When it comes to lipodystrophy research, few clinicians have their hand in so many different studies—or are consistently consulted for expert advice and assistance—as Dr. Donald Kotler. Knowing that Dr. Kotler would be attending the 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, held in Dublin in November, Physicians’ Research Network asked him to check in with its membership at the November PRN meeting. What follows are highlights from the 7th International Workshop, with new data indicating that we are perhaps one step closer to better understanding what HIV-associated lipodystrophy really is (and what it’s not), factors that contribute to its development, and potential treatments to consider.
| I. Defining Lipodystrophy: Lumpers vs. Splitters | Top of page |
Lumpers include Dr. Andrew Carr and his colleagues, who published results from their lipodystrophy case definition (LDCD) study in The Lancet in 2003 (Carr, 2003). Now we have the splitters, most notably Dr. Carl Grunfeld and his colleagues, who recently published much anticipated data from the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study (Bacchetti, 2005).
| II. Identifying Risk Factors | Top of page |
| Thymidine Analogues and Lipoatrophy | Top of page |
In the original 2002 MITOX study published by Dr. Carr and his colleagues, some basic comparisons between patients with and without lipoatrophy were reported (Carr, 2002). Total fat measured 17.1 kg in a control group of patients, compared to 12.8 kg in the patients with subjective lipoatrophy. Trunk fat weighed in at 9.1 kg in both lipoatrophic patients and control patients. Limb fat, however, was found to be 7.3 kg in control patients and only 3.7 kg in the patients with lipoatrophy, a difference of 3.6 kg.
Two years later, long-term follow-up data from MITOX were reported (Martin, 2004). After 104 weeks, the median limb fat increase among patients who switched to abacavir (Ziagen) was only 1.3 kg, compared to a 0.24 kg increase among patients who remained on a stavudine- or lamivudine-containing regimen (see Figure 2). “The patients who switched got somewhat better—a 39% increase in their limb fat,” Dr. Kotler commented. “What we want to know is why these patients didn’t get completely better.”
Possible answers may come from two adipose tissue studies reported at the 7th International Workshop. In one study by Dr. Cecilia Shikuma and her colleagues at the John A. Burns School of Medicine in Honolulu, levels of proviral HIV-DNA in peripheral blood mononuclear cells (PBMCs) were significantly higher in patients with lipoatrophy (80 copies in 106 cells), compared with HIV-infected patients without lipoatrophy (22 copies in 106 cells) (Shikuma, 2005). While the jury is still out regarding the significance of this finding, it does suggest the PBMCs are a potential reservoir of HIV in patients with lipoatrophy. Of even greater interest was another finding of the study: increased numbers of macrophages in SAT from patients with lipoatrophy. Evaluating PBMCs in adipose tissue expressing CD68—a hallmark marker of macrophages—Dr. Shikuma’s group reported macrophage contents of 3.2% in HIV-negative study volunteers; 9.5% in HIV-positive, antiretroviral-naïve volunteers; 4.0% in non-lipoatrophic HIV-positive patients, and 9.4% in lipoatrophic HIV-positive patients. “It wasn’t just that there was less fat,” Dr. Kotler said; “there was also an inflammatory infiltrate in the adipose tissue from these patients.”
In an Australian study, conducted at Royal Perth Hospital, Dr. Emma Hammond and her colleagues investigated risk factors for lipoatrophy in 32 HIV-infected patients participating in a Western Australia cohort (Hammond, 2005). None of the patients had evidence of an effect of HIV disease on adipose tissue prior to initiating treatment. Histologic analysis of subcutaneous fat biopsies from patients on antiretroviral therapy revealed a distinct pathologic signature associated with lipoatrophy, including the loss of tissue architecture, adipocyte pleomorphism, mitochondrial toxicity, cell loss, increased macrophage infiltration, and elevated proinflammatory cytokines. “As they evaluated people over time, macrophage infiltration became more prominent,” Dr. Kotler said. “This infiltration clearly preceded lipoatrophy. This research team—and others—have shown that macrophages produce proinflammatory cytokines, which may be at least partly responsible for the adipocyte damage we see in lipoatrophy.”
The potential role of macrophages in lipoatrophy was hypothesized by Dr. Shikuma’s group. “Dr. Shikuma explained that it’s not just the nucleosides that are causing lipoatrophy, it’s also the macrophages,” Dr. Kotler summarized. “The nucleosides caused mitochondrial and cellular dysfunction in the adipose tissue, eventually causing cells to become sick and sometimes die. That death causes a recruitment of macrophages. These macrophages then become active. This activation gives rise to inflammation, resulting in further cellular dysfunction and death, which keeps going on and on and on.” In turn, Dr. Kotler argues, switching off of thymidine analogues may not be the end-all, be-all solution; dealing with macrophage infiltration may be another piece of the reversal puzzle.
| III. Treatment/Management Issues | Top of page |
| Uridine | Top of page |
The study presented at the 7th International Workshop set out to determine the effect of uridine on SAT during unchanged antiretroviral therapy containing either stavudine or zidovudine (Sutinen, 2005). The study also assessed the effects of uridine on insulin resistance, along with the safety of uridine in patients receiving antiretroviral therapy. Twenty patients were randomized to receive either NucleomaxX (36 g three-times-daily for 10 days/month) or placebo for three months.
At baseline, patients in the NucelomaxX group had 3.3 kg limb fat, compared to 3.1 kg limb fat in the placebo group. After three months, patients in the NucleomaxX group had 4.2 kg limb fat, compared to 3.3 kg in the placebo group (see Figure 3). This difference was statistically significant, as were differences between leg-fat increases, arm-fat increases, and truncal-fat increases.
