AZT not linked to worsening anaemia in patients starting ART in Uganda

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Starting HIV treatment with a drug combination that includes AZT is not associated with a risk of developing severe anaemia during the first six months of therapy, Ugandan investigators report in The Journal of the International AIDS Society.

Haemoglobin levels increased in the overwhelming majority of patients after HIV treatment was started. This included those with severe anaemia at baseline who initiated therapy with an AZT-containing regimen.

“ART [antiretroviral therapy] should not be withheld from patients with severe anaemia if regimens containing AZT are either the only ones available or are preferred for other reasons,” comment the investigators.

Glossary

anaemia

A shortage or change in the size or function of red blood cells. These cells carry oxygen to organs of the body. Symptoms can include shortness of breath, fatigue and lack of concentration.

haemoglobin (HB)

Red-coloured, oxygen-carrying chemical in red blood cells.

advanced HIV

A modern term that is often preferred to 'AIDS'. The World Health Organization criteria for advanced HIV disease is a CD4 cell count below 200 or symptoms of stage 3 or 4 in adults and adolescents. All HIV-positive children younger than five years of age are considered to have advanced HIV disease.

toxicity

Side-effects.

sample

Studies aim to give information that will be applicable to a large group of people (e.g. adults with diagnosed HIV in the UK). Because it is impractical to conduct a study with such a large group, only a sub-group (a sample) takes part in a study. This isn’t a problem as long as the characteristics of the sample are similar to those of the wider group (e.g. in terms of age, gender, CD4 count and years since diagnosis).

Risk factors for severe anaemia included six months after starting HIV therapy included the development of tuberculosis (TB) and severe anaemia at baseline.

Anaemia (low haemoglobin) is a common condition in HIV-positive patients. In the period before effective HIV therapy was introduced, the prevalence of the condition ranged from 15% in patients without symptoms to 50% in patients with AIDS.

Starting HIV therapy has been shown to lead to improvements in anaemia in both resource-rich and resource-poor settings.

AZT is widely used as a component of antiretroviral treatment in resource-limited settings. The drug has been associated with an increased risk of developing anaemia, especially during the three months of treatment.

Therefore both World Health Organization and Ugandan national guidelines recommend that patients who develop severe anaemia (haemoglobin below 8g/dl) should stop taking AZT. These guidelines also recommend that patients with severe anaemia should take tenofovir in preference to AZT. However, cost constraints mean that this is not always possible.

Investigators therefore wished to analyse the risk factors for the development of severe anaemia during the first six months of HIV therapy. In particular they wanted to see if AZT could be safely prescribed to patients with severe anaemia at the time antiretroviral therapy was initiated.

Their study sample included 5494 patients who started antiretroviral therapy between 2004 and early 2009. The majority of patients (3264, 59%) initiated therapy with a combination that included d4T. In 2008 d4T ceased to be recommended because of the severe short- and long-term side-effects that it can cause.

At baseline, 15% of patients had anaemia (below 9.5g/dl) and 5% had severe anaemia. Just over a fifth (22%) of patients with severe anaemia initiated therapy with an AZT-containing regimen. The other severely anaemic patients were treated with d4T.

Significant factors associated with severe anaemia at baseline included advanced HIV disease and being female (both p < 0.001).

Haemoglobin was measured six months after starting HIV therapy in 3105 patients.

The biggest increases in haemoglobin were seen in patients who had anaemia at baseline (median change 2.9g/dl vs 0.7g/dl in non-anaemic patients, p < 0.0001). Haemoglobin increased by a median of 3.5g/dl among patients who were severely anaemic at baseline.

Larger increases in haemoglobin were seen in patients who initiated therapy with d4T than in those whose treatment included AZT (median increase 3.1g/dl vs 2.5g/dl, p < 0.012).

Two-thirds of patients with severe anaemia at baseline had an increase in their haemoglobin to above 9.5g/dl. Similar proportions of patients taking AZT and d4T had this increase.

A total of 4% of the patients who had their haemoglobin measured six months after starting treatment had severe anaemia at baseline. Just over a quarter of these patients still had severe anaemia at the time of the second haemoglobin measurement. However, only four of these thirty patients with persistent anaemia were taking AZT.

For men, risk factors for severe anaemia six months after starting HIV therapy were incident TB (p = 0.006) and severe anaemia at baseline (p = 0.002). These were also risk factors for women (p < 0.0001 and p < 0.0001 respectively). In addition, more advanced HIV disease was also a significant risk factor for women (p = 0.046), but not men.

Treatment with AZT was not associated with a risk of early severe anaemia in either men or women.

The outcomes of patients with anaemia were also monitored. The researchers found that 96% of those who started therapy with d4T had an increase in their haemoglobin as did 92% of individuals initiating therapy with AZT.

When analysis was restricted to patients with severe anaemia, 89% of those taking d4T had an increase in their haemoglobin compared to 97% of AZT-treated patients.

“ART led to an increase in haemoglobin in the majority of our patients,” comment the investigators. They add, “AZT was not associated with an increased risk of early severe anaemia after highly active ART despite its known toxicity when used as a single agent in the pre-ART era.”

The investigators conclude that it would be preferable to treat patients with anaemia with a tenofovir-containing regimen. However, when this is not an option, therapy based on AZT should not be withheld from severely anaemic patients.

References

Kiragga AN et al. Baseline severe anaemia should not preclude use of zidovudine in antiretroviral-eligible patients in resource-limited settings. Journal of the International AIDS Society, 13:42, Doi:10.1186/1758-2652-13-42, 2010 (for access to the free article click here).