Structured treatment interruptions
Graeme Moyle, MD, for HIV&Hepatitis.com
Professor Bernard Hirshel from Geneva, Switzerland went on to further discuss the potential for using structured interruptions of treatment (SIT) within the management of persons with HIV infection. There are several areas where this approach is of interest. One is in individuals with primary HIV infection (PHI), where the goal of therapy is to establish an individual with low viraemia without the need for drug therapy.
A second is in individuals with chronic HIV infection with full viral suppression, where several goals of therapy may be possible. As for PHI patients, to use the immune situation of structured interruptions of treatment to establish low viraemia without the need for medication. However, the second use in these individuals of SIT is to manage toxicity. The final circumstance is an individual with chronic HIV infection who has resistant virus present where the interruption of selective pressure of therapy may allow an outgrowth of wild-type virus diminishing the population of resistant virus and (potentially) increasing the chances of at least a short-term response to antiretroviral therapy. A further advantage of this approach in all circumstances is to improve reductions in total cost of antiretroviral therapy.
Use of SITs in Primary HIV Infection (PHI)
Regarding the use of SIT’s in individuals with primary HIV infection, Professor Hershel pointed to some recent data published in Nature which represented the largest anecdote in this area, totalling 8 individuals, which included an outcome in which three individuals have sustained viral load responses below 5,000 copies per millilitre over 4-6 months follow-up. The suggestion is in individuals who initiate antiretroviral therapy during primary HIV infection, cytotoxic T-lymphocyte responses are protected. When these individuals undergo a series of SITs, the responses are further enhanced, leading to better control of the virus after the drugs are stopped.
There are, however, no baseline values on these individuals to assess where their viral load set point would have been in the absence of initial treatment and currently, no randomised data to look at the benefits of short interruptions of treatment before cessation of antiretroviral therapy versus simple cessation of therapy. Thus we can only be left with an impression that this may be an approach worthy of investigation, as a cause and effect relationship for these observations in primary HIV infection has not been established for SIT.
SITs in Chronic HIV Infection
In chronic infection the largest study which has evaluated SITs is the Swiss/Spanish Interruptions of Treatment Trial. This study has recruited over 100 patients of whom 54 patients are through week 52. The trial is assessing several issues, including whether the remission of virological control of HIV can occur in the absence of drugs following interruptions of treatment, what are the clinical correlates if this remission does occur, and in individuals where control of viral load does not occur, does re-induction of therapy work?
The study has recruited individuals who’s viral load has been undetectable for longer than six months (median 21 months), and who were previously treatment-naive before starting their current fully-suppressive antiretroviral regimen. The study population has a mean CD4 count of 727. Over the course of the study it is planned to undergo four cycles of two weeks off therapy followed by eight weeks on therapy – completing these cycles at week 40 when the therapy is then stopped.
End points under evaluation are at week 52 and at week 76 – success being assessed as a viral load of less than 5,000 copies per millilitre. Looking at the peak viral load during each interruption cycle with values at weeks 2, 12, 22 and 32, the viral load rebound at each of these has been a mean of 2.7, 2.9. 3 and 2.89 log copies of virus, suggesting no change in the degree of control or lack of control of virus over these four cycles of therapy.
A number of patients totalling around 7% have failed to achieve within 9 weeks of therapy re-induction to an undetectable viral load and have therefore failed to go on to the next cycle of therapy interruption. However, only one individual has developed resistance over time. This individual developed resistance to both 3TC and nelfinavir during re-induction after his first SIT.
Of the 54 patients who have reached the week 52 time-point, 17 patients are off study, 9 patients have restarted therapy and 19 patients have viral loads maintained over 5,000 and 9 patients have viral loads below 5,000 copies/mL. Overall, 30% of patients have a viral load plateau which is significantly below the values for these individuals prior to the initiation of antiretroviral therapy.
Looking at correlates in the 9 patients with viral loads less than 5,000 compared with other groups completing this time point, whilst a formal statistical analysis has not been performed, Professor Hershel said his impression was that these were mostly individuals who had high CD4 counts, but that there appeared to be no correlation with the pre-treatment CD4 count, viral load or baseline cytotoxic T-lymphocyte response.
Thus far, it would be reasonable to conclude in this large study, there appears to have been no benefit for cycling of therapy. However, there may be a subset of individuals who have an apparent benefit and further work is needed to identify whether this approach is feasible and safe in chronically-inflicted individuals.
SITs in Persons with Documented HIV Resistance
Briefly, Dr Hirshel went on to discuss the potential to use SIT in individuals with documented resistance, quoting predominantly from the work of Veronica Miller in Frankfurt. In a cohort study they have demonstrated that, over a 12-week interruption of therapy the majority of individuals interrupting therapy have an outgrowth of a wild type virus and the resistant virus disappeared below detection limits of viral resistance assays.
Those patients who undergo wild type outgrowth appear to have greater falls in CD4 count and greater rises in viral load than those who did not undergo the genotypic switch, and that substantial falls in CD4 count may occur during short periods of interruption. Patients who undergo switch from resistant to wild type appear to have more favourable initial viral load responses than individuals who have not undergone a resistance switch.
However the durability of this response appears to be incomplete in the majority of individuals and recovery of CD4 count to pre-interruption levels may take six months to a year. Patients with high CD4 count and low viral load prior to the interruption of therapy appear to be those who benefit most from this interruption, as do individuals who have the greatest number of drugs in their new regimen.
Thus, this approach to therapy carries with it the risk of a rapid CD4 count drop into a range where that individual may experience an opportunistic infection, but has the potential benefit that resistance to the new regimen is partially suppressed by the outgrowth of wild type virus and increases the chances of response to mega-HAART regimen.
Dr Hirshel closed by saying that what is urgently needed in the area of Structured Treatment Interruptions, in all the main categories where this has been suggested to be useful, are randomised clinical trials which include comparison arms and are adequate to assess the risks as well as the potential benefits of therapy. He also suggested that these trials may consider including arms where co-therapies are included such as immuno-modulators such as GM-CSF or interleukin-2 or vaccines such ALVAC or Remune vaccines, or indeed combinations of both. Several of these trials are now being planned within Europe and the United States.
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The SSIT trial used a set 2 weeks treatment interruption. During these 2 weeks many patients did not develop the viraemia which may be essential to immune stimulation. More than 4 weeks interruption however may have negative effects (see below).
As each individual responds uniquely to an interruption in terms of viral rebound dynamics there should be an attempt at individuation of interruption, even within clinical trials.
Hirschel B. Structured Interruptions of Treatment. Plenary on Treatment Strategies in 2000. 5th International Congress on Drug Therapy in HIV Infection. October 22-26, 2000. Glasgow, Scotland.