An Anti-Inflammation Antiretroviral? CCR5/CCR2 Antagonist TBR-652 Monotherapy Study Results

By Myles Helfand

July 19, 2010

When it comes to health problems in people with HIV, inflammation is the flavor of the day. In the case of TBR-652, a CCR5 inhibitor in the earliest stages of testing in humans, that’s an awfully good thing. What sets TBR-652 apart from other CCR5 inhibitors — heck, all other antiretrovirals on the market today — is that it’s also designed specifically to block another receptor, CCR2.

CCR2 has nothing to do with HIV, but appears to have quite a bit to do with inflammation. Drugs that can inhibit CCR2 are being explored as potential treatments for a number of health problems tied to inflammation, including rheumatoid arthritis, asthma, multiple sclerosis and psoriasis.

In TBR-652, we may well end up with a case of the right drug being developed at the right time. Well, if the drug actually works, that is. Here at AIDS 2010, David E. Martin, Pharm.D, presented results from a proof-of-concept study on TBR-652: A 10-day monotherapy study involving 54 HIV-infected people. Hopefully we’ll be able to post the slides soon, but the gist is that the drug looked good enough to warrant starting a Phase 2b trial in early 2011.

Five different doses of TBR-652 were tested (there was also a placebo arm). Among the four highest doses, HIV-1 RNA levels dropped between 1.4 log and 1.8 log over the 10-day trial, a decent showing for an antiretroviral taken as monotherapy. Side effects were, generally speaking, similar to those seen among people taking placebo, with the exception of the highest-dose (150 mg) arm. A greater number of side effects occurred in that arm, though Martin noted that these side effects weren’t any more severe or longer-lasting than those experienced at other doses. The drug appears to have both a long half-life (30 to 40 hours) and a long “ramp-up” time (2 to 3 days), however, so there’s much left to learn about both its efficacy and safety over the longer term. 

The impact of TBR-652 on inflammation was gauged by assessing levels of MCP-1, a protein that contributes to inflammatory responses when it binds with CCR2. If TBR-652 is doing its job as a CCR2 inhibitor, one would expect free-floating MCP-1 levels to increase, since the protein is unable to bind with CCR2. And, indeed, levels were found to increase in each of the five groups taking TBR-652 (with the difference compared to placebo reaching statistical significance in three of the dosing groups). Martin also offered up a brief case study of one patient in particular who began the study with low levels of MCP-1 and high levels of C-reactive protein (CRP), another marker of inflammation. MCP-1 levels jumped from virtually nil up to more than 160 pg/mL by day 10, and CRP levels dropped from around 15 mg/L to 5 mg/L.

Of course, this is all much ado about very little at this point. Sure, the drug looks pretty good as an antiretroviral and as a CCR2 inhibitor, but we’re talking about 10 days of monotherapy. The drug’s long-term efficacy and safety as part of an optimized antiretroviral regimen will be explored in research set to begin next year. During the question-and-answer period after Martin’s presentation, a couple of people raised the question of what impact blocking CCR2 might have on a person’s body over the long term. One person noted that CCR2 inhibition has been associated with tuberculosis risk, while others touched on a pretty key point: Despite the bad name it gets in the current HIV care climate, inflammation is a fundamental part of the body’s response to infections. If you take away a chunk of that inflammatory response, do you potentially make a person more susceptible to immune system damage? It’d be a bitter irony if a drug designed to hurt HIV’s ability to suppress the immune system ends up suppressing the immune system itself. Martin assured the audience that close attention would be paid to all of these issues as TBR-652 progressed through phase 2b study.

There’s also a conundrum down the road even if TBR-652 is proven safe and effective: namely, that it’s a CCR5 antagonist. CCR5 antagonists are most likely to work in people with HIV who recently became HIV positive. The longer a person has been living with HIV, the more likely he or she is to have CXCR4-tropic or dual/mixed-tropic virus, which means a CCR5 antagonist won’t work for them. Yet it is precisely those long-term HIV survivors who may be most at risk for inflammation-related complications.

I don’t mean to be a buzzkill here. After all, in a year that has featured precious few drugs in development to get remotely excited about, it’s nice to see one that’s actually moving forward through clinical trials. But at this very early stage in its development, a cautious hope about TBR-652 seems the prudent approach.

Send Myles an e-mail.

