February 28, 2007
The sudden interest in the metabolic complications of HIV and its therapies is remarkable considering how not long ago this topic was the forgotten stepchild at the Conference on Retroviruses and Opportunistic Infections (CROI); symposia on metabolic issues at past CROIs were often relegated to small meeting rooms and too often scheduled opposite more popular sessions. It was enough to give metabolic-minded investigators a complex! But at this year's CROI, metabolic issues were front and center. A dedicated session on the first day of the conference was packed, as was the agenda. Some of the most exciting CROI presentations were those that focused on metabolic issues, including evaluations of changes in body fat and lipids during HIV therapy as well as therapeutic approaches to the treatment of dyslipidemia and osteopenia/osteoporosis.
What we learned is that metabolic complications are complicated. Just when we thought we were getting a handle on what causes those love handles and fat-free limbs, well-designed studies come along to burst our ill-informed bubbles. Below are the details of the major metabolic-related studies presented at this meeting and my attempts to reckon with what these results mean.
The most important clinical study examining the metabolic complications of HIV therapy is AIDS Clinical Trials Group (ACTG) study A5142.1 This was a large (n = 753), three-arm trial of initial HIV therapy in which patients were given one of the following regimens:
The clinician and patient chose the NRTIs in the first two study arms. Importantly, during the initial phase of the study, the only NRTI provided to participants by the study was extended-release stavudine (d4T, Zerit). Later, tenofovir (TDF, Viread) was also made available by the study at no cost to patients. As a result, 42% of participants took zidovudine (AZT, Retrovir), 34% tenofovir and 24% stavudine. There were no major differences in the proportion of participants on a particular NRTI across the study arms.
The study provided unique opportunities to rigorously examine the effect of the disparate study regimens on metabolic parameters. Previously, despite their popularity, no study had compared the metabolic impact of efavirenz and lopinavir/ritonavir. Likewise, the relative effects of different NRTIs on body fat have remarkably not been compared in large studies. The nuke-sparing arm also provided a chance to investigate whether this approach prevented the development of lipoatrophy. Fortunately, the study team and the ACTG sponsor recognized the potential to gain important insights into the relationship between specific HIV therapies and metabolic outcomes and incorporated evaluations such as fasting lipid levels and DEXA (dual energy X-ray absorptiometry) scans into the protocol.
The first data to emerge from this trial were presented at the XVI International AIDS Conference (AIDS 2006) in Toronto, Canada, last summer.2 At that time the relative parity of efavirenz and lopinavir/ritonavir as far as high-grade hypertriglyceridemia and elevated low-density lipoprotein (LDL) cholesterol -- not to mention the interesting virologic and immunologic results of the study -- suggested that long-held assumptions about these agents were about to crumble. At CROI 2007, those expecting the unexpected from an expanded report on body shape and lipids during A5142 were not disappointed.
At a session on metabolic complications that was held the first day of the meeting, the results were presented and the shocker was the finding that more patients who were receiving a regimen of two NRTIs + efavirenz experienced lipoatrophy than patients in the other study groups. After 96 weeks of therapy, limb fat had increased from baseline a median of 18% in the lopinavir/ritonavir + efavirenz group compared to a 9.8% median gain in the lopinavir/ritonavir + two NRTI group (P = .013). The efavirenz + two NRTI group experienced a median increase in limb fat at 48 weeks of over 8%, but by 96 weeks this was largely lost and the overall change from baseline was reduced to only 1.4% -- a result that was significantly less than that seen in the lopinavir/ritonavir + two NRTI group (P = .007).
When looking at the definition of extremity lipoatrophy chosen a priori by the study team (more than 20% loss of overall limb fat), a substantial proportion of patients who had been assigned to efavirenz + two NRTIs developed lipoatrophy; at 96 weeks, 32% of the participants in this group had lipoatrophy detected by DEXA versus 17% in the lopinavir/ritonavir + two NRTI group and only 9% in the nuke-sparing group. The difference in the incidence of lipoatrophy was statistically significant between the lopinavir/ritonavir + two NRTI arm and the efavirenz + two NRTI arm (P = .003), but was not significantly different between the nuke-sparing arm and the lopinavir/ritonavir + two NRTI arm.
