Day 265: Wasn’t this news released last December?

I am never opposed to more press coverage of HIV, but the big story today seems to be an old one. The CDC reports that instead of the approximately 40,000 new HIV infections in the U.S every year, in 2006 we actually had about 56,000 new infections. That’s a huge difference. They used a new surveillance method to come up with this number.

 

As you may note (as carried in this blog), the same data were released on World AIDS Day last year. The Wall Street Journal reported then that the U.S. incidence was about 60,000.  The CDC is saying this is a wake-up call—but the wake-up call should have been (at least) 8 months ago! Well, we’ve never done enough on HIV, and I don’t think the increased U.S. incidence estimates will do anything to change that. Should we start taking bets on whether HIV gets any debate time in the upcoming elections?

 

M. Linde

Day 81: What to do with maraviroc?

I read in the Wall Street Journal today that Pfizer is going to try and reformulate maraviroc (Selzentry) as a microbicide—something I have been saying they should do ever since I saw the efficacy data. Maraviroc is exciting because it is a new class of drug. It’s an entry inhibitor that works by blocking HIV’s interaction with one of the co-receptors, called CCR5. 

For those of you who don’t know, HIV predominantly uses two different co-receptors. The CD4 molecule is the primary receptor. HIV binds CD4, which causes a change in the viral entry proteins, allowing them to bind the co-receptor and enter the cell. Along with CCR5, CXCR4 acts as a major co-receptor (there are other minor co-receptors that HIV can use, but I am not sure how important these players are). So, any cells that HIV is going to infect need to have CD4 and either CXCR4 or CCR5. These are mainly CD4 cells, which carry CXCR4 and sometimes CCR5, and macrophages, which have CD4 and CCR5. 

A virus can be CCR5-trophic, CXCR4-trophic, or dual trophic. These used to be called M-trophic and T-trophic (for macrophage and T-cell, respectively), but these names changes when the co-receptors were discovered. As you might have figured out, M-trophic virus is also CCR5-trophic and T-trophic is CXCR4-trophic. When someone is infected with HIV via sexual contact (I am not sure about intravenous transmission), the virus that is almost always transmitted is CCR5-trophic. (One day I need to write about the viral genetic shift to baseline during transmission).  For some reason, the predominant strains in the body shift to CXCR4 as disease progresses. I don’t know this for fact, but I had always assumed that the reason why the transmitted virus is CCR5-trophic is because of virus-macrophage interaction in the genital tract. This could be totally wrong, though, so please don’t take this as fact. 

Getting back to Maraviroc, you might understand how a CCR5-inhibitor might have some limitations. First, it would only be effective for patients that have predominantly CCR5-trophic virus. This means you have to test the patients for their predominant strain, which can be expensive. Second, viral trophism changes and patients at later stages of disease progression tend to have the CXCR4 virus. Therefore, maraviroc would probably be useful for patients at earlier stages of disease progression, like first- or maybe second-line. The problem is that we already have good regimens for first line therapy, so maraviroc would have to be pretty efficacious to crack the line-up. The other problem is that most medications start as salvage therapy (multiple failures); maraviroc is probably not going to help these patients because it likely won’t be active against their viral strains. So you can see where Pfizer might have a problem with this drug. It is approved for human use, though, so why not try to use it in another manner? 

It seems to me like a good candidate for a microbicide. It’s a small molecule, so it should be fairly stable. Formulation is always an issue, but the real test is going to be what it does to the genital tract. We know it has antiviral activity—that’s not the issue. But there are a lot of compounds that have antiviral activity, which doesn’t mean they’ll work as microbicides. One of the more famous cases is nonoxinol-9, the spermicide. It can kill virus and was thought to be a potential microbicide. The problem was that it increased the infection rate, instead of decreasing it (sound familiar?). It turns out that N-9 also causes inflammation, and HIV loves inflammation. So, any compound that works as a microbicide cannot be inflammatory. Another issue is that microbicide trials are essentially like vaccine trials; that is, they are big and expensive. Last year a promising microbicide was halted early during Phase III trials because it increased the transmission rate. This trial had over 3,000 patients and was at something like eight trial centers on three or four continents. Lastly, it may be that a microbicide is going to need to be used in combination with another microbicide, similar to HAART. This would be to prevent the development of strains that are resistant to the microbicide. Unfortunately, we don’t have any microbicides right now, so that would be a problem. 

I hate to end on a pessimistic note, though. I think it is great that Pfizer is taking my advice and doing this (well, they never consulted me, but they should have). Not only do I hope it is successful, I hope maraviroc makes oodles of money as a microbicide and spurs other pharmaceutical companies to look at microbicide development as a viable business plan. 

M. Linde

Day 46: The high prevalence of HIV among black MSM

There was an interesting brief report in the journal AIDS recently looking at HIV rates, risk factors, and ethnicity. Using a survey of men who have sex with men (MSM) at a San Francisco clinic, Berry and colleagues found that black men were more likely to have partners of the same race and partners who were at least ten years older than themselves compared with white, Latino, or Asian/pacific islander respondents. The authors undertook the survey to help address why HIV prevalence is higher among the black MSM compared with white MSM, despite lower risk behavior patterns among black MSM. Based on the findings, the authors suggest that older black MSM are passing HIV to younger black partners, potentially explaining the noted prevalence patterns.

