Integrase Inhibitors

When HIV enters a cell it carries with it three viral enzymes essential to it's replication.

1. Reverse transcriptase which synthesizes a double helix HIV DNA chain from the single strand viral RNA template.
2. Integrase which has four known functions:
   1. It prepares the viral DNA for integration into the host DNA.
   2. It transports the viral DNA through a nuclear pore
   3. It cleaves specific regions on the host DNA.
   4. It inserts the viral DNA segment.
3. Protease acts in the host cytoplasm to cleave long viral polypeptide chains. The resulting shorter glycoproteins accumulated at the cell membrane. When requisite components are aggregated, the assembly buds and separates from the host. Once separated, protease acts again to cleave the enveloped glycoproteins into active viral components and the virus becomes infectious.

There are currently two FDA approved Intergrase inhibitors, raltegravir and elvitegravir. Raltegravir and elvitegravir are integrase strand transfer inhibitors(InSTIs). InSTIs act on integrase by blocking the primary site used to attach to the host DNA. Raltegravir and elvitegravir bind to the central domain of the integrase molecule blocking it's ability to attach to and cut the host DNA and transfer the strand of viral DNA.

Raltegravir was the first InSTI to be FDA approved. Clinical trials have demonstrated that InSTIs' unique mechanism of action make them a valuable tool in the treatment of HIV resistant to other antiretrovirals. In a large study published by Steigbigel, R.; Cooper, D.; Kumar, P. et al. "Raltegravir Well Tolerated and Associated With Significantly Higher Virologic Response vs Placebo Through Week 48 Among Patients With Multidrug Resistant HIV-1".

In cases of InSTI virologic failure, a mutation in the integrase molecule central domain was usually identified. Raltegravir and elvitegravir block the same site on the integrase molecule. Therefore in the event of raltegravir virologic failure elvitegravir will likely be ineffective and visa versa.

Raltegravir and elvitegravir are not approved to be used as a monotherapy. Raltegravir and elvitegravir are approved to be used as part of combination antiretroviral therapy. There is no human equlvalent of integrase. Blocking integrase activity has resulted in few significant side effects.