Given the mix of NRTIs, it is essential that any analysis include the potential influence of these agents on the changes in limb fat observed. As expected, lipoatrophy was more common in those exposed to stavudine; however, fat wasting of the limb was even more likely when participants were also taking efavirenz compared to participants assigned to lopinavir/ritonavir + two NRTIs.
Among those combining efavirenz and stavudine, lipoatrophy was documented in 51%, compared to 33% among those combining lopinavir/ritonavir and stavudine. Approximately 40% of those pairing efavirenz with zidovudine experienced peripheral lipoatrophy, compared to 16% of those combining lopinavir/ritonavir and zidovudine. As a whole, patients in the lopinavir/ritonavir + NRTI and efavirenz + NRTI groups who used tenofovir were not statistically more likely to develop lipoatrophy. However, in the comparison between the two groups, lipoatrophy was seen in 12% of patients taking efavirenz plus tenofovir versus 6% of patients taking lopinavir/ritonavir plus tenofovir. In a logistic regression model, taking efavirenz along with the NRTIs increased the odds of developing study-defined limb lipoatrophy by 2.7 fold (95% CI: 1.5-4.6).
|Table 1. Percentage With Limb Lipoatrophy at 96 Weeks by Treatment Assignment|
The study also supports an effect of zidovudine on fat wasting that falls between that of stavudine and tenofovir. Zidovudine treatment increased the odds of developing lipoatrophy by 1.9 fold (95% CI: 1.1-3.5). Tenofovir assignment reduced the odds of lipoatrophy compared to that of zidovudine.
Before moving on to the lipid data, let's look at the data on fat and their implications. Prior to the presentation of these results, the interpretation of the available in vitro and in vivo data was that certain NRTIs drive fat wasting. In several studies, the substitution of stavudine with abacavir (ABC, Ziagen) or tenofovir has led to increases in peripheral fat -- all but confirming a role for this NRTI in fat loss.3,4 The data have been a bit more mixed with zidovudine.
Zidovudine has been implicated in limb fat loss by Gilead 934, an ongoing study of zidovudine/lamivudine (AZT/3TC, Combivir) + efavirenz versus tenofovir/emtricitabine (TDF/FTC, Truvada) + efavirenz. In that study, DEXA scans detected losses of limb fat on the zidovudine/lamivudine + efavirenz regimen compared to gains in peripheral fat with the tenofovir/emtricitabine + efavirenz combination.5
In contrast, A5005s, a metabolic sub-study of an ACTG treatment trial (study 384) that had much fewer participants than A5142, observed no evidence of limb fat loss by DEXA at 144 weeks among study participants receiving zidovudine/lamivudine + efavirenz, but did see a drop from baseline limb fat among those taking zidovudine/lamivudine + nelfinavir (NFV, Viracept).6 However, A5142 has much greater power to detect meaningful differences in fat changes than either the Gilead 934 or A5005s studies and, as such, should be considered definitive in regards to the effect of zidovudine/lamivudine + efavirenz on fat wasting.
In summary, the study A5142 finds that:
No data on trunk fat were presented and only the foolish or extremely lucky would hazard a guess as to what these will show.
The lipid data were also fascinating. As suggested in Toronto,2the differences between efavirenz and lopinavir/ritonavir when either was combined with NRTIs were fairly minimal. The median change in non-high-density lipoprotein (HDL) cholesterol (total cholesterol minus HDL cholesterol) was 26 mg/dL in the patients taking lopinavir/ritonavir + two NRTIs versus 22 mg/dL in the group taking efavirenz + two NRTIs (P < .005).
HDL cholesterol increases were almost the same at 8 mg/dL and 9 mg/dL, respectively. These are incredible data given the perception that non-nucleoside reverse transcriptase inhibitors (NNRTIs) are great HDL cholesterol boosters. We now know that ritonavir (RTV, Norvir)-boosted PIs also raise HDL cholesterol and in the case of lopinavir/ritonavir, at least, to the same extent as efavirenz. The median change in triglyceride levels was modestly, but statistically significantly, higher at 96 weeks with lopinavir/ritonavir than efavirenz in the NRTI-receiving study arms, 46 mg/dL versus 19 mg/dL, respectively (P = .006).
