Low baseline CD4 cell count associated with greater bone loss after starting HIV therapy

A low baseline CD4 cell count is associated with loss of bone mineral density (BMD) during the early years of HIV therapy, US investigators report in the online edition of Clinical Infectious Diseases. Results of three studies conducted between 1998 and 2007 were included in their analysis. DEXA-scan monitoring showed that immune suppression before starting HIV therapy was a risk factor for loss of BMD during treatment.

“We found a strong and independent association between low baseline CD4+ count and total BMD loss in the first two years of treatment,” write the authors. “We did not find any evidence that the extent of immune reconstitution…was associated with BMD change after controlling for baseline CD4+ count.” The investigators believe their findings underline the importance of early HIV treatment.

HIV infection is associated with loss of bone mineral density and an increased risk of fractures. Loss of bone continues after HIV therapy is started, and decreases in BMD of between 2 and 6% typically occur in the first two years of antiretroviral therapy.

The reasons for this are not clear. To gain a better understanding of the causes, investigators examined BMD in approximately 800 people who underwent whole body DEXA scanning before starting HIV therapy and again after 96 weeks.

The participants in the study had a median age of 39 years and 83% were male. Baseline BMI was 25 kg/m². Median baseline CD4 cell count and viral load were 208 cells/mm³ and 63,000 copies/ml, respectively. Almost two-thirds of participants (62%) started HIV therapy with a regimen based on a protease inhibitor and 27% received tenofovir (Viread, also in Truvada and Atripla). These drugs have been associated with reduced BMD in other research.

The mean loss of total BMD at week 96 was 2%. Baseline CD4 cell count was strongly associated with BMD loss. Participants with a pre-therapy CD4 cell count of below 50 cells/mm³ lost 3% more BMD than people with a baseline CD4 cell count above 500 cells/mm³ (p < 0.001) and approximately 2% more BMD than people with CD4 counts between 350 and 499 cells/mm³.

A greater relative, but not absolute, CD4 cell count 16 weeks after starting therapy was initially shown to increase BMD loss (-2.3% per tenfold increase, p < 0.001). However, this association disappeared after controlling for baseline CD4 cell count.

After taking into account confounding factors, a low baseline CD4 cell count remained strongly associated with BMD loss at week 96. Individuals with a pre-therapy count below 50 cells/mm³ lost 2.27% more BMD at this follow-up point compared to people with a baseline CD4 count above 500 cells/mm³ (p < 0.001).

“We found that even after controlling for multiple confounders such as BMI that there was a robust relationship between low baseline CD4+ count and greater bone loss after ART [antiretroviral therapy] initiation,” comment the authors. “The underlying reason for the relationship between low baseline CD4+ count and bone loss with ART initiation is not known but suggests a potential role for the immune system in skeletal maintenance.”

Older age (each additional year, p < 0.001), female sex (p = 0.007), low BMI (p < 0.001) and a high HIV viral load (p = 0.002) were also associated with greater bone loss.

Participants whose initial regimen included tenofovir lost on average 1.38% more BMD at week 96 (p < 0.001) compared to people taking an alternative drug. Individuals taking a protease inhibitor lost approximately 1% more BMD at follow-up (p = 0.001) compared to individuals taking an alternative class of drugs.

There was also a significant interaction between lower CD4 cell count and higher viral load and BMD loss (p = 0.043). In patients with a higher viral load, the negative effect of a low CD4 cell count on BMD was greater than in individuals with a lower viral load.

The investigators note that the BMD changes found in their study were relatively “modest” and of unknown clinical significance. They also emphasise that they did not have data on some factors associated with bone loss such as tobacco and alcohol use, testosterone and vitamin D levels, and use of medicines that can affect BMD.

Nevertheless, the authors conclude: “low pre-treatment CD4+ count, but not early CD4+ change with ART was a strong and independent risk factor for bone loss after ART initiation, providing further evidence for the benefits of early initiation of ART.”