And yet the fate of the Savvy Ghana trial overshadowed many of these calculations and projections of incidence.
Savvy is a surface active microbicide which entered into a phase III efficacy study in March 2004 at two sites in Ghana. The study enrolled 2,142 women who were considered to be at especially high risk for HIV (including many commercial sex workers). (LINK) The trial had an 80% power to detect a 50% reduction in the HIV infection rate, and planned for, at most, a 20% loss to follow-up at 12 months. The researchers estimated that there would be at least five infections per 100 person years in the placebo group, and that they would observe at least 66 incident infections.
However, halfway through the study, an interim analysis found that only 17 total seroconversions had occurred: nine on placebo and eight on Savvy. This translates into an HIV incidence of 1.0% (95% confidence interval 0.3-1.7%) for Savvy and 1.1% (0.4-1.8%) for the placebo; for a risk ratio of 0.9 (0.3-2.3).
This HIV incidence was dramatically lower than anyone anticipated, and the trial was closed on the recommendation of the Data Safety and Monitoring Board because HIV incidence in the study population was too low to demonstrate whether or not the microbicide had an effect. This doesn’t mean that Savvy doesn’t work.
“We cannot make any conclusion about product effectiveness using this protocol in the Ghana cohort,” stressed Dr Leigh Peterson of FHI, who presented these results.
So what happened? No one is exactly sure but there are a number of theories.
One is that the HIV epidemic in Ghana, or at least these parts of Ghana, has matured and that the incidence in the area is simply on the decline.
Another is that the high rate of pregnancy (LINK) (about four times as common as HIV seroconversion in this study) decreased the likelihood of the study to reach a result, because the women who were most likely to become infected simply became pregnant first, and then either dropped out of the study or changed their sexual risk taking behaviour for the sake of the pregnancy.
A final possibility (that might be even more problematic for the conduct of these studies) is that simply participating in an ethical patient-centred prevention trial reduces the risk of HIV acquisition dramatically.
It's important to remember that these women get the best available safer sex counselling and support, which is reinforced with every clinic visit. The stress of being repeatedly tested for HIV may be a fairly effective motivator to reduce one’s risk taking behaviour. And when is a placebo not a placebo? Answer #1: when it is a condom (at least in microbicide studies).
“For ethical reasons we have to promote condom use within the trial. In my 35 years of experience working with clinical trials, I’ve never been in such a difficult situation were you have to promote another treatment that will work as good, and probably better, than the product you are testing,” said Dr Johansson.
In fact, self-reported condom use has increased significantly in several of the microbicide studies. For example, in Savvy Nigeria, participants reported that condoms were used for 66% of their last sex acts. After follow-up, however, participants reported that they now used condoms for 88% of their sex acts within the last seven days (gel use, however, was not as high). In the CS #2 study, self-reported condom use during the last week went up from 58% at screening, to 90% at follow-up.
There is also another answer, for "when a placebo is not a placebo?" When you receive free medical treatment to which you previously didn’t have access, including treatment of sexually transmitted infections (STIs). Treatment of STIs directly impacts the likelihood of HIV acquisition. (LINK).
If simply conducting a good HIV prevention study dramatically lowers HIV incidence, it would be a happy outcome for the trial participants, but many of these studies could find that they are underpowered.