ACTG A5187 assessed the safety, immunogenicity and viral load set-point following discontinuation of antiretroviral therapy in HIV-1-infected subjects who received either HIV-1 DNA vaccine or placebo. All subjects enrolled in the study were healthy HIV-1-infected subjects who were diagnosed and treated with antiretroviral therapy during acute or early HIV-1 infection. Twenty subjects were followed through phase 1 (the immunization phase) of the study and entered phase 2 (the treatment interruption) of the study. Of the 20 subjects who discontinued antiretroviral therapy, 2 subjects restarted therapy and 18 remained off therapy at the end of the study. This study was designed using a relatively small sample size based on limited availability of vaccine and anticipated difficulty in recruitment of subjects with treated acute or early HIV-1 infection.
The primary objective of this study was to determine the safety of the HIV-1 DNA vaccine when used therapeutically in healthy HIV-1-infected subjects. In this study, no subject experienced any serious (grade 3 or 4) adverse events during the administration of the HIV-1 DNA vaccine, and the vaccine was safe and well tolerated. These safety data are consistent with a prior study utilizing this vaccine in HIV-1-uninfected individuals
All subjects safely discontinued antiretroviral therapy at week 30, and no safety endpoints were reached during this phase of the trial. No subjects met predetermined criteria to restart therapy. These findings contrast with those reported in the SMART study that assessed the efficacy of continuous versus episodic use of antiretroviral therapy in persons with chronic HIV-1 infection
. Results from the SMART study suggested that episodic use of antiretroviral therapy resulted in a significantly increased risk of opportunistic infections and death compared to persons taking continuous antiviral therapy
. In ACTG A5187, antiretroviral therapy was similarly discontinued although there were differences between the treatment interruption strategies employed in ACTG A5187 compared to the SMART study. The main differences were that subjects enrolled in ACTG A5187 were treated during acute or early HIV-1 infection compared to subjects enrolled in the SMART study who were treated during the chronic phase of infection. Subjects enrolled in ACTG A5187 were therefore likely healthier with more intact immune systems then subjects enrolled in the SMART study
. Moreover, the method of treatment discontinuation was different in ACTG A5187 compared to the SMART study. In the present study, individuals underwent a “terminal interruption” as opposed to the episodic interruption guided by CD4+ T cell counts used in the SMART study and also had more frequent CD4 and HIV-1 RNA measurements. It is important to establish the safety of discontinuing treatment in individuals who begin therapy during acute or early HIV-1 infection, since the clinical benefit of early treatment has not yet been demonstrated. The present study therefore begins to provide safety data for treatment interruption in this population, although the results are limited by the small number of subjects studied.
Although the HIV-1 DNA vaccine was safe and well tolerated, the vaccine exhibited minimal immunogenicity that appeared lower than what has been reported in prior studies in HIV-1-uninfected volunteers in which significant humoral and cellular immune responses were observed
. It is not clear why this vaccine was not as immunogenic in HIV-1-infected individuals. One possible explanation is that the subjects in this clinical trial had pre-existing HIV-1-specific immune responses at baseline and that the HIV-1 DNA vaccine may not have been able to boost these responses above that baseline. Given the small size and limited power of this study, only large effects on immunogenicity would be detected. Therefore, it is possible that more modest immunogenicity was not detected due to the power of the study. Although all study subjects had relatively healthy CD4 counts, it is notable that the placebo group had higher baseline CD4 counts then the vaccine recipients although this was not a statistically significant difference.
One notable finding of this study is the low viral load set-point in subjects who completed the treatment interruption phase of the study. Although there were no evidence for vaccine efficacy in terms of a difference in viral set-points between subjects receiving the vaccine compared to the placebo (p
0.50), both the vaccine group and the placebo group had low median viral set-points of 3.5 and 3.7 log 10
respectively. When these viral load set-points are compared to those described in the natural history Multicenter AIDS Cohort (MACS) study
, the set-points appear markedly lower. In the MACS cohort, the average viral load in untreated subjects approximately 12 months following seroconversion was 4.45 log10
(28,240 RNA copies/ml)
compared to an average viral load of 3.6 log 10
(4,000 RNA copies/ml) in subjects completing the treatment interruption phase of the present study. Since there was not a significant difference between the vaccine group and placebo group, it is unlikely that administration of the HIV-1 DNA vaccine contributed to the low viral load set-point in this study. It is therefore possible that early treatment during acute or early HIV-1 infection may have resulted in better control of viral replication once antiretroviral therapy was discontinued, although this hypothesis needs to be evaluated in larger prospective studies. Such a finding would be consistent with previously described observations
, although the durability of control following treatment interruption may be limited
. Subjects that were observed over a long period of time (through week 72 of the study), had higher levels of viremia that trended towards levels reported in the MACS cohort
. These findings suggest a possible role of antiretroviral therapy in persons with acute and early HIV-1 infection and indicate that further studies should be performed to determine if such therapy is beneficial. Therapeutic vaccine studies utilizing more potent HIV-1 vaccine candidates should also be considered.