STEP PERSPECTIVE, Volume 8, No. 3 - Winter/1996; A Publication of the Seattle Treatment Exchange Project e-mail: step@eskimo.com
Jane Woodward, Pharm.D.

New Findings in Viral Dynamics One of the most important advances in HIV/AIDS care is the ability to measure the amount of viral particles in the blood stream. More commonly known as "viral load,"the measurement gives a more complete picture of immune system. At high viral levels, it is a sensitive marker of those who are at risk to progress rapidly to AIDS. Viral measurements have also given us a better idea of the velocity of replication and the damage that can occur to the immune system when replication is allowed to continue unchecked. It has now been estimated that the half life of an infected CD4 cell that is rapidly producing viral particles is about 1.6 days and for a free virion in plasma it is 0.3 days. Thus, the number of virions produced daily is at least 10.3 x 109. It is estimated that up to two billion immune cells are destroyed daily (Science).

Protease inhibitors are a new class of drugs designed to block viral replication. They work late in the life cycle and thus are effective in newly and chronically infected cells. When used in combination with nucleoside analogs such as zidovudine (AZT) and lamivudine (3TC) it is possible to block viral replication within the bloodstream. When this occurs viral levels decline rapidly - an initial lag is followed by exponential decay. This phase of decay is due to clearance of free virions and productively infected cells. The half life of this phase is estimated at 2.1 days. Once the plasma is cleared of infecting virus, a second elimination phase begins that is due to the drugs' effect on macrophages and latently infected CD4 cells. This is a much slower phase with the average cell life span of 13.3 days. In theory, administering potent antiretroviral medications over an extended period of time would allow all compartments to burn out cells that have been infected with HIV (XI Int AIDS Conf (ThB930 Ho, David).

While these are exciting theories, there are many questions left to be answered. It is not known how long these potent antiretroviral regimens would have to be administered to completely clear virus particles and infected cells. It has been estimated that at least 1.5-3 years will be required (XI Int AIDS Conf (ThB930 Ho, David). Antiretroviral regimens have always lost their efficacy over time. The reasons for this are unknown, but considerable evidence has pointed to development of resistance. Thus, there is some skepticism that these regimens will remain effective or will be tolerated for the time required to eradicate the virus. Previous regiments were never able to completely stop replication in the bloodstream and thus, viral replication occurred in the presence of the drug, driving resistance mutations. Completely stopping replication may result in resistance being avoided altogether. However, even if the regimen was successful, it is unknown if the immune system would be able to recover.

Post Exposure Prophylaxis (PEP)

Theories on viral dynamics and aggressive antiretroviral regiments both play a role in the decision of how to treat someone exposed to HIV in the health care setting. Potent antiretroviral drugs, if introduced early after exposure, could theoretically block the first cycle of replication, preventing infection of multiple cells lines. It has also been hypothesized that they may also be used to eradicate infection, again, if introduced soon enough after exposure. Even if they do not completely eradicate the virus, they could potentially alter the natural history of the disease by lowering the set point of initial viremia after infection has occurred ( Gerberding NEJM 1995).

What is the Risk?

Needlestick exposures are thought to be the most risky, yet seroconversion rates are only 0.2-0.3%. Factors which increase the risk of seroconversion are deep injuries, devices visibly contaminated with blood, procedures involving a needle placed directly in a vein or artery and advanced AIDS in the source patient (probably indicative of high viral load or syncytium inducing virus) (MMWR 1995). Injuries with hollow core needles and injuries that do not occur through gloved skin are thought to be more risky as well.

