Abstract: The human immunodeficiency virus (HIV) is a global problem in today's society. Presently, there is no cure for this devastating disease, but there are many treatment modalities from which to choose. The medications called antiretroviral agents must be carefully selected and customized for each person who is being treated for an HIV infection. Physicians and pharmacists must use extreme care when these drugs are ordered, because if they are used improperly, there will be an increase in resistance to the virus. In order to prevent resistance, people should be properly educated about these agents, how they should be taken, as well as the specific schedule to which they should comply. Education is the major factor in assisting with bringing this disease under control and reducing transmission. Antiretroviral agents recommended for HIV infection through the stages of reproduction, transmission, and treatment are discussed.
Key Words: HIV, Antiretroviral Agents, Transmission, Treatment
HIV is presently the only causative factor known to cause the acquired immunodeficiency syndrome (AIDS). Even before the full-blown status of AIDS is noted in an HIV-positive individual, the virus has already started to destroy the immune system. Studies have shown that the virus invades the body during the stages of no visible symptoms and resides in high concentrations in lymph nodes where it continues to increase (Mulvihill et al., 2001).
The stages of HIV reproduction begins when HIV enters a CD+ cell. HIV is a retrovirus, meaning that its genetic information is stored on a single-stranded RNA instead of the double-stranded DNA found in most organisms. To replicate, HIV uses an enzyme known as reverse transcriptase to convert its RNA into DNA. HIV enters the nucleus of the CD4+ cell and inserts itself into the cell's DNA. HIV DNA then instructs the cell to make many copies of the original virus. New virus particles are then assembled, leave the cell and are ready to infect other CD4+ cells (Bartlett, 1997).
There are three classes of antiretroviral agents: nonnucleoside reverse transcriptase inhibitors, nucleoside analogues and the protease inhibitors. The first effective class of antiretroviral drugs was the nucleoside analogues. They act by incorporating themselves into the DNA of the virus, thereby stopping the building process. The resulting DNA is incomplete and cannot create new virus. Some of these drugs are Retrovir (zidovudine - also known as ZDV or AZT), Videx (didanosine - also known as ddl), and Combivir (lamivudine/zidovudine) (Armstrong, Goldman, Lacy, & Lance, 1999).
Protease inhibitors work at the last stage of the virus reproduction cycle. They prevent HIV from being successfully assembled and released from the infected CD4+ cell. This group of drugs include: invirase (saquinavir mesylate), Crixivan (indinavir), and Fortovase (saquinavir).
The newest class of antiretroviral agents are the nonnucleoside reverse transcriptase inhibitors (NNRTIs) that stop HIV production by binding directly on to reverse transcritase and prevent the conversion of RNA to DNA. These drugs are called "non-nucleoside" inhibitors because even though they work at the same stage as nucleoside analogues, they act in a completely different way. Examples of these drugs are VIRAMUNE (nevirapine), Rescriptor (delaviraline mesylate) and SUSTIVA (efavirenz).
The HIV virus is a member of the Lentivirus family consisting of retroviruses. HIV is known to be transmitted through three major routes, i.e., sexual contact, parenteral inoculation and passage of the virus from infected mothers to their newborns (Barlett, 1997).
HIV carries its genetic information as RNA rather than DNA. The virus infects certain white blood cells of the body's immune system, namely the helper T-4 lymphocytes, and destroys their ability to fight infection. The virus replicates itself within the lymphocyte, killing it, and spreading to others ( Mulvihill et al., 2001). HIV is transmitted via contaminated body fluids including blood semen, vaginal secretions, and breast milk. Therefore, HIV is transmitted during unprotected anal, oral, or vaginal intercourse, birth, breastfeeding, and the sharing of needles. HIV is found in saliva, but in such small concentrations that it is estimated a person would have to ingest a bucket of saliva to actually get the virus from saliva. In some cases, recipients of blood transfusions before blood screening was done developed AIDS. Reliable tests for the presence of the virus now minimize the risk of contracting it through contaminated blood transfusion. Blood donors do not contract the virus from giving blood because a new needle is used each time (Mulvihill et al. 2001).
According to Bartlett (1997), HIV approaches a cell in the body and the viral antigen gp 120 pro attaches to CD4+, uncovering gp 41. The gp 41 attaches to a proposed receptor and HIV fuses with the cell. Following fusion, viral RNA enters the cytoplasm of the host cell. At this point, the virus produces a DNA copy of itself (cDNA) using its viral RNA as the template. The viral RNA can't be duplicated into a double-stranded DNA structure. The cDNA istransported to the nucleus where it is integrated into the chromosomal DNA (provirus). The virus becomes a part of the cell and will remain there until the cell dies. The provirus remains "latent" and an expression of HIV occurs.
