RIVER recruited people who were diagnosed and started ART within the first few weeks of HIV infection, and who were therefore likely to have a smaller number of cells containing HIV DNA.
Sixty people, all male, and all but five gay men, were recruited, with an average age of 32. They all had recent infection and early treatment, with an average length of time of 28 weeks between HIV infection and entering RIVER. They had an estimated maximum length interval of 16 weeks between HIV infection and diagnosis, so a minimum time on ART of 12 weeks before entering the study. Their average CD4 count was 708 cells/mm3 and all but one had a viral load below 50 copies/ml at randomisation.
They were randomised to continue on ART alone or take ART plus the ‘kick’ and ‘kill’ therapies. As these consisted of a vaccine followed by the gene stimulating drug vorinostat, this was called the ARTVV arm.
RIVER gave the ‘kill’ part of ARTVV first: it administered a vaccine designed to amplify and broaden the immune system’s natural reaction to HIV. This makes sense, as you need a vigilant immune response already in place to recognise the woken-up virus.
It gave people two vaccine shots, one at randomisation and one eight weeks later. The vaccine was a so-called vector vaccine: it consisted of parts of the HIV genetic code that are particularly ‘conserved’, i.e. which are essential to the virus, vary little from type to type and do not change over time, wrapped up in the shells of two different viruses, an adenovirus at week zero and a vaccinia virus at week eight. See this report on the APPROACH vaccine study for more on vectors.
The ‘kick’ part of the study was then given: the drug vorinostat (Zolinza) was given as one dose every three days for the next 30 days after week eight. Vorinostat is an HDAC (histone deacetylase) inhibitor: what this means is that it loosens DNA strands inside cells and enables inactive genes, including ones that activate immune-system cells, to switch back on, so the cells become active again.
The theory was that the newly active infected cells would start assembling the cellular machinery to make more HIV, and that this would get noticed by the immune system that had been primed by the vaccine. The cells would be killed, and the reservoir of HIV DNA purged. There should be little danger of active HIV therapy developing though, as all RIVER patients remained on ART.
There were more adverse events (AEs) in people given the ARTVV regimen, but the excess was entirely due to AEs classed as mild; in fact there were more severe adverse events (six versus one) in the ART-only arm.
The primary outcome was that there was no decrease in HIV DNA in people given the ARTVV regimen. There was a decrease in DNA between diagnosis and starting RIVER, due to patients being put on ART, but absolutely no change thereafter, and no difference between people on ART alone and people on ARTVV. There was also no difference in the amount of new HIV viruses produced by people’s cells in the lab dish.
The ARTVV regimen did have some effects. It boosted the number of HIV-specific CD4 cells nearly tenfold, and CD8 cells to a lesser degree. The CD8 cells of patients given ARTVV was preserved at pre-ART levels, meaning that the vaccine did create what could be a useful immune response in other circumstances. The vorinostat also produced a measurable increase in HIV gene expression, though tests are ongoing to find out what the effects of this were.
However, the lesson from RIVER is that the effects of the two therapies did not combine to produce a decline in cells containing HIV DNA.