hepatotoxicity
• Skin rash (10%)
Formulation: Darunavir 600 mg tablet • Diarrhoea, nausea, headache
Dose: one Tablet twice a day • Hyperlipidaemia
(with tablet Ritonavir 100 mg twice daily) • Serum transaminase elevation
• Hyperglycaemia
• Lipodystrophy
 Summary of commonly used PIs
Generic Name Dose Adverse Effects
Unconjugated hyperbilirubinemia, lipid
Atazanavir/ 300 mg Atazanavir + 100 mg
abnormality, hyperglycaemia, fat maldistribution,
ritonavir (ATV/r) Ritonavir once daily
nephrolithiasis, cholelithiasis, PR prolongation

Lopinavir / ritonavir FDC:200 mg Lopinavir / 50 mg

Ritonavir Diarrhoea, nausea, vomiting, abnormal lipid
(LPV/r)
profiles, glucose intolerance
Heat stable tablets 2 tablets twice daily

600 mg twice a day (when used Hepatotoxicity, skin rash (10%), diarrhoea, nausea,
Darunavir (DRV) with Ritonavir 100 mg twice headache, hyperlipidaemia, serum transaminase
daily) elevation, hyperglycaemia
Common-gastrointestinal (diarrhoea, nausea,
100 mg once or twice daily
Ritonavir (RTV) vomiting, abdominal pain (upper and lower), rarely
according to the PI to be boosted
neurological disturbances (including paraesthesia)

Source: Table-2.2.7, Chapter-2.2, National Guidelines for HIV Care and Treatment 2021
 Summary of Major Toxicities with ARVs

CVD- Cardiovascular disease CNS- Central nervous system GI- Gastrointestinal Most commonly reported Adverse Drug reaction

Source: WHO workshop report on Clinical Aspects of ADRs in HIV and ARV toxicity monitoring approaches, June 2018
 Drug-Drug Interactions
• Pharmacokinetic drug-drug interactions between ARV drugs and concomitant
medications are common
• It may lead to increased or decreased drug levels.
• When prescribing or substituting one or more ARVs, consider the potential for drug-
drug interactions
• Management of particular drug interaction may differ when
o a new ARV is being added in a stable patient on ART
or
o a concomitant drug is being added in a stable patient on ART
 Drug-Drug Interactions (DDIs)
• Be vigilant in monitoring for,
o therapeutic efficacy
o concentration-related toxicities.
• ISTI, NNRTI and PIs have many DDIs with-
o Anti TB Drugs
o Anti HCV drugs
o Oral Contraceptives
o Antacids and Proton Pump Inhibitors
(PPIs)
o Anti-convulsants
 Important drug-drug interactions with DTG
Key drug interaction Suggested management
Amodiaquine Use an alternative antimalarial agent
Carbamazepine Use DTG twice daily or substitute with an
alternative anticonvulsant agent
Phenytoin and phenobarbital Use an alternative anticonvulsant agent
Dofetilide Use an alternative antiarrhythmic agent
Metformin (DTG increases the drug Limit daily dose of metformin to 1000mg when
levels of metformin) used with DTG & monitor glycemic control
Polyvalent cation products containing Use DTG, 2 hours before or 6 hours after
Al, Ca, Fe, Mg and Zn (eg: antacids, polyvalent cations containing product
multivitamins & supplements)
Rifampicin Use DTG twice daily or substitute with rifabutin

*Source: Table-2.2.6, Chapter-2.2, National Guidelines for HIV care and treatment. 2021.
 Drug – Drug Interactions: Anti TB drugs
Drug ARV Effect Recommendation

Rifampicin DTG DTG AUC* ↓ 54% • Dose adjustment. Use DTG 50 mg twice daily (BD).
• Continue 2 weeks after stopping rifampicin
• Do not use EFV 400 mg with rifampicin.
EFV EFV AUC *↓ 26% • Maintain EFV dose at 600 mg once daily and
Rifampicin monitor for virologic response
NVP NVP ↓ 20% to 58% • Do not co-administer
• Contraindicated
↓ PI concentration by • Additional RTV does not overcome this interaction
Rifampicin All PIs >75% and may increase hepatotoxicity.
• Consider rifabutin if a rifamycin is indicated.

EFV ↓ Bedaquiline possible • Do not co-administer

Bedaquiline
NVP ↔ Bedaquiline AUC* • No dose adjustment necessary.

* AUC is the ”Area under the curve”, defined in the field of pharmacokinetics as “the definite integral of a curve
that describes the variation of a drug concentration in blood as a function of time”,
 Drug – Drug Interactions: Anti Hepatitis C Drugs
Drug ARV Effect Recommendation
Ledipasvir/Sofosbuvir TDF Increases TDF levels
Sofosbuvir/ Velpatasvir • Monitor for TDF toxicity

• Reduce dose of Daclatasvir to 30 mg once

Daclatasvir ATV/r Daclatasvir levels daily
• If used with TDF, monitor for TDF toxicity

Daclatasvir activity • Recommended dose Daclatasvir 90 mg

Daclatasvir EFV, NVP reduced once daily
• If used with TDF monitor for TDF toxicity

Sofosbuvir/ Velpatasvir EFV Velpatasvir levels • Do not co-administer

reduced
Drug – Drug Interactions: OC Pills and Anti-fungals

Drug ARV Effect Recommendation

Oral Hormonal Levels of all oral hormonal • Use alternative or

Contraceptives EFV contraceptives are reduced additional contraceptive
methods.

Voriconazole AUC* ↓ 77% Dose Adjustment:

Voriconazole EFV EFV AUC ↑ 44% Voriconazole 400 mg BID,
EFV 300 mg daily

* AUC is the ”Area under the curve”, defined in the field of pharmacokinetics as “the definite integral of a curve
that describes the variation of a drug concentration in blood as a function of time”,
Drug – Drug Interactions: Antacid, H2 Antagonist and PPI
Drug ARV Effect Recommendation
Antacids (Al, Mg, • Administer DTG at least 2 hrs before or at least 6 hours
DTG ↓ DTG
+/- Ca containing) after antacid that contains polyvalent cations
When given Give ATV at least 2 hours before or 1–2 hours after
Antacids simultaneously, • antacids or buffered medications
↓ ATV levels
• H2 receptor antagonist dose should not exceed
--ART-naive patients famotidine 40 mg BID
H2 Receptor ↓ ATV --ART-experienced patients famotidine 20 mg BID
Antagonists ATV/r

• PPIs should be administered at least 12 hours before ATV/r.

ATV • PPIs not recommended in PI-experienced patients.
PPIs • PPIs dose not exceed a dose of omeprazole 20 mg daily in
PI-naive patients.
Summary of Major Drug interactions with ARVs

Source: WHO report on Clinical Aspects of ADRs in HIV and ARV toxicity monitoring approaches, June 2018
 Key Messages

• There are six major classes of antiretroviral drugs available

• NsRTIs and NtRTI act as DNA chain terminators
• NNRTIs inhibit the HIV reverse transcriptase enzyme by directly binding to it
• Integrase inhibitors block the action of enzyme Integrase
• Protease inhibitors bind to the active site of the protease enzyme and prevent assembly
and maturation
• Consider drug dosage, diet, liver and kidney function, co-existing diseases and drug
interactions while using ARVs
• Monitor PLHIV for Adverse Drug Reactions(ADRs) and drug-drug interactions
Thank You