Study examines role of AZT and d4T in metabolic changes

An observational cohort study of factors that contribute to changes in body composition in HIV-infected individuals on antiretroviral therapy (ART) has found that use of AZT (zidovudine, Retrovir) but not d4T (stavudine, Zerit) is associated with ongoing limb and trunk fat loss. In addition, use of highly active antiretroviral therapy (HAART) and AZT was associated with ongoing bone loss. The study, published in the December 1^st issue of Clinical Infectious Diseases, also found that baseline viral load, CD4 cell count, and changes in CD4 cell count predicted alterations in trunk and limb fat, as well as in lean mass.

Despite many published studies examining body shape (limb and trunk fat and lean mass changes) and bone mineral content changes in people on ART (dual or triple therapy without a protease inhibitor [PI] or non-nucleoside reverse transcriptase inhibitor [NNRTI]) or HAART (highly active antiretroviral therapy containing a PI or NNRTI), it remains unclear whether these changes continue to evolve with continuous ART or HAART use. In order to investigate ongoing changes in individuals receiving stable ART or HAART, investigators from Tufts and Harvard Universities longitudinally analysed a medication-stable cohort of men and women for independent predictors of regional body composition alterations by DEXA.

Participants in the Nutrition for Healthy Living study were included in the analysis if they had a minimum of two DEXA scans between eleven and 24 months apart as well as complete medication information. This resulted in 110 men and 42 women providing data for 194 DEXA scan intervals during the periods June 1997 to June 2001.

In those individuals on HAART at baseline, the median time of continuous HAART use prior to the initial assessment visit was 15.3 months (interquartile range, 7.0-26.7 months), and the median time between DEXA scans was 12.9 months (interquartile range, 12.1-17.6 months). The women in the study were less likely to use HAART (76.2% vs. 90.9%; p= 0.02) and had been receiving HAART for a shorter duration (median duration, 6.8 vs. 15.2 months; p =0.02) than the men. In addition, at baseline, the women had nearly double the fat mass, two-thirds the lean mass (defined as mass that was not fat or bone), and less bone mineral content than the men (p

The cohort as a whole experienced an average annual loss of 3.6% of fat in the arms and legs (p=0.011), with greater changes seen in the men. Although DEXA cannot distinguish between upper and lower trunk fat, nor between visceral and subcutaneous fat, increases in trunk fat mass were found not to be significant (p=0.66). Trunk lean mass increased 0.9% per year (p=0.002), whereas limb lean mass did not change. Whilst small decreases in limb bone mineral content were not found to be statistically significant in the cohort as a whole, compared to the men the women were found to have a statistically significant annual loss of trunk bone mineral content (p =0.004).

Although baseline CD4 cell count was not associated with changes in lean mass or bone mineral content, in both genders trunk fat increased by 2.3% a year with every 100 CD4 cells/mm³ rise (p=0.006). In addition, baseline CD4 cell count predicted a 1.8% increase per year in limb fat mass per 100 CD4 cells/mm³ in men only (p =0.005).

Higher viral load at baseline predicted a subsequent loss of limb fat mass (mean decrease per year, -3.4% per log₁₀ copies/mL; p =0.02) and trunk fat mass (mean decrease per year, -5.0% per log₁₀ copies/mL; p =0.03).

No association was found between changes in viral load whilst on therapy and body composition, but for every 100 CD4 cells/mm³ rise from baseline there was an increase in limb lean mass (mean increase per year, 0.59% per 100 cells/mm³; p =0.03).

HAART use was associated with a mean annual 1.6% loss of limb bone mineral content in both genders (p =0.04) and a mean 2.5% annual lean mass increase in women (p=0.02) but with no other body composition changes.

AZT use was associated with an annual decrease in limb fat mass (mean decrease per year, -4.9%; p=0.049) and trunk fat mass (mean decrease per year, -10.8%; p=0.02). AZT use was also associated with an annual decrease in trunk bone mineral content (mean decrease per year, -2.6%; p = .005).

Although use of ddc (zalcitabine, Hivid, due to be discontinued next year) was associated with a decrease in trunk fat mass, d4T use was not. However, d4T use was associated with an increase in trunk bone mineral content (mean increase per year, 2.0%; p=0.01). In addition, 3TC (lamivudine, Epivir) use was associated with increased trunk lean mass (mean increase per year, 3.0; p=0.04).

According to the investigators, "this analysis confirms an average annual loss of extremity fat in the cohort." Whilst an individual's disease status prior to starting ART was associated with body composition changes, "HAART use or its duration did not contribute to change... These findings agree with the current literature that suggests lipoatrophy is the unique physical manifestation of HIV infection, and they support the findings from our group and others that disease status is involved."

Although their findings suggest that AZT and not d4T is associated with fat loss, they say "it remains impossible to separate the individual effects of antiretroviral therapy agents, because they are used in combination."

Regarding bone health, they comment that their "analysis supports the involvement of antiretroviral therapy, as well as known risk factors, reinforcing the need for additional longitudinal studies that account for diet, cigarette smoking, and medications concurrently."

They point out that although this observational cohort does not provide as robust data as would a randomised control trial, "our data do assist in understanding the real-world situation for many patients who experience ongoing body changes over time while receiving treatment. Though our numbers were small for some analyses, statistical differences were apparent."

They conclude: "These findings suggest the importance of peak viral load and nadir CD4 cell count on the subsequent loss of fat, a concurrence in the improvements in CD4 cell count and lean mass, and the primary influences of medications and traditional risk factors in bone demineralisation. Many details about HIV-associated body composition alterations remain unanswered, but this work confirms the growing body of evidence that such changes are multifactorial."