The nuke-sparing regimen led to greater changes in lipids than the other two study arms, raising triglycerides by a median of 62 mg/dL and non-HDL cholesterol by 44 mg/dL, but HDL cholesterol by an impressive 16 mg/dL -- all were significantly higher than in the other study groups.
The Bottom Line
These results need to be added to the scale on which we balance efavirenz and lopinavir/ritonavir. Some of the findings will tip us one way and the others will lean us to the opposite side. The size and rigor of this study mean these results cannot be easily dismissed -- although it will be important to see on-treatment analyses of body shape and lipids. As opposed to the intent-to-treat approach presented, the on-treatment analysis will help us better understand the associations between these drugs and the changes observed.
Meanwhile, for patients extremely fearful of fat wasting, avoidance of zidovudine/lamivudine + efavirenz may make sense. It is more difficult to advocate for avoidance of efavirenz when combined with tenofovir given that 88% of patients on such a regimen did not develop major fat loss (compared to 60% on zidovudine/lamivudine + efavirenz).
Further, it must be remembered that the efavirenz + two NRTI group had better virologic results than the lopinavir/ritonavir + two NRTI arm during this study. Foregoing NRTIs altogether is currently impractical and, in this study, led to concerning increases in atherogenic lipoproteins.
In addition to influencing treatment initiation, this data may lead to interest among patients who have experienced peripheral fat loss on an efavirenz-containing regimen to switch from this NNRTI. It is not without some irony that we would now be tempted to change from an NNRTI to a PI to ameliorate a body shape change! It is premature to suggest this as a strategy, but HIV physicians are not typically inclined to wait the few years it takes for the definitive study to come along.
The lipid data are reassuring and prove once again the beauty of the head-to-head comparative trial.
The results raise many questions and have many an expert scratching their heads. The pieces of the puzzle may not all fit together yet, but the findings of A5142 are not completely incongruent with the overall understanding of fat depot change during HIV therapy. We have evolved from blaming antiretroviral therapy classes to pointing the finger at specific agents. We now see in this study, as well as A5005s, that particular combinations can exacerbate or attenuate the fat effects we ascribed to individual drugs.
It is traditional to end a study summary by indicating that further research is needed. However, in this case such a recommendation is not hollow. The ACTG is in the midst of recruiting for another large clinical trial comparing ritonavir-boosted atazanavir (ATV, Reyataz) versus efavirenz when each is combined with either abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa) or tenofovir/emtricitabine (i.e., there are four study arms). This study, A5202, also collects DEXA and lipid data. Consider yourself warned.
While A5142 attracted almost as much attention as Beyoncé in her one-shouldered Armani Privé gown at the Academy Awards ceremonies in another part of Los Angeles, there was another interesting study comparing the metabolic effects of lopinavir/ritonavir and efavirenz at CROI 2007 that helps us wrap our brains around the A5142 results: M03-613.
M03-613 was one of a slew of lopinavir/ritonavir monotherapy studies that were presented at the AIDS 2006 meeting in Toronto last summer;7 the data on changes in fat were presented at CROI 2007 by W. Cameron et al. In this study, 155 treatment-naive patients were randomized 1:2 to either start zidovudine/lamivudine + efavirenz or begin an induction-maintenance strategy in which lopinavir/ritonavir + zidovudine/lamivudine would be taken until three consecutive viral load levels of less than 50 copies/mL were achieved, at which point the NRTIs would be discontinued.8 DEXA scans were performed every 24 weeks during the 96 weeks of study follow-up.
As in A5142, the efavirenz + two NRTI group experienced an early median increase in limb fat -- peaking at week 24. Then at week 48 these gains were largely lost. By week 96, this group had a median 9% loss in limb fat compared to baseline. These data alone are extremely helpful in understanding the effects of zidovudine/lamivudine + efavirenz and complement the data from A5142 nicely.
In contrast to the peripheral lipoatrophy seen with efavirenz, the lopinavir/ritonavir arm experienced a sustained gain in limb fat during the 96 weeks -- again, similar to the changes seen in the lopinavir/ritonavir + two NRTI group in A5142. Here, though, the NRTIs were cast off before week 48, which could have contributed to the further increases in median limb fat seen in this study arm from weeks 72 to 96. Thus, jettisoning the NRTIs led to further gains in peripheral fat while on this boosted PI.
