Day 143: Why is the FDA investigating these drugs?

Apparently, the FDA is investigating Bristol-Myers Squibb and GlaxoSmithKline for the drugs didanosine and abacavir, respectively. Data from The DAD Study Group published in the Lancet suggests that these drugs are associated with a higher risk of myocardial infarction. One can only assume that the FDA is under increased scrutiny for these types of events considering the recent history of Vioxx. 

While the findings of the DAD group were unexpected, I think an FDA investigation is utterly ridiculous. As I am sure you are well aware, HIV is a fatal disease when untreated. These drugs are truly life saving. I am not saying they don’t have some serious side effects, but increasing an already very low rate of MI among high risk patients should not be a primary barrier to prescribing these drugs. Conducting this investigation will only serve to scare patients away from these antiretrovirals (and maybe other antiretrovirals), which would not be a good thing. 

Now, having said that, I can’t help but find myself wondering whether the abacavir hypersensitivity reactions, slight increase in MIs, and recent troubles in ACTG 5202 (among which was an increase in general adverse events) have something in common. Could there be some inflammatory effect with abacavir? I don’t know and I probably shouldn’t even write this, as there’s no data to back it up. It would be interesting if there was a common etiology, though.

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 72: The first new NNRTI in a decade

The FDA approved Tibotec’s Etravirine (TMC 125) on Friday—the first new non-nucleoside reverse transcriptase inhibitor approved in almost 10 years. Just thought you might be interested. Apparently, it will cost about $8,000 a year.

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 60: HAART and cardiovascular events

For a number of years now there has been some concern over the potential for increased risk of cardiovascular events among patients on HAART. Bozzette and colleagues weigh in on the debate with a very large study from the VA system. They compiled relative risk rates from over 41,000 patients between January 1993 and December 2003, comprising over 168,000 person-years of follow up. The date range is such that it covers pre-HAART, early-HAART, and modern-HAART.

The article, published in JAIDS, shows that, not surprisingly, the risk of death declined between 1995 and 2003. If they hadn’t seen that, you would have to ask some serious questions. Of note, risk of serious cardiovascular event was about the same for any death, dropping over time as mortality did. Inpatient stays for myocardial infarction did not increase significantly over the study and there was no significant increase in risk of cardiovascular event for patients on HAART at 2, 4, or 6 years of HAART use.

The authors note that their cohort is mostly older men who are not as advanced in disease progression. However, the large scale nature of the study is reassuring that these adverse events should not affect HAART use on a population level. Certainly, individual patients may have other cardiovascular factors that play into treatment choice.

M. Linde

Day 55: Maintaning resistance

One of the fascinating aspects of HIV (and really all virology and microbiology) is the relationship between viral evolution and the selective pressures on the virus. HIV, like living creatures, adapts to its environment. If conditions are very harsh or not harsh at all, the viral population tends to be very uniform. In a very harsh environment, only viral particles with a very specific make-up may be able to spread; in the absence of these pressures, the viral particles that can replicate the fastest end up dominating the population. Somewhere in the middle, the viral population becomes diverse, with a number of different quasispecies or genetic variants. This is a key concept for antiviral therapy. Antiviral therapy needs to be stringent enough to place extremely harsh conditions on the virus. That’s why anti-HIV therapy needs to include three active drugs. 

Now, if the selective pressure on the virus during antiviral therapy lessens, which can happen for several reasons (not the least of which is non-adherence to a regimen), the virus can replicate and a viral variant will emerge that can replicate in the less harsh environment. In common terms, this is called resistance development. For useful drugs, there are usually only a few viral variants that can survive in these conditions. These viral variants may have to sacrifice certain advantages they would normally have to replicate under a moderate selective pressure. Often, they don’t replicate as well as normal virus (called wild-type) does in the absence of selective pressure. So, you get a scenario where it is believed that a resistant virus replicates alright when the drug is around, but not quite as well as a wild-type virus does in the absence of drug. 

This may have clinical importance. If the rate a viral variant replicates (called the replicative capacity) is slower, does that mean that a person carrying this variant as the predominant quasispecies will have a slower disease progression? Well, several studies have suggested that this is the case, but unfortunately it is difficult to determine how fast a viral variant replicates in the body. Outside of the body, yes, you can determine this rate, but no one knows if what happens outside the body is true in the body. Now, if the answer to the above question is “yes”, it would argue that for certain antiretrovirals, the development of resistance should not necessarily mean that drug is no longer a useful component of ant-HIV therapy. The idea is to maintain selective pressure on the virus and keep the predominant variant a person carries less fit than the wild-type virus, hopefully delaying disease progression. 

Recently in the Journal of Medical Virology, Gianotti and colleagues looked at the replicative capacity of HIV from people on lamivudine (3TC) monotherapy who have 3TC-associated resistance mutations (the methionine-to-valine switch at position 184 in reverse transcriptase, noted as M184V). Now, since you can’t measure the replicative capacity in the body, the authors looked at ex vivo samples from patients with the M184V mutation, comparing variants at 24 and 48 weeks from patients on 3TC monotherapy to patients who had stopped all therapy. What the authors found was that virus from patients who maintained their resistance mutations had reduced replicative capacity compared with those who “lost” these mutations (note: you don’t really lose these mutations, they just become a minority population while another variant takes over the majority role). Furthermore, those patients who lost the mutations had greater reductions in their CD4/CD8 T cell ratio. 

The study is important because it helps tie the reduced fitness hypothesis to what is observed in the clinic. This strategy of maintaining drugs to keep the viral replicative capacity down may help extend the options for patients who have been through several treatment options or those who have difficulty with adherence (provided they already have the M184V mutation). Of course drug companies also love this stuff because it suggests that some patients should stay on their meds, even after the development of resistance. There are necessary questions to answer; such as, is it really worth staying on these drugs for the reduced replicative capacity? Antiviral therapy is not without side effects and cost. However, now that there has been at least a preliminary link between reduced viral fitness and an immunologic parameter, the answer appears to be headed in the affirmative. Whether this holds for drugs other than 3TC remains to be determined. 

