ASHM Report Back

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

CROI 2016 : Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss : Proof of concept study

HIV infection is an independent risk factor for osteoporosis. Initiation of ART induces additional 1-6% loss in bone mineral density (BMD). ART-associated bone loss occurs early and happens with most of ART agents.

Zoledronic acid is a biphosphonate drug licensed for the treatment of bone-related cancers alongside chemotherapy and for the treatment of osteoporosis in men and women at increased risk of fracture. It is administered as an infusion once a year. The drug slows down the loss of calcium from the bones, reducing the risk of fractures.

Reduced bone mineral density is common in people living with HIV, and as previously noted, modest bone mineral loss is a common occurrence during the first year of antiretroviral therapy. Investigators from Emory University School of Medicine, Atlanta, designed a study to investigate whether a single infusion of zoledronic acid could limit bone mineral loss during the first year of antiretroviral therapy.

This was a single-centre, randomised, double-blind, placebo controlled phase 2 study. Patients starting HIV therapy for the first time with no history of bone loss were eligible for inclusion. All participants received an antiretroviral regime of atazanavir with tenofovir/emtricitabine. Patients were randomised to receive a single 5mg infusion of zoledronic acid or placebo. The study lasted 48 weeks with assessment of bone turnover and bone mineral density at baseline and weeks 12, 24 and 48.

Therapy with zoledronic acid was associated with a 74% reduction in bone loss by week 12. The benefits persisted through to week 24 and 48 (65% and 56% reduction, respectively, relative to placebo).

By week 12, patients in the treatment arm had an 8% increase in lumbar spine bone mineral density relative to placebo, the difference increasing to 11% at weeks 24 and 48. At week 48, lumbar spine bone mineral density had increased by 2% in patients treated with zoledronic acid; this compared to a 4% decrease among patients who received the placebo. Lumbar spine T- and Z-scores were significantly higher among patients who received zoledronic acid versus placebo at all follow-up points (all p < 0.05). Similar trends were also observed at the hip and femoral neck.

Zoledronic acid was well tolerated with no major adverse events reported. Rates of viral suppression and CD4 cell increase were similar between the treatment and placebo arms.

The investigators conclude that a single infusion of zoledronic acid at the time HIV therapy was started prevented antiretroviral-induced bone resorption and bone loss at key fracture-prone body sites. The benefits of therapy were present at week 12 and persisted through 48-weeks of follow-up. The researchers suggest that zoledronic acid could be used as a prophylaxis against bone mineral loss during the first year of antiretroviral treatment and call for a multicentre randomised trial to confirm their findings.

Take home message: Single dose of zoledronic acid infusion may be an effective preventative measure of BMD loss in HIV

Tagged in: CROI2016
With or without ART, CVD risk matters

Session 0-4 Complications from Head to Toe

Early Antiretroviral Therapy Does Not Improve Vascular Function: A START Substudy. Abstract 41

Presenter: Jason V. Baker (Minneapolis, MN, USA)

They utilised diastolic aspect of cardiac BP waveforms to assess elasticity and vessel function.

Participants were generally a young cohort in their 30s and with CD4 counts >600

CVD (Cardio-vascualr disease) risk was low for the study cohort that was on ARVs, but was slightly increased for those participants that were in the ARV deferred group.

For HIV +ve patients consistent changes were noted across all age groups. 

It was notable that both HIV +ve groups (Those on ARVs and those in deferred arm) had lower elasticity baseline in comparison to the general (non-HIV) population, from CARDIA.

No specific difference in elasticity between ARV and deferred HIV +ve groups.

Overall the findings of the substudy did not show any benefit on vascular elasticity from commencing ART early. It did however highlight how vascularity is compromised within HIV +ve patients and hence for all our HIV +ve patients regardless of age we should take assessment of their CVD risk seriously and conduct this routinely, even for the young of age and those with suppressed viral loads and good CD4 counts. 

Tagged in: CROI2016

Two sub-studies, which formed part of START trial, were presented this morning.

 

The first study looked at lung-function decline in the immediate versus deferred arms of the START trial. The authors acknowledge the emergence of COPD as a co-morbidity in HIV, with prior studies showing mixed results on the the effects of ART on COPD risk.