As opposed to A5142, trunk fat data were presented. Again, the results were reaffirming, demonstrating the increase in abdominal fat that has been seen in every study of body shape in initial potent antiretroviral therapy. Increases in trunk fat were seen in both study arms and were not different.
Cleverly, the investigators looked at the correlation between limb and trunk fat changes, as well as the predictors of lipoatrophy and lipohypertrophy. The combination of limb fat loss and truncal fat gain was rare. Only 16% of the trial participants experienced this combination of changes -- all were receiving efavirenz.
This was illustrated gorgeously in one of the researcher's slides, which, as far as the correlation between changes in fat depots, looks remarkably similar to data generated from A5005s.9
A low CD4+ cell count at baseline was found to be associated with fat gain in both the limb and trunk regions.
The Bottom Line
These data should not be overshadowed by the results of A5142. The body fat data on efavirenz + zidovudine/lamivudine alone is of great interest and adds considerable heft to the argument that this combination causes peripheral fat loss over time. Certainly, the overall favorable body fat changes seen in the lopinavir/ritonavir group may be a consequence of an absence of an effect of this boosted PI on peripheral fat or the result of ditching the zidovudine/lamivudine. Probably it is both. The data on the correlation between changes in fat depots can be considered the gravy on top.
Anyone looking for answers to explain A5142 should look at this study. It does not explain everything, but it certainly does provide some help.
The body shape data from the M03-613 study described above demonstrated again what almost every HIV treatment trial that has bothered to evaluate fat changes has discovered: Regardless of regimen, truncal fat increases following the initiation of antiretroviral therapy. Much of this gain in fat is not completely undesirable and often represents a return to improved health and better appetite subsequent to control of HIV infection. For some patients, however, the increase in fat is too much of a good thing -- especially when it seems to be disproportionately centered deep in the abdomen. That some degree of abdominal fat gain is an expected consequence of antiretroviral therapy is now clear. Much more murky is what to do about it.
There are limited data regarding a beneficial effect of switching HIV treatment regimens to reduce visceral adipose tissue and this makes sense given both NNRTI- and PI-based regimens have been demonstrated to produce increases in abdominal fat.
The most consistently effective approach to truncal fat accumulation has been to use recombinant human growth hormone (rhGH). Reduced growth hormone secretion has been associated with fat redistribution.
In a study presented by Carl Grunfeld et al at AIDS 2006, rhGH was found to reduce visceral adipose tissue (VAT) mass following 12 weeks of induction therapy with 4 mg administered daily subcutaneously.10 However, 40% of the patients receiving rhGH had regained at least 50% of the VAT lost during maintenance therapy at a dose of 2 mg every other day. In addition, side effects including peripheral edema, myalgia, arthralgia and elevated blood glucose were fairly common during induction.
At CROI 2007 Steven Grinspoon presented the results of a large clinical trial of TH9507, a synthetic growth hormone releasing factor (GHRF) that is designed to elicit the release of growth hormone from the pituitary in a pulsatile manner, mimicking the physiologic secretion of the hormone and avoiding the high levels achieved with direct injection of rhGH.11
In the study, individuals with HIV and an increased waist circumference (> 95 cm for men and > 94 cm for women) and an elevated waist-to-hip ratio (> 0.94 for men and > 0.88 for women) while receiving antiretroviral therapy were assigned to inject 2 mg of TH9507 daily (n = 275) or to take a matching placebo (n = 137).
Change in VAT volume at six months, as assessed by computed tomography (CT) scan, was compared and there was a mean 15% decrease in VAT among patients who were taking the active drug versus a mean 5% increase in VAT among patients who were assigned to placebo (P < .001). The mean VAT mass lost with TH9507 was 1 kg in contrast to a 0.4 kg gain in the control group.
A concern with rhGH is that as a lipolytic agent, subcutaneous fat is also lost with therapy. In this study of TH9507, subcutaneous abdominal fat increased slightly in both study groups, tending to be a tad higher in the placebo study arm (P = .05).
