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 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 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

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