 

This sub-study involved approximately 1000 patients divided between immediate and deferred treatment arms. The median follow-up time was relatively short - just 2 years. No difference of FEV1 slope was detected between the study arms, in both smokers and non-smokers.

 

This study suggests immediate vs deferred ART has no impact on lung function decline in HIV with CD4 >500. Further longitudinal data continues to be collected on this study population.

 

The second START sub-study presented looked at the effects of immediate versus deferred ART on bone density (abstract not available at time of writing this post). 424 naive patients with CD4 counts over 500 were enrolled (206 in the immediate group, 218 in the deferred arm).

 

Bone mineral density (BMD) was assessed by DEXA at the hip and lumbar spine at baseline and annually. The median age was young, 32 years old, with 26% female patients. Osteoporosis and low BMD were lower than in other cohorts (3.3% and 38%, respectively).

 

Over the course of the follow-up, 37% of patients in the deferred arm ended up on treatment. In the immediate treatment arm, 79% were on tenofovir containing regimens. Controlling for variables, significantly greater BMD loss was seen at both the hip and spine in those randomised to immediate ART. This effect was most pronounced in the first year, after which point it stabilised. No difference in the development of osteoporosis was seen between groups (or fractures - as presented in the results from the full START study population).

 

Both of these studies were extremely well presented, as one would expect from such a large multi-centre, multi-national trial. The presenter of the lung function sub-study acknowledges that they do not anticipate significant differences between the two study arms at the 3 year mark.

 

Clearly smoking status remains the most significant risk factor for lung function decline in HIV-infected individuals, and our focus should remain on supporting smoking cessation in this group. As for the bone sub-study, with the advent of TAF, I suspect the relevance of this study and associated concerns, certainly in Australia, will be further diminished.

Tagged in: EACS2015

 

Things got off to an early start this morning at EACS, starting with 4 different ‘Meet the Expert’ sessions to chose from. I attended the session on vaccination in HIV.

This session provided a nice overview of recommended vaccinations and their rationale in HIV positive patients. This was a good reminder to me to ensure patients are appropriately vaccinated at baseline and to intermittently check antibody status where indicated. In a day and age where many patients seem to be commencing antiretroviral therapy so early in their care (and at increasingly higher CD4 counts), it is easy to forget that such individuals still carry an elevated risk of complications.

Four Cases

Four cases were used to demonstrate infections that were preventable through vaccination. The first case was about measles. The presenter highlighted the fact that in some European countries, up to 13% of patients with HIV have no detectable antibodies against measles (particularly in patients born after 1983).

Many patients are unsure of their vaccination history and it may therefore be important to check antibody status. Another important consideration relates to the measles vaccine being a live attenuated vaccine (along with Yellow fever and varicella). European guidelines recommend only using live attenuated vaccines in people well controlled on ART with CD4 counts >200 (14%), or off ARVs with higher CD4 counts (500, >20%).

The presenter suggested considering antibody titres where indicated. However, it is important to remember that antibody responses are used as a surrogate marker and may not reflect impaired cell-mediated immunity in HIV positive patients.

The second case was a reminder to ensure all patients with HIV have an annual influenza vaccine. They highlighted a study which showed no increase in immunogenicity through booster doses or increased antigen dose of influenza vaccine in HIV positive patients.

The second presenter discussed a case of a patient with pneumococcal pneumonia. Whilst the most vulnerable patients are those with low CD4 counts and those not on ART, strep pneumonia remains a problem even in the HAART era, with patients with HIV at greater risk of complications. I found this particularly interesting as I feel there is a lot of uncertainty around appropriate pneumococcal vaccine choice and timing in patients with HIV. 

In patients with HIV, conjugate vaccines (such as 13-PCV) have been shown to have greater immunogenicity (compared with polysaccharide vaccines such as 23-PPV) and it is for that reason they are recommended for initial vaccination where available in the EACS guidelines (and DHHS). EACS guidelines do not recommend booster doses at present. whereas the DHHS guidelines do. 23-PPV can be given 8 weeks after 13-PCV (or after CD4 increases over 200 on ART). In patients who has 23PPV initially, 13-PCV can be given after 1 year. The full DHHS guidelines can be found here: http://aidsinfo.nih.gov/guidelines

The final case discussed was around hepatitis B vaccination. Serological responses to standard dose vaccines are impaired in HIV-infected individuals (with lower response in low CD4 setting and off-ART). There are numerous schemes for non-responders which can be used - one study showed good response (86%) with re-vaccination with the standard schedule (especially if less than 3 months from the last dose of first schedule). Additionally, both double-dose schedules and intradermal vaccination showed improved response rates.

