• Immune Basics
• Can medications work too well?
• Research Results

It’s Spring Break season, and many HIVers are talking about holidays, "drug holidays," that is. Although the name is casual, the discussions about temporarily stopping HIV therapy are not. The April community forum provided participants with an opportunity to learn more about the way the body fights infection, the role that HIV medications play in this process, and the theory behind both drug holidays, more accurately called "structured treatment interruptions," and therapeutic vaccines such as Remune. With a thorough presentation highlighting recent research in the field, Richard Jefferys expressed cautious optimism that HIV medications may not be a lifelong prescription. At the same time, he emphasized the need for further research and stressed that a haphazard approach to stopping medications is harmful. Always discuss changes to your medication regimen with your primary care provider – do not attempt treatment interruptions without his or her input.

Immune Basics

We all know that HIV damages the immune system, and that someone infected with HIV may eventually lose the ability to fight infection. Before the viral load test was widely available, the only way to track the progression of HIV was by measuring CD4 cell (T cell) count. When an individual’s CD4 cell count falls to less than 200 cells in a cubic millimeter of blood, it indicates that the body is not as effective at fighting infection.

CD4 cells are extremely important in the body’s response to antigens, which are foreign materials (including viruses and bacteria) in the blood. When a CD4 cell recognizes an antigen, an elaborate procedure is initiated to rid the body of the invader. CD4 cells divide at a rapid rate to produce both helper T cells and memory T cells, all of which recognize the same antigen. This rapid division is called the lymphocyte proliferative response (LPR). The helper T cells secrete substances that coordinate the body’s response to the antigen. One such substance promotes the maturation of cytotoxic T cells, which destroy virus-infected cells. Memory T cells remain in reserve for the next exposure to the same antigen. When exposed again, the memory T cells are activated faster, divide more rapidly, and last longer than their "naïve" counterparts.

What’s described above is the body’s response to a typical antigen, like the virus that causes chicken pox. Most people are infected with the chicken pox when they’re young, break out in some itchy lesions, and recover once the immune system mounts a response and gets the viral infection under control. The memory T cells stick around to control the infection if you’re exposed later. But the immune system is not able to control HIV infection in this manner. Upon exposure to HIV, the immune system responds – CD4 cells are activated, cytotoxic T cells mature, memory T cells are generated. But the response is thwarted by HIV. Activated T cells are susceptible to infection with HIV. Once inside a T cell, HIV takes over, and uses the cell to make copies of itself, destroying the T cell in the process. The end result is that the immune system cannot eliminate HIV, and damage to the immune system continues. Some individuals, known as long-term non-progressors, seem able to generate a stronger immune response to HIV infection and live for long periods without HIV disease progression than most people. It has been shown that these individuals have a more robust LPR to HIV and have functional memory cells that are able to control HIV.

When changes in body fat were first seen, many researchers believed that protease inhibitors-the class of drugs that includes Crixivan, Norvir, and Viracept-were the main culprit. While research still suggests that protease inhibitors are associated with a buildup of fat around the gut and back of the neck, some new study results suggest that nucleoside analogues-the class that includes AZT, 3TC, and d4T-are associated with a loss of fat in the arms, legs, and face, as well as weight loss.

Can medications work too well?

Enter HIV medications. They work by interrupting HIV as it copies itself within T cells. Sounds great, right? No replication, no problem. Unfortunately, this is not the case. A few things can go wrong: First, the medications are tough to take. Both the short- and long-term side effects can be harmful. Second, HIV develops resistance to the medications. The virus copies itself quickly, and makes mistakes. Sometimes, these mistakes lead to a strain of the virus that is not affected by medication, and the unaffected strain quickly becomes the prominent strain in the body. Third, when the medications are working well, and there is little virus circulating in the blood, the immune system is not stimulated by HIV. The body "forgets" that the virus is present, and does not generate an immune response against it. No memory T cells are generated, no HIV-specific cytotoxic T cells mature.

