Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART. The American National Institutes of Health and other organizations recommend offering antiretroviral treatment to all patients with AIDS. Because of the complexity of selecting and following a regimen, the severity of the side-effects and the importance of compliance to prevent viral resistance, such organizations emphasize the importance of involving patients in therapy choices, and recommend analyzing the risks and the potential benefits to patients with low viral loads.
There are different classes of antiretroviral drugs that act at different stages of the HIV life-cycle.
Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits.
- Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI) inhibit reverse transcription by being incorporated into the newly synthesized viral DNA strand as a faulty nucleotide. This causes a chemical reaction resulting in DNA chain termination.
- Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase directly by binding to the enzyme and interfering with its function.
- Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for final assembly of new virons.
- Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravirbecame the first to receive FDA approval in October 2007.
- Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class.
- CCR5 receptor antagonists are the first antiretroviral drugs which do not target the virus directly. Instead, they bind to the CCR5 receptor on the surface of the T-Cell and block viral attachment to the cell. Most strains of HIV attach to T-Cells using the CCR5 receptor. If HIV cannot attach to the cell, it cannot gain entry to replicate.
- Maturation inhibitors inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved, thereby blocking the conversion of the polyprotein into the mature capsid protein (p24). Because these viral particles have a defective core, the virions released consist mainly of non-infectious particles. Alpha interferon is a currently available agent in this class.Two additional ones under investigation arebevirimat and Vivecon.
Combination therapy
The life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other cells. HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Its short life-cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability of HIV. Most of themutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more active copies of the virus the greater the possibility that one resistant to antiretroviral drugs will be made.
When antiretroviral drugs are used improperly, these multi-drug resistant strains can become the dominant genotypes very rapidly. Improper serial use of the reverse transcriptase inhibitors zidovudine, didanosine,zalcitabine, stavudine, and lamivudine can lead to the development of multi-drug resistant mutations. The mutations can include the V75I, F77L, K103N, F116Y, Q151M, and the M184V mutation. These mutations were observed before protease inhibitors had come into widespread use. The mutants retained sensitivity to the early protease inhibitor saquinavir. These mutants were also sensitive to the rarely used reverse transcriptase inhibitor foscarnet.
Antiretroviral combination therapy defends against resistance by suppressing HIV replication as much as possible.
Combinations of antiretrovirals create multiple obstacles to HIV replication to keep the number of offspring low and reduce the possibility of a superior mutation. If a mutation that conveys resistance to one of the drugs being taken arises, the other drugs continue to suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result, the standard of care is to use combinations of antiretroviral drugs. Combinations usually comprise two nucleoside-analogue RTIs and one non-nucleoside-analogue RTI or protease inhibitor.This three drug combination is commonly known as a triple cocktail.
Combinations of antiretrovirals are subject to positive and negativesynergies, which limits the number of useful combinations.
In recent years, drug companies have worked together to combine these complex regimens into simpler formulas, termed fixed-dose combinations. For instance, two pills containing two or three medications each can be taken twice daily.This greatly increases the ease with which they can be taken, which in turn increases adherence, and thus their effectiveness over the long-term. Lack of adherence is a cause of resistance development in medication-experienced patients. Patients who maintain proper therapy can stay on one regimen without developing resistance. This greatly increases life expectancy and leaves more drugs available to the individual should the need arise.
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