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 67: Is it time to coformulate Viread with Viagra?

Ok, so I am sure the title of this entry will be the standard joke among HIV docs for a bit. Actually, it has probably been made far too many times already. The joke is based on recent data indicating that Viread (FTC/TDF) was shown to decrease the rate of vaginal infection among humanized mice. The mice essentially have human immune systems, which is why the can acquire HIV. Mice that received pre-exposure prophylaxis (PrEP) with Viread did not get infected when exposed vaginally, while 88% of the mice that did not receive PrEP acquired infection. The mice that received PrEP were given Viread 48 hrs and 24 hrs prior to HIV exposure and every 24 hrs for 5 days after exposure. The study was published by Denton and colleagues in PLoS Medicine this month. 

So, these data are kind of exciting. It’s humanized mice, so you can’t get too excited yet. I would assume a monkey study would be next and then a large-scale human trial. You have to take animal studies as they are—they don’t always translate to the same results in humans. But the data could be a boon for high-risk populations, especially women. One of issues with condoms is that it requires the cooperation of your partner. If there is an alternate method to block infection—one that does not require the partner’s cooperation—hopefully the transmission rate might be reduced. This could also be really helpful for serodiscordant couples who want to conceive. Granted, sperm-washing techniques (the process of eliminating virions from semen) are very successful, but this might be considerably less expensive and a lot easier. Viread PrEP could also be helpful for intravenous drug users, but it has yet to be established (as far as I know) if this method would protect against HIV acquired via needles.

Of course, there are also concerns. While I don’t think anyone would advocate using Viread PrEP instead of condoms (especially at this point), we have to establish whether Viread PrEP is as efficient in preventing infection as condom use. If PrEP with Viread is not as efficient as condom use for blocking infection, then you have to question the common utility of Viread PrEP. Additionally, condom use is one time and Viread PrEP might require a weeks worth of adherence, which might be difficult for some. Finally, Viread is not without side effects, although I doubt this would be a major concern considering Viread’s toxicity profile and the fact that the dosing would be intermittent instead of chronic. And cost is always an issue, especially in underdeveloped nations where HIV transmission is rampant. 

All in all, the study is good news. We desperately need more ways to prevent infection. A pill is a good start as it would help circumvent some of the social and political problems faced with condoms. We still need a barrier microbicide, but the data for PReP are encouraging. So, assuming this does work, does Viread go over the counter?

M. Linde

Day 47: Great news from D.C.!

The Associated Press reports that D.C will needle exchange programs. I wrote about the ban on needle exchanges in the city earlier on Day 21. It’s about time needle exchanges were rolled out in the District. Maybe D.C. wouldn’t have the highest HIV prevalence in the US if Congress and the White House had not blocked the District from using funds to provide these programs in the 90s. Hopefully we will learn from this experience.

M. Linde

Day 47: Thoughs on “Will there ever be an HIV vaccine?”

Robert Steinbrook presents an interesting commentary on the prospect of an HIV vaccine in this week’s New England Journal of Medicine. The article focuses on the Merck vaccine failure and what it means for the future of HIV vaccines. The most sobering part of the article comes not from Dr. Steinbrook, though, but Anthony Fauci, who says “To be brutally honest with ourselves, we have to leave open the possibility . . . that we might not ever get a vaccine for HIV. People are afraid to say that because they think it would then indicate that maybe we are giving up. We are not giving up. We are going to push this agenda as aggressively and energetically as we always have. But there is a possibility—a clear finite possibility—that that’s the case.”

In my interactions with HIV basic scientists and immunologists, I get the impression that most researchers are not too favorable on the prospect of a workable vaccine anytime in the near future. While I hate to be pessimistic and I think all options must be considered, I tend to agree. There are only two approaches to a preventative vaccine that I think are really worth merit and, unfortunately, most of the vaccine candidates are not looking at these options (more below). Currently, most vaccine candidates are relatively traditional, focusing on generating an immune response against viral proteins. HIV reverse transcriptase is so error prone, though, that I think the virus will be able to squeak out of any response targeted against the viral proteins. Everyone knows this and yet all of the vaccines I see still target the viral proteins. Other methods have looked at creating antibodies that target the CD4-gp120 complex—when conserved aspects of the viral spike are no longer shielded by sugars and are exposed. While I think that these antibodies might block infection, I wonder about the concentrations needed to provide protection. These epitopes are exposed for extremely brief periods of time, meaning that you need an antibody with a very fast on-rate at very high concentrations. It doesn’t seem reasonable to me. Then again, as I like to frequently point out, I am often wrong.

One of the roads that I do find promising that some are looking at is the composition of the virus at infection. When HIV infection is established, there are certain aspects of the virus that are conserved. Once infection is established, the virus quickly mutates and evolves to be better suited to the environment. Thus, the viral particles that establish infection are different from the majority of viral particles during infection. It may be that there are certain characteristics of HIV that are important for establishing infection that can be targeted by a vaccine. If we can tease out the aspects of the virus that are important for the initial establishment of infection, we could design vaccines against these features. It’s a tricky prospect, though, because you have to get viral samples very soon after initial infection. I know that at least a couple of groups are working on this, including Julie Overbaugh at the University of Washington.

The other road that I think is at least worth considering is looking at host factors on the virus. I have mentioned this a couple of times in the blog, but HIV is highly enriched in host proteins in the envelope including MHC molecules. Unlike viral proteins, host proteins won’t mutate and evade a vaccine. Plus, MHC molecules are some of the most immunogenic molecules out there. An allovaccine would be easy to create and might have activity against HIV and other retroviruses. There are, of course, serious considerations with this type of vaccine, though, not the least of which is its effect on fertility. It’s still worth looking at, although I fear that almost no one is considering this option.