Bingo! Here’s the theory behind structured treatment interruptions and therapeutic vaccines – that the immune system can be "trained" to control HIV infection, if it’s given the chance. Through either occasional exposure to an individual’s own virus (in structured treatment interruption) or through exposure to a therapeutic vaccine (a vaccine consisting of pieces of HIV), it may be possible for the immune system to generate an effective response.

More specifically, it has been theorized that stopping HIV medications allows HIV to replicate in the blood, activating naïve T cells. Activated T cells initiate a lymphocyte proliferative response, producing memory T cells and stimulating cytotoxic activity against HIV-infected cells. Therapy is reinitiated to protect some naïve cells from infection by HIV. After a cycle of starts and stops, there is the potential that enough HIV-specific memory T cells are in reserve to permanently withdraw therapy and let the immune system control HIV on its own.

Research Results

But that’s theory. What’s the research saying? The results are mixed. Studies have been conducted in people in early HIV infection (primary infection) who have never taken HIV medications and also in people who have been infected with HIV for a while (chronic infection) and are antiretroviral experienced.

Several studies have shown that it is possible to restart the same drug regimen to suppress viral load after a treatment interruption without developing drug resistance. In a study by Garcia and colleagues, eight patients with HIV who began therapy during early infection discontinued therapy after 1 year of treatment. Viral load was below 20 copies in all participants when they stopped therapy, and rebounded within a month in all participants. Treatment was restarted as soon as viral load rose to above 200 copies, and returned to undetectable as soon as therapy was restarted. The downside to the interruption was a decrease in CD4 cell counts, which fell by an average of 45%.

Treatment interruptions have been shown to have beneficial effects on immune function in this population. In a study by Walker and colleagues, a series of treatment interruptions was performed, and HIV-specific immune responses were found to be stronger after each interruption. Cytotoxic T cell response to a broader range of HIV antigens was observed.

In people with long-term HIV infection, the news is also mixed. Lori and colleagues discontinued therapy for eight weeks in a group of chronically infected individuals treated with hydroxyurea and Videx (ddI). These eight subjects had a low, detectable viral load and measurable HIV-specific immune responses. They were compared to a group of eight patients treated with standard triple drug therapy. The subjects were followed to see if their viral load rebounded to above 10,000 copies or if their CD4 count decreased to less than 200. Five patients on standard triple-drug therapy failed by week 6 and had to restart therapy, but none of the subjects on hydroxyurea/ddI failed during the 8-week follow-up period. Viral loads jumped from an average of 97 copies to 16,863 copies in patients on three drug therapy, coupled with an average drop of 208 CD4 cells. In those treated with hydroxuyrea/ddI, the increase was from an average of 843 copies to 1,596 copies, with stable CD4 cells.

A study by Papasavvas and colleagues showed that it is possible to boost HIV-specific immune responses in chronically infected individuals. Five chronically infected individuals on therapy stopped treatment for an average of 46 days. Three subjects reinitiated treatment at that time. Their viral loads returned to undetectable and they maintained HIV-specific immune responses. The other two subjects retained a low viral load (less than 1100 copies), and also maintained HIV-specific immune responses without restarting therapy.

Rizzardi and colleagues studied two immune-based therapy options in people who had never taken HIV medications. The study groups consisted of individuals with viral loads greater than 5000 copies and more than 250 CD4 cells. The participants took a protease-containing regimen for over a year, and then those with an undetectable viral load added either Remune, a therapeutic vaccine, IL-2, an immune-stimulating substance, or no additional treatment. Administration of Remune and IL-2 resulted in an increase in memory and naïve CD4 cells. Administration of Remune generated more HIV-specific immune responses than administration of IL-2 – 80% of people who got Remune, 30% of people on IL-2, and 20% of people who got neither had enhanced HIV-specific immune response.

These studies were all short-term, and the results should not be interpreted as a green light to try treatment interruptions. Trying treatment interruptions within the structure of a clinical trial may be your best bet, as it is only through further research that we will understand the full implications of these new theories in HIV treatment.