Download Article PDF/SlidesThe advent of highly active antiretroviral therapy in the mid 1990s resulted in a dramatic increase in survival of HIV patients, especially among those with advanced disease,” Dr. Wafaa El-Sadr said in beginning her February 2006 PRN lecture. Follow-up studies, she explained, demonstrated the durability of this effect, with decreasing HIV-associated morbidity and mortality during the late 1990s and early 2000s. She also acknowledged, however, that while combination antiretroviral treatment has changed the face of the HIV epidemic and enabled physicians to provide truly effective therapy, several issues and limitations of these regimens have emerged.
The most significant limitation has been the necessity and challenge of continued daily adherence to the medications. “Taking these medications day in, day out is difficult for patients,” she said. The frequently cited study of antiretroviral adherence, conducted by Dr. Sharon Mannheimer and her colleagues, demonstrated that after eight months of therapy, only 60% of patients reported 100% adherence (Mannheimer, 2002). Extrapolating these data implies worsening of compliance over years of therapy, resulting in drug resistance and subsequent elimination of treatment options.
Metabolic effects are another concern with HIV treatment. More alarming is evidence of increased myocardial infarction rates among patients on antiretroviral therapy. An important study on this subject was the DAD study (Data Collection on Adverse Events of Anti-HIV Drugs), which found an increased risk of coronary artery disease in people on all types of antiretroviral therapy (Law, 2003).The DAD study also found that some of the risk was lowered upon discontinuation of anti-HIV drugs. Additional metabolic and general side effects of antiretroviral therapy include cardiovascular complications, lipoatrophy, peripheral neuropathy, and accelerated liver disease (Julg, 2006).
Rates of severe therapy-related adverse events are also worrisome. In a cross-protocol study, rates of grade 4 adverse events associated with antiretroviral treatment were shown to be higher than that of AIDS events or deaths (Reisler, 2003). “While we see a dramatic decrease in the development of AIDS as well as associated deaths, there has been an increase in the development of adverse events of avariety of organ systems,” noted Dr. El-Sadr.
The high cost of medications also continues to be an issue. Although programs exist in New York State and New York City for financial support for treatment, many parts of the United States and most other parts of the world do not have such programs established. The continued inability to eradicate or cure HIV gives the prospect of lifelong drug treatment enormous monetary implications.
| Rationale and Strategies for Treatment Interruption | Top of page |
“There is a need for strategies that can optimize the use of available antiretroviral drugs in order to maximize the benefits while minimizing the risks,” Dr. El-Sadr explained. Treatment interruption is one way to optimize antiretroviral therapy. However, while interruption of antiviral therapy carries clear benefits, its safety and efficacy have yet to be established.
Two main strategies for treatment interruption have been studied: time-defined and CD4+ cell-guided. Time-defined strategies involve predetermined treatment interruption, such as medication breaks on weekends and one-month-on/one-month-off scheduling, in an effort to improve quality of life, promote adherence, decrease antiretroviral exposure, and minimize the development of resistance. The CD4+ cell-guided strategy, used in the National Institutes of Health’s Strategies for Management of Antiretroviral Therapy (SMART) study, utilizes CD4+ cell counts to determine the starting and stopping point of intermittent therapy (IT). In other words, antiretroviral treatment is started when the CD4+ cell count falls below a certain threshold, stopped when it increases above a certain level, restarted when the CD4+ cell count again falls below the threshold, and so on.
The potential risks and benefits of continuous therapy (CT) are familiar to most practitioners. Potential benefits include maximal suppression of HIV-RNA, consistent CD4+ cell count gains, and a decreased risk of HIV transmission. The potential risks of CT include higher rates of drug side effects, more difficult adherence, and potentially more drug resistance resulting in fewer drug options secondary to higher antiretroviral therapy exposure.
Conversely, the potential benefits of IT include fewer side effects, better adherence, and improved quality of life. The risks include possible increase in the development of resistance, lasting damage to the immune system, and an increase in the risk of HIV transmission due to non-suppression of viral load.
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