M. Linde

Day 40: New DHHS guidelines

The new Department of Health and Human Services adult HIV treatment guidelines were updated earlier this month. There were a number of changes, none of which were particularly shocking. Of note, though, the entire section on when to start therapy has been re-written. This section seems to change every so often; this time it has shifted back towards starting therapy at higher CD4 counts. It is by no means the “hit hard, hit early” scenario when HAART was first introduced, but it is the most significant shift in a while. The DHHS recommends that patients initiate therapy at CD4 levels <350. The evidence has been building up to this in the past few years, so this probably reflects what is already happening in the clinics.

The DHHS also recommends initiating therapy for pregnant women regardless of CD4, for patients with HIV-associated nephropathy, and for those starting anti-hepatitis B virus therapy. Out of the three, the HBV recommendation is the most controversial, as patients may start HBV therapy with high CD4 counts. The DHHS panel makes the recommendation based on the anti-HIV activity of entecavir, noting that use of the agent without combination anti-HIV therapy may result in the emergence of M184V reverse transcriptase mutations.

A few lab tests were also recommended. The DHHS panel recommends HLA-typing for patients who may receive abacavir. It is fairly clear that patients who carry the HLA-B*5701 allele are at risk for ABC-associated hypersensitivity reactions, while those who do not carry the allele are not. The guidelines also recommend the tropism assay for those patients starting maraviroc—which you would expect for a CCR5 inhibitor. There’s no point in taking a drug if it is not going to have activity against the predominant tropism. As an aside, I still think maraviroc should be reformulated as a microbicide. Finally, the DHHS recommends that all patients entering care receive viral genotyping, as it may be easier to detect resistance during initial infection, prior to the outgrowth of wild-type virus.

Other than that, the guidelines take on the two new medications (maraviroc and raltegravir). The guidelines are always worth a read, but I think we have all seen these changes coming down the line.

M. Linde

Day 5: What happened with the Merck vaccine?

While the prospect of a therapeutic vaccine might be looking up, there still isn’t much good news on the prospect for a preventative vaccine. Merck announced last week that their new vaccine candidate may have actually increased subjects’ risk for HIV infection. How they didn’t see this until the large scale clinical trial is amazing, but I am guessing that they were as surprised by this as everyone else was.

 

But should they have been so surprised? We know that HIV infects activated CD4 cells. Some in the field have wondered whether providing a source of activated T cells by traditional vaccination would actually increase the risk of infection. So maybe that’s the answer to the question. Add to this that it has been shown that HIV preferentially infects HIV-specific CD4 cells and you can see a pattern where an immediate immune reaction might give HIV a greater chance of establishing infection. It’s hard to prove that this is what happened, but I certainly think it is a possibility.

 

The other possibility of that the vector had some synergistic effect with HIV. The vaccine was a modified adenovirus, designed to express parts of HIV. There are several examples of two viruses working synergistically. There’s even some evidence that mutants from the same virus can work together to increase pathogenesis (Vignuzzi Nature 2006—really interesting article). Maybe a viral vector isn’t the proper vehicle for the vaccine. I suppose we can’t say until Merck sorts out what happened. Either way, in spite of the vaccine failure, we are going to learn something about immunology and HIV. So I guess the trial wasn’t a total loss.

 

M. Linde

Day 3: The first good therapeutic vaccine idea in a long time

There was an interesting paper that came out of Doug Nixon’s lab at UCSF. The paper, reported in PLoS Pathogens (open access), looks at the relationship between HIV and human endogenous retroviruses (HERVs). HERVs are retroviruses that are already in your genome. Presumably, they entered into the human genome in ancient times and now are stably integrated. They are held in check by host proteins that presumably evolved in response to these retroviruses.

 

As HIV is a retrovirus, some of these proteins can also hold HIV in check. It would be nice if they did (I would happily be out of a job), but HIV has found a way to negate the action of these proteins. Further, some HIV proteins that help HIV replicate also help HERVs replicate. So HIV also activates the dormant HERVs in the cells it infects. Lots of work in this field has been done by Brad Jones (who is second author on the paper), a grad student at University of Toronto who seems poised to be a real player in HIV research. Let’s hope he stays in the field.

 

Now, when the immune system is presented with cells producing proteins that are abnormal, it generates a response. This usually results in suppression of whatever it is that causes the abnormal proteins. HIV, however, mutates rapidly and can escape from the immune system. HERVs are encoded in the genome, though, so they don’t mutate like HIV. Therefore, the immune system can generate a response against HERVs and kill the cells that express them. As these would also be HIV infected cells, this would likely be a good thing.

 

First, Garrison and colleagues show that HIV-positive subjects have significantly greater HERV expression than HIV-negative subjects. They also found that the HIV-positive subjects generated an immune response to HERV-specific sequences, while the HIV-negative subjects did not. These responses looked normal for what one would expect in a controlled response against an infection. One of the patients who showed good response against HERV sequences was also able to control HIV infection without the use of antiviral therapy and, overall, patients who showed good response to HERV sequences also had lower amounts of virus in the blood. It’s easy to visualize how HERV responses might also help control HIV spread in the body.

 

So, the authors suggest that maybe by vaccinating infected patients against HERV sequences could help HIV-positive patients control their infection without anti-HIV therapy. It would be cheap and easy—more than I can say for most therapeutic vaccine ideas out there. Seems like a good idea, don’t it? I hope it pans out.

 

M. Linde