A prospective study of strategic treatment interruptions in patients with chronic HIV-infection
Strategic treatment interruptions (STIs) are under investigation both for their utility in reverting drug resistance (see report below ‘Do resistance mutations disappear off therapy?) and as an attempt to stimulate host immune responses to HIV to achieve better control of viral replication (both in the presence and absence of antiretroviral treatment).
Felipe Garcia from the University of Barcelona presented the results from a study designed to investigate the dynamics of viral load rebound and HIV specific immune responses after three consecutive cycles of STI . Any effect of STI on viral load set-point and the safety of this approach were also assessed.
A total of 10 patients from the EARTH study (Early AntiRetroviral THerapy) were recruited for this STI study. Data on 8 subjects were presented (one became pregnant after the 2nd interruption and another was lost to follow-up after the 1st stop). All were na•ve to antiretroviral treatment and had pre-treatment CD4 T-cell counts >500 cells/mm3 and viral load >10,000 copies/mL. All patients had been treated with d4T/3TC and indinavir or ritonavir for 52 weeks within the EARTH study and had achieved viral loads of less than 20 copies/mL for more than 32 weeks before entering the STI study. In all cases the same antiretroviral combination was reintroduced after each STI.
Treatment was reintroduced during the 1st interruption when plasma viral load became greater than 200 copies/mL. Treatment was reintroduced during the 2nd interruption one month after viral load became >200 copies/mL if it did not drop spontaneously. During the 3rd stop treatment was reintroduced only after reaching a stable plasma viral load (set-point) if this was more than 10,000 copies/mL. The interruption points were at 0, 28 and 96 weeks and subjects had to be below 20 copies/mL before interruption was allowed.
Virological response to STI
Viral rebound was detected in all subjects after each of the 3 interruptions. Mean doubling time of plasma viral load was, however, significantly longer after the 3rd stop when compared to the 1st (3.2±0.2 vs 2.0±0.2, p=0.05). Eight patients remained off therapy 32 weeks after the 3rd stop six of whom maintained a viral load set-point of <0.5 log (range 0.5 – 1.7) of the baseline value before entering the EARTH study. Four of eight patients maintained a viral load of less than 10,000 copies/mL (range 650 – 9,000).
Immune response to STI
CD4+ proliferative response to HIV p24 antigen was detected in 0/10 subjects during the first interruption, 4/9 during the second interruption and in 6/9 during the third stop. These responses were, however, undetectable in all subjects before each interruption. Measures of HIV specific CTL responses were not available before or during the first interruption but were detectable in 5/9 and 5/8 subjects during the second and third interruptions respectively. As with the CD4+ proliferative responses, the CTL responses were undetectable in all subjects prior to each interruption. A series of graphs on individual patient responses gave the impression that the strength of both HIV specific CD4+ and CTL responses correlated with control of viraemia.
Genotypic or phenotypic drug resistance was not detected after any of the 3 interruptions and a rapid virological response was observed after reintroduction of the same regimen in all cases and always led to a viral load of <50 copies/mL. CD4+ T-cell counts fell significantly after each interruption to levels similar to those seen before starting any antiretroviral therapy.
The investigators concluded that HIV specific immune responses (both T-helper and CTL) can be recovered in chronic HIC-infection after two or three cycles of STI. In some patients (4/8) this was associated with spontaneous and sustained resetting of the plasma viral load set-point to less than 10,000 copies/mL.
Data was also presented on a further 5 patients with similar characteristics and schedule of STI. After 3 cycles of STI rebound of plasma viral load was detected in 4 out of 5 of these subjects. At six months off therapy after the third interruption 2/5 patients had a viral set-point <0.5 log of baseline and 2/5 sustained viral loads < 5,000 copies/mL (one < 5 copies the other 3,470 copies).
- Garcia F, Plana M, Ortiz GM et al. Continuous and spontaneous control of plasma viral load after 8 months without antiretroviral therapy and three cycles of structured therapy interruption in chronic HIV-1 infection. Correlation with induced cytotoxic and helper HIV-1-specific immune responses. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 189.