Interestingly, lipid parameters improved with TH9507. Total cholesterol and triglycerides fell, while HDL cholesterol increased with active drug. In contrast, in the control group, triglycerides increased and HDL cholesterol decreased. There was no change seen in either glucose or insulin parameters.
There were more treatment-limiting adverse events in those taking TH9507; 12% on active drug compared to 3% in the placebo arm (P < .01). Myalgia and rash, in particular, were more common with TH9507. The rash, seen in 2% of treated participants, appears to be a hypersensitivity reaction that Dr. Grinspoon stated was not completely unfamiliar to endocrinologists prescribing injectable hormones.
The Bottom Line
This is an exciting compound that is undergoing continued study as a potential treatment of HIV-associated visceral fat accumulation, as well as conditions beyond HIV. This study will continue and will involve a cross-over design so that longer-term data will be available. If TH9507 is ultimately found to be efficacious, one can only hope that it will be more accessible and affordable than its predecessor rhGH.
Deciphering the forces that influence cardiovascular risk during HIV infection is complicated. Findings from two important studies offer a hint of the complexity involved. The D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study finds that the risk of myocardial infarction (MI) rises with each year of exposure to highly active antiretroviral therapy (HAART).12 The SMART (Strategies for Management of Anti-Retroviral Therapy) study discovers higher rates of cardiac events among HIV-infected patients who stop their antiretroviral therapy.13 Before launching into an attempt to make the results of these two impressive studies jive, it is worth looking at a few related presentations at CROI 2007.
Researchers from the SMART study provided details regarding the cardiovascular events that were recorded during the trial.14 SMART was a landmark clinical trial in which participants were randomized to:
The main results of the trial, stopped early due to excessive morbidity and mortality among those discontinuing HIV therapy, have recently been published.13 Interestingly, cardiovascular events were discovered to be more common among patients who had interrupted their antiretroviral treatment compared to those who were taking continuous treatment.
At baseline, the 5,472 SMART study participants had run-of-the-mill lipid levels for an HIV-infected cohort. Total cholesterol was 191 mg/dL, LDL cholesterol was 111 mg/dL, HDL cholesterol was 41 mg/dL and triglycerides were 164 mg/dL. Lipid-lowering drugs were used by 16% of the trial participants at study entry. Almost three quarters of the cohort were male and an astounding 40% were smokers.
As previously reported, there were 48 cardiovascular disease (CVD) events among patients interrupting HIV therapy compared to 31 among those who stayed on their meds. (The definition of cardiovascular disease events included clinical myocardial infarction, silent myocardial infarction, coronary artery disease [CAD] requiring an invasive procedure or death from cardiovascular disease.) The difference in cardiovascular disease rates between the study arms was marginal with a relative hazard of 1.57 (95% CI: 1.00, 2.46) -- a result that was just statistically significant with a P value of 0.05.
However, when the definition of cardiovascular disease was expanded to include peripheral vascular disease, congestive heart failure and coronary artery disease requiring drugs, the confidence intervals narrowed and the difference between the study groups favoring the continuous treatment arm became even more significant with a P value of 0.03.
Adding in unobserved death from an unknown cause increased significance even further (P = .009). Therefore, cardiovascular disease was more common among those interrupting HIV therapy and the differences between this group and the continuous therapy group only strengthened when cardiovascular disease was defined more broadly.
Interestingly, the investigators could find little to explain the excess cardiovascular disease events among patients discontinuing antiretroviral therapy. Neither HIV viral load nor CD4+ cell count -- whether on or off antiretroviral therapy -- during follow-up and cumulative years on antiretroviral therapy were associated with cardiovascular disease risk.
However, in general, lipid parameters among the participants stopping HIV therapy were not as favorable as those in the continuous treatment group -- largely a consequence of a drop in HDL cholesterol during treatment interruption. This may help to explain the slightly higher incidence of cardiovascular disease seen early in this study arm.
The association of HIV infection with cardiovascular disease (SMART) and with HIV therapy (D:A:D) has led many to consider HIV itself as a cardiovascular disease risk factor, to be included alongside traditional risks such as diabetes, smoking, strong family history of heart disease and hypertension.