Vienna AIDS 2010: Global Health Leaders Say Stigma Exacerbates HIV Epidemic Among Black Gay/Bi Men

By Rod McCullom

July 22, 2010

AIDS 2010: Global Health Leaders Say Stigma Exacerbates HIV Epidemic Among Black Gay/Bi Men Vienna, Austria — From pre-conference events to the massive human rights march through downtown Vienna, world leaders, public health experts and HIV activists honed in with laser-like precision on a common message at The 18th International AIDS Conference in Vienna : The ongoing persecution and criminalization of gay, bisexual and other men who have sex with men — “MSM”, in public health shorthand — are undermining efforts to control the global HIV/AIDS pandemic.

Chief among the obstacles: More than 80 nations have laws that still criminalize same sex behavior. In some of these countries, conviction can even result in the death penalty, reports UNAIDS.

Further exacerbating the problem, according to a report by Planned Parenthood, “58 countries have laws that criminalize HIV or use existing laws to prosecute people for transmitting the virus. Another 33 countries are considering similar legislation.’

The trend is “even more pronounced” across Africa and the Diaspora, said Joel Gustave Nana, executive director of the Johannesburg, South Africa-based African Men for Sexual Health and Rights (ASMSHer). The West African laws vary in extremity — just “exposing a person to HIV, regardless of if the virus is transmitted, is a crime in Benin, and Tanzanian law carries a possible sentence of life in prison for intentional transmission,” reports Medical News Today. While the overall life for Black MSM may be better for in North America, there are drawbacks. The United States and Canada lead the world when it comes to prosecuting people who infect or expose others to HIV, a surprising new study reveals. Black men have been disproportionately targeted with these prosecutions. A Black, gay, HIV positive Michigan man was recently as charged as a bioterrorist for allegedly biting a neighbor’s lip during a scuffle, Black AIDS Weekly reported in June.

“The prosecutions are arbitrary,” said Nana, in an interview after a press conference organized by The Global Forum on MSM & HIV. On Sunday, the day before the conference officially opened, the Global Forum held a 24-hour event to address the soaring global rates of MSM seroconversions.

“The stigma, discriminatory laws and criminalization of HIV transmission encourage the spread of this disease,” adds Nana. “Why should someone seek testing or medical advice come forward if you could be arrested? There is no incentive.”

The fear of “coming out”, pop culture which celebrates homophobia and churches and churchgoers that demonize gay Black men compound the problem for black MSM in America, the Caribbean and Africa.

“This is the context in which you have a runaway, dangerous HIV epidemic in Jamaica,” adds Robert Dr. Robert Carr, the co-chair of ICASO, the International Council of AIDS Service Organizations (ICASO). “There is a clear link between religious condemnation, criminalization, stigma and HIV infections. We see this all the time in the Caribbean.”

Carr adds: “Politicians and church leaders endorse homophobic violence. Police refuse to protect MSM or are complicit or directly involved in the violence,” he said, referring to a now-infamous incident of a 2,000-strong mob surrounding several gay men and stoning them. The police were called to the scene and the officers also struck the young men.

Carr sighs. “With Jamaican MSM infection rates at 32 or 33 percent, it became obvious that you couldn’t do effective HIV work in this context.”

Although a state sponsored, religious-based terror campaign has targeted African MSM from Algeria to Zimbabwe, there are some positive developments to report from AIDS 2010.

“We now have 14 countries out of 54 that include men who have sex with men in their national HIV strategic plans,” AMSHer’s Joel Nana said. “It doesn’t mean the services will be delivered to those populations, but it is an acknowledgment. That’s a first step.”

“Kenya was the first African nation to include MSM in their national HIV strategy,” Nairobi-based peer educator Job Akuno told Black AIDS Weekly. Akuno is a counselor with the Nairobi-based SHAP, Scaling Up HIV and AIDS Prevention, partially funded by PEPFAR, the President’s Emergency Plan for AIDS Relief. “That was in 2006. But … it seems like we are rolling back on some of the gains that we made.”

“Kenya is starting to look like one of the countries that we should look up to,” Nana adds. “The HIV movement is more open to include MSM. And there is a strong MSM movement in Kenya, too . It is one of the few countries in Africa where a MSM organization was able to place an ad in the newspaper for the International Day Against Homophobia on May 17.”

Akuno says the HIV Prevention and Control Act criminalizes deliberate HIV transmission. “The sentences are up to 10 years. No one has been prosecuted, but now there is talk to make the law harsher. If you criminalize HIV transmission or only target MSM, that will further stigmatize the disease and drive many people into not wanting to know their results. ”

Job Akuno shrugs. “What can you do but hope for the best?”

Rod McCullom, a writer and television news producer, blogs on Black gay, lesbian, bisexual and transgender news and pop culture at rod20.com.