One week on, one week off experimental regimen might reduce the cost and toxicities of HIV therapy

9 December 2001. Related: Antiretrovirals.

A pilot study at the National Institute of Allergy and Infectious Diseases (NIAID) suggests that it may prove feasible for certain people with human immunodeficiency virus (HIV) disease to move from a continuous regimen of antiHIV therapy to a strategy in which they discontinue and then resume anti-HIV therapy in a preplanned, cyclic fashion.

This approach is known as -structured intermittent therapy. – In the NIAID study, 10 patients received repeated -onoff – cycles of therapy: seven days of treatment with potent combinations of HIV medications, followed by seven days off the drugs. At the time of study enrolment, the patients were being successfully treated with continuous highly active antiretroviral therapy (HAART). For the study, they switched to the intermittent HAART regimen with no apparent deleterious effects on the course of their disease, and with a significant reduction in certain HAARTrelated side effects.

Because it halves the total time during which patients receive antiHIV medications, structured intermittent therapy could significantly reduce the costs and side effects of antiHIV drugs, important issues in both resourcerich and poor countries, – notes lead author Mark Dybul, M.D., NIAID assistant director for medical affairs. -It is important to stress, however, that the results of randomised, controlled clinical trials currently under way are needed to prove the benefits of this experimental approach before it can be recommended to patients outside the setting of a controlled clinical trial. Don’t try this at home! –

The NIAID researchers, led by Dr Dybul and NIAID Director Anthony S. Fauci, M.D., report their findings in the December 4 online early edition of the Proceedings of the National Academy of Sciences. The bulk of the research was conducted within the NIAID Laboratory of Immunoregulation, which Dr Fauci directs and where Dr Dybul is a staff clinician.

The authors note that HAART has provided extraordinary benefits to many people infected with HIV, substantially reducing HIVrelated morbidity and mortality. Unfortunately, the utility of HAART is limited by significant short and longterm toxicities, complicated dosing regimens and associated problems with adherence, and the development of drug resistance. In addition, high monetary costs have precluded the widespread use of HAART in resourcelimited countries.

– With further research, we would hope that the approach of structured intermittent therapy for HIV disease will lead to decreased HAARTrelated toxicities, reduced costs, and, potentially, to improved adherence, – says Dr Fauci. -Ultimately, structured intermittent therapy might be adapted for use in developing nations, where more than 95 percent of the world’s HIVinfected people live, but where very few have access to HAART because of the cost of antiretroviral agents. –

Study details

Upon study entry, patients were receiving HAART daily, in regimens that included combinations of three or four antiHIV drugs. This therapy had kept patients’ HIV levels below 500 copies per millilitre (mL) of plasma for more than six months, and below 50 copies/mL at the time of enrolment. All patients entering the study had CD4+ Tcell counts of at least 300 cells per cubic millimetre (mm3) of blood. CD4+ T cells are crucial immune cells typically depleted during HIV disease.

After enrolment in the NIAID study, the patients received a fourdrug regimen comprising stavudine, lamivudine, indinavir and ritonavir, administered twice per day in the intermittent schedule of seven days on therapy followed by seven days off therapy. This onoff cycle was repeated 16 to 34 times that is, for 32 to 68 weeks.

While receiving sevendayon, sevendayoff cycles of intermittent HAART, study participants had no significant increases in the amount of HIV in their bodies, as determined by tests that measured HIV in their plasma and lymph nodes, as well as within immune cells. In addition, patients’ CD4+ Tcell counts were maintained at prestudy levels, and no evidence suggested the development of resistance to HAART medications.

Importantly, the investigators also noted significant decreases in serum cholesterol and triglyceride levels, which frequently are elevated in HIVinfected individuals receiving HAART and can contribute to heart disease and other problems. Mean serum cholesterol and triglyceride levels dropped 22 percent and 51 percent, respectively, after 24 weeks of intermittent therapy.

These provocative findings have spurred larger, controlled clinical trials of structured intermittent therapy by our group and others, – says Dr Fauci. -Hopefully, data obtained from these larger studies will validate the potentially important findings in the pilot study. –

Copies of the article are now available to reporters from the PNAS news office, tel. (202) 3342138, or email pnasnews@nas.edu.

Comment

The obvious caveat in such approaches (as with triple nucleoside regimens) is that they may be applicable only to certain narrow categories of patients. Triple nucleoside regimens demand that patients be treatment naïve for acceptable efficacy, or when switching, that patients have never previously experienced virological failure on nucleoside analogue containing combinations.

Structured intermittent therapy (SIT) in this study required successful suppression on continuous therapy, suppression to less than 50 copies/mL at time of switch to SIT, and CD4 counts greater than 300 cells/mm3. It is unclear from this report if successful virological suppression prior to SIT occurred with the first ever regimen in these patients or if some had experienced varying degrees of virological failure on prior partially suppressive regimens.

It is now becoming increasingly clear that individual histories of HIV infection and attempts at antiretroviral therapy may be crucial in determining suitability for these experimental protocols.

Reference:

M Dybul et al. Short cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: Effects on virologic, immunologic, and toxicity parameters. Proceedings of the National Academy of Sciences Early Edition online (December 4, 2001).