Once potent combination therapy for HIV (commonly called ART or HAART) is initiated, several clinical trials have found that bone mineral density tends to decrease, usually between 2% and 6%, and then stabilize. The reasons for this initial decrease are not clear.
Some studies suggest that exposure to the anti-HIV drug tenofovir (Viread and in Truvada, Atripla, Complera and Stribild) may be linked to decreased bone mineral density (BMD) in some people. However, it is important to bear in mind that most HIV-positive people who use tenofovir in prospective clinical trials have not developed decreased BMD and subsequent fractures.
Researchers in several countries conducted a pilot study called Progress to compare the effect of the following two regimens:
When it was first introduced in 1996, the drug ritonavir (sold as Norvir) was meant to be used at very high doses as part of ART. However, at such high doses ritonavir has many side effects. Today when ritonavir (Norvir) is used, it is generally taken in relatively small doses to help boost the level of another drug, usually an HIV protease inhibitor. When used in this way ritonavir does not have anti-HIV activity, as it is merely a boosting agent. The other drug that is boosted has powerful anti-HIV activity.
In all cases in this study, Kaletra was taken twice daily, as was raltegravir. Truvada was taken once daily.
Researchers recruited 209 volunteers who had not been previously exposed to treatment and monitored them for up to two years.
On average, participants were about 40 years old and mostly male (85% men, 15% women).
Similar proportions of participants (71%) taking each regimen achieved a viral load less than 40 copies/ml at week 96, according to an assessment called the Food and Drug Administration's "snapshot" analysis.
Participants who experienced virologic failure were distributed as follows:
Participants had their CD4+ counts increase by 300 cells/ml by the end of the study.
In general, side effects reported by patients were similar with each regimen. According to researchers, the most common side effect of "at least moderate severity was diarrhea," distributed as follows:
They also stated that the following proportions of participants left the study prematurely due to side effects:
Overall, two participants taking each regimen (for a total of four participants) left prematurely because of diarrhea. Thus, about 2% of participants taking each regimen left prematurely because of diarrhea.
The proportions of participants taking each regimen who took anti-diarrhea medicines were distributed as follows:
Elevated levels of lipids (cholesterol and triglycerides) in the blood are common when protease inhibitors are used. Rates of severely elevated levels of total cholesterol were distributed as follows:
Rates of severely elevated triglycerides were distributed as follows:
Among participants for whom bone mineral density scans were available, researchers noted that bone thickness was generally similar at the start of the study. However, at the 96-week mark, on average, BMD had changed as follows:
This difference was statistically significant; that is, not likely due to chance alone.
There were four fractures during the study that were distributed as follows:
The study was not designed to assess the statistical importance of fractures so we cannot draw firm conclusions about their distribution and if that has any link to the regimens used in this pilot study. It is possible that the distribution of fractures may simply have been due to chance.
Researchers also assessed what they termed "clinically significant loss of bone mineral density." These were cases where participants lost BMD of 5% or more by the 96th week of the study. Overall, 12% (19 of 160 participants) had a large decrease in BMD during the study, distributed as follows:
Factors that were statistically linked to having decreased BMD included the following:
Although bone may feel stiff and hard, it is not dead. Bone tissue is dynamic -- in adults small portions of bone are always being torn down and replaced. Researchers refer to this tearing down and building up of bone as "bone turnover." There are proteins in the blood and urine that are associated with bone turnover and can be assessed in research studies. In Progress, researchers assessed the following markers of bone turnover at several points throughout the study:
Bone turnover markers were, on average, elevated in all participants, reaching their highest level at week 48 of the study.
Early changes in some bone turnover markers were connected to a significant loss of BMD (at least 5%) at week 96, specifically these changes at week 4:
Changes at week 4 in the following markers appeared to be protective from significant loss of bone density:
These findings in bone markers seem novel and deserve further study in clinical trials with other medicines.
The Progress study and its sub-analyses provide important signals about changes that bones undergo once ART is initiated. Such changes should be studied with other commonly used regimens. Findings from Progress suggest that replacing Truvada with raltegravir may lead to very modest increases in BMD rather than significant loss of bone.
Bear in mind the following points:
Overall, the findings from Progress and the Australian study are intriguing but require further larger randomized studies for confirmation.
Gilead Sciences, the manufacturer of tenofovir, is testing a new form of tenofovir called TAF. Interim results from clinical trials have led Gilead Sciences to suggest that TAF may be safer for the bones and kidneys than tenofovir.
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