Missing doses or stopping antiviral therapy

It is strongly advised that individuals on an antiviral regimen should not miss any doses of their medications. Unfortunately, life is such that doses often are missed. Reasons for missing doses range from just forgetting to take the medication, leaving town without the medication, or because of a medical emergency, such as the need for urgent surgery. For example, after an appendectomy for acute appendicitis, a patient may not be able to take oral medication for up to several days. When a dose is missed, the patient should contact his or her physician without delay to discuss the course of action. The options in this situation are to take the missed doses immediately or simply resume the drugs with the next scheduled dose.

Although every missed dose increases the chance that the virus will develop resistance to the drugs, a single missed dose should not be cause for alarm. On the contrary, it is an opportunity to learn from the experience and determine why it happened, if it is likely to happen again, and what can be done to minimize missing future doses. Furthermore, if a patient cannot resume medication for a limited time, such as in a medical emergency, there still is no cause for alarm. In this circumstance the patient can be assured that as long as all medications are stopped simultaneously and then restarted in the future; the risk of developing drug resistance is small. Nevertheless, stopping is associated with some risks of developing drug resistance and those who wish to stop therapy for any one of a number of reasons, should discuss this with their health care provider in advance to establish the best strategy for safely accomplishing this.

Should patients with the "flu-like" or "mono-like" illness of primary HIV infection be treated?

Patients who are identified with HIV around the time they are first infected (primary, acute infection) may benefit from potent antiviral therapy given at that time. The rationale for initiating this early treatment is primarily theoretical. Preliminary evidence, however, suggests that unique aspects of the body's immune response to the virus may be preserved by this strategy. It is thought that treatment during the primary infection may be an opportunity to help the body's natural defense system to work against HIV. Thus, patients may gain an improved control of their infection while on therapy, and perhaps even after therapy is stopped. At one time, the hope was that if therapy was started very early in the course of the infection, HIV could be eradicated. Most evidence today however suggests that this is not the case. Consequently, early treatment is not likely to result in a cure, although other benefits may still exist. Therefore, the current recommendation is that patients with primary infection should be referred to clinical studies where the potential role of therapy can be discussed and further explored. If emotional or social situations make adherence to such treatment questionable, however, the patients are clearly better off delaying therapy. After all, on the average, infected persons can expect to remain healthy for a prolonged period of time. Regardless, patients need to be aware that initiating treatment early puts them at risk for developing short and long-term side effects as well as resistance to the drugs.

What about treatment for HIV during pregnancy?

One of the greatest advances in the management of HIV infection has been in pregnant women. Prior to antiviral therapy, the risk of HIV transmission from an infected mother to her newborn was approximately 25-35%. The first major advance in this area came with studies giving ZDV after the first trimester of pregnancy, then intravenously during the delivery process, and then after delivery to the newborn for 6 weeks. This treatment showed a reduction in the risk of transmission to less than 10%. Although less data are available with more potent drug combinations, clinical experience suggests that the risk of transmission may be reduced to less than 5%. Current recommendations are to advise HIV-infected pregnant women regarding both the unknown side effects of antiviral therapy on the fetus, and the promising clinical experience with potent therapy in preventing transmission. In the final analysis, however, pregnant women with HIV should be treated essentially the same as non-pregnant women with HIV. Exceptions would be during the first trimester, where therapy remains controversial, and avoiding certain drugs that may cause greater concern for fetal toxicity, such as EFV.

All HIV-infected pregnant women should be managed by an obstetrician with experience in dealing with HIV-infected women. Maximal obstetric precautions to minimize transmission of the HIV virus such as avoiding scalp monitors, and minimizing labor after rupture of the uterine membranes. In addition, the potential use of an elective Caesarean section (C- section) should be discussed, particularly in those women without good viral control of their HIV infection where the risk of transmission may be increased. Breastfeeding should be avoided if alternative nutrition for the infant is available since HIV transmission can occur by this route. Despite the reduced risk of transmission associated with antiviral therapy, pregnant women with HIV need to be thoroughly counseled regarding all risks, as well as all options, including therapeutic abortions when appropriate. Updated guidelines for managing HIV-infected women are updated on a regular basis and can be found at www.hivatis.org.

What about treating people exposed to the blood or genital secretions of an HIV-infected person?

Recently, a great deal of interest has focused on preventing transmission to uninfected persons that are inadvertently exposed by the early administration of antiviral therapy. Because the risk of infection after most isolated exposures is relatively small, generally less than 5%, formal studies are difficult to perform. Animal studies and some human experience, however, suggest that post-exposure treatment may be effective. In fact, the current recommendation is that health care workers who experience a needlestick from an infected person take antiviral medication for 4 weeks in order to reduce the risk of infection. Extending that recommendation, many physicians have proposed similar preventive treatment for people with sexual exposures to HIV. Those individuals considering this type of preventative treatment must be aware that post-exposure treatment cannot be relied upon to prevent HIV infection. Second, such treatment is not always available at the time most needed and is probably best restricted to unusual and unexpected exposures, such as a broken condom during intercourse. Third, although regimens with 2 or 3 drugs generally are recommended for those exposed in the healthcare setting, the best therapy for sexual exposure still is unknown. Fourth, therapy probably will be most effective if started within the first 2 hours after an exposure. And finally, a 4-week supply of a three-drug combination of antiviral drugs costs approximately $1000 and generally is not covered by insurance. Updated guidelines are published and available at www.hivatis.org.

