Acting on RNA viruses, antiretroviral agents
The analogs of purine and pyrimidine bases active by inhibition of reverse transcriptase of HIV, RNA virus, are zidovudine, zalcitabine, stavudine, lamivudine, didanosine, emtricitabine, abacavir, and tenofovir. They act after conversion in triphosphate metabolites.
Beside these inhibitors with a nucleoside structure, there are inhibitors without a nucleoside structure such as nevirapine and efavirenz, which are called nonnucleoside reverse transcriptase inhibitors.
The HIV-1 is commonly at the origin of the infection and exceptionally the HIV-2.
Nucleosides reverse transcriptase inhibitors
Zidovudine, the first antiretroviral agent, also called azidothymidine or 3 '- azido-3'-deoxythymidine or AZT, molecule known since 1964, is a deoxythymidine structural analog: the OH group in 3 ' of the deoxyribose having been replaced by the azido N3 group. Zidovudine, because of the absence of OH group in 3 ', inhibits reverse transcriptase, prevents the elongation of the DNA chain resulting from viral RNA.
Zidovudine is active only after its conversion into AZT triphosphate, conversion carried out both in healthy and infected cells. AZT triphosphate is at the same time substrate and inhibitor of the reverse transcriptase, enzyme responsible transcription of viral RNA into DNA. Zidovudine has more affinity for the viral reverse transcriptase than for the human DNA polymerase. Reverse transcriptase catalyzes the transcription of a simple strand of viral RNA into a double DNA strand, which, using the machinery of the host cell, will be at the origin of the synthesis of viral RNA.
The markers of the efficacy of an anti-HIV drug are the increase of the number of lymphocytes CD4, diminished during the disease, and the diminution of the circulating viral load.
The antiviral action of zidovudine is antagonized by ribavirin or thymidine supply.
Concerning pharmacokinetics, AZT is absorbed from the digestive tract to about 70%, its plasma half-life is short, about one hour, explaining the need of repeated intakes every four hours. Probenecide prolongs the half-life of AZT by reducing its renal elimination.
AZT (Retrovir*) is used for the management of HIV infection. AZT is also used during pregnancy, after the fourteenth week for the prevention of maternal-fetal HIV transmission.
To avoid the emergence of resistance, the treatment of HIV-infection is based on combination therapy with 2, 3, or 4 different drugs and there are mullti-ingredient preparations such as Combivir* with lamivudine and Trizivir* with lamivudine and abacavir.
AZT has several adverse effects:
The simultaneous intake of AZT and paracetamol increases the incidence of neutropenia.
Zalcitabine, also called ddC, has not, like cytosine, a –OH group in position 3 ' necessary to the formation of the DNA strand. Zalcitabine is a reverse transcriptase inhibitor. To be active, ddC must be converted into ddC triphosphate which, incorporated in the DNA strand, stops its lengthening by the reverse transcriptase, disturbing the copy of RNA into DNA. Zalcitabine (Hivid* in some countries) is used in the treatment of HIV infection. Its main adverse effect is a sensorimotor neuropathy, frequent and severe, not easily reversible after its discontinuation. Among the others adverse effects, are oral ulcerations and pancreatitis.
Stavudine or didehydro-deoxythymidine or d4T act by its phosphorylated metabolites which inhibit the reverse transcriptase. Stavudine (Zerit*) is used in the treatment of HIV infection in combination with other drugs to avoid resistance. Its most outstanding undesirable effect is a dose-dependant peripheral neuropathy. It can also give pancreatitis. Its combination with zidovudine is not advised because zidovudine could inhibit intracellular phosphorylation of stavudine and make it less effective.
Lamivudine or deoxythiacytidine or 3TC (Epivir*, Zeffix*) is a nucleoside analog in which a carbon atom of the ribose is replaced by a sulfur atom. It is a reverse transcriptase inhibitor used for the treatment of HIV infections and also of chronic hepatitis B. Its main adverse effects are hematological (anemia, neutropenia) and hepatic (rise in transaminases).
Didanosine or dideoxyinosine, ddI, (Videx*) analog of purine bases, inhibits the reverse transcriptase and the elongation of the chain of the viral nucleic acids. It is used in the treatment of HIV infections. Among adverse effects of didanosine, one can quote peripheral neuropathies and pancreatitis.
Abacavir, (Ziagen*) a guanosine analog, is a nucleoside reverse transcriptase inhibitor. Active against the HIV 1 and the HIV 2, it is used in the management of HIV infections . It can induce severe and sometimes life-threatening hypersensitivity reactions, in particular respiratory, such as dyspnea, bronchospasm, These reactions must lead to the discontinuation abacavir and its later non-utilization.
Tenofovir, (Viread*) monophosphate nucleoside analog, it is a nucleotide, which acts after transformation in diphosphate. It is used for the treatment of HIV infections.
Emtricitabine (Emtriva*) is a nucleoside analog of cytosine, whose structure is closely related to that of lamivudine. It is active against the VIH1 and the VIH2 and hepatitis B virus.
Nonnucleoside reverse transcriptase Inhibitors
Nevirapine (Viramune*) is a nonnucleoside and noncompetitive inhibitor of reverse transcriptase of HIV-1 but not of HIV-2, directly active. It also inhibits DNA polymerase. Resistance to its effect appears very quickly when it is used alone. It has a good bioavailability (> to 90%) and a long half-life, approximately 30 h.
Its adverse effects are skin rashes sometimes very severe, fever, hepatitis
Efavirenz (Sustiva*, Stocrin*) is a nonnucleoside inhibitor of HIV-1reverse transcriptase, directly active without having to be converted into triphosphate metabolite. Its bioavailability is little modified by food intake, except lipids which increase it. It is metabolized into inactive metabolites mainly by cytochromes CYP3A and CYP2B6. It is an enzyme inducer but the possible consequences of this effect remain to be evaluated. It is used in the treatment of HIV-1 infections, in combination with other drugs.
Delavirdine is a nonnucleoside reverse transcriptase inhibitor marketed in certain countries.
The other types of treatment of HIV infections, antiproteases, viral integrase inhibitors, inhibitors of entry into the cell, are studied elsewhere.