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Antiretroviral therapy (ART)


 Understanding the specific steps in the HIV replication cycle is critical in order for scientists to develop drugs that attack vulnerable stages within the cycle. HIV belongs to a unique group of viruses known as retroviruses, so named because these viruses reverse the usual flow of genetic information within an infected cell. Most viruses store their genetic material in deoxyribonucleic acid (DNA), the double-helix structure that makes up genes.

 When a virus infects a cell, the viral DNA forms the template for the creation of messenger RNA, a type of ribonucleic acid. This messenger RNA directs the formation of specific proteins, and these proteins, in turn, build new virus particles (see Genetics). In HIV, however, genetic material is stored in two single-stranded RNA molecules. When HIV infects a cell, an enzyme called reverse transcriptase copies the genetic instructions in the virusís RNA and moves it into the DNA. This movement of genetic information from RNA to DNA is the opposite of that which occurs in most cells during protein synthesis

 Another HIV enzyme, called integrase, helps the newly formed viral DNA to become part of the structure of the infected cellís DNA. The viral DNA then forces the infected cell to manufacture HIV particles. A third HIV enzyme, called protease, packages these HIV particles into a complete and functional HIV virus. Over the last decade researchers have created a variety of drugs that block the action of some of the enzymes used in HIV replication. The main classes of drugs used against HIV are nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors.

 Nucleoside analogues impede the action of reverse transcriptase, the HIV enzyme that converts the virusís genetic material into DNA. During this conversion process, these drugs incorporate themselves into the structure of the viral DNA, rendering the DNA useless and preventing it from instructing the infected cell to make additional HIV. The nucleoside analogue known as azidothymidine (AZT), which became available in 1987, was the first drug approved by the United States Food and Drug Administration (FDA) to treat AIDS. AZT slows HIV growth in the body, permitting an increase in the number of CD4 cells, which boosts the immune system. AZT also prevents transmission of HIV from an infected mother to her newborn.

 Since the introduction of AZT, additional nucleoside analogues have been developed, including didanosine (sold under the trade name Videx), zalcitabine (HIVID), stavudine (Zerit), lamivudine (Epivir), and abacavir (Ziagen). These drugs are not particularly powerful when used alone, and often their benefits last for only 6 to 12 months. But when nucleoside analogues are used in combination with each other, they provide longer-lasting and more effective results.

 Non-nucleoside reverse transcriptase inhibitors (NNRTIs), introduced in 1996, use a different mechanism to block reverse transcriptase. These drugs bind directly to reverse transcriptase, preventing the enzyme from converting RNA to DNA. Three NNRTIs are available: nevirapine (Viramune), delavirdine (Rescriptor), and efavirenz (Sustiva). NNRTIs work best when used in combination with nucleoside analogues.

 The third group of antiviral drugs, called protease inhibitors, cripples protease, the enzyme vital to the formation of new HIV. When these drugs block protease, defective HIV forms that is unable to infect new cells. Protease inhibitors are more powerful than nucleosides and NNRTIs, producing dramatic decreases in HIV levels in the blood. This reduced viral load, in turn, enables CD4 cell levels to skyrocket. The first protease inhibitor, saquinavir (Invirase), was approved in 1995. Since then other protease inhibitors have been approved, including ritonavir (Norvir), indinavir (Crixivan), nelfinavir (Viracept), and amprenavir (Agenerase).

 A new class of drugs, known as fusion inhibitors, became available in 2003 when the FDA approved the use of enfuvirtide, sold under the brand name Fuzeon. Fusion inhibitors prevent the binding or fusion of HIV to CD4 cells. When used with other antiretroviral medicines, fusion inhibitors can reduce the amount of HIV in the blood and increase the number of CD4 cells.

What is ATR?


 Antiretroviral drugs inhibit the replication of HIV. When antiretroviral drugs are given in combination, HIV replication and immune deterioration can be delayed, and survival and quality of life improved.

Why it is Important?


 Effective HIV/AIDS care requires antiretroviral therapy as a treatment option. Without access to antiretroviral therapy, people living with HIV/AIDS cannot attain the fullest possible physical and mental health and cannot play their fullest role as actors in the fight against the epidemic, because their life expectancy will be too short. Health care workers will remain disempowered and cannot contribute to the fight against HIV to the fullest of their potential. Children will be orphaned earlier, stigma and discrimination will continue to be fuelled by the perception that HIV infection is a death sentence.