In this study, the investigators saw patients entering with approximately 3 kg of leg fat and were able to increase their leg fat by 1 kg after three months,” Dr. Kotler explained. “However, we really want to see legs with 8 kg of fat, like the controls in the MITOX study, so a jump of 1 kg isn’t all that terrific. However, these really are impressive data, especially since the underlying antiretroviral regimen was continued and the study duration was only three months. It’s possible that they would have seen even more pronounced fat gains if they switched therapies and began uridine supplementation, continuing it for more than three months. Unfortunately, though, nothing else changed. Patients’ insulin levels didn’t come down, nor did their lactate levels or liver fat. Hopefully we’ll see more data involving this product soon.”
| Creatine Monohydrate | Top of page |
The study reported at the 7th International Workshop set out to evaluate changes in strength in response to creatine-aided resistance training, along with changes in body composition, mitochondrial energy metabolism, and safety measures. Twenty sedentary patients were randomized to creatine (20 g/day loading dose for five days, followed by 4.8 g/day maintenance therapy) and 20 sedentary patients were randomized to placebo. For the first two weeks, patients only received creatine or placebo, without resistance training. For weeks 3 through 24, resistance training was added.
After two weeks of supplementation alone, lean body mass increased by approximately .4 kg in the placebo group and .9 kg in the creatine group. This difference was not statistically significant. By week 14—12 weeks after the addition of resistance training—a significant difference in lean body mass gains was seen: approximately 1.4 kg gain over baseline in the placebo group, compared to an approximate 2.3 kg gain over baseline in the creatine group.
“While people in the creatine group definitely got bigger,” Dr. Kotler noted, “the study also demonstrated that muscle strength increased in all subjects following resistance training, without statistically significant differences between groups. There was a 44% increase in muscle strength in the creatine group, compared to a 42% increase in muscle strength in the placebo group. And the fact of the matter is that people in the creatine group actually got bigger before they even started exercise.”
| Niacin | Top of page |
Niacin, a B vitamin, has been shown to lower both cholesterol and triglycerides in HIV-negative study volunteers. It has been shown to reduce total cholesterol by approximately 20% to 30%, lower triglycerides by 35% to 55%, and increase HDL cholesterol by 20% to 35%. However, the side effects of niacin are noteworthy and include nausea, diarrhea, vasodilatory symptoms, insulin resistance, and increased liver enzymes. As a result, niacin has generally been avoided in HIV.
To get a clearer sense of the effectiveness and safety of niacin in HIV-infected patients, the AIDS Clinical Trials Group conducted a study (A5148) evaluating Niaspan (an extended release formulation of niacin) involving an open-label, dose escalation, single-arm protocol (Dubé, 2005). A5148 was a 48-week study and enrolled 33 patients. “Patients were started at 500 mg daily,” Dr. Kotler said. “They were then increased to 1,000 mg, 1,500 mg, or 2,000 mg, depending on their lipid response.”
At baseline, the median total cholesterol was 253 mg/dL. Also at baseline, the median HDL cholesterol was 34.5 mg/dL, the median non-HDL cholesterol was 217 mg/dL, and the median triglyceride level was 478 mg/dL. After 48 weeks of treatment, total cholesterol decreased by 8 mg/dL, HDL cholesterol increased by 5 mg/dL, non-HDL cholesterol decreased by 19 mg/dL, and triglycerides decreased by 153 mg/dL.
As for safety and tolerability, there were one grade 3 and two grade 2 increases in ALT/AST. There were three grade 2 and three grade 3 reports of flushing. “Increased insulin resistance was seen in this study,” Dr. Kotler added. “What we gain in terms of lowering lipids may actually worsen insulin resistance, meaning that we may be trading one toxicity for another. While HOMA-IR testing demonstrated that insulin resistance increased and stayed increased through to 48 weeks, an oral glucose tolerance test demonstrated insulin resistance decreased to near baseline levels after 48 weeks. So the jury is still out with niacin. Despite demonstrating evidence of benefit in dyslipidemia in HIV-infected individuals, these data kind of put us back where we started.”
| Treatment Switching and Facial Lipoatrophy | Top of page |
But what about facial lipoatrophy? To study the effects of switching on this very important parameter, the investigators conducted a substudy involving 47 patients who underwent three-dimensional laser assessment of the face (Benn, 2005). “It sounds really fancy,” Dr. Kotler wryly noted, “but companies are now using the exact same technology to fit people for suits and dresses. It’s a topography measure. Essentially, somebody sits in a chair and a laser is beamed at the face. They eyes are covered. The data is fed into a computer and a topographical image is rendered. This is done two different times and the images are then placed on top of one another, figuratively, to detect additions and subtractions in volume.”
The investigators noted little change in forehead fat 48 weeks after switching to abacavir or tenofovir. Combined cheek-fat gains—meaning fat increases in both the left and right cheeks—averaged 2,812 mm3 in the tenofovir group and 2,208 mm3 in the abacavir group. These differences were statistically significant compared to baseline, with no statistically significant difference between the two groups. “The cheeks actually increased by approximately a gram each,” he commented. “The total increase in cheek volume was somewhere around 2 ½ to 3 ccs. The investigators also compared the difference in the RAVE patients to a group of patients who received collagen injections. Essentially, they saw the same level of improvement. Finally, the study also showed a positive correlation between an increase in limb fat, measured by DEXA, and an increase in cheek fat, measured using the three-dimensional imaging. “They really change together,” Dr. Kotler said. “It’s not like you’re going to get your legs back and your face is not going to improve. Where there is improvement in one parameter, there should be an improvement in the other.”
| References | Top of page |
