Antiretroviral therapy

Retroviridae
 Genome: Plus-sense RNA

Capsid: Protein

 Envelop: Lipid, Glycoproteins

Enzymes:
 Reverse transcriptase
 Integrase enzyme
 Protease enzyme

E.g: HTLV-I (Human T-cell lymphotropic virus I).

And HIV (Human Immunodeficiency Virus )
Human Immunodeficiency Virus (HIV)
 HIVis a single stranded RNA retrovirus that causes
Acquired immunodeficiency syndrome (AIDS),

 AIDS individuals are at increased risk for

developing certain infections and malignancies.

 The virus is found in two major forms:

 HIV-1, the most prevalent worldwide, and
HIV-2, the most common in western Africa

 HIV is a typical retrovirus.

The nucleocapsid contains 2 copies of RNA genome

(capped & polyadenlyated)
 AIDS remains a serious threat because of
the expense and inaccessibility of antiretroviral agents
in the developing countries

the emergence of multidrug- resistant virus

Classification of Anti-Retroviral drugs (Anti-HIV drugs):

A. Nucleoside(tide) reverse transcriptase inhibitors (NRTIs):

Zidovudine (AZT,ZDV), Stavudine (d4T), Lamivudine (3TC), Abacavir
(ABC), Zalcitabine(DDT), Emtricitabine (FTC), Didanosine (ddI).
Tenofovir disoproxil fumarate(TDF) :NtRI

B. Non nucleoside reverse transcriptase inhibitors (NNRTIs):

Efavirenz (EFV), Nevirapine (NVP), Delaviridine.

C. Protease inhibitors (PIs): Saquinavir (SQV), Indinavir (IDV),

Nelfinavir (NFV), Amprenavir, Fosamprenavir, Ritonavir (RTV), Lopinavir
(LPV) , Atazanavir (ATV).

D . Entry/Fusion inhibitors: Enfuvirtide

E. Integrase inhibitors: Raltegravir

A. Nucleoside reverse transcriptase inhibitors (NRTIs)

E.g: Zidovudine, Stavudine, Lamivudine, Abacavir,

Zalcitabine, Emtricitabine, Didanosine.

 Mechanism of action:
 They act by incorporating themselves into the DNA of the
virus (competing with natural nucleotides), thereby
stopping the building process of transcription from RNA to
DNA.

The resulting DNA is incomplete and cannot create a new

virus.

 Block the HIV replication, block the infection of new cells

 No effect on already infected cells.

Mechanism of action

IC kinase
Drug drug-triphosphate

Cellular
triphosphates X  pro-viral DNA
Reverse
Transcriptase 
viral
replication

N.B. HIV reverse transcriptase is 20-30 times

more susceptible than alpha DNA
polymerase of the mammalian cells, but
gamma DNA polymerase is equally
susceptible
Nucleoside reverse transcriptase inhibitors (NRTIs)
 Therapeutic uses:
 Generally used in combination with other drugs to avoid
development of resistance for HIV.

• HAART(Highly active antiretroviral therapy): Synergistic

combinations of NRTIs and Protease inhibitors

• Popular HAART combinations :

Adverse effects: Lactic acidosis, severe hepatomegaly, hepatic

steatosis.
NRTI Nucleoside/ Nucleotide base
Zidovudine thymine
Didanosine adenine
Lamivudine cytosine
Zalcitabine cytosine
Stavudine thymine
Abacavir guanine
Emtricitabine cytosine
*Tenofovir disoproxil adenine
fumarate
* Adenine mono phosphate
Zidouvidine (AZT, ZDV)
 First antiviral drug used against HIV.
 It is a thymidine analogue, effective against HIV-1, HIV-2, and HTLV I and II.

 Zidovudine, in combination with one or more other antiretroviral agents, is

approved
 for the treatment of HIV infection in adults and children and for
post-exposure prophylaxis.

 It is used alone or in combination for the prevention of prenatal

and perinatal transmission to the baby by HIV-infected pregnant
women.
Resistance
Due to mutations in the reverse transcriptase gene
more frequent after prolong therapy and in persons with HIV

ADR: Myelosuppression, including anemia and neutropenia

GI intolerance, headaches, and insomnia
Stavudine (D4T)
 It is a thymidine nucleoside analogue

 Active against HIV-1 and HIV-2.

It is approved for

the therapy of HIV infection as part of a multidrug
regimen and
is also used for Postexposure prophylaxis.

Adverse effects:
 Headache, diarrhoea, skin rash, nausea, vomiting,
insomnia, anorexia, myalgia, peripheral neuropathy.

 Lactic acidosis occurs more frequently with

Stavudine than with other NRTIs.
Lamivudine (3TC)

 It is a cytosine nucleoside analogue

 Activite against HIV-1, HIV-2, and hepatitis B virus.

 It is approved as
part of a multidrug regimen for the therapy of HIV
infection in adults and children and

has been used for HIV post exposure prophylaxis.

 Lamivudine is the best-tolerated NRTI.

