The use of therapeutic vaccines for treating both primary and chronic HIV infection - with and without concurrent HAART - was the major topic at the Immune Reconstitution and Control of HIV meeting in Stresa, Italy last week.
Although IL-2 remains the only immunomodulator likely to be approved in the near future, there are several exciting candidates that promise to not only boost CD4 cell counts (as IL-2 does) but also reduce HIV viral load (which IL-2 does not). In this way, argued Juliana Lisziewicz of RIGHT (Research Institute for Genetic and Human Therapy), Washington DC, we should consider the best therapeutic vaccines to be similar to antiretroviral therapy, but with different resistance profiles and toxicities.
The most promising new therapeutic vaccine - about to enter Phase I clinical trials in both adults (ACTG 5176) and children (PACTG 1049) - is DermaVir, a topical DNA vaccine. Made from a mix of HIV’s genetic material it stimulates immune cells located in the epidermis (including CD8 and Langerhans cells) and is applied to the skin only once every six weeks.
DermaVir has so far been tested in macaques with late-stage simian immunodeficiency virus (SIV, the monkey equivalent of HIV). Treatment was randomised into four arms: no treatment, DermaVir alone, HAART alone and DermaVir + HAART. The last three arms were given as cycles of structured treatment interruption: three weeks on, three weeks off. After four cycles of treatment and interruptions, the macaques in the HAART+DermaVir arm had significantly decreased levels of SIV (from a median of over 5 million copies/ml to below 50 copies/ml) and increased levels of CD4 cells, compared to those macaques who received DermaVir alone or HAART alone.
Lisziewicz is hopeful this data will translate into humans for use in chronic HIV treatment, and results will be available from the two Phase I studies next year.
Meanwhile, Sabine Kinloch of London’s Royal Free Hospital reported intial results from the QUEST trial, which is comparing standard HAART with one or two therapeutic vaccines and structured treatment interruption (STI) given during primary HIV infection (within four weeks of infection and before seroconversion). This is the first ever study of therapeutic vaccines and a planned STI in primary infection and is a huge multinational effort that has recruited 148 people from Europe, Australia and Canada since 1998.
All people in the study receive four-drug HAART (amprenavir, abacavir and Combivir) for 18 months, and then are randomised to receive HAART alongside either ALVAC (a live recombinant canarypox vaccine) or ALVAC and Remune (an envelope-depleted, inactivated HIV-1 vaccine) or both vaccines for an additional six months. The patients will then stop all therapy in order to see which of the treatments best achieve viral control.
Disappointingly, Kinloch reported only on the first 48 weeks of the study. Significantly, however, by week 48, nearly a quarter had either dropped out or stopped HAART and only 115 of the original 148 were available for follow up: 12 had stopped therapy, 80 were still on four drugs, one was on five drugs, and 22 had decreased to a three-drug regimen. Nausea was the most common side effect. Of those still on therapy, 69% achieved less than 10 copies/ml and 50% less than 3 copies/ml (using a hyper-sensitive viral load test with a limit of detection of 3-10 copies).
Results from the next phase - after 96 weeks when the treatment interruption takes place - will not be available for some time.
Another therapeutic vaccine reported on in Stresa was the impossibly-named Autologous monocyte-derived dendritic cells loaded with inactivated autologous HIV which achieved a viral load 0.5 log below baseline in four of 12 individuals with primary HIV infection after three STIs (Jose Gatell, University of Barcelona, Spain). Two other therapeutic vaccines reported on here have so far been studied in mice and monkeys: Env/rev + gag/pol CTE and IL-15 + gag (David Weiner, University of Pennsylvania, USA) with disappointing results. However, most attendees were upbeat about good therapeutic vaccines being used in the clinic well before the end of the decade.