Structured treatment interruptions (STIs) and structured intermittent therapy (SITs)
Mark Dybul, for www.hivandhepatitis.com
The 1st IAS Conference on HIV Pathogenesis and Treatment in Buenos Aires, Argentina had numerous oral and poster presentations on approaches to treatment interruptions. There were updates on auto-immunization strategies as well as new insights into the important issues of toxicity and resistance.
The three main strategies of treatment interruption were well represented for 1) auto-immunization in patients treated with HAART during acute or chronic HIV infection, 2) reducing the amount of time patients receive HAART and 3) allowing reversion to wild type in salvage therapy.
Auto-immunization in acute HIV Infection
Bruce Walker [Abstract 139] provided an update of the work being done in his group with 14 individuals who were treated during acute HIV infection: nearly all patients were begun on HAART prior to developing a positive HIV ELISA. All individuals achieved and maintain a viral load below the limit of assay detection for a mean of approximately 1 year prior to beginning structured treatment interruptions (STIs). In this strategy, patients resume therapy if their plasma HIV reaches greater than 5,000 copies/mL on 3 measurements or greater than 50,000 copies/mL on a single measurement.
To date, these 14 individuals have undergone between 1 and 4 treatment interruptions. Only 2 individuals were termed ‘failures’ or individuals who have not had clear changes in viral dynamics following multiple STIs. In contrast, several individuals have remained off therapy for greater than 1000 days following 1-3 STIs with plasma viraemia less than 5,000 copies/mL and relatively stable CD4+ T cell counts.
However, Dr. Walker noted that in a small number of patients, there may be a slow decline in CD4+ T cell counts that requires monitoring. Of interest, 2 patients who developed relatively high rebounds of greater than 20,000 copies/mL after several hundred days off therapy had spontaneous declines in viral load back to less than 5,000 copies/mL without therapeutic intervention.
During a presentation focused on other aspects of treatment interruptions, Anthony Fauci [Abstract PL4] presented new data from their group on 6 individuals who had begun therapy during recently acquired HIV infection, i.e., within 6 months of infection. These individuals had participated in a pilot study comparing 4-drug HAART using stavudine, lamivudine, indinavir and efavirenz alone or in combination with 3 cycles of subcutaneous interleukin-2 (IL-2) during the first 12 months of therapy.
In this extension of that study, 3 individuals from each arm elected to undergo treatment interruptions, resuming therapy if plasma viraemia exceeded 10,000 copies/mL on 3 measurements or 50,000 copies/mL on one measurement. None of the patients received IL-2 during the treatment interruption phase of the study. Of these individuals, 1 patient remained off therapy for 6 months after the 1st interruption with plasma HIV RNA less than 5,000 copies/mL. Three patients, who met virologic criteria to resume therapy with the first interruption, experienced a prolonged period to rebound with the second interruption and a significant decrease in the peak plasma viraemia from the first to the second interruption. One individual had similar peak viraemia and rebound kinetics from the first to the second interruption and one had only undergone a single interruption that met failure criteria.
There was no apparent difference between those individuals who had or had not received IL-2. Thus, patients treated within 6 months of infection may have responses similar to those treated during acute HIV infection.
Both Drs. Walker and Fauci emphasized that there is no direct clinical applicability to these data and that the risks of resistance and immunological damage from this strategy require further evaluation. However, the results do lead to important avenues of research in terms of the components of immune control of HIV infection.
Auto-immunization in chronic HIV infection
Franco Lori [Abstract 56] briefly presented data from an STI study in which monkeys underwent cycles of 3 weeks on HAART followed by 3 weeks off HAART for 3 cycles. This strategy did not result in a change in peak viraemia or the kinetics of viral rebound regardless of whether the regimen included hydroxyurea. He then went on to present data from a human study with a similar schedule. Sixty patients who were previously antiretroviral naive with CD4+ T cells greater than 200 cells/mm3 and a viral load greater than 5,000 copies/mL were randomised to receive didanosine, stavudine and either indinavir or hydroxyurea for 12 weeks.
Following the initial 12 weeks, patients were further randomised to undergo 4 cycles of structured treatment interruption (STI) according to a fixed schedule of 3 weeks on therapy followed by 3 weeks off therapy or to remain on continuous therapy. At the end of a 36 week interval, patients in both arms interrupted treatment for a final 3 weeks period. In the STI arm the mean rebound viraemia with each of the 4 off periods was unchanged, and there was no difference between the groups treated with hydroxyurea or indinavir. Plasma HIV RNA was 172 and 70 copies at the end of the 36 week period (the last on-treatment period for STI).
During the final off-HAART period, there was rebound viraemia in both the STI and continuous HAART groups; statistical analyses had not yet been performed. Thus, there was no evidence for auto-immunization in this study.
Less time on drugs
In his plenary lecture, Anthony Fauci [Abstract PL4] provided an update on the work being done in his group on what they call structured intermittent therapy (SIT) to differentiate it from “auto-immunization” approaches. The NIH team, of which the author of this article is a part, has been studying both long cycle, 2 months off HAART followed by 1 months on HAART, and short cycle, 7 days on HAART followed by 7 days off HAART, SIT. Fifty-two patients have been enrolled in the long cycle study: 26 receiving intermittent therapy and 26 receiving continuous therapy.
All of the patients had a viral load less than 50 copies/mL and CD4+ T cell counts greater than 300 cells/mm3 at enrolment with equivalent pre-HAART CD4+ T cell counts and viral loads between the groups. From the first to the second, third and fourth interruptions of 1 month among 22 patients, there was a mean log difference of 0.6, 0.3 and 0.5 log10 copies/mL, respectively. After up to 6 cycles in some patients, by 8 weeks back on HAART, all patients had a viral load less than 500 copies/mL, and most had a viral load less than 50 copies/mL.
