Saturday, August 31, 2019
Antiretroviral Therapy Essay
There is no other field of medicine that has been through such dramatic developments as that of antiretroviral therapy. In September 1995, the results of Eurpean-Australian DELTA study, and the American ACTG pointed out that two nucleoside analogues were more effective than monotherapy. This led to the belief, thatlonger survival was possible in HIV. Protease inhibitors (PIs) came about in 1995, and in June 1996, the first non-nucleoside reverse transcriptase inhibitor (NNRTI) neviparine arrived, and so did Nelfinavir which was a new PIs. This led to the start of HAART (Highly Active Anti-Retroviral Therapy). Antiretroviral drugs have been divided into a number of groups on the basis of the phase of the retrovirus life-cycle that the drug inhibits. 1         Nucleoside & nucleotide reverse transcriptase inhibitors (NRTI) inhibit reverse transcription by incorporating into the newly synthesized viral DNA and slowing its elongation. Apricitabine (AVX-754) is a heterocyclic cytidine analog, which may enter the market in 2009. Elvucitabine is currently in phase II trials. Stampidine is 100 times more potent than AZT and has potential role against HIV mutants 2         Non-nucleoside reverse transcriptase inhibitors (nNRTI) inhibit reverse transcriptase directly by binding to the enzyme and not allowing its function. Efavirenz has been the agent that has been most successful, but is facing lot of viral resistance. Rilpivarine has a long half life of 40 hours. 3         Protease inhibitors (PIs) target viral architecture by inhibiting the activity of protease, an enzyme used by the virus to form new virons from the older protein framework. PL-100 is given as a prodrug and is active against multi PIs resistant strains. It has a long half life of 37 hours, and can act as a co-drug. 4         Integrase inhibitors inhibit the enzyme integrase, (integrates  viral DNA into  DNA of the infected cell). Raltegravir became the first to receive FDA approval in October 2007. it is the most exciting of all anti HIV agents in the market. It acts against HIV-2 also. Elvitegasir has a potential as monotherapy. 5         Entry inhibitors (or fusion inhibitors) prevent the  binding, fusion and entry of HIV-1 virus into the host cell. It acts via the gp 120 envelope protein to the CD 4 receptor. Maraviroc and enfuvirtide are marketed agents of this group. 6         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). These virons are thus incomplete and thus uninfective.  Two drugs in this group  are under investigation, bevirimat,`and Viveconâ„ ¢. Immunotherapy. IL-2 is a cytokine from the activated T – cells, which induces proliferation in T, B, and NK cells. It causes an increase in CD 4 and CD 8 cells. It is useful in patients with poor immunological response to antiretroviral therapy to stimulate the immune system. G-CSF, GM CSF are used for treatment of prolonged neutropenia in patients with advanced HIV infection to reduce bacterial infection. Why is treatment of HIV difficult ? The retrovirus has an extremely short life span, as short as 1 ½days. In addition the protective enzymes which prevent mutation in RNA to DNA conversion via reverse transcriptase in absent in the virus. Thus the virus mutates very rapidly, and produces many genotypes, some of which escape the cytotoxic effect of the antiretroviral drugs and proliferate. When the antiretrovirals are combined, the number of genotypically active virons is low, and so combinations are a must, as no single agent has been shown to suppress virus for long. Fixed dose combinations A major change in the therapy today has been the advent of fixed doses combinations. Earlier patients had to take larger number of tablets per day, but now combinations of these complex regimens are available in single tablets, which increases the compliance of patients, thus reducing chances of treatment failure. Current treatment guidelines for HAART The status of ‘hit hard, hit early’ approach which was recomneded earlier has now changed. Some clinicians use the 350 and 500 CD4+ T cells/mm ³ levels to initiate treatment, but this needs individualization. Today it is recommended that HIV patients should start ART after confirmation of the HIV disease and the presence of Clinically advanced HIV disease – WHO Stage IV HIV disease, irrespective of the CD4 cell count; WHO Stage III disease with consideration of using CD4 cell counts less than 350/ µl to assist decision making; WHO Stage I or II HIV disease with CD4 cell counts less than 200/ µl. the guidelines for adults and adolescents for the USA are set by the United States Department of Health and Human Services (DHHS). In this all patients with history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4+ T cell count receive ART. Antiretroviral therapy is also recommended for asymptomatic patients with less than 200 CD4+ T cells/ µl. Asymptomatic patients with CD4+ T cell counts of 201–350 cells/ µl should be offered treatment. For asymptomatic patients with CD4+ T cell of greater than 350 cells/ µl and plasma HIV RNA greater than 100,000 copies/ml, most experienced clinicians defer therapy but some clinicians may consider initiating treatment. Therapy should be deferred for patients with CD4+ T cell counts of greater than 350 cells/ µl and plasma HIV RNA less than 100,000 copies/mL. Treatment regimes Important aspects are that the first regimen offers the best chance to the patient, meaning that the viral load must be below detectable level within 3-6 months of treatment initiation. The combination used initially consist of two nucleoside analogs plus a PI or either a NNRTI. A regimen containing an NNRTI is often the regimen of choice for initial antiretroviral treatment when adherence is expected to be good because of convenience, superior virological suppression, lower rates of toxic effects, and fewer interactions between drugs than with boosted protease inhibitor regimens Thus various acceptable regimens are (Wikipedia) two NRTI’S + One NNRTI two NRTI’s + PI. For initial regimens that include a protease inhibitor, those that are ritonavir boosted are recommended because of the improvement in protease inhibitor pharmacokinetics and potency Threre NRTI ( referred to as triple nukes) once daily combinations – like emtriva. This regimen needs strict compliance, as if one dose is forgotten, then that days therapy is lost The preferred initial regimens are (Department of Health and Human Services) 1   efavirenz + zidovudine + lamivudine 2   efavirenz + tenofovir + emtricitabine 3   lopinavir boosted with ritonavir + zidovudine + lamivudine 4   lopinavir boosted with ritonavir + tenofovir + emtricitabine Referance Cahn P, Cassetti I Wood R etal. Efficacy and tolerability of 10 day monotherapy with apricitabine in antiretroviral naà ¯ve, HIV infected patients. AIDS 2006, 20:1262-8. Department of Health and Human Services (August, 2006). HIV and Its Treatment: What You Should Know. Accessed on 31 mar, 2008 United States Department of Health and Human Services (2004). A Guide to Primary Care for People With HIV/AIDS, 2004 Edition Antiretroviral drug – Wikipedia, the free encyclopedia – en.wikipedia.org/wiki/Antiretroviral_drug HAART, HIV Treatment HIV Medicine 2007, 15th edition. Hoffman C, Rockstroh JK, Kamps BS. Flying Publishers. HIV Therapy: Highly active antiretroviral therapy (HAART)
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