Antiretroviral Therapy

HIV Replication
HIV targets cells with a CD4 surface marker. The interaction between the virus surface protein gp120 and the host cell CD4 receptor causes a structural change of the CD4 receptor to expose a co-receptor (CCR5 or CXCR4).
Binding of HIV gp120 to the CD4 receptor and the CCR5 or CXCR4 co-receptor leads to the release of gp41 with subsequent fusion of the viral and the host membrane. Fusion allows HIV to expel its contents into cell. The reverse transcriptase enzyme converts viral RNA into proviral DNA. The proviral DNA is transported to the cell’s nucleus and through the action of the integrase enzyme integrated into the host DNA to form a provirus.
When the cell is immunologically activated the constituents of the virus are made which is assembled at the cell’s surface to bud off the cells as an immature virus. The protease enzyme then processes the protein chains and transforms the virus into a mature virus capable of infecting other CD4 + cells.

Antiretrovirals (ARVs) are divided into classes according to where they act to block HIV replication:
• Entry Inhibitors – CCR5 co-receptor antagonists and Fusion Inhibitors
• Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
• Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• HIV integrase strand transfer inhibitors (INSTIs)
• Protease Inhibitors (PIs)

Entry & Fusion Inhibitors
Entry inhibitors:
• Maraviroc, Selzentry

Fusion inhibitors:
• Enfuvirtide, T-20, Fuzeon

Maraviroc (MVC) is a chemokine receptor type 5 (CCR5) antagonist approved for use in treatment-experienced adults who are infected with CCR5-tropic HIV. The tropism of the HIV must be determined before starting therapy with MVC, as MVC is ineffective in individuals who harbor CXCR4-tropic or dual-tropic (CCR5 and CXCR4-using) virus. Maraviroc binds to the CCR5 co-receptor allosterically, inducing conformational changes that prevent gp120 from binding.
Fusion inhibitors interact with components of the HIV envelope (gp 41) to prevent fusion of the virus with the host cell membrane. Enfuvirtide (T-20) is the first drug of this class approved for treatment-experienced HIV-infected adults and children over 6 years of age. In trials, individuals naive to T-20 who added it to their optimized background regimen saw improved outcomes compared with those not receiving it.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Single NRTIs:
• Videx EC (Enteric coated didanosine)
• Videx (Didanosine)
• Viread (Tenofovir disoproxil fumarate)
• Zerit (Stavudine)
• Ziagen (Abacavir sulfate)
• Emtriva (Emtricitabine)
• Epivir (Lamivudine)
• Retrovir (Zidovudine)

Dual NRTI combinations:
• Combivir (Lamivudine and zidovudine)
• Truvada (Tenofovir disoproxil fumarate and emtricitabine)
• Epzicom (Abacavir and lamivudine)

Triple NRTI combinations:
• Trizivir (Abacavir, zidovudine, and lamivudine)

The antiviral activity of NRTIs depends upon the host’s cellular kinases to perform intracellular serial phosphorylation to form the active triphosphate drug. This drug class has no effect on previously infected cells, as proviral DNA is already integrated into cellular chromosomes.
The mode of action of NRTIs and NtRTIs are essentially the same; they are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA chain. However, unlike the natural deoxynucleotides substrates, NRTIs and NtRTIs lack a 3′-hydroxyl group on the deoxyribose moiety. As a result, following incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide cannot form the next 5′-3′ phosphodiester bond needed to extend the DNA chain. Thus, when an NRTI or NtRTI is incorporated, viral DNA synthesis is halted, a process known as chain termination.

All NRTIs and NtRTIs are classified as competitive substrate inhibitors.

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• Edurant (Rilpivirine)
• Intelence (Etravirine)
• Rescriptor (Delavirdine)
• Sustiva (Efavirenz)
• Viramune (Immediate Release nevirapine)
• Viramune XR (Extended Release nevirapine)

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) also inhibit RT but, unlike the NRTIs/NtRTI, they non-competitively bind to RT to disrupt the catalytic site.
They do not require intracellular phosphorylation to become active.

HIV integrase strand transfer inhibitors (INSTIs)
• Raltegravir, Isentress
Integrase catalyzes the viral DNA insertion into the host’s chromosomes, integrase inhibitors interfere with strand transfer activity of the HIV integrase protein.
INSTIs show remarkable suppression of HIV replication in treatment-naive and treatment-experienced adults, even if the latter is infected with an extensively drug-resistant virus.

Protease Inhibitors (PIs)

• Agenerase (Amprenavir)
• Aptivus (Tipranavir)
• Crixivan (Indinavir)
• Invirase (Saquinavir mesylate)
• Kaletra (Lopinavir and ritonavir)
• Lexiva (Fosamprenavir Calcium)
• Norvir (Ritonavir)
• Prezista (Darunavir)
• Reyataz (Atazanavir sulfate)
• Viracept (Nelfinavir mesylate)

HIV-1 Protease is composed of 2 identical sub-units (Homodimer), 99 amino acids bases each, that form a substrate binding cleft, covered with a mobile flap. Protease cleaves poly proteins at the active site, forming fully functioning HIV virions. PIs prevent polyproteins from entering the active site and being cleaved, thus preventing assembly of fully functional HIV virions
PIs Act at a post-integration step of the viral life cycle, they are therefore effective in inhibiting replication in both newly and chronically infected cells.
Ritonavir is used in a low nontherapeutic dose as a booster (r). RTV can enhance the drug plasma concentration of other PIs by selectively inhibiting CYP450 activity. Clinically significant drug interactions can occur when a PI is administered concomitantly with drugs metabolized by the CYP450 system.
Fat redistribution, lipodystrophy syndrome and hyperlipidemia are the main adverse effects of PIs seen in adults and children. In addition, hyperglycemia, new-onset diabetes mellitus and worsening glycemic control of diabetics are reported with all available PIs.

HAART
Combination therapy (cART) has led to better clinical, immunologic and virologic outcomes.
Currently, a combination regimen of at least three drugs, referred to as highly active antiretroviral therapy (HAART), is recommended.
Such regimens increase survival, improve growth and neurocognitive function, and reduce the occurrence of opportunistic infections and other complications of HIV infection.

Multi-class combinations:
• Atripla (Efavirenz, emtricitabine and tenofovir disoproxil fumarate
• Complera (Emtricitabine, rilpivirine, and tenofovir disoproxil fumarate)