Antiretroviralni lek

HIV/AIDS menadžement normalno obuhvata upotrebu više antiretroviralnih lekova u pokušaju da se zauzda HIV infekcija. Postoji nekoliko klasa antiretroviralnih agenasa koje deluju u različitim stupnjevima HIV životnog ciklusa. Istovremena upotreba višestrukih lekova koji deluju na različitim viralnim metama je poznata kao visoko aktivna antiretroviralna terapija (HAART). HAART umanjuje sveukupno HIV opterećenje pacijenta, olakšava održavanje funkcije imunskog sistema, i sprečava oportunističke infekcije koje često dovode do smrti. HAART takođe sprečava prenošenje virusa HIV-a između serodiskordantnih istospolnih i suprotnopolnih partnera, dokle god HIV-pozitivni partner održava neodrediv virusni sadržaj.

Tretman je u toj meri uspešan da je u mnogim delovima sveta, HIV postao hronično oboljenje čija progresija u AIDS je izuzetno retka. Antoni Fauci, načelnik američkog Nacionalnog instituta za alergiju i infektivne bolesti, je napisao, „Sa sadašnjom kolektivnom i odlučnom akcijom i nepokolebljivom posvećenosti u narednim godinama, generacija bez AIDS-a je zaista na dohvatu ruke.“ U istoj publikaciji, on napominje da je po nekim procenama 700.000 života spašeno samo u 2010. godini primenom antiretroviralne terapije. Kao što je jedan drugi komentar u The Lancet napomenuo, „Umesto da se bore sa akutnim i potencijalno opasnim po život komplikacijama, lekari se sada suočavaju sa upravljanjem hroničnog oboljenja što će u odsustvu leka potrajati decenijama.“

Američko Ministarstvo zdravlja i ljudskih resursa i Svetska zdravstvena organizacija preporučuju primenu antiretroviralnog tretmana kod svih pacijenata sa HIV. Zbog složenosti izbora i sprovođenja režima, potencijala razvoja nuspojava, kao i značaja redovnog uzimanja lekova kako bi se sprečila pojava virusne otpornosti, ove organizacije ističu značaj uključivanja pacijenata u izbor terapije i preporučuju analiziranje rizika i potencijalne koristi.

Svetska zdravstvena organizacija je definisala zdravlje kao više od odsustva bolesti. Iz tog razloga, mnogi istraživači su svoj rad posvetili boljem razumevanju efekata stigme povezane sa HIV-om, barijera koje stvara za intervencije lečenja i načina na koji se te prepreke mogu zaobići.

Klase lekova

Schematic description of the mechanism of the four classes of currently available antiretroviral drugs against HIV

There are six classes of drugs, which are usually used in combination, to treat HIV infection. Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include 2 Nucleoside reverse-transcriptase inhibitors (NRTI) as a "backbone" along with 1 Non-Nucleoside reverse-transcriptase inhibitor (NNRTI), protease inhibitor (PI) or Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) as a "base."

Inhibitori ulaza

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. Maraviroc works by targeting CCR5, a co-receptor located on human helper T-cells. Caution should be used when administering this drug, however, due to a possible shift in tropism which allows HIV to target an alternative co-receptor such as CXCR4.

In rare cases, individuals may have a mutation in the CCR5 delta gene which results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow progression of the disease. However, as mentioned previously, this can be overcome if an HIV variant that targets CXCR4 becomes dominant. To prevent fusion of the virus with the host membrane, enfuvirtide can be used. Enfuvirtide is a peptide drug that must be injected and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive hetero six-helix bundle, therefore preventing infection of host cells.

Nukleozidno/nukleotidni reverzbi-transkriptazni inhibitori

Nucleoside reverse-transcriptase inhibitors (NRTI) and nucleotide reverse-transcriptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse transcription. HIV is an RNA virus and hence unable to become integrated into the DNA in the nucleus of the human cell; it must be "reverse" transcribed into DNA. Since the conversion of RNA to DNA is not done in the mammalian cell it is performed by a viral protein which makes it a selective target for inhibition. NRTIs are chain terminators such that once incorporated, work by preventing other nucleosides from also being incorporated into the DNA chain because of the absence of a 3' OH group. Both act as competitive substrate inhibitors. Examples of currently used NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and tenofovir.

Nenukleozidni reverzno-transkriptazni inhibitori

Non-nucleoside reverse-transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine. HIV-2 is naturally resistant to NNRTIs.

Integrazni inhibitori

Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral 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 raltegravir became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg²⁺ ions at the metal binding site of integrase. As of early 2014, two other clinically approved integrase inhibitors are elvitegravir and dolutegravir.

Proteazni inhibitori

Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins. Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are lopinavir, indinavir, nelfinavir, amprenavir and ritonavir. Darunavir and atazanavir are currently recommended as first line therapy choices. Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, bevirimat and vivecon, was halted in 2010. Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.

Kombinovana terapija

Životni ciklus HIV-a može da bude kratak sa oko 1,5 dana od viralno ulaza u ćeliju, 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 the mutations 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, multi-drug resistant strains can become the dominant genotypes very rapidly. In the era before multiple drug classes were available (pre-1997), the reverse-transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of multi-drug resistant mutations.

Vidi još

• Antiviralni lek
• Otkriće i razvoj inhibitora HIV Proteaze
• Otkriće i razvoj inhibitora nenukleozidne reverzne transkriptaze
• Otkriće i razvoj inhibitora nukleozidne i nukleotidne reverzne transkriptaze

Spoljašnje veze

• AIDSinfo - Comprehensive resource for HIV/AIDS treatment and clinical trial information from the U. S. Department of Health and Human Services
• ASHM - Australian Commentary on HHS Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
• Origins of antiretroviral combination therapy
• Viral Load research papers, including effectiveness of HAART on reducing viral load
• Current status of gene therapy strategies to treat HIV/AIDS