Dr. Fauci also provided an update on the group’s novel strategy of short cycle intermittent therapy. Eight patients receiving stavudine, lamivudine and indinavir/ritonavir in cycles of 7 days on followed by 7 days off for 8-15 months maintained suppression of plasma viraemia; all determinations are done after the on-HAART period. Several patients experienced infrequent low-level ‘blips’ of 52-350 copies/mL. In addition, Fauci reported that during 6 months in 5 individuals, and 12 months in 3 individuals, there was no evidence for a significant increased in HIV replication by several virologic and immunologic assays including lymph node evaluations in 5 patients.
Dr. Fauci reported that despite re-establishing virologic control during the 8 weeks on-HAART period, 4 patients receiving long-cycle intermittent therapy developed genotypic and phenotypic resistance to efavirenz (K103N) and/or Lamivudine (M184V) during the 4th to 6th cycle of treatment interruptions. Interestingly, all of the patients who developed resistance had relatively high levels of plasma viraemia during the off drug periods.
Dr. Fauci also showed data from 4 individuals receiving efavirenz who have had high level rebound viraemia but have not developed resistance; although in some cases the levels of plasma HIV RNA were too low to perform standard resistance testing. Dr. Fauci concluded that at this point NNRTIs can not be recommended for treatment interruption strategies that are conducted for long intervals of time and that may, therefore, result in significant rebound plasma viraemia. There was yet no evidence for the development of resistance in patients receiving protease inhibitor-based regimens.
In addition, Zala and colleagues presented data [Abstract 142] in 14 individuals treated within 6 months of acquiring HIV infection who received stavudine, didanosine and nevirapine with or without hydroxyurea for a mean of 54 weeks. Patients were subsequently offered sequential treatment interruptions. In 6 of 9 patients who had genotypic analysis done (VIRCO) during the peak of viraemia during the first interruption, there was evidence for resistance to nevirapine (K103N, 190A, Y181C).
As in the data presented by Dr. Fauci, the development of resistance was not suggested by clinically significant virologic failure. In addition, there were several reports of individuals participating in STI studies who developed resistance to Lamivudine while receiving PI-containing regimens.
In regards to short cycle SIT with cycles of 7 days off and 7 days on HAART, Dr. Fauci reported that here was no evidence for genotypic or phenotypic resistance as determined by the VIRCO assay out to 12 cycles in 8 individuals; since the patients had such low plasma viraemia the virus for the assays was obtained by inducing it from activated CD4+ T cells. As noted above, while none of these individuals were receiving nNRTIs, all were receiving Lamivudine.
There is clearly a risk to developing resistance to nNRTIs and lamivudine with treatment interruption strategies that utilize relatively long intervals off therapy. Further evaluation of this risk is required.
Reporting the data on the NIH study of short cycle HAART, Dr. Fauci showed that at 24 weeks of SIT, there was a significant decrease in total cholesterol, LDL and triglyceride levels (all with p=0.001). These decreases were maintained out to 52 weeks in the 3 patients who had been on study longer.
It is clear that there are differences in responses to treatment interruption strategies in patients who began HAART during acute and possibly recently-acquired HIV infection, compared to patients who began HAART during chronic HIV infection.
A significant proportion of individuals who begin therapy during recently-acquired HIV infection seem to be capable of controlling HIV plasma viraemia during 1-4 STI cycles, while only a small minority of individuals who begin therapy during chronic HIV infection seem to have a similar result.
Understanding the mechanisms of viral control may provide important insights for future therapeutic options and vaccine strategies. However, at this point there is no clear clinical applicability to STI in either acute or chronic HIV infection and STI for auto-immunization cannot be recommended outside of a research setting.
Regarding treatment interruptions for salvage therapy, the data presented at the meeting corroborates previous findings that there is a clear risk to patients in terms of enhanced HIV viraemia and significant declines in CD4+ T cell counts. Given the low levels of CD4+ T cells in individuals in the salvage situation, this strategy also was not recommended outside of a research setting by any of the presenters.
Finally, in terms of intermittent therapy with the sole purpose of reducing total time individuals receive antiretroviral drugs, approaches that use relatively long cycles of interruptions, and therefore lead to relatively high rebound plasma viraemia in many individuals, may pose a significant risk for the development of drug resistance. This was especially true for patients receiving regimens that included nNRTIs and Lamivudine.
The relative risk to individuals receiving PI-containing regimens is unknown. Despite the development of resistance, patients seem to be able to re-establish virologic control and CD4+ T cell counts during the on-HAART periods. This approach requires further investigation.
In contrast, there was no risk of developing resistance at up to 52 weeks (26 cycles on and off therapy) in patients who received short cycle intermittent therapy of 7 days on HAART followed by 7 days off HAART. In addition, 10 patients maintained suppression of HIV in the peripheral blood and lymphoid tissue while preserving CD4+ T cell counts for up to 64 weeks of intermittent therapy. These individuals also had significant decreases in markers of toxicity.
However, it is important to note that this a relatively small number of patients with relatively high CD4+ T cell counts who had done very well on HAART for a long period of time prior to SIT. In addition, all patients received the same double PI-containing regimen.
Thus, for these approaches larger, randomised, controlled clinical trials are necessary and they cannot be recommended in clinical settings. Finally, analyses of the data may provide important insights into the replication kinetics of rebounding HIV.
Unless otherwise stated, all references in the text are to the 1st International IAS Conference on HIV Pathogenesis and Treatment. July 8-11, 2001. Buenos Aires, Argentina.
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