The Buzz: Structured Treatment Interruption and Immune Reconstitution
Drug holidays, treatment interruptions, and strategic or structured treatment interruptions: many names, many questions but only a few answers. Structured treatment interruptions (STI) were originally investigated due to the hypothesis that stimulation of the immune system would occur with intermittent exposure of the blood to virus. Patients who maintained undetectable viral loads with treatment were thought to have too small a quantity of virus in the blood for the immune system to react to HIV. Immunologic improvements would occur while interrupting treatment due to a cytotoxic T-cell immune response to HIV. In other words, the scheduling of treatments with regular interruptions would provide intermittent exposure to virus and thus repeated stimulation of the immune response (meaning the immune system would attack and keep the virus at bay on its own without the need of antivirals). It was theorized that possible results from these repeated interruptions could lead to eventual discontinuation of antiviral therapy completely. However, several structured treatment interruption studies have failed to demonstrate evidence of this possibility becoming a reality. While treatment of HIV-positive patients with highly active antiretroviral therapy (HAART) has shown to reduce HIV viral loads to below detection in the blood, the significant degrees of immune restoration that followed did not result in eradication of the virus.
At the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held in December of 2001, several studies were presented and several lessons were learned. Data from an 18-month observational study by K. Wolfe, et al., described the outcome of 115 patients with treatment interruptions compared to 186 individuals who did not interrupt therapy. At the start of study, the average CD4 T cell counts were in the 400-500 range and viral loads were less than 50 in 52% of participants undergoing treatment interruption, compared to 43% of the on-treatment control group (not undergoing treatment interruptions). The average length of the first interruption in treatment was 5.4 weeks and interestingly 29% of the participants had more than one interruption. As expected with an interruption of treatment, CD4 count decreased by an average of 72 cells and viral load increased 2.1 logs. However, cholesterol and triglycerides decreased significantly. The significance is that not everyone who underwent interruption had undetectable viral loads.
After 18 months of observation, the patients undergoing treatment interruptions showed no significant change in their CD4 count. Seventy-six percent vs. 47% changed their antiviral regimen, but viral loads remained less than 50 in 66% vs. 73%. Of the remaining patients whose viral loads did not end up under 50, they still had an eventual decrease in viral RNA: -.6 log vs. -.3 log (regimen change and no change respectively).
In another study, Dr. Anthony Fauci from the National Institute of Allergy and Infectious Disease presented results of 10 patients who underwent 32 cycles of seven days on and seven days off treatment (64 weeks). These individuals were on Norvir (ritonavir) + Crixivan (indinavir) + Epivir (3TC) + Zerit (d4T). There was no change in plasma (blood), cellular (within the cells), proviral HIV RNA (building blocks of the virus) or latently infected CD4 cells. There was no evidence of HIV resistance by either genotype nor phenotype testing, and lymph node biopsies done on some of the participants showed no negative changes. Also, there was no change in patients' CD4 T cell counts nor CD4 percentages. However, cholesterol and triglycerides improved steadily during the course of the study, which is ongoing.
Results from STI studies presented at the 13th International AIDS Conference noted the development of resistance in a few patients, but more notably when non-nucleosides were included in their regimen. This can be explained by the fact that non-nukes, especially Sustiva (efavirenz), have long "half-lives," meaning they remain in the blood much longer than the other antiviral agents. Thus when interrupting treatment, unlike most other antivirals which are cleared from the blood faster, non-nukes remain present. Because the drug is acting against the virus alone, the virus can more easily circumvent the effect of non-nukes and develop resistance to this class of antivirals. Thus we can infer that traditional treatment interruptions should be avoided for those patients on the non-nucleoside class as a backbone for their antiviral regimen.
Interruption situations are found to be useful for patients who have been highly exposed to antiviral agents and resulting multi-drug resistance. These individuals may have little viable options for treatment. Wild-type virus, the typical viral population present during initial infection and susceptible to the effects of antiviral drugs, is stronger and domineering over the presence of resistant virus. To invoke the emergence of wild-type virus, HIV drug therapy is interrupted for several months. As wild-type virus begins to emerge and replicate it suppresses resistant strains, thereby allowing drug treatment to become effective again. This approach is investigative, but is increasingly getting more attention from clinicians and researchers.
At the present time we still do not know enough to boast of a clear understanding about how to best structure treatment interruptions, which patients will benefit most, and what intervals are most optimum. There is the valid concern that patients will stop treatment on their own with little supervision. Due to the risks of the development of resistance and possible opportunistic complications, an STI should not be undertaken without the guidance and care of a trained physician.
However, several essential facts can be abstracted from the valuable studies already done. Firstly, interruptions probably can be performed safely in certain patients within several parameters. Secondly, certain and substantial numbers of patients who have taken treatment holidays for up to a median of five months have had their CD4 T cells restored and viral loads decrease to undetectable within three months of resumption of treatment (J.F. Braun, et al., 41st ICAAC). Finally, most studies have shown benefits regarding blood lipids: cholesterol and triglycerides decreased significantly during interruption of therapy.
The fact remains that patients can not be expected to consume fists full of pills forever. As lives are extended, the toxicities of medications have become rather obvious, and pill fatigue has set in. Attention must now focus on dealing with HIV infection in the long-term. Structured treatment interruptions need to be investigated for the good of our patients. Perhaps as the risks of developing lipodystrophy and metabolic abnormalities are minimized, patients may be less likely to develop treatment fatigue and non-compliance. Treatment interruptions can also result in large cost savings. While STIs remain a new avenue for research and hope, it is important to recognize that more studies are needed to examine the many issues discussed in this article. We will continue to explore this approach, patiently.
Daniel S. Berger, M.D. is Medical Director for NorthStar Healthcenter and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago. He is editor of AIDS Infosource (www.aidsinfosource.com) and also serves as medical consultant and columnist for Positively Aware. For further inquiries Dr. Berger can be reached at DSBergerMD@aol.com or (773) 296-2400.
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