 

M. Linde

Day 34: HIV infectivity in semen

In a rather unexpected paper, Frank Kirchoff’s group and others (about 20 authors or so) show that amyloid fibers in semen enhance the infectivity of HIV. According to the Cell paper, HIV piggybacks on the fibers. Now, the issue of HIV attachment to spermatozoa has always been a controversial one. You see data for and against, much of it terrible. There are a couple of papers out there that claim that HIV actually enters (and possible infects) spermatozoa. I’ve seen papers with electron micrographs of spermatozoa with enveloped cytoplasmic particles that the authors claim are virions. Never mind that this seems virtually impossible—I might buy it if the particles were in a vesicle or there was just a viral core, but I wish they would explain how the virus manages to pass the cell membrane and retain its envelope. There are also data with pull-downs of spermatozoa/virus that show by RT-PCR that no virus attaches to the spermatozoa. The only problem is that the process used to pull-down the spermatozoa in these papers is the same process used to “wash” HIV from sperm, so the authors never actually show that the pull-down process doesn’t shear or detach HIV from the spermatozoa surface. My own (unpublished) data indicate that HIV does attach to spermatozoa, in a ratio of approximately 12 virions per cell.

 

How attachment is mediated is also controversial. Some people claim that spermatozoa carry CD4 (which I do not believe); while others claim it is mediated by gp120 affinity for glycosphingolipids. I am not certain whether this is the whole story. Semen contains a lot of what are called “prostasomes”. Prostasomes are exosomes made by the prostate. If you look at the prostasome protein composition and compare it to HIV composition, they look very, very similar. Prostasome, electron micrographs look almost identical to immature HIV particles. It’s known that prostasomes are important for spermatozoa viability, although it is not entirely clear how. If I remember correctly, prostasomes attach to spermatozoa and some believe that they may dampen an immune response targeted against the sperm (sexual reproduction is an evolutionary war waged by the immune system, but that is another story). So, it stands to reason that HIV may use the same methods as prostasomes to attach to spermatozoa.

 

Why is this important? I believe the key to creating a viable preventative vaccine is by preventing the key steps that aid in the establishment of infection (not a shocking statement—kind of like saying the key to driving is starting the car). As my old advisor was fond of saying, once the puck gets past the goalie, the game is over (only true in overtime). Preventative vaccines right now focus on priming the adaptive immune response so it will occur before the viral replication gets out of control. I think a better response is to target conserved aspects of the virus that allow it to infect those first few cells. So, what happens to the billions spermatozoa that don’t fertilize an egg? I imagine some of them are taken up and cleared by macrophages (I am not sure, but it seems reasonable). Any virions attached to these sperm would love to be exposed to macrophages.

 

This brings us back to the Cell paper by Munch and colleagues. They show that prostatic acid phosphatase (PAP) fragments forms amyloid fibers capture HIV and present virus to target cells. They call these fibers SEVI, for semen-derived enhancer of viral infectivity. They suggest that the by piggybacking on the SEVI fibers, the virus is presented to target cells that are normally protected by the mucosal barrier. The fibers increased infectivity by at least 1000-fold. This is important, because it has been observed that sexual transmission of HIV is actually not that efficient—although it is obviously efficient enough to result in a massive epidemic. If you could target these fibers in some capacity (like a microbicide) and decrease the sexual transmissibility by 1000-fold, that would be a very good thing.

 

One aspect of the findings that the group does not discuss, which I would like to see, is the effect of these fibers on the immune cell activation. It is hypothesized that the adaptive immune system is primed by “danger signals”. Do these amyloid fibers activate immune cells? Do macrophage toll-like receptors recognize them? It could be that one of the reasons HIV attached to these fibers is more infectious is because these virions are presented to cells in that are in a state of initial activation, which would be the perfect target. This might also be true for dendritic cells, which may travel to the lymph nodes following interaction with SEVI fibers. If that is the case, than a small molecule which blocks this activation could also be a reasonable microbicide. That’s all conjecture, though.

 

M. Linde

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 8: What we have here is a failure to communicate

Apparently many people don’t think AIDS is fatal. How one could think this with the estimated 20 million people dead from the disease is beyond me. I can only conclude that education efforts are (as usual) failing.

 

The data come from a survey of over 4,500 respondents conducted by the MAC AIDS Fund in the US, UK, India, Russia, France, China, Mexico, Brazil, and South Africa. Reuters reported that close to 60% of respondents in India believe a cure is available and that about 42% overall did not understand that HIV is fatal. Almost half of all polled believe that most people living with HIV are being treated. While I don’t expect most people to know the scope of the disease or even specific about the treatment, I do expect that we at least have education initiatives explaining that AIDS is fatal.

 

This brings me to what I believe is the saddest aspect of the epidemic: AIDS is an entirely preventable disease. We know how to reasonably protect ourselves from acquiring HIV. However, obviously we are doing a terrible job at this, as evidenced by the estimated 40 million people infected with the virus. Why is this not a top priority? Education and prevention measures are loaded issues, as they deal with sex and drugs, but why can’t we put aside our moral judgments and try to curb the spread of HIV? It’s a complete tragedy, because the epidemic never had to reach this level and I am sure it is destined to get worse.

 

M. Linde