Whether HIV-infected patients experience more cardiovascular disease than HIV-uninfected individuals has been difficult to determine since prospective studies such as D:A:D do not include a control group of HIV-uninfected persons.
However, in another CROI 2007 presentation, rates of coronary heart disease were found to be higher in HIV-infected men compared to HIV-uninfected men. Daniel Klein et al conducted a retrospective analysis of data from 1996 to 2006 from the Kaiser Permanente group in Northern California.15 They compared rates of coronary heart disease -- as determined by ICD-9 (International Classification of Diseases, 9th revision) coding -- among about 5,000 male HIV-infected members without known coronary heart disease and 43,000 age-matched uninfected controls. They found that rates of coronary heart disease were higher among HIV-infected men compared to HIV-uninfected men (6.1 versus 2.9, P < .0001). Among the HIV-infected men, PI treatment was associated with a higher coronary heart disease rate compared to those not on a PI (7.1 versus 4.5, P = .02). Further, the duration of PI therapy was associated with risk of myocardial infarction.
Looking at hospitalizations for myocardial infarction in a larger group of members followed over time, HIV-infected patients had higher rates of myocardial infarction-related admissions dating back to 1996-1997. However, the rate of hospitalization for myocardial infarction among the HIV-infected patients trended down from 1997 through 2000 and has since stabilized -- possibly due to less use of antiretroviral therapies linked to severe dyslipidemia and increases in the use of lipid-lowering therapy among HIV-infected patients.
Unfortunately, this study has limited ability to control for the traditional risk factors for coronary heart disease and myocardial infarction, such as smoking and family history of coronary heart disease, that may be unevenly distributed among HIV-infected and HIV-uninfected patients and confound the results.
The Bottom Line
So, how do we make sense of these data? Both D:A:D and the Kaiser study clearly indicate that exposure to HAART can increase the risk of cardiovascular disease. In both studies the relative risk of cardiovascular disease was higher with therapy; however, the absolute risk -- that is the number of events that occurred -- was pretty low, at least so far.
Yet, results from the SMART study informs us that not being on effective HIV therapy can also contribute to cardiovascular disease risk, perhaps by way of inducing inflammatory states during uncontrolled HIV. This suggests that the consequences of a treatment interruption may trump the risks of continuous HIV therapy.
Reassuringly, rates of myocardial infarction or cardiovascular disease are not increasing in D:A:D or the Kaiser study. Data from both studies and the HIV Outpatient Study (HOPS)16 actually find that rates of cardiovascular disease seem to be stable if not declining -- this is possibly due to better clinical lipid management.
If all this is confusing to you, imagine how our patients must feel. It is important that we help patients understand that, although HIV therapy can slightly raise the risk for cardiovascular disease, the consequence for not taking antiretroviral therapy is even worse.
The hallmarks of HIV-associated dyslipidemia are low HDL cholesterol and hypertriglyceridemia. However, some HIV-infected patients do have undesirable LDL cholesterol levels and the reduction of LDL cholesterol is central to cardiovascular disease risk reduction. As such, statins are the most popular family of lipid-lowering medicines prescribed to HIV-infected persons. Yet, statins can have clinically significant drug-drug interactions with antiretrovirals and may lead to treatment-limited adverse effects.
Ezetimibe (Vytorin, Zetia) is a novel agent that selectively blocks the absorption of cholesterol in the duodenum by approximately 50%. Further, the drug is not metabolized via the cytochrome P450 system used by many antiretrovirals. Compared to statins, ezetimibe is less potent in lowering LDL cholesterol and, therefore, is typically used in conjunction with these drugs.
The safety and efficacy of ezetimibe in HIV-infected patients has not been well studied. Two small studies of the drug in HIV-infected individuals with elevated LDL cholesterol have been published: One examined ezetimibe added to a statin in 19 patients and the other looked at ezetimibe alone versus fluvastatin (Lescol) in 20 patients.17,18 Both studies found a reduction in LDL cholesterol levels of 15% to 20%.
