Mathematical Model Measures Hidden HIV. More meds needed?

[Tadeys]

May 8, 2013 — Scientists have long believed that measuring the amount of HIV in a person's blood is an indicator of whether the virus is actively reproducing.

A University of Delaware-led research team reports new evidence that hidden virus replication may be occurring within the body's tissue, despite undetectable virus levels in the blood.
The findings were reported in the Journal of the Royal Society Interface on May 8.
The discovery came after the paper's lead author, Ryan Zurakowski, assistant professor of electrical and computer engineering, and his research team created a mathematical model to represent how HIV infected cells reproduce.
Antiviral therapy, Zurakowski explained, suppresses HIV replication in most patients until the concentration of virus in a blood sample is undetectable. It is unclear whether similar suppression occurs in other tissues, known as sanctuary sites, including lymph nodes where most HIV is found.
"The majority in the HIV community have always believed that the drugs are penetrating sanctuary sites perfectly well and that the blood is a good surrogate measurement of these sites," he said. "Our model gives us a way to measure this hidden virus replication, which has not been done before."
The research team used the model to analyze data from a clinical study in which researchers added a new drug, an integrase (enzyme) inhibitor, to the cocktail HIV patients were already taking. Patients tested were on a steady three-drug protocol for at least two years before adding the fourth drug, and never exhibited any measurable virus in their bloodstream.
According to Zurakowski, the inhibitor prevented the HIV DNA from integrating into a cell's chromosomes and caused the HIV DNA to bind its two ends together making a small DNA circle called a 2-LTR. The team's mathematical model revealed that 2-LTR circles can be measured in the blood and demonstrate virus replication in other tissues. It also showed that several patients with undetectable virus levels in their blood nevertheless had significant uncontrolled HIV replication in other tissues
"The genius of looking for 2-LTR circles is that infected cells can't survive the trip from the sanctuary site to the blood, and neither can the HIV, but the 2-LTR circles live as long as the cells that they are resident in, which is about 10-20 days," he said.
He continued on to say that the only thing stopping the virus from infecting more cells was that it was running out of healthy cells to attack. The team calculated that the virus infected and killed between 1 million and 100 million cells daily, numbers Zurakowski said are high enough that eventually it would lead the patient to develop a drug resistant HIV virus and to experience treatment failure.
Zurakowski said that for 30 percent of the patients in the study, adding integrase inhibitor caused 2-LTR measurements only explainable if the patient had uncontrolled virus replication in sanctuary sites in the body.
For HIV patients and the scientific community, the discovery implies that current antiretroviral therapies may not be as complete in suppressing HIV as previously hoped. Because the fourth drug causes additional 2-LTR's to be created, the model may also offer a new way to measure, through a blood test, whether HIV is reproducing in sanctuary sites in the body.
Zurakowski's team is collaborating with researchers at the IrsiCaixa Institute in Barcelona, Spain, and at the University of California, San Francisco, to design a new study to confirm these findings, and to quantify the HIV turnover rates in the sanctuary sites. The team will also look at whether the model can suggest new treatment approaches that could be more effective.
http://www.sciencedaily.com/releases/2013/05/130508093056.htm

[Tadeys]

The article published in Journal of The Royal Society: http://rsif.royalsocietypublishing.org/content/10/84/20130186.full

[Tadeys]

From the scientific article:

"The activation of reservoir cells, which does not involve a new round of reverse transcription, does not result in the production of new viral mutants and cannot by itself drive the evolution of antiviral resistance." This might not be news to some on here; it is to me.

The following--if validated with more investigation--, perhaps could be important for erradication:

"4.1. Clinical significance
The level of efficient replication indicated by the patterns of measured 2-LTR in circulating PBMCs following treatment intensification by raltegravir is quite high. Replication rates of 1 × 10^7 cells day−1 are high enough to make it probable that important resistance mutations are generated, and the fact that the replication is occurring in a site that allows for efficient replication makes it possible for the mutated cells to persist long enough to acquire additional mutations. This would provide a mechanism for sequentially acquiring the multi-drug resistance necessary to escape therapy, and would explain the experimental results showing evidence of such a lineage of acquired mutations in episomal DNA recovered from patients who experience treatment failure [17].

It is also interesting that this level of replication is occurring in patients who have measured plasma viral loads persistently below the detection threshold. This implies that this replication is cryptic, unobservable from standard viral load assays. The existence of cryptic, efficient replication of HIV in patients with plasma viremia persistently below the limit of detection is a troubling result.

The data seem to indicate that the addition of raltegravir reduces the level of cryptic replication to undetectable levels. There are a number of possible explanations for this. The addition of raltegravir could cause the residual activity of the antiviral drugs to cross a threshold of efficacy, bringing the basic reproductive ratio of the virus in the site of 2-LTR formation below 1. In this case, the effect is not unique to raltegravir, but is instead merely a result of using four antiviral drugs simultaneously. It is also possible that the properties of raltegravir allow it to penetrate the site of 2-LTR formation better than the other antiviral drugs. The experiment does not provide sufficient data to distinguish between these hypotheses."

[vaboi]

This makes me wonder if I should ask the doc to add Isentress as a 4th drug to my current regimen.  I wonder if he'd allow it.  Who cares if it's twice a day.  If I forget to take it every now and then, it's not like it's going to effect much, except perhaps my 2-LTR circle count for that day.  =)

[phillypinko]

Other then AZT in the early 90's I have never had to switch drugs due to resistance. My doctor said that just as there are different strains of the flu there are different strains of HIV. Some mutate easily and some never mutate. The ability of the virus to mutate depends on the strain and the hosts immune response.

[Miss Philicia]

I've had to be on an extra 4th HIV med in my regimens for about a decade, due to longstanding resistance issues that I developed back in the 1990's. However I think when dolutegravir gets FDA approved soon my doctor will switch me to that and also take away one other drug so I won't be on 4 meds any longer. I'll believe that when it happens.

The "action date" for FDA approval of that drug is now set for 17 August according to a Glaxo newsletter from the end of April to shareholders, so only three months to go!

[Matts]

Yes I would wait for DLG, it seems to be much better than RAL and is once daily.
I asked the question some days ago, so far nobody wanted to answer it.

Do they mean in the CROI abstract that DLG also works against latent macrophages and lymphozytes, or only acute infected cells? I dont understand it properly 

http://www.retroconference.org/2012b/Abstracts/44329.htm

[Tadeys]

Conclusions:  DTG efficiently reduces HIV-1 replication in both MDM and lymphocytes, with the potential to be effective in different cellular targets of HIV infection. RAL-resistant viruses show reduced replication capacity in both MDM and lymphocytes, underlining the importance and the peculiar role of also MDM as reservoirs of either wild type or resistant strains in human organs.

"with the potential to be effective in different cellular targets of HIV infection"

Potential is all we get.
 Cheers