This seems the simplest explanation and certainly seems reasonable, but I can’t help but wonder if some other factors are at play. This is just a though, but there have been studies showing that MHC divergence between serodiscordant partners seems to be protective for transmission. One possible explanation for this finding is that alloimmunity may provide a protective response against incoming virus—which is loaded with MHC molecules. Alloimmunity is very strong—a normal reactive antigen may stimulate 1% of T cells, while an allo-antigen can stimulate 5% of T cells. So, if black MSM are having sex with other black men, the level of MHC discordance may be lower than white MSM. This all depends on the amount of MHC divergence within the black community. The other factor that may be involved is the age difference. The authors don’t report the ages within the cohort. Now, a ten year discrepancy between partner ages could be a surrogate for younger age. Younger age coupled with fewer risk behaviors (fewer partners) might mean that many black MSM have not developed alloreactivity to divergent MHCs. Other ethnicities, which have a smaller age discrepancy, may be a surrogate for an older population—one which has a more developed alloimmune response as a result of repeat exposures. It is a bunch of hand waving and there are a bunch of “ifs” involved, but I couldn’t help but think this might be involved.

It reminds me of a friend I had who had a really unique ethnic background—he was pretty much part everything. He had several partners who were positive, yet he was never infected. I always wondered whether he had some really strange MHC combination and had strong alloresponses against any virus he came in contact with. Anyway, I just thought I would throw that out there.

Day 21 (World AIDS Day): A higher U.S. incidence

In honor of World AIDS Day, the CDC reports that the HIV incidence in the U.S. may be higher than previously reported. I have heard that the incidence was stable at about 40,000 new infections per year, for several years. I read in the Wall Street Journal today that the incidence may be as high as 60,000 new cases a year. This leads to the inevitable question: regardless of the actual number of new infections, why is the incidence not decreasing in the U.S.?

 

As I often say, the greatest tragedy about HIV is that it is an entirely preventable infection. If you take the proper precautions, the risk of infection should be minimal. So, why are so many people still getting infected? Certainly, there is a level of personal accountability for everyone, but as a society, we need to do everything we can to make to easier to prevent infection. My blood still boils when I think back to the moratorium on needle exchange programs from the late 90s. I was living in D.C. when there was a ballot measure on needle exchanges, but the results would not be tabulated because Congress would not fund the District if it enacted such a program. Is it a coincidence that D.C. now has the highest prevalence of HIV in the country, at a whopping 5%? Regardless of the moral implications, we need to make needles and condoms available to those who are at risk. Nobody deserves this disease because they made a bad decision or didn’t have access to preventative measures.

 

While I am on the topic of prevention, why can’t we have some more discussion on microbicides? A preventative vaccine is always the goal, but given the recent track record, can we spend a little more time and money looking into microbicides? Sure, the record with microbicide trials is about as bad as preventative vaccines—and the clinical trials are just as expensive and difficult as the vaccine trials—but as a former virologist and immunologist, I think we are going to have a lot more success at creating a microbicide than we are at making an effective preventative vaccine. There are conserved features of the virus that you can target with a microbicide that you cannot target with a vaccine. So, President Bush, can you talk about microbicides when you propose $30 billion for AIDS?

 

M. Linde

Day 14: CDC releases health disparities report

The Centers for Disease Control and Prevention released a report on health disparities in HIV/AIDS, viral hepatitis, TB and STDs this month. The report follows data from 2001 through 2004 in the US.

 

As we have been hearing for years, HIV rates among blacks and Hispanics are considerably higher than rates for other ethnicities. According to the report, HIV rates were 8.5 times higher for blacks than for whites (69.3 cases/100,000 vs. 8.2 cases/100,000). Notably, blacks accounted for 50% of new HIV cases.

 

The good news is that rates declined over this period for blacks, Hispanics, and in the Northeast. Levels were stable for other ethnicities and US regions. By region, the Northeast had the highest rate of infection (despite the decline), with 30.1 cases/100,000; comparatively, the South had rates of 23.5 cases/100,000. I have always heard that the rates of infection were increasing most rapidly in the South, but these data show that new cases were stable in this region for this period.

 

The report also broke down the new cases by age group. The highest rate of infection was among persons aged 35-39. I can only assume that this has to do with the latency period of HIV and that this age group reflects people who are getting infected in their 20s.

New infections were observed primarily in men, who accounted for 73% of new cases in 2004. Of these men, men who have sex with men accounted for 65% of cases.

 

The mode of transmission among males was predominantly reported as male-to-male sexual contact, with a slight upward tick in 2004. Infection due to injection drug use had a slight steady decrease over this period. For females, heterosexual contact was the main reported cause of infection, although this category decreased over the course of the study.

 

So, what does this study tell us? For many years, I have read and heard that the incidence of HIV was increasing the most among black and Hispanic women and in the South. It is important to note that the data in the CDC report are the number of new cases, which may differ slightly from the actual incidence. So, the face of HIV in the US may be changing compared to the early epidemic, but what we see in this study is a slightly different story. New cases of HIV are still dominated by men who have sex with men and the Northeast US appears to be the epicenter. Clearly, there is an issue when blacks have a considerably higher rate of new infections compared with whites. The reason for this difference is not clear, it could be due to prevention efforts, HIV education, access to treatment or care, or it could also be biological. Certainly, all of these issues need to be examined so we can reduce the incidence of HIV among all demographic groups.

 

M. Linde

Day 9: Some good news

The UN revised its estimate on the number of HIV-infected persons, reducing the estimate from almost 40 million to just under 33 million. While this is still an astounding number, at least it means that the epidemic is not as advanced as was feared. Granted, 33 million infected people and growing means HIV is still the #1 threat to humanity–in my book at least. I hope the correction in the estimate doesn’t cause others out there to believe that HIV is not as important a cause as it was yesterday.