HIV research hits a dead end

By Arthur Okwemba (HORIZONS, The Daily Nation - Kenya) 24 April 2008: It is bad news all around as HIV defy all scientific efforts to create an effective vaccine or microbicide while managing to resist most antiretrovirals.

It is bad news all around as HIV defy all scientific efforts to create an effective vaccine or microbicide while managing to resist most antiretrovirals. Local researchers, like most others in the world, have stopped work on HIV vaccines after the failure of what was thought to be the most promising candidate - at least until they can come up with new science.

The Kenyan trials, and several others around the world, were based on a similar concept as the failed candidate which was stopped late last year by its sponsor, Merck & Co after some volunteers became infected with HIV. The experiment, called STEP, began in December 2004 and had enrolled 3,000 volunteers in Australia, Brazil, Canada, the Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico and the United States.

Although the Kenya Aids Vaccine Initiative (KAVI) researchers had registered major successes in the phase one trial of their vaccine, they say they cannot proceed to Phase II using a concept that might not work.

A similar sad story of interrupted progress and failures is haunting scientists involved in the development of anti-HIV microbicides and those working on drugs for its management where distressing resistance rates are being registered. By early this year, trials on five microbicide candidates had been halted.

The Merck & Co., vaccine, which failed to prevent HIV infection or delay progression to Aids was using a concept called, the recombinant adenovirus serotype 5 (rAd5), same as the one being used by KAVI.

But refusing to give up, the Kenyan researchers have set their eyes on another vaccine candidate which could go for trials as soon as the necessary ethical protocols are worked out .

"Although we have finally taken the painful decision of discontinuing the study, there are plans to have new candidates in future," says Prof Omu Anzala, the KAVI director, in an interview with Horizons.

While the Merck candidate used one construct, KAVI's had two- possibly explaining why the phase one trials had made a good showing.. At the moment, over 30 HIV vaccines, which are under different stages of trial are designed to work in a similar way with the one from Merck & Co. Ideally, researchers would wish to develop a vaccine that works on the same lines like the one for polio or measles but so far have not been able to decipher just how to do it.

Nevertheless, what is keeping the hopes of many vaccine scientists alive are new observations on how certain individuals are able to control the virus without using drugs. There are high expectations that research around these areas is likely to lead to the development of an effective vaccine.

One of this are the HIV positive people, who scientists call Elite Controllers of the virus. In this category are people who are not on any medication, but have a CD4 (These "helper" cells initiate the body's response to invading micro-organisms such as viruses) count of over 500 and undetectable viral load.

This means they are infected but are not progressing to Aids, leaving researchers convinced that their immune system is capable of destroying infected cells and/or have broadly neutralizing antibodies. This new information is going to help improve the existing vaccines or form the basis of developing new ones, they say.

Locally, KAVI is partnering with International Aids Vaccine Initiative in a new project focusing on HIV positive people who are not on any medication, but have CD4 count of 350 above and are able to control their viral load at low levels. Majority of the people with HIV and not on medication usually have a CD4 count of below 200.

Another area likely to boost efforts of finding an effective vaccine is information coming from discordant couples, where despite an HIV positive partner having unprotected sex with the negative partner, the latter remains uninfected.

Scientists are burning the midnight oil to understand what makes the uninfected partner tick, and if the information can be used to develop a vaccine.

The third area receiving a lot of attention in the last three months is the possibility of using live vaccines in human beings the way it has been done with measles and polio.

While results of such HIV vaccines in non-human primates have shown tremendous success, the scientific community is hesitant to test them in human beings for safety purposes.

One of the reasons is unlike measles and polio in which majority of the people recover if the live attenuated vaccines results in an infection, the case is not the same with HIV which has no cure.. The disease has no cure as yet.

As scientists grapple with developing an effective HIV vaccine, their counterparts who are working on microbicides are not having it easy either; indicating that the virus might be getting smatter each passing day. Several microbicide candidates have been abandoned or stopped after they failed.

One of this is the recent stoppage of trials on the Ushercell also known as Cellulose Sulphate. During the trials, the microbicide was found to increase the chances of HIV infection among women volunteers who were using it compared to those were not using it (the placebo group). Trials on this microbicide were being conducted by Conrad in Uganda, Benin, South Africa and India, while Family Health International did similar trials in Nigeria. Of the 1,333 women who participated in the Conrad studies, 35 got infected with HIV.

In the Nigerian study, 21 of the 1,644 women volunteers got infected. This numbers were too high than expected, forcing an independent Data Safety Monitoring Board to advice the termination of the studies and ordered a detailed investigation conducted to establish why women were getting infected.

Researchers however suspected some of these women might have been sharing the gel or engaging in unprotected sexual encounters believing they were protected.

A microbicide is a gel or cream inserted in the vagina or rectum to prevent the transmission of HIV and sexually transmitted diseases. Others also act as contraceptives by immobilizing or killing the sperms.

In addition to the Cellulose Sulphate microbicide, trials on other microbidies have too been stopped prematurely. Among this are the Nonoxynol-9 or N9 and Savvy microbicide trials. The N9 was stopped after it was found to be ineffective in protecting women from HIV infections. It irritated the vaginal lining and caused lesions when used in higher doses; factors that facilitated HIV entry.

In one of the studies, 15 per cent of HIV negative female sex-workers who received the N-9 gel became infected with HIV compared to 10 per cent of those who did not receive it during the study.

Likewise, studies on another microbicide, SAVVY, in Ghana were stopped after a review of interim data indicated that the study was not likely to provide convincing evidence on the efficacy of the gel.

Other two microbicides, Carraguard and MIRA, which were promising, returned disappointing results after going through efficacy trials. Another difficulty for microbicide studies has been the high numbers of women volunteers who get pregnant while on trials.

When this happens, the women are taken off the study to protect the foetus; but the action makes it difficult for researchers to move on or come up with conclusive results.

And as if the vaccine and microbicide troubles are not enough, scientists are being forced to deal with the increasing number of people developing resistance to the antiretroviral drugs.

What HIV experts now fear is the circulation of these resistance strains in the population. For now, the HIV seems to be mutating at rate faster than what the scientists can handle and adopting different survival mechanisms.