HIV & AIDS

PHAR3201 - 2019
 Human Immunodeficiency Virus
•HIV is an enveloped single stranded
RNA virus and belongs to the retrovirus
family

•HIV infects human cells that express

CD4 antigen i.e. T-cells and
macrophages
Life Cycle of HIV
HIV Symptoms

•When T-cells are < 0.2 x 109 cell/L secondary infections and malignancies
start occurring
•Lack of T-cells will also impair the function of B-cells further reducing
immunity
HIV to AIDS

https://www.youtube.com/watch?v=68I7JlVhuhY
HIV-Associated Opportunistic Infections
HIV-Associated Opportunistic Infections
Bacteria: Mycobacterium avium complex (MAC) (rifabutin), salmonella
enterocolitis, campylobacter enterocolitis and shigella enterocolitis

Protozoa: Toxoplasmic encephalitis, isosporiasis, cryptosporidium parvum

Fungi: Candida albicans (fluconazole), pneumocystis jiroveci pneumonia

(sulfamethoxazole + trimethoprim or pentamidine), cryptococcal
meningitis (fluconazole + amphotericin), histoplasmosis

Viruses: herpes simplex, varicella zoster, human papilloma virus,

cytomegalovirus (ganciclovir)
HIV Diagnosis
•Enzyme-linked immunosorbent assay (ELISA) against HIV p24 protein.
This test detects HIV from as little as 15-20 days post-infection. Some
labs also perform HIV IgG and IgM testing as well.

•If patient is HIV positive further laboratory tests are conducted before
treatment is initiated, including:
-CD4 count
-HIV viral load
-Resistance testing
-Screening for other STDs (usually performed initially)
-CBC, LFT, RFT, urine-analysis
-Glucose and lipid profile
-Pregnancy test
HIV Treatment Goals
•Decrease morbidity and mortality
•Improve quality of life
•Restore and preserve immune function
•Prevent further transmission

These goals are achieved by ensuring maximum and durable inhibition of

HIV replication i.e. HIV RNA is lower than the minimum levels of
quantitation (undetectable viral load <50 copies/mL)
When To Start Therapy?

Antiretroviral therapy (ART) should start as soon as HIV diagnosis is made

regardless of CD4 cell count or HIV RNA load
 Highly Active Antiretroviral Therapy (HAART)
•The most commonly prescribed HAART regimen consists of 2 nucleoside
reverse transcriptase inhibitors (NRTI) and an integrase strand transfer
inhibitor (INSTI)

•Other regimens substitute INSTI with either non-nucleoside reverse

transcriptase inhibitors (NNRTI) or a protease inhibitor (PI or called booster)

•Resistance is very high using monotherapy. The toxicity and side effects are
decreased when using combination therapy. and that’s why we use triple
therapy to manage HIV.
 NTRI
•NTRI: Abacavir, emtricitabine, lamivudine and zidovudine

•MOA: Inhibiting HIV reverse transcriptase inhibits viral DNA synthesis and
therefore HIV replication

•Drugs from this class work at different specific sites of the HIV DNA synthesis
process. This is why we use 2 NTRIs when managing HIV

•Common adverse effects: headache, nausea, vomiting, anorexia, myalgia and

asymptomatic hyperlactataemia
 NTRIs Specific Side Effects
•Abacavir: Increased incidence of hypersensitivity –which can be fatal- is
observed in patients with HLA-B*5701 allele (5% of patients or more).
Increased risk of MI is debatable

•Emtricitabine: Diarrhoea, cough and hyperpigmentation of palms and soles

•Lamivudine: well tolerated, but an increase in liver enzymes may be observed

•Zidovudine: Myelosuppression is a rare, but life threatening side effect

 NNRTI
•NNRTI: Efavirenz, etravirine, nevirapine and rilpivirine

•These medications (except for rilpivirine) are inducers of CYP3A4/5. Therefore,

interactions with other medications should be assessed

•Common side effects: rash that sometimes is severe and fatal (nevirapine most
commonly), nausea, vomiting, headaches, fever and elevated liver enzymes

•Nevirapine may cause hepatotoxicity, efavirenz is most commonly associated

with CNS side effects
 Protease Inhibitors
•PI: Atazanavir, darunavir, fosamprenavir, indinavir, lopinavir + ritonavir, ritonavir,
saquinavir and tipranavir

•MOA: Inhibits HIV proteases preventing viral maturation and replication

•All PIs are inhibitors of CYP3A4/5 and therefore, their drug-drug interactions
are numerous

•Ritonavir is the most potent inhibitor of liver enzymes and is the most likely to
reduce the hepatic metabolism of other drugs; saquinavir is the least potent.
 Protease Inhibitors
•Most PIs are now given with a low dose ritonavir. By inhibiting CYP, ritonavir
increases the plasma concentration of other PIs. This decreases the dosing
frequency improving patient compliance. Also increases activity against
moderately resistant strains of HIV.

•PIs: May cause hyperglycaemia (and new onset diabetes), and they increase
lipids
 Protease Inhibitors
•Most PIs are now given with a low dose ritonavir. By inhibiting CYP, ritonavir
increases the plasma concentration of other PIs. This decreases the dosing
frequency improving patient compliance. Also increases activity against
moderately resistant strains of HIV.

•PIs: May cause hyperglycaemia (and new onset diabetes), and they increase
lipids
 Integrase Inhibitors
•Bictegravir, dolutegravir, elvitegravir + cobicistat and raltegravir

•MOA: Inhibit HIV integrase enzyme which prevents viral replication by stopping
viral insertion of viral DNA into the host DNA

•Usually this class of medications is active against HIV that is resistant to other
retroviral classes
 Fusion Inhibitor
•Enfuvirtide

•MOA: Binds to viral glycoprotein subunit gp41 inhibiting its function. Therefore,
it blocks viral fusion with the CD4 receptor and viral entry into host cell as a
result

•The medication is given SC. All patients develop injection site reaction
especially in the first week of treatment. Reaction include pain, induration,
erythema, itch, nodules and cysts. The symptoms last for a week and analgesia
is sometimes required. 4.5% of patients stop treatment as a result.
 CCR5 Antagonist
•Maraviroc

•MOA: HIV enters CD4 cells by binding to chemokine receptors CCR5 and
CXCR4. CCR5 acts as a viral co-receptor that facilitates entry of the virus into
the cell. Maraviroc prevents the entry of CCR5-dependent strains by selectively
binding to the CCR5 receptor

•Maraviroc is a substrate for CYP3A4

 Nucleotide Analogue
•Tenofovir

•MOA: tenofovir is metabolised to the active metabolite tenofovir diphosphate,

which inhibits viral polymerases and terminates the DNA chain after
incorporation into viral DNA

•Tenofovir is not combined with 2 NRTIs as the combination is less effective

when compared to PIs or NNRTIs
PrEP