To better understand the effects and tolerability of ezetimibe in HIV-infected individuals, our group (which included this author) at the University of North Carolina, along with colleagues at the University of California, San Francisco, conducted a double-blind, cross-over study of ezetimibe in 48 HIV-infected patients who had an LDL cholesterol level of greater than 75 mg/dL and who were not receiving another lipid-lowering agent.19 Patients were randomized to six weeks of ezetimibe or placebo followed by a two-week washout period and another six weeks of the alternative assignment study medication.
After six weeks of treatment, there was a mean 12% reduction in LDL cholesterol among the patients while they were taking the ezetimibe compared to a 3% rise when they were receiving placebo. There was no change in HDL cholesterol or triglyceride levels with ezetimibe therapy and the drug was well tolerated.
The Bottom Line
Ezetimibe is an LDL-cholesterol-reducing agent that is free of many of the limitations of existing statins. The drug does not have pharmacological interactions with antiretrovirals and does not cause rhabdomyolysis. This study demonstrates that ezetimibe has moderate activity and, in addition to its use along side a statin, is a reasonable monotherapy option for patients who will not or cannot take a statin.
Alendronate Is Safe and Effective for Osteopenia in HIV-Infected Patients
Reduced bone mineral density (BMD) is common among HIV-infected patients. In one meta-analysis by Todd Brown et al, 67% of over 880 HIV-infected patients were found to have osteopenia and 15% osteoporosis -- rates that are several fold that of HIV-uninfected individuals.20
The cause of low bone mineral density among HIV-infected men and women is not entirely clear, but it appears to be largely a consequence of the same factors that promote bone loss in the HIV-uninfected and includes smoking, low body weight, sedentary life style and hypogonadism -- factors common among HIV-infected patients. Further, there may be HIV- and antiretroviral-related influences contributing to bone loss, although these remain poorly characterized.
Bisphosphonates are a mainstay of the treatment of osteoporosis; however, studies of the management of low bone mineral density in the setting of HIV infection have been limited to small trials. Two studies of the bisphosphonate alendronate (Fosamax) have been published and demonstrated improvements in bone mineral density during therapy.21,22
At CROI 2007, a larger trial of alendronate for low bone mineral density in HIV-infected patients was presented by Grace McComsey et al.23 ACTG study 5163 was a prospective, randomized, placebo-controlled multicenter trial attempting to evaluate the safety and effectiveness of calcium and vitamin D supplementation with or without once-weekly alendronate (70 mg) in improving bone mineral density in HIV-infected individuals.
A total of 82 patients on stable antiretroviral therapy with a DEXA-derived lumbar spine t-score worse than -1.5 were enrolled and randomized. At baseline, the median lumbar t-score was -2.15 in the alendronate arm and -1.95 in the calcium/vitamin D alone arm. Osteoporosis (t-score less than -2.5) was observed in 24% of the alendronate-assigned patients and 18% of the controls.
Seventy percent of each arm was male and, by design, a targeted number of women were enrolled. Importantly, there were a number of major exclusion criteria, including vitamin D deficiency (a 25-OH vitamin D level less than 15 ng/mL is rightly considered to be low, despite being within the stated normal range reported by many commercial laboratories), hyperthyroidism and untreated hypogonadism. Each are underlying conditions that when treated can improve bone mineral density.
Over 48 weeks, there were increases in lumbar spine (the primary outcome measure), total hip and trochanter bone mineral density. However, the median change from baseline was consistently greater in the alendronate arm. There was no difference between the arms at the femoral neck.
In terms of adverse effects, although alendronate is known to cause esophageal irritation, in this study there were no reports of this occurring. In fact, there were more moderate to severe clinical adverse events during the trial in the placebo arm than the alendronate arm. Laboratory abnormalities between the groups were indistinguishable.
The Bottom Line
This study should be the final word on the tolerability and efficacy of alendronate plus calcium/vitamin D in HIV-infected patients with reduced bone mineral density. The study's positive results raise three major issues. First, exactly who should be screened for reduced bone mineral density has not been clear. For A5163, participating sites were instructed to consider the following questions when considering obtaining a screening DEXA bone scan.
The more "yes" answers, the greater the likelihood that reduced bone mineral density would be present. These questions can be used clinically to identify patients for bone density screening. In addition, the guidelines for osteoporosis screening developed for the HIV-uninfected patient should also be followed.
