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Risks of Treatment Interruptions: a fully informed decision
Reported by Jules Levin
  It has become accepted that there is little or no indication from research study results so far that Structured Treatment Interruptions (STIs) can stimulate an immune response in patients with chronic HIV after stopping HIV therapy that can control HIV while off therapy. In the Spanish-Swiss Therapy Interruption Study, about 8-15% of patients had a response, able to achieve low or undetectable viral load, off drugs & following STIs. But, it is uncertain what the reason is and it's a low number of individuals. The study authors found that a response may not be associated with an immune response (CTL response) which is what was hoped for; but they found the response may be due to proviral DNA levels.
Perhaps more important, it has increasingly come to light by recently released studies within the last 6 months that there are real risks associated with taking treatment interruptions or "drug holidays".
Several studies reported at the Resistance Wksp this Summer 2002 in Spain that resistance can emerge during interruptions when viral load is undetectable. The greatest risk is probably associated with drugs with a long half-life such as 3TC and NNRTIs, but this does not mean resistance to other drugs are not also a risk. Drugs with a long half-life stay in the blood for longer and at decreasing levels after other drugs with a shorter half-life are eliminated. This may create a risk for resistance. One interruption may not be as risky as taking multiple interruptions. The risk from one interruption is not well defined. The studies discussed here show risks from multiple interruptions. But the study below by Hance suggests, as other studies do, that low level drug resistance may be present even when viral load is <50. Low level resistance may develop, but it is not established what the clear risk of resistance is when stopping therapy once under such circumstances.
A study reported at the Retrovirus Conference in February received much attention, which showed that soon after interrupting therapy when viral load is undetectable virus re-populates the brain and the central nervous system. We have also known for a while that CD4 counts can decline, HIV viral load in blood can increase, and there is potential for an OI to develop. This is a particular concern if CD4 count declines to low level. If a patient had at any time in their history a low CD4 count of say 50, interrupting therapy may be more risky. General consensus is that such a patient may face a greater risk for seeing a more precipitous decline in CD4 count.
In the journal Nature (May 2, 417, 95-98, 2002), Daniel Douek, from the NIH, reported the following. This was reported at the Retrovirus Conference in February 2002: HIV preferentially infects HIV specific CD4s, this occurs during interruptions, and Douek cautions against interruptions.
HIV infection is associated with the progressive loss of CD4+ T cells through their destruction or decreased production. A central, yet unresolved issue of HIV disease is the mechanism for this loss, and in particular whether HIV-specific CD4+ T cells are preferentially affected. Here we show that HIV-specific memory CD4+ T cells in infected individuals contain more HIV viral DNA than other memory CD4+ T cells, at all stages of HIV disease. Additionally, following viral rebound during interruption of antiretroviral therapy, the frequency of HIV viral DNA in the HIV-specific pool of memory CD4+ T cells increases to a greater extent than in memory CD4+ T cells of other specificities. These findings show that HIV-specific CD4+ T cells are preferentially infected by HIV in vivo. This provides a potential mechanism to explain the loss of HIV-specific CD4+ T-cell responses, and consequently the loss of immunological control of HIV replication. Furthermore, the phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of structured therapy interruption.
At the Resistance Wksp July 2002, several research studies raised concerns about risks of interruptions. Alan Hance reported low-level or minority resistance mutations could be found using a sensitive test for many months before the mutation was present in the majority of plasma virus using standard genotypic test.
Karen Metzner studied patients in the well-known Swiss-Spanish Therapy Interruption study. She found resistance developed in 25 chronically infected patients in the study undergoing repeated cycles of STIs. In particular, she concluded resistance could develop even if the interruption was as short as 2 weeks. 36% developed low level 3TC resistance during interruption, and 40% were found to have a low level mutation. However, none of these patients have failed therapy yet after resuming treatment.
Studies Find Low-Level HIV Drug Resistance During Therapy and Interruptions. Effects of 8 week (GigHAART) & 3 month Interruptions.
At the Intl AIDS Conference Barcelona, Mark Dybul, from the NIH, reported findings from a small study of 24 patients that raised questions about the potential benefit of reduced lipids (cholesterol, tryglicerides) during interruptions. Patients either received repeated cycles of 2 months off and 2-4 months back on therapy or continuous therapy. After repeated interruptions patients experienced decreased cholesterol and triglycerides. Patients on therapy experienced increased cholesterol and triglycerides. But patients who had interruptions saw their triglyceride and cholesterol levels return to baseline levels after going back on therapy. In his small study of cycling patients with 7 days on and 7 days off therapy, 8 patients remain in study (once daily ddI+efavirenz+3TC). And reduced lipids appear to remain reduced. LDL cholesterol, total cholesterol, and tryglcerides were reduced during the first 24 weeks in study, and remain reduced as patients are followed out to 53 and 72 weeks. As well, patients remain under 50 copies with no viral load blips. Taking a regimen and adherence for 7 days on and 7 days off on an ongoing basis will be challenging for many patients.
For sure, therapy is complicated and adhering continuously to HIV regimens is difficult. Patients get adherence fatigue and want to take breaks from therapy. That is the choice of the patient to make in consultation with their doctor. But such a decision should be an informed decision, where the doctor and patient are aware of the risks.
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