Adverse effects: Headache, malaise, fatigue, insomnia.

Abacavir (ABC)

It is a guanosine nucleoside analogue

 Indicated for
the therapy of HIV-1 infection in adults and children as
part of a multidrug regimen.

 It is also used for Postexposure HIV infection prophylaxis.

Adverse effects:
Anorexia, nausea, vomiting, malaise, headache &insomnia.
A potentially fatal hypersensitivity reaction develops in
approximately 5% of patients.
Fever and rash are the most common symptoms of this
reaction; respiratory and GI complaints may also occur.
Didanosine (DDI)
 It is an adenosine analogue

 Active against HIV-1, HIV-2, and HTLV-I.

 It is approved as
 part of a multidrug regimen for the therapy of HIV infection
and

is also used as Postexposure HIV prophylaxis.

Adverse effects: Diarrhea, abdominal pain, nausea, vomiting, anorexia

and dose-related peripheral neuropathy, pancreatitis, hyperuricemia, bone
marrow suppression, retinal depigmentation, and optical neuritis.
B. Non nucleoside reverse transcriptase inhibitors
(NNRTIs): E.g: Efavirenz, Nevirapine, Delaviridine.
Mechanism of action:
 stopping HIV production by binding directly onto
reverse transcriptase (non-competitively) and
preventing the conversion of RNA to DNA.

 Do not require activation through phosphorylation.

Therapeutic Uses
All NNRTIs are active against HIV-1 reverse transcriptase only
 use with NRTIs or PI provide synergistic effects
due to sequential block at two different steps
required for viral replication

Adverse effects:
 Skin rashes including Steven-Johnson syndrome
 Elevation of liver enzymes
Efavirenz (EFV)
 Therapeutic uses: It is approved for
the therapy of HIV infection of adults and children and
is also used for Post-exposure prophylaxis.

 It is the only NNRTI approved for once-daily dosing.

Adverse effects: Rash, elevated liver enzymes and serum

cholesterol also may occur.
CNS effects may include:
dizziness, headache, insomnia, drowsiness, euphoria,
agitation, impaired cognition, nightmares, vivid dreams, and
hallucinations.

 Efavirenz should be avoided during pregnancy because

primate studies have shown it to be teratogenic at doses
near therapeutic levels.
Nevirapine (NVP)
Therapeutic uses: It is approved for
the treatment of HIV infection in adults and children as
part of a combination therapy.
Nevirapine- prevents transmission of HIV from mother to
newborn when given at onset of labor and to the neonate
at delivery
 ADR: During the first 12 weeks of treatment, patients must
be closely monitored for the development of potentially

fatal hepatic toxicity (i.e., hepatitis, hepatic necrosis, and

hepatic failure) and
Skin reactions (i.e., Stevens-Johnson syndrome, toxic
epidermal necrolysis, and hypersensitivity reactions).

Other rxns: Mild to moderate rash, fever, nausea, fatigue,

headache, and elevated liver enzymes.
C. Protease inhibitors (PIs):
E.g. Saquinavir (SQV), Indinavir, Nelfinavir (NFV), Amprenavir,
Fosamprenavir, Ritonavir, Lopinavir (LPVr), Atazanavir (ATV),Indinavir (IDV)
Ritonavir (RTV)

• Mechanims of action:
 HIV protease is a viral enzyme responsible for
the cleavage of polyproteins into structural proteins and
certain enzymes that are required for the final assembly of
the new infectious virions.

 PIs act by binding to the viral protease and preventing the

correct cleavage of viral proteins.

Thus, they prevent HIV from being successfully assembled and

released from the infected cells.
They block cell to cell spread of HIV
Protease inhibitors (PIs):
Therapeutic uses:
Combination therapy wth Pis and other ART
significantly improve the clinical efficacy by blocking HIV
replication at different stages in the intracellular life cycle.

Adverse effects:
 GI disorders and associated with metabolic abnormalities
such as insulin resistance , high blood sugar
(hyperglycemia) and hyperlipidaemia & Bleeding episodes
in hemophilics

Long-term use may lead to

an unusual redistribution of cutaneous fat:
less subcutaneous fat, increased abdominal fat, breast
enlargement, 'buffalo humps'.
Saquinavir (SQV)
 a potent inhibitor of HIV-1 and HIV-2 protease.

 usually well tolerated and produces mild GI side effects.

M.O.R.: mediated by expression of multiple and variable protease
amino acid substitutions

Ritonavir (RTV)
 a potent inhibitor of HIV-1 and HIV-2 protease.
 It is not well tolerated in higher doses.
 It is mainly used in low doses to increase blood levels of other Pis
and to extend their dosing interval.

ADR: GI side effects, altered taste sensation, paresthesias and hypertriglyceridemia.