Mucocutaneous exposures resulting in seroconversion have never occurred in studies, but the risk has been estimated at 0.08% ( XI Int AIDS Conf 1996 TuC120). Higher risk is associated with large volumes of blood, prolonged duration of contact and a potential portal of entry such as non-intact skin (Gerberding NEJM 1995). Host defense may also play a role since evidence of cellular immune response has been found in exposed but uninfected health care workers. Treatment of HIV exposure has been hampered with concern over lack of efficacy of available treatments and also high toxicity rates. Zidovudine (AZT) is the only antiretroviral agent formally studied for this indication and there have been well documented failures despite early administration. The Center for Disease Control (CDC) surveillance data found AZT used in 31% of exposures overall and 31% of patients did not complete the course. Adverse events occurred in 75% of those treated. Failure of AZT occurred in at least nine cases, although five failures had exposures greater than a needle stick ( Annals of Int Med 1993;118(12) 913-19). Failure can occur because of inadequate control of replication, timing, lack of penetration into target tissues, compliance with the regimen and resistance.

Interest in post exposure prophylaxis was renewed recently with the results of a study reported in 1995 (MMWR 1995). A case-control study was reported of 31 workers who seroconverted after occupational percutaneous exposure to HIV. Results found a significant reduction in seroconversion in those who took AZT early after exposure. Taking AZT reduced the risk 79% (MMWR Dec 22, 1995 vol 44 no 50:929-933). Although a prospective, placebo-controlled trial would have given more reliable results, such a study is not feasible at this time, (given the very low seroconversion rate and the participants' understandable hesitation at being randomized to the placebo arm).

Although AZT alone has proven efficacy in reducing the risk of seroconversion after exposure to HIV, failures have kept investigators searching for better regimens. As previously discussed, potent combinations of antiretrovirals that include protease inhibitors afford much better control of viral replication and will probably be more effective at preventing seroconversion. Using the knowledge of viral dynamics and the properties of these medications, the United States Public Health Service (USPHS) has published new recommendations for post exposure prophylaxis (see table 1). If possible, these drugs should be started within 1-2 hours of exposure, preferably as soon as possible, and continued for four weeks. The University of Washington and Harborview Medical Centers have adopted these recommendations and are prepared to provide these medications quickly following accidental exposure.

Careful evaluation of the severity of the exposure is necessary, as these medications are not innocuous. There is not much information of the incidence of adverse events in people not already infected with HIV, but considerable toxicity does occur. Zidovudine, when used for this indication, is hampered by nausea (61%), vomiting (15%), fatigue (49%), abdominal pain (15%), headache (12%), myalgias (12%), anemia (12%) and neutropenia (8%) (Int Con AIDS TuC122). All serious exposures should receive three medications - zidovudine (ZDV or AZT), lamivudine (3TC) and the protease inhibitor indinavir (IDV). Please see table 2 for details regarding dose, adverse reactions and possible drug interactions. Changes may be made to this regimen on a case-by-case basis, particularly if the source patient is known to be taking any of these medications. Some providers may elect to use a loading dose (high initial dose) to achieve therapeutic drug levels as quickly as possible. It is unknown whether a loading dose will offer additional prophylactic benefit, but will possibly cause more transient side effects. Compliance with the medication regimen is of paramount importance. Resistance can develop quickly if the regimen is not adhered to, and efficacy may compromised.

Prophylaxis Following Risky Behaviors

It has become a concern that antiretroviral medications are being used by some people following potential exposure to HIV, especially following unsafe sex and needle sharing. This "morning after" use of these medications is fraught with problems. If these drugs are not taken in combination, very soon after exposure, at correct dosages, and at least for four weeks, incomplete viral suppression will occur, thus potentially breeding resistance. AZT alone will not prevent HIV infection when used in this setting. These medications are anything but innocuous, and require frequent monitoring by someone well-versed in HIV care to avoid toxicities that may be irreversible. "Morning after" therapy should not be used in place of well-accepted methods to prevent HIV transmission.

About The Author

Jane Woodward, Pharm.D, is a pharmacist currently in practice at the University of Washington.

These articles were provided by the Seattle Treatment Education Project - Copyright (c) 1997 - Seattle Treatment Education Project. Noncommercial reproduction encouraged. Distributed by AEGIS - http://www.aegis.com
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