The various drugs used to treat HIV infection are nonnucleoside reverse transcriptase inhibitors (NRTIs), nucleoside analogues and protease inhibitors are called Clinical Trials. Non-nucleoside reverse transcriptase inhibitors (NRTIs) have activity against the virus by binding to reverse transcriptase. NRTIs block the RNA dependent and DNA dependent and DNA polymerase activities which include HIV - 1 replication. VIRAMUNE (nevirapine), an example of a NRTI) has a usage adult daily dosage of one (200 mgm) tablet twice a day. Adverse reactions may include headache, fever, rash, diarrhea, and neutropenia (Armstrong, Goldman, Lacy, & Lance, 1999).
Nucleoside analogues cause inhibition of HIV reverse transcriptase via viral DNA chain termination. These drugs inhibit RNA and DNA dependent DNA polymerase activities of reverse transcriptase. This action results in DNA chain termination. The most popular drug of the nucleoside analogues is Retrovir (zidovudine, also known as ZDV or AZT). The usual adult daily dosing is two (100 mgm) capsules three times a day or one (300 mgm) tablet twice a day. The adverse reactions may include severe headache, fever, rash, nausea and vomiting, anorexia, pain, anemia and weaknesses in the muscles (Armstrong, Goldman, Lacy & Lance, 1999).
Protease inhibitors work at the last stage of the virus reproduction cycle. These drugs bind to the protease activity site and inhibits the activity of this enzyme and prevents HIV from being successfully assembled and released from the infected CD4+ cell. A popular protease inhibitor is Crixivan (Indinavir). The usual adult dosing is two (400 mgm) capsules three times a day. Some adverse reactions that may occur include: headache, insomnia, abdominal pain, nausea and vomiting, taste perversion, and kidney stones (Armstrong, Goldman, Lacy, & Lance, 1999).
A pharmacotherapy with a pathological approach should be used on each individual person as drugs for HIV infection are ordered. At the present time, resistance is a significant problem in many persons and as a result these persons have very limited, if any, effective treatment options using currently FDA-approved antiretrovirals.
Several companies are in the process of developing new, novel therapies for treating HIV and further information regarding these potential treatments were presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy held in Toronto, Canada last September, and at the XIII International AIDS Conference held in Durban, South Africa, last July.
THE TRUE CONCERN
There are many different drugs to choose from to help treat HIV infection, but still there is no cure. The desired outcome is strongly affected by the patients' compliance to their therapeutic regimen (Patterson, 2000). Patterson (2000), states "that patients often skip or delay medication regimen." Many people have different reasons why they are non-compliant to taking medications according to their prescribed regimen. Some of these reasons may include living conditions, lifestyles, work schedules or their mental status. According to Echenwiler (1999), many people infected with HIV live in conditions where adherence to a complex drug regimen is difficult. Persons may be homeless and transient, and may have a history of drug use. These people may be hindered in their ability to take multiple medications at different times that require special meals and/ or preparation, large quantities of water, or even refrigeration. If these medications are taken differently from how they are ordered, the person's welfare maybe compromised and leading to viral resistance or drug toxicities such as diarrhea, nausea and vomiting, fatigue, headache or changes in distribution of subcutaneous fat.
For HIV therapy to be effective, patients cannot afford to skip or delay medications in their daily regimen. According to Patterson (2000), "investigators from the University of Pittsburgh Medical Center found that patients with 95% or greater adherence had a greater chance of success. These factors were measured by disappearance of detectable HIV in their bloodstream, greater increases in CD4 lymphocyte count and lower hospitalization rates than did patients with levels of adherence lower than 95%." Echenwiler (1999) also feels "that people need to be educated about HIV, their drug regimens, importance of compliance and other factors that can further inhibit the spread of the HIV virus."
The HIV virus that causes AIDS is extremely dangerous and of great concern for health care professionals of all interdisciplinary teams. This virus is transmitted through sexual contact, parenteral inoculation, and passage of the virus from infected mothers to their newborns (Bartlett, 1997). This disease kills and it has no respect to any persons. People must be well educated about this virus and the medications that are given to slow t he progression of viral resistance. There are many drugs used for the treatment of HIV, but only if persons infected with HIV are compliant with their medication regimen.
Armstrong, L.L., Goldman, M.P., Lacy, C.F., & Lance, L.L. (1999). Drug information handbook (Rev. ed). Hudson, OH: LexiComp.
Bartlett, J.A. (1997). Care and management of patients with HII infection. Durham, NC: Clean Data.
Echenwiler, L. (1999). Justice and access to therapies for AIDS. AIDS & Public Policy Journal, 14(1), 20 - 25.
Mulvihill, M.L., Zelman, M., Holloway, P., Tompary, E. & Turchany, J. (2001). Human diseases: A systemic approach (5th Ed.). Upper Saddle River: NJ: Prentice Hall.
Patterson, D.L. (2000, September). Antiretroviral drugs require 95% adherence. Pharmaceutical Representative, 13.
Wilhelmina Harris is a doctor of pharmacy student at Howard University and Geraldine Brown, PhD, RN, is an assistant professor in the Division of Nursing at Howard University in Washington, DC.