If you made it to the end of this blog, my take home points from this session were: 

  • don’t assume prior vaccination (particularly with primary vaccines), take a full vaccine history and check titres where indicated
  • use live attenuated vaccines with caution and as per guidelines
  • conjugate vaccines appear to have higher immunogenicity and are therefore preferred (e.g. pneumococcal vaccine)
  • double dose Hep B vaccinations in non-responders are easy to administer and show improved response rates 

 

Tagged in: EACS2015

Day 1 of EACS always features a comorbidity workshop and this year all 5 of the presentations in the workshop were about bone loss.

The background to this of course is that in 2010 the metabolic sub-study of ACTG 5052 showed a 2-4% bone loss as measured by BMD over 96 weeks when naive patients commenced ART. Since then more studies have echoed this, we continue to worry about it and the pendulum has swung between how much of this is ART and how much is immune activation-reconstitution bone loss.

The current evidence base suggests it is mostly TDF, particularly when it is boosted and the robust evidence for this comes from studies such at TROP, PROGRESS and the newer naive and switch studies for TAF

The first presentation was a retrospective analysis of markers of bone turnover from 52 patients in the MACS cohort who initiated ART during seroconversion. Seroconversion is indeed a state of heightened immune activation and disturbances of bone markers having a net negative effect on bone formation were seen in both the seroconversion and ART initiation stages.

The other compelling argument for bone loss being driven by ART as opposed to immune activation is PrEP because these are men without either viraemia or immune activation. This brings us to the best presentation in the workshop which is the title above 

ATN 110 is an open label PrEP safety and demonstration study that enrolled 200 at risk young men who have sex with men (YMSM) in panamerican sites. 54% are black. DXA scans of the spine, hip and whole body (WB) were performed at baseline, 24 and 48weeks and adherence is assessed objectively using RBC TFV-DF levels in dried blood spots.

Interestingly baseline median BMD Z scores were below zero (spine -0.50, hip -0.45, WB -0.40). At week 24 there was a modest but significant decrease in BMD by WB (-0.61%, p<0.001). The iPrEx study also reported a similar bone loss.

What is good about this study however is, unlike iPrEx, it included stratification of the BMD analysis according to objective adherence. At week 48, a comparison was made between YMSM who had TFV-DP levels indicative of dosing 4 or more days a week and the subset that had levels below the level of quantification. Respective changes in BMD from baseline to week 48 in these subgroups were: spine -1.33% vs +1.54% (p<0.001); hip -1.68% vs 0.00% (p<0.001); WB -1.01% vs 0.34% (P=0.33)

So in conclusion there is a statistically significant TDF driven signal

In terms of clinical applicability however I think overall it is reassuring that there was no substantial bone loss from PrEP here. One could argue that 48 weeks is only a snapshot and what will accumulate with time but you have to remember that PrEP is not for life and does not share the same concerns as treating established HIV infection with TDF. Even in the case of naive HIV patents starting ART there seems to be some stabilization of the loss after 96 weeks and the fracture studies we have in HIV patients are based on population data which is subject to confounding such that we can't really say that any of this is tipping over into fractures.

Don't forget that bone is a very dynamic tissue as well with changes likely to be reversible with therapy change, not to mention lifestyle modification.

Additionally for our HIV patients the greatly reduced signals for bone of TAF over TDF in the naive and switch trials are really quite promising.

Putting my GP hat back on, the other interesting finding from this study is the baseline low BMD. Avoiding osteoporosis is still mostly about encouraging young people to reach their peak bone mass through adequate nutrition, tension loaded exercise and not smoking.

There is not much else to report back on today, it is opening ceremony day

There will be much more to report tomoz, here from sunny Barthththththththelona

CLINICAL APPLICABILITY OF THIS DATA:

Tagged in: EACS2015

Please join us for a memorial event celebrating the life of one of Australia’s leading HIV advocates, Levinia Crook… https://t.co/N7dof5xaGa

ASHM ASHM