The second issue is: At what level of reduced bone mineral density is pharmacological intervention warranted? There is little argument that patients with osteoporosis are candidates for treatment. Fuzzier is the use of alendronate at less severe t-scores (i.e., in cases of osteopenia). This study suggests that, at a minimum, patients with osteopenia (t-score -1.0 to -2.5) should take adequate doses of calcium and vitamin D twice daily as this intervention alone led to significant gains in bone mineral density.
For patients with worse scores within this range and/or multiple risk factors for osteoporosis, the addition of alendronate seems reasonable. (A note about calcium supplementation: Calcium carbonate is an antacid and it remains unclear if the effects of this formulation of calcium can interfere with atazanavir absorption. It still is unclear whether taking calcium carbonate and atazanavir apart from one another helps avoid this interaction. An alternative would be to use calcium citrate, which is not an antacid. However, using calcium citrate would require a higher dose to achieve the same level of elemental calcium and, therefore, require that a patient take more pills.)
Lastly, a legitimate question is whether improving bone mineral density will reduce fracture risk. Data from the HIV-uninfected has correlated bone mineral density to the risk of atraumatic bone fractures. There is no reason to think that among HIV-infected people this is not also the case -- especially as those living with HIV infection enjoy the prospects of decades of AIDS-free survival.
Reduced Bone Mineral Density Is More Common Among HIV-Infected Individuals
As mentioned above,20 there is considerable data indicating that patients with HIV infection have less dense bones than HIV-uninfected persons. In an analysis by Turner Overton et al of DEXA data from the SUN (Seguimiento Universidad de Navarra) Cohort, a prospective observational study of HIV-infected patients cared for at clinics in Denver, St. Louis, Providence and Minneapolis, the bone health of cohort participants were compared to those in the National Health and Nutrition Examination Survey III (NHANES III), a large sample of the general U.S. population.24 The HIV-infected SUN Cohort patients were matched according to age, sex, race, and BMI with NHANES III controls to identify the prevalence and predictors of osteopenia and osteoporosis among the HIV-infected participants.
The HIV-infected population included 22% women, was 60% white and 28% black and 75% of the participants were receiving antiretroviral therapy. Mean age was 41 years. Low bone mineral density was very common among the HIV-infected patients, with 51.7% meeting DEXA criteria for osteopenia and 9.8% for osteoporosis. Only 29.1% of the controls had osteopenia and 1.0% osteoporosis. Overall, the HIV-infected group had a significantly lower femoral neck t-score (-0.77) compared to the controls (-0.36) (P < .001).
Factors associated with low bone mineral density included male gender, a BMI less than 22.6 kg/m2, age greater than 46 years and being unemployed. Exercise was found to be protective. For osteoporosis, low BMI, older age, longer duration since HIV diagnosis and a CD4+ cell count less than 308 cells/mm3 was predictive.
Another study presented at CROI 2007, this one by Sara Dolan et al included only women and compared bone mineral density in HIV-infected (n = 152) and HIV-uninfected controls (n = 100) and examined the effects of androgen levels, weight, body composition and menstrual dysfunction on bone density.25 HIV-infected women had lower bone mineral density at the lumbar spine, total hip and femoral neck. Even HIV-infected women in the same weight range as the HIV-uninfected women had lower bone mineral density in these areas compared to the controls. Risk factors for reduced bone mineral density in the women with HIV infection included low free testosterone, low weight and oligomenorrhea.
Another analysis of total body bone mineral content data collected during A5005s also found that low testosterone levels were associated with reduce bone mineral density.26 Further, bone mineralization declined subsequent to treatment initiation regardless of treatment assignment (efavirenz or nelfinavir, zidovudine + lamivudine [3TC, Epivir] or didanosine [ddI, Videx] + stavudine). There was a median decline in total body bone density by 2.25% (IQR: 0.35% to 4.75%) by 96 weeks after the start of HIV therapy. It appeared that demineralization did not progress after week 96.
The Bottom Line
The results of these analyses help us better understand which patients should be screened for low bone mineral density and validate the list of screening questions above. The A5005s data further demonstrate that bone demineralization can be seen in patients receiving disparate HIV regimens and, as in most studies, seems to stabilize over time.