Nelfinavir (NFV)
 the most commonly used PI because of its low incidence of serious ADR.
Adverse effetcs: Diarrhea and flatulence; these may resolve with continued use.
 Nelfinavir and Amprenavir

M.O.A.: Specific inhibitors of the HIV-1 protease enzyme

M.O.R.: mediated by expression of multiple and variable

protease amino acid substitutions

Less cross-resistance with Amprenavir

Side Effects: diarrhea and flatulence

Amprenavir can cause Stevens-Johnson syndrome

Contraindications: inhibitor/substrate for CPY3A4

D. Entry/Fusion inhibitors:
E.g. Enfuvirtide (T-20)
• Mechanism of action:
Binds to gp41 subunit of viral envelop glycoprotein

 Thus prevents the entry of HIV-1 into CD4+ cells by

interfering with fusion of viral and cellular membrane

 differ from other drugs b/se they work on the

outside of the cell to prevent HIV from fusing with,
and infecting the CD4 cells in the first place.
Pharmacokinetics:
 Oral bioavailability: Poor, Hence give S/C
 Distribution: PB 90%, Plasma T1/2: 3-4 Hrs

• Therapeutic uses:
 Used along with other antiretroviral drugs for the
treatment of advanced HIV-1 infections (which is not
managed despite other antiretroviral therapy)

Adverse effects: Local reaction (nodule) at injection site,

skin rash, eosinophilia, pneumonia like manifestation
E. Integrase Inhibitors (HIV integrase strand transfer inhibitors)
• HIV integrase
 Responsible for transport and attachment of proviral DNA
to host-cell chromosomes

 Proviral integration involves 2 catalytic reactions:

 3'-processing in host-cell cytoplasm to prepare proviral
strands for attachment

 Strand transfer whereby proviral DNA is covalently linked to

cellular DNA

 Integrase nhibitors Competitively inhibit strand transfer

reaction by binding metallic ions in active site.
Eg. Raltegravir & Elvitegravir
Pharmacokinetics
Raltegravir
Rapid absorption, taken with or without food.
half-life of 10-12 hours

83% bound to plasma proteins

Metabolized by uridine diphosphate glucuronyl transferase

 Other antiretroviral agents may alter metabolism

Antacids may decrease absorption by divalent cation binding,

Elvitegravir
 administered with low-dose ritonavir (100 mg)
 to reduce its first-pass metabolism and systemic
clearance.
 Coadministration results in a 20-fold increase in systemic
exposure and a terminal half-life of 10-13 hours.

metabolized through CYP3A4.

 Drug-drug interactions with other medications are

likely
because of ritonavir

Antacids may decrease absorption

WHO Recommendations of ART
• WHEN TO START:

All adolescents and adults including pregnant women

with HIV infection and CD4 counts of ≤350 cells/mm3,
regardless of the presence or absence of clinical
symptoms.

• Those with severe or advanced clinical disease (WHO

clinical stage 3 or 4) should start ART irrespective of their
CD4 cell count
WHO recommendations of ART
 First-line therapy : NNRTI(1) + NRTIs (2).
 one NRTIs should be zidovudine (AZT) or tenofovir
(TDF).

 Take steps to progressively reduce the use of stavudine

(d4T) in 1st-line regimens b/se of its well-recognized
toxicities.

2nd-line ART : A. Ritonavir-boosted PI + NRTIs (2),

 one of which should be AZT or TDF, based on what was
used in first-line therapy.
 Ritonavir-boosted atazanavir (ATV/r) or
lopinavir/ritonavir (LPV/r) are the preferred PIs.
HIV/TB co-infection
• ART should be initiated as soon as possible in
all HIV/TB co-infected patients with active TB

• when a person needs TB and HIV treatment concurrently

 first line treatment options include ZDV/3TC or D4T/3TC
plus either an NNRTI or ABC.
 If an NNRTI-based regimen is used,
EFV would be the preferred drug
b/se its potential to aggravate the hepatotoxicity of TB
treatment appears less than with NVP.

 Except for SQV/r, PIs are not recommended during TB

treatment with Rifampicin.
E.g: AZT or TDF (tenofovir disoproxil fumarate) + 3TC

or FTC(emtricitabine)) + EFV

HIV/HBV co-infection
• Irrespective of CD4 cell counts or WHO clinical stage,
patients who require treatment for HBV infection should start
ART.

• First-line and second-line regimens for these individuals should

contain TDF and either emtricitabine (FTC) or lamivudine (3TC).

• E.g: TDF + 3TC (or FTC) + EFV

HIV+ pregnant women
 NRTIs (2) + NNRTI(1)

 AZT preferred but TDF acceptable

 EFV included as a NNRTI option (but do not initiate EFV during

first trimester)

• Benefits of NVP outweigh risks where CD4 count is 250−350

cells/mm3

E.g: AZT + 3TC + NVP

ART combinations that need to be avoided

The following combinations should not be offered

because of antagonism:

 AZT (Zidovudine)+ D4T (Stavudine)

DDC (Zalcitabine) + 3TC (Lamivudine)

The following combinations should not be offered

because of the overlapping toxicity profile:

 DDC (Zalcitabine) + D4T (Stavudine)

 DDC (Zalcitabine) + DDI (Didanosine)