CATIE News - The Assert study-a look at drug safety
2010 June 17 - Two common nuke components of HIV treatment regimens in high-income countries are as follows:
- Kivexa - a fixed-dose once-daily formulation of two anti-HIV drugs (abacavir and 3TC) sold under the brand name Kivexa in Canada and the European Union and as Epzicom in the United States
- Truvada - a fixed-dose once-daily combination of two anti-HIV drugs (tenofovir and FTC) sold under the brand name Truvada in high-income countries
Before tenofovir (Viread) was tested in people, results of some animal experiments suggested that kidney toxicity and thinning bones were potential side effects. Clinical trials that
enrolled relatively healthy HIV-positive people were used to generate data for regulatory approval of tenofovir. In these trials there were either rare or no reports of severe kidney toxicity.
Since tenofovir's approval, there have been increasing reports of individuals with severe kidney toxicity associated with its use. Recently, large data-sets in Western Europe and Australia
have reported that severe kidney damage can occur in a relatively small proportion (3%) of tenofovir users. In some cases, the kidneys of affected people may take longer than a year to recover.
The use of abacavir (Ziagen) is linked to a hypersensitivity reaction that occurs in 5% to 8% of users. This hypersensitivity reaction can be fatal if the drug is not discontinued. In
Canada and most high-income countries, a simple blood test is available that can help reveal if a person is at high risk for an abacavir-related hypersensitivity reaction.
A large data-set called DAD, which has recruited patients mostly from the European Union, has reported that about 2% of abacavir users can develop a heart attack. Another data-set, the
French Hospital Database, has linked these heart attacks among abacavir users largely to the injection of illicit drugs such as cocaine and heroin. And another large data-set, the Veterans Affairs
Database in the U.S., has found that kidney disease, which increases the risk for a heart attack, may explain many of the heart attacks seen in abacavir users, at least in the VA's data-set.
These conflicting results have caused confusion among doctors and their patients and there is no international consensus about how to reconcile them. For now, most treatment guidelines
in high-income countries suggest that abacavir be used cautiously in people at high risk for cardiovascular disease.
Researchers in Western Europe are conducting a randomized study called Assert. This clinical trial is primarily designed to assess the safety of either a Kivexa- or Truvada-based regimen.
Results after one year using routine assays suggest that both regimens are generally safe. However, using an emerging biomarker of kidney toxicity, researchers have found that the tubules
(the kidneys' complex network of tubes and pipes) of Truvada users sustained more damage compared to users of Kivexa. Furthermore, exposure to Truvada was linked to thinner bones.
On the other hand, Truvada-based regimens had stronger anti-HIV activity than ones based on Kivexa. Similar rates of serious cardiovascular problems occurred with Kivexa- and Truvada-based regimens.
In 2007, researchers randomly assigned 385 participants to receive one of the following regimens:
- Kivexa and efavirenz (Sustiva) - 192 people
- Truvada and efavirenz - 193 people
Participants were adults who had no or minimal prior exposure to anti-HIV agents. Their average profile at the start of the study was as follows:
- 19% females, 81% males
- age - 37 years
- CD4+ count - 240 cells
- viral load - 115,000 copies/ml
- family history of premature cardiovascular disease - 11%
- current smokers - 37%
- hepatitis C co-infection - 9%
- normal kidney function - 68%
Conventional assessments of kidney function-based on the waste product creatinine-to calculate eGFR (estimated glomerular function) showed that both regimens improved the kidney health of
participants. However, when the researchers used an emerging biomarker called beta 2 -microglobulin, there were clear differences between the two study regimens.
Before reporting these results we first provide some background information about beta 2 -microglobulin. This substance is an emerging biomarker of kidney damage.
It is produced throughout the body and filtered by the kidneys. Under normal conditions it is completely reabsorbed by the kidney and broken down in the kidney tubules so
that only 0.3% of filtered beta 2 -microglobulin is found in the urine.
When the kidney tubules are damaged, the concentration of beta 2 -microglobulin in the urine reaches several hundred times above normal levels. In experiments with
several hundred rats, researchers have found assessments of beta 2 -microglobulin to be significantly superior to creatinine for help in diagnosing kidney damage.
In these animal experiments, urinary beta 2 -microglobulin appeared to detect subtle kidney damage when creatinine could not. Specifically, elevations in beta 2 -microglobulin concentrations in the urine suggested that:
- the parts of the kidneys that filter blood (the glomeruli) are damaged
- the parts of the kidneys that recover proteins and other essential substances after filtration of the blood are damaged
Beta 2 -microglobulin in Assert
In people who received Kivexa, the concentration of urinary beta 2 -microglobulin fell throughout the study, reaching a low of 53% of pre-study levels.
In contrast, the concentration of beta 2 -microglobulin in the urine of people who received Truvada rose to 124% of pre-study levels and remained elevated throughout the study. This difference was statistically significant.
After one year, there was a greater decline in bone density among Truvada users than Kivexa users, as follows:
- Kivexa - 1.9% decline in bone density
- Truvada - 3.6% decline in bone density
- Kivexa - 1.6% decline in bone density
- Truvada - 2.4% decline in bone density
These differences between the two regimens were statistically significant.
