Treatment interruptions do not prime the immune system to control HIV. But nor are they associated with an increase in AIDS defining illness, and with only low levels of resistance, according to data from the Swiss-Spanish Intermittent Treatment Trial published in the May 26th edition of the Archives of Internal Medicine.
It has been suggested that intermittent treatment with HAART can lead to autovaccination against HIV. Investigators wished to test this hypothesis, and to assess the safety and feasibility of structured treatment interruptions in patients with chronic HIV infection with well-controlled HIV viral load.
The study involved 133 patients, who had had an undetectable viral load (either below 50 or 400 copies/mL depending on the test used) for six months and a viral load of below 50 copies/mL at enrollment to the study. A CD4 cell count of at least 300 cells/mm3 was also necessary for entry to the study. Patients were excluded if they had ever had to change therapy due to virological failure, or had ever taken NNRTIs. Patients had been taking HAART for an average of 26 months at baseline and had had an undetectable viral load for an average of 21 months. The CD4 cell count average was 740 cells/mm3.
HAART was interrupted for two weeks, and then recommenced for eight weeks in four cycles provided that viral load was below 50 copies/mL at the end of each treatment cycle. HAART was then indefinitely stopped at week 40 if viral load was below 50 copies/mL. In addition, a CD4 cell count below 400 cells/mm was necessary at week 40 to remain on the study. The study then ran for a further twelve weeks. However patients were required to restart HAART if they had symptoms of acute HIV infection or three viral load results above 50,000, two above 100,000 or one above 500,000 copies/mL.
Patients who remained on the study to the end of week 52 and had a viral load below 5,000 copies/mL were considered responders/. For responders viral load was then measured at four weekly intervals to week 64 and then every eight weeks to week 96.
Of the 133 patients who started the study, just under a third were excluded before the end of week 40, the main reason being an increase in HIV viral load. By week 52 only 17% of patients were responders and still had a viral load below 5,000 copies/mL. Responders tended to have lower peak viral loads prior to starting HAART than non-responders (approximately 11,000 copies/mL versus 35,000 copies), and no patient who had had a viral load above 60,000 copies/mL was a responder. CD4 cell counts were not a significant predictor.
By week 96, only 8% of patients were still responders.
No HIV-related illnesses occurred during the study, and there was a slight increase in average CD4 cell count to 792 cells/mm3 by week 40. However, by week 52 this had fallen to 615 cell/mm3 and fell to 569 cells/mm3 by week 96.
One patient developed resistance to anti-HIV drugs during the study. At week nine he had a viral load of 141 copies/mL and recommenced his initial regimen of AZT, 3TC and nelfinavir, with his viral load increasing to over 2,700 copies/mL by week 23.
Acute retroviral syndrome, characterised by symptoms including fever, rash and sore throat were experienced by two patients, both of whom had viral loads above 500,000 copies/mL.
Although HIV-specific CD8 cell counts did increase in the study population, this did not lead to control of viral load.
The investigators conclude that the results of their study “do not favour the autovaccination hypothesis.” However, they note that their findings suggest as the CD4 cell counts of patients remained well above levels associated with an increased risk of HIV disease, patients on HAART with CD4 cell counts close to the study average of 740 cells/mm3 may be able to safely interrupt therapy for several months. However, they caution that whether such discontinuation is harmful in the longer term can only be determined by further studies.
Further information on this website
Structured treatment interruption - overview
Treatment interruption - fact sheet
Fagard C et al. A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Archives of Internal Medicine 163: 1220 – 1226, 2003.