Contributed by guest blogger: Julia Ding ’12
Once preliminary studies suggest that a drug is safe for human use, clinical trials are conducted in order to further investigate the effects and possible adverse reactions of the drug. The example of HIV microbicides has shown that caution and careful scrutiny is highly important for these trials. HIV microbicides are chemical entities which, when applied before vaginal or rectal intercourse, prevent the transmission of the virus. Of the potential microbicide agents that have been studied, two compounds classified as polyanions were thought to be promising for inhibiting HIV-1 transmission: carrageenan and cellulose sulfate (CS). However, these compounds were deemed in phase III clinical trials to be ineffective as microbicides.
In addition to that discovery, the more surprising and disturbing result of these trials was that the HIV microbicides appeared to actually enhance the rates of HIV infection. Pirrone and colleagues examined the validity of this claim in a study reassessing the in vitro activities of the compounds. Cells were infected with different strains of HIV-1 in the presence of three different polyanions: CS, λ-carrageenan (LC), and destran sulfate (DS). Resulting assays showed that all of these compounds exhibited antiviral activity against both R5 and X4 HIV-1 strains. However, further experiments also discovered that application and removal of polyanion microbicides prior to HIV exposure enhanced and increased the rates of HIV-1 infection. The compounds were added to cell cultures and washed out prior to HIV-1 infection to simulate the natural loss of the compound after vaginal application. In both HIV-susceptible cells and regular human cells, the results indicated an increase in the percentage of cells infected, unrelated to any change in cell viability. The level of enhancement was found to be dependent on the target cell, its co-receptor phenotype, the compound identity and concentration, and the timing of the viral challenge. While the mechanism through which HIV-1 transmission increased in the in vitro experiments is still unclear, these factors suggest that the nature of the host cell also plays a role in polyanion-dependent HIV-1 infection. This data provides a discouraging outlook on the use of these compounds as effective microbicides, while introducing new questions about its mechanisms of action.
This study provides us with many valuable insights about not only the microbicide technology itself, but also the risks and complications associated with clinical trials. The data suggested a significant increase in HIV-1 infection after the application and removal of the two microbicides. Furthermore, it emphasized the need for intense scrutiny of compounds prior to clinical trials, considering the dangers they may pose on human subjects. While previous studies supported the use of polyanion microbicides as a safe and possibly effective means of preventing HIV-1 transmission in women, the effects of the leakage and loss of the product over time was not taken into consideration, and significantly more women on the drug were found to have contracted HIV than if they had not taken it. The study also provides us with an example of the vital role clinical trials play in the testing of a drug, and how certain adverse effects may be missed through in vitro studies that only become apparent when applied to real world uses.
Julia Ding is a senior at Vassar College, with a major in Science, Technology and Society.