Another way to assess the effects of the study medications is to compare changes in osteopenia, a condition in which bone thinning has occurred but not as severely as in its more extreme form, osteoporosis.
First we present changes in osteopenia at the hip:
Hip osteopenia at the start of the study
- Kivexa - 25% of participants entered the study with osteopenia
- Truvada - 27% of participants entered the study with osteopenia
Hip osteopenia - week 24
- Kivexa - 25% had osteopenia
- Truvda - 32% had osteopenia
Hip osteopenia - week 48
- Kivexa - 27% had osteopenia
- Truvda - 34% had osteopenia
Now we present changes in osteopenia of the spine:
Spine osteopenia at the start of the study
- Kivexa - 26%
- Truvada - 31%
Spine osteopenia - week 24
- Kivexa - 27%
- Truvada - 39%
Spine osteopenia - week 48
- Kivexa - 30%
- Truvada - 38%
Researchers assessed biomarkers of bone formation and resorption (or reduction) with the following:
- bone-specific alkaline phosphatase
- procollagen type 1 amino terminal propeptide (P1NP)
- C-terminal teleopeptide of type 1 collagen (CTx)
In general, the researchers found that the higher the level of bone biomarkers in the blood, the greater the loss of bone mineral density. Levels of these biomarkers were generally higher in participants who received Truvada.
Results-General side effects
In total, 87% of participants reported at least one side effect during the study, with the following being the most common:
- symptoms of a flu-like illness
General side effects were well distributed between the two study regimens.
As mentioned earlier, some studies have found an association between the use of abacavir and an elevated risk of a heart attack. However, the distribution of cardiac adverse events (heart attack, severe narrowing of coronary
arteries, etc.) in the first year of Assert was as follows:
- Kivexa - 5 of 192 people
- Truvada - 4 of 193 people
This difference between Kivexa and Truvada was not statistically significant.
Although lipid levels increased more in Kivexa users, the average ratio of total cholesterol to HDL-c (good cholesterol) fell in both Kivexa and Truvada users. This is a favourable trend and suggests a reduced risk of cardiovascular disease.
No statistically significant increases were detected in blood concentrations of the following markers of inflammation:
- high-sensitivity C-reactive protein (hsCRP)
- interleukin-6 (IL-6)
Researchers also assessed changes in the concentration of the protein adiponectin. This protein is released by fat cells and may play several roles in the body, perhaps enhancing the effects of the hormone insulin.
A separate review of 13 studies with nearly 15,000 HIV-negative participants arrived at this conclusion about adiponectin: "Higher adiponectin levels are associated with a lower risk of type 2 diabetes".
In Assert, researchers found that after one year adiponectin levels in the blood rose by the following, compared to pre-study values:
- Kivexa - 30%
- Truvada - 20%
This difference between the two regimens was statistically significant.
The proportion of participants with a viral load less than 50 copies/ml after one year was as follows:
- Kivexa - 59%
- Truvada - 71%
This difference was statistically significant.
When results of Assert were analysed only in participants whose pre-study viral loads were less than 100,000 copies/ml, the proportion of people who achieved a viral load less than 50 copies/ml was as follows:
- Kivexa - 64%
- Truvada - 75%
This difference at lower viral loads has not been previously reported in larger studies and is surprising.
Assert researchers found that there were more early withdrawals of participants taking Kivexa from the study. Indeed, the rate of withdrawals from Assert was unusually high. Furthermore, the researchers
noted that these withdrawals occurred "before virologic suppression [was achieved]." Many of these withdrawals were due to what the researchers termed "administrative reasons," which they defined in the following way:
- the inability to remain in contact with participants
- violations of the study protocol
- participants deciding to leave
It is possible that many withdrawals in Assert were related to the emerging news (at the time) of abacavir being associated with an increased risk for heart attack in database studies. This would have
been possible because while Assert was a randomized clinical trial, it was not double-blind-both researchers and participants knew who received which regimen.
Because the drop-out rate in Assert approached nearly 30%, this may have weakened the study's statistical ability to discern differences between Kivexa and Truvada.
Putting it in context
The findings from Assert are one piece of a larger puzzle-understanding the safety of drugs after they have been approved by regulatory authorities. Assert raises many
questions, some of which can only be answered in future studies. Examples of such questions include the following:
- What is the rate of bone loss in untreated HIV infection?
- Why was bone loss more pronounced in Truvada users?
- Did efavirenz have a role to play in bone loss seen in Assert?
- Does efavirenz intensify tenofovir's apparent impact on bone health?
Although not investigated in Assert, emerging research suggests that exposure to efavirenz may interfere with the body's production of vitamin D 3 , the active form of this vitamin. Because vitamin
D 3 plays a role in maintaining the health of bones (and other organ systems), it is possible that exposure to efavirenz may have reduced D 3 levels and enhanced the loss of bone density in Assert.
Researchers are planning further studies to explore these and other safety issues raised by Assert's interim results.
-Sean R. Hosein
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CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.
From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE