Microbicides - Women Wait

posted: 18/05/2010

Next week’s International Microbicides Conference in Pittsburgh, USA will hear about the progress made in producing microbicides, that will help protect women and gay men from HIV.
 

Numerous past attempts at microbicides have failed. Using an anti-HIV drug in a microbicide is one of the attempts now being made to find some method of HIV prevention that women can use themselves. Women face problems protecting themselves from HIV, especially when their partners refuse to use condoms, or when simply suggesting condoms may put the woman in danger.
 

Is tenofovir part of the answer?

Tests are underway to see if tenofovir, one of the commonly used anti-HIV drugs, would work in vaginal gels and contraceptive-style rings. Experiments are also underway with quick-dissolving anti-HIV films, like those used for breath-fresheners or allergy medicines, but these are made for vaginal use.
In July we should have the results from the first study to see if tenofovir works in a microbicide — South African women are testing a gel made with it.
 

Cautious Hope
"Frankly, blocking transmission of the virus appears to be a lot harder than anyone understood it would be at the beginning," says co-chair Dr. Sharon Hillier of the University of Pittsburgh and a principal investigator of the Microbicide Trials Network. "The reason we're not depressed in the microbicide world? We actually have learned a lot and moved on to think about potent drugs and really cool delivery methods."
 

Pills for Prevention?
More than half a dozen studies of ‘pre-exposure prophylaxis’ (taking pills as treatment to prevent HIV infection happening) are also under way, and these mainly use tenofovir, because the side effects are more limited than with some other anti-HIV drugs. But even if pills for prevention works, taking HIV pills daily has drawbacks. There are the side effects, the risk of drug resistance, and people may miss doses or share the tablets with others so they wouldn’t be effective. It’s more expensive protection than condoms and the risks make it controversial.
 

Microbicide action
Microbicides are needed too. Women already make up half of the more than 33 million people worldwide living with HIV, and most of the new infections in hardest-hit sub-Saharan Africa are among young women.
"I have in fact so little to offer women in terms of HIV prevention that I sort of tear my hair out," says Dr. Salim Abdool Karim of the Centre for the AIDS Program of Research in South Africa at the University of KwaZulu-Natal. He’s leading the tenofovir gel study, his ninth microbicide study since 1994. "It must take a certain level of perseverance to want to stay in this field." Much more of the tenofovir reaches the vaginal tissue from a gel than any pill, and it doesn’t seem to move elsewhere into the body, so side effects may be minimal. He’s studying 900 HIV-negative heterosexual women to test whether tenofovir gel, applied up to 12 hours before intercourse and again within 12 hours afterward, lowers the risk of infection.
 

Next step soon
While awaiting his results in July, the U.S. National Institutes of Health is funding the next step: Researchers are already looking for 5,000 healthy women in several African countries to try two other approaches - vaginal tenofovir gel used daily rather than before and after sex, or or daily tenofovir pills. Which way is best?
 

Contraception teaches us that offering more choice about method leads to more women using something. So researchers are looking at other methods, too: a quick-dissolving tenofovir vaginal film, which should be completely invisible to the partner. Vaginal rings might be used to trickle-dose the vagina over a month. And for gay men ways to protect the rectum with tenofovir are in prospect.
Health promotion workers should get themselves ready to deal with the challenges should any of these attempts work, Dr. Regina Osih of the University of Witwatersrand will advise next week's microbicide conference.
 

Abacavir - Check for Heart Attack Risks

posted: 06/10/2008

Abacavir: risk of heart attacks compared to tenofovir

Two studies into abacavir, probably caused the most controversial discussions at the AIDS Conference in Mexico.

Abacavir is widely prescribed and recommended as a first-line combination here.

These studies asked:
i) Does abacavir increase risk of heart attack and other cardiovascular problems?
ii) Is abacavir less effective in people who start treatment with a viral load over 100,000 copies/mL, especially when compared to tenofovir?

Both questions were highlighted by independent researchers and GSK, who make and market abacavir have tried to downplay the studies' findings.

Abacavir and heart disease: SMART study supports links found by D:A:D study

In February 2008 at the Retrovirus conference (CROI), the D:A:D researchers reported finding that current or recent abacavir use approximately doubled the risk of having a heart attack compared to other nukes. This was most pronounced in real terms in people who already had high risk of heart disease.

Even though D:A:D was the largest study ever designed to look at heart disease and HIV treatment (over 33,000 people were followed for over seven years), many people wanted confirmation of these results in other studies before they would believe them.

In Mexico, we heard that the large randomised SMART study found similar results (seeing 2 to 4-fold increases in risk) when they looked at abacavir use by patients in their database. This risk was increased however heart disease was defined (ie strictly by having a heart attack, or more broadly including other aspects of heart disease).

They found the risk was most significant in people with high cardiovascular risk (those with 5 or more other risk factors) and that this was seen whether abacavir was compared to all other nukes, or just to tenofovir. They also reported that baseline inflammatory markers (IL-6 and hsCRP were higher in people on abacavir and that this could explain the higher risk, although the design of these studies can only report the association and not show that abacavir caused this. See also the HEAT study below).

Whenever a safety signal is found in a licensed drug, the manufacturer has to investigate. Earlier in the conference, GSK had presented the results from their own database of clinical trials, where they couldn’t find a link to heart disease. However, this doesn’t balance the findings from D:A:D and SMART for several reasons.

Firstly, patients in GSK studies were generally younger and healthier and people with higher cardiovascular risk are usually screed out from taking part in new drug studies.
Age increases cardiovascular risk and GSK patients were around 10 years younger. The GSK database was not designed to look for or record cardiovascular disease, and most importantly, it was not powered to be able to see any link to abacavir use – whether or not they saw anything, there were too few events to make this statistically
meaningful.

HIV-positive people need to check their risk of heart disease using online Framingham calculators . If it is high (20% risk of heart attack in the next 10 years), then use an alternative drug to abacavir, and look at other lifestyle changes that could reduce this risk (exercise, diet, stopping smoking etc).

SMART study (THAB0305)

GSK response (WEAB0106)



Is abacavir/3TC (Kivexa) less effective than tenofovir/FTC (Truvada)?

The second abacavir controversy in Mexico related to whether Kivexa is less effective than Truvada at high viral loads.

This was raised by an independent US study called ACTG A5205 that randomised 1800 patients to either abacavir/3TC or tenofovir/FTC. Earlier this year the study was changed after a safety analysis showed a higher rate of treatment failure in almost 800 patients who started treatment with a viral load that was higher than 100.000
copies/mL. Other drugs in the study were either efavirenz or atazanavir/r, but results from use of these drugs are not yet available.

GSK responded to these findings with results from the HEAT study and a combined analysis (called a meta analysis) from six  abacavir studies.

The HEAT study is the first randomised study comparing abacavir/3TC to tenofovir/FTC and an analysis by baseline viral load showed no differences after 2 years in terms of risk of virological failure or tolerability – although it is a smaller study (with under 700 patients, with only around 150 patients in each group with baseline viral load higher
than 100,000 copies/mL).

Interestingly, the HEAT study found that IL-2 and hsCRP inflammatory markers both dropped significantly during the first year of treatment, but that this occurred in both the abacavir and tenofovir groups at a similar rate.
The meta analysis was not able to measure outcomes in exactly the same way as ACTG A5205 and wasn’t comparing abacavir to tenofovir, but reported similar response rates at higher and lower viral load levels.
Nevertheless, both European (EACS) and UK (BHIVA) guidelines have thought these results important enough for tenofovir to be either preferred as a first-line regimen or preferred in patients with higher baseline viral loads.

Both studies were presented at the late-breaker oral presentations on Thursday:
www.aids2008.org/Pag/PSession.aspx
HEAT study: (late breaker poster)

Source: i-Base about abacavir and i-Base Mexico report