How it is Done


 All people who need antiretroviral therapy should have access to it. WHO proposed as a target that by 2005, 3 million people should have access, and called for the adoption in resource-limited settings of a public health approach to antiretroviral treatment as a tool to reach this goal.

 Selection of ARV treatment regimens for programmes and individual patients should consider: potency, frequency of dosage, side effects, maintenance of future treatment options, the anticipated adherence of the patient population to a regimen, need for storage, concurrent conditions, the potential for resistant viral strains, and cost and access. Additional considerations may include access to only a limited number of ARV drugs, limited health service infrastructure, the need to deliver drugs to rural areas, a high incidence of tuberculosis and hepatitis B and/or C, and the presence of varied HIV groups and subtypes.

 WHO recommends that in ARV treatment programmes in resource-limited settings HIV infected adolescents and adults should start ARV therapy when they have clinical AIDS, regardless of CD4 count. When total lymphocyte count can be assessed, in addition people with WHO stage II or III HIV disease should be offered treatment. When CD4 counts are available, all HIV infected people with less than 200 CD4 cells/mm3 should be offered treatment.

 WHO recommends that in resource-limited settings a single first-line regimen should be identified for the treatment of the majority of new patients. This regimen would consist of 2 nucleoside analogs and either a non-nucleoside or abacavir, or a protease inhibitor. Zidovudine (ZDV)/3TC is the initial recommendation for a dual nucleoside analog with d4T/3TC, ZDV/ddI and ddI/3TC as possible alternatives. Efavirenz and nevirapine are recommended non-nucleosides, while recommended protease inhibitors include ritonavir-boosted PIs (indinavir, lopinavir, saquinavir) or nelfinavir. A second line regimen should be chosen to substitute first line regimens when needed (for toxicity or treatment failure).

 Clinical assessment prior to the initiation of ART includes documentation of past medical history, identification of current and past HIV related illnesses, identification of co-existing medical conditions and medications in use that may influence choice of therapy (such as TB or pregnancy) as well as current symptoms and physical signs.

 Minimum laboratory tests include an HIV antibody test, and (if ZDV is part of the regimen) haemoglobin or hematocrit level. Highly desirable tests are white blood cell count and differential, CD4 count, serum alanine, aspartate aminotransferase level, serum creatinine, blood urea nitrogen, serum glucose, bilirubin, amylase and serum lipids, and pregnancy tests for women.

 Toxicity should be monitored clinically based on patient reports and physical examination, supplemented by a limited number of laboratory tests depending on the symptoms that arise and the specific combination regimen that is used.

 Treatment failure will require that a second line regimen be used. When a change in treatment is indicated because of toxicity or resistance, either an entirely new second line regimen can be prescribed, or, when the toxicity or resistance is related to an identifiable drug in the regimen, the offending drug can be replaced.

 Countries planning to implement ART programmes should also concurrently implement an HIV drug resistance sentinel surveillance system. This will allow the detection of drug resistance at the population level and allow to modify recommended treatment regimens accordingly.

Human Resources, Infrastructure and Supplies Required


 For the successful use of ARVs there should be access to specific services and facilities:

 HIV counselling and testing and follow-up counselling services to ensure psychosocial support and adherence to treatment;
Capacity to appropriately manage HIV related illness and opportunistic infections;
A laboratory that provides tests for monitoring treatment;
A continuous supply of antiretrovirals and medicines for the treatment of opportunistic infections and other HIV related illnesses;
Reliable regulatory mechanisms.

 In addition, there is a need for adequately trained doctors, clinical officers, nurses, laboratory technicians, pharmacists, counsellors and clerks to provide the services required. Last, there needs to be a reliable source of financing of the services and medicines provided. In many settings there are already some people who can provide quality services, there is already some infrastructure that can be used, and there are already some people who can pay for the service they need. In these settings treatment should be offered now, while resources are sought and the health service is strengthened to do more in the future. Today, with the increased availability of funds through the Global Fund, the World Bank and other donors, there is a considerable window of opportunity for developing countries to scale up access to antiretroviral therapy.

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