What can be done for people who have severe immunosuppression?

Although one goal of antiviral therapy is to prevent the development of immune suppression, some individuals are already immunosuppressed when they first seek medical care. In addition, others may progress to that stage as a result of resistance to antiviral drugs. Nevertheless, every effort must be made to optimize antiviral therapy in these patients. In addition, certain specific antibiotics should be initiated, depending on the number of CD4 cells, to prevent the complications (that is, the opportunistic infections) that are associated with HIV immunosuppression. Guidelines for the prevention of opportunistic infections can be found at www.hivatis.org.

In summary, patients with a CD4 cell count of less than 200 should receive preventative treatment against Pneumocystis carinii (the opportunistic bacteria that causes pneumonia and is now known as Pneumocystis jiroveci) with trimethoprim/sulfamethoxazole (BactrimTM, SeptraTM), given once daily or three times weekly. If they are intolerant to that drug, patients can be treated with an alternative drug such as dapsone, or atovaquone (MepronTM). Those patients with a CD4 cell count of less than 100 who also have evidence of past infection with Toxoplasma gondii, which is usually determined by the presence of toxoplasma antibodies in the blood, should receive trimethoprim/sulfamethoxazole. Toxoplasmosis is an opportunistic parasitic disease that affects the brain and liver. If a person is using dapsone to prevent Pneumocystis carinii (P. jiroveci), pyrimethamine and leucovorin can be added once a week to their regimen to prevent toxoplasmosis. Finally, patients with a CD4 cell count of less than 50 should receive preventive treatment for Mycobacterium avium complex (MAC) infection with weekly azithromycin (ZithromaxTM), or as an alternative, twice daily clarithromycin (BiaxinTM) or mycobutin (RifabutinTM). MAC is an opportunistic bacterium that causes infection throughout the body.

What is in the future for HIV-infected individuals and for those at risk to contract HIV?

Trends continue towards simplifying drug regimens to improve adherence and decrease side effects. In addition, many new drugs are being developed. These new drugs are in both the currently available classes of anti-HIV medications as well as in new classes of drugs, such as those that block the virus from entering cells or from incorporating itself into the human genetic material. Both of these actions prevent the virus from duplicating itself, thereby inhibiting an increase in the viral load. Perhaps even more importantly, researchers are attempting to enhance the body's natural defenses against HIV in order to control viral growth. An example of this approach is the use of an HIV vaccine, with or without antiviral therapy. Also, innovative studies are underway to try to purge or eliminate the HIV from the body. The rationale for purging is to allow for the withdrawal of therapy without a rebound increase in the number of viral particles in the blood. For example, drugs have been developed to stimulate HIV-infected CD4 cells, which then would be expected to undergo viral or immune self-destruction. Although all of this research is exciting and promising, the reality is that in the near future, patients will need to remain on antiviral therapy.

The good news is that the development of antiviral therapy has led to a marked decline in AIDS-related deaths in many parts of the world. The majority of infected individuals, however, do not have access to the expensive antiviral medications. Accordingly, the best hope for limiting the current epidemic of HIV around the world remains an effective vaccine. Unfortunately, despite increasing research in this area, the development of a vaccine continues to lag far behind the progress that has been made in antiviral therapy.

HIV At A Glance

• The human immunodeficiency virus (HIV) is a type of virus called a retrovirus, which infects humans when it comes in contact with tissues such as those that line the vagina, anal area, mouth, or eyes, or through a break in the skin.
• HIV infection is generally a slowly progressive disease in which the virus is present throughout the body at all stages of the disease.
• Three stages of HIV infection have been described.
  1. The initial stage of infection (primary infection), which occurs within weeks of acquiring the virus, and often is characterized by a "flu-" or "mono-"like illness that generally resolves within weeks.
  2. The stage of chronic asymptomatic infection (meaning a long duration of infection without symptoms) which lasts an average of 8 to10 years.
  3. The stage of symptomatic infection, in which the body's immune (or defense) system has been suppressed and complications have developed. This stage is called the acquired immunodeficiency syndrome (AIDS). The symptoms are caused by the complications of AIDS, which include one or more unusual infections or cancers, severe loss of weight, and intellectual deterioration (called dementia).
• When HIV grows (that is, by reproducing itself), it acquires the ability to change (mutate) its own structure. This mutation enables the virus to become resistant to previously effective drug therapy.
• The goals of drug therapy are to prevent damage to the immune system by the HIV virus and to halt or delay the progress of the infection to symptomatic disease.
• Therapy for HIV includes combinations of drugs that decrease the growth of the virus to such an extent that the treatment prevents or markedly delays the development of viral resistance to the drugs.
• The best combination of drugs for HIV has not yet been defined, but one of the most important factors is that the combination be well tolerated so that it can be followed consistently without missing doses.