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Studies look at bone changes during second-line therapy, fractures, and HIV- and HCV-related bone loss
Liz Highleyman, 2013-07-08 09:10:00
People with HIV experience less bone loss if they switch to a NRTI-sparing second-line regimen containing raltegravir, researchers reported last week at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur. Other studies showed that HIV infection is associated with increased risk of hip fractures and shed light on different mechanisms of bone loss associated with HIV and hepatitis C.
Numerous studies have reported a link between HIV and reduced bone mineral density (BMD), including osteopenia and the more severe osteoporosis. It is not yet clear whether this is attributable due to HIV infection itself, resulting inflammatory and metabolic changes, antiretroviral toxicity or some combination of factors.
While several studies have looked at bone changes after starting initial antiretroviral therapy (ART) or switching drugs while on suppressive treatment, what happens after switching from a failing regimen to second-line therapy is less well understood.
In general, initial ART studies typically show early bone loss soon after starting therapy, which stabilises after a few months. Bone loss has been linked to use of NRTIs – especially tenofovir (Viread, also in single-tablet regimens) – and protease inhibitors; the effect of integrase inhibitors on bone density is not well characterised.
Jennifer Hoy from the Alfred Hospital in Melbourne and colleagues looked at changes in bone density among a subset of participants in the SECOND-LINE trial who switched regimens due to virological failure of their initial non-nucleoside reverse transcriptase inhibitor (NNRTI) combination.
Conducted in 37 countries across the globe, SECOND-LINE compared the safety and efficacy of a World Health Organization-recommended second-line regimen – lopinavir/ritonavir (Kaletra or Aluvia) plus two or three nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) – versus a NRTI-sparing regimen of lopinavir/ritonavir plus the integrase inhibitor raltegravir (Isentress).
The bone sub-study included 210 participants at eight sites in five middle-income countries (Argentina, India, Malaysia, South Africa and Thailand) that had capacity to do dual energy X-ray absorptiometry (DEXA) scans. DEXA was performed at baseline and at week 48, measuring BMD at the proximal femur and the lumbar spine.
Men and women were equally represented, though there were more men in the NRTI-containing arm. The mean age was 38 years and very few of the women were menopausal. Participants were mostly Asian (51%) or African (43%). Hoy noted that this differs from most ART bone studies to date, which have looked largely at white men.
Participants had been on their NNRTI-based first-line regimen for approximately three years on average; prior use of protease or integrase inhibitors was excluded. Half had used d4t (stavudine, Zerit), a third had used AZT (zidovudine, Retrovir) and 17% had used tenofovir. The median CD4 count was low, around 200 cells/mm3. Most people saw their viral load re-suppressed after they started their study regimen.
Two thirds of study participants had a body mass index (BMI) below 20 kg/m2 (with 18.5 the threshold for being considered underweight). While 17% were current smokers, two-thirds were past smokers. About 30% had spine osteopenia and 20% had femur osteopenia already at baseline.
As hypothesised, people randomised to the raltegravir-containing regimen saw less decline in bone density. BMD decreases at 48 week were significantly smaller in the raltegravir group compared with the NRTI group both at the femur (-2.9 vs -5.2%, respectively) and at the spine (-2.0 vs -4.2%). This finding was mirrored by significant differences in T-scores and Z-scores, two standardised comparative measures of bone density.
However, the likelihood of developing osteopenia or osteoporosis was similar between the two groups. Among raltegravir recipients, the incidence of osteopenia was 7.6% at both the femur and spine, compared with 7.5 and 8.6%, respectively, among NRTI recipients. Corresponding osteoporosis rates were 1.0% at the femur and 3.8% at the spine for raltegravir recipients compared with 3.2 and 5.4%, respectively, for NRTI recipients.
In a multivariate analysis, factors significantly associated with femur bone loss included longer duration of tenofovir use during the study, lower baseline BMI, lower nadir (lowest-ever) CD4 cell count and vigorous physical activity. For spine bone loss, the significant predictors were tenofovir use during the study, tenofovir use prior to the study, lower BMI and not being Asian.
The magnitude of bone loss seen in this first study looking at ART-experienced patients with virological failure on a first-line regimen was "similar to that observed in ART-naive patients initiating therapy", the researchers concluded.
"The loss of BMD was least in participants treated with raltegravir and greater in those exposed to tenofovir throughout the study," they continued. "These data confirm that reduction in BMD secondary to ART remains a significant co-morbidity in the long-term management of HIV."
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