Indian J Med Res 132, October 2010, pp 359-361
Commentary
Zidovudine-induced anaemia in HIV/AIDS
Several studies have shown that the prevalence
of anaemia is high in patients with human
immunodeficiency virus (HIV) infection and acquired
immunodeficiency syndrome (AIDS)1,2. Anaemia
in HIV infection is associated with uniformly
adverse outcomes such as opportunistic infections
and neurologic deterioration and progression to
AIDS2. Anaemia is associated with several other
consequences including fatigue3, poor quality of
life4 and increased requirement for erythropoietin
therapy5. Several observational studies have also
reported a higher mortality in HIV infected patients
from low haemoglobin levels even after adjusting
for CD4 cell count and viral load2,6-8. The aetiology
of anaemia in HIV infection is multifactorial and
typically the anaemia results from underproduction
of red blood cells and frequently the laboratory
features are compatible with anaemia of chronic
disease with a low reticulocyte count, normocytic
and normochromic red blood cells with normal iron
stores and cytokine mediated poor erythropoietin
response9-11. The use of highly active antiretroviral
therapy (HAART) is associated with an increase in
haemoglobin concentrations and a decrease in the
prevalence of anaemia. Amelioration of HIV-related
anaemia with HAART has several benefits including
improvements in functional status, energy levels and
fatigue and overall improvement in quality of life2.
Combination antiretroviral (ARV) therapy is the
current standard of care for treating patients with HIV/
AIDS. Use of HAART has remained the only regimen
potent enough to decrease viral replication in patients
with HIV/AIDS and its use has been shown to reduce
anaemia by inhibiting acceleration of the disease. In
resource-limited settings, combination chemotherapy
consisting of 2 nucleoside analogues (reverse
transcriptase inhibitors) [either zidovudine (AZT) or
359
stavudine (d4T) along with lamivudine (3TC)] and 1
non-nucleoside reverse transcriptase inhibitor (NNRTI)
[either nevirapine (NVP) or efavirenz (EFV)] are
frequently used. AZT, a nucleoside reverse transcriptase
inhibitor (NRTI) is one of the earliest antiretroviral
agents used as a combination in some of the HAART
regimens for the treatment of HIV /AIDS, and it was
the first drug which was approved by the US FDA for
use in HIV/AIDS. In most of the instances, when the
haemoglobin level is >8g/dl, AZT is used in the first-
line drug combination as stavudine is more frequently
associated with mitochondrial toxicity. Its use, however,
is associated with haematological toxicity particularly
bone marrow aplasia leading to varying degrees of
cytopenias especially anaemia in some patients. The
mechanism of this anaemia is attributed to 50-70 per
cent inhibition of proliferation of blood cell progenitor
cells1,11 in a time-and dose-dependent fashion. Further,
laboratory studies have also shown that zidovudine
exhibits cytotoxicity to the myeloid and erythroid
precursors in the bone marrow at drug concentrations
close to those associated with the optimal antiviral effect
in vitro. This haematological toxicity is observed in most
of the patients within 3-6 months and is reversible. Female
gender has been found to be a risk factor for anaemia in
some studies. This adverse effect of anaemia from AZT
limits its use in some patients. Zidovudine has also been
reported to produce pure red cell aplasia (PRCA)12,13
with a selective depletion of red blood cell line and
this adverse event is also reversible. Therefore, patients
who are started on AZT combination regimen for HIV/
AIDS treatment, should be closely monitored during
follow up for development of bone marrow toxicity. Co-
trimoxazole preventive therapy has been recommended
along with HAART especially in those with HIV-TB to
decrease incidence of serious opportunistic infections14.
The impact of co-trimoxazole on haematological
360 INDIAN J MED RES, OCTOBER 2010
cytotoxicity when it is used concurrently with AZT,
should be systematically evaluated in future studies.
In this issue, Agarwal et al15 in their retrospective
study report a high incidence of ZDV induced anaemia
in HIV infected patients from eastern part of India.
Zidovudine was initiated in 1256 of 2941 (42.7%)
patients between March 2005 to December 2007.
Measurement of haemoglobin was done regularly in
these patients. Patients were carefully excluded if they
had gastrointestinal diseases, iron deficiency or vitamin
B12 deficiency aneamia; 203 patients (16.2%) developed
anaemia (haemoglobin <8g/dl) and 100 (7.9%) of these
had haemoglobin < 6.5g/dl. In majority of patients
(94.4%), ZDV induced anaemia occurred within 6
months of initiation of therapy and the peripheral smear
showed normocytic, normochrmic anaemia in almost
half of the patients and in the remaining it showed
macrocytic changes. Bone marrow was done only
in 27 patients and was normocellular in 18 patients.
Dysplastic changes were seen in myeloid (30%) and
erythroid cell lines (28%).
Though it is a good attempt on the part of authors, the
study suffers from all drawbacks such as confounding
and bias of a retrospective study. This study reveals a
very high incidence of anaemia supposedly related to
zidovudine as haemoglobin levels rose after stopping
zidovudine. Another retrospective south Indian study16
has reported a relatively lower incidence (5.4%) of
anaemia due to AZT. How do we explain these different
results? These differences can be attributed to different
study designs, use of different methodologies including
inclusion and exclusion criteria and different cut-offs
used to define anaemia.
Ideally, a very systematic, prospective, cohort study
with application of stringent inclusion and exclusion
criteria should be planned to find out the exact incidence
of anaemia due to ziduvudine. Preferably, it should be
a multicenter study with adequate clinical supervision
and appropriate monitoring provisions for laboratory
quality control. Nutritional anaemia, multiple worm
infestations which are rampantly prevalent in India
should be carefully ruled out. Patients with microscopic
and macroscopic blood losses, those using aspirin and
other non-steroidal anti-inflammatory drugs require
careful exclusion. Bone marrow examination should
be done in those who develop haematological toxicity.
In addition to clinical follow up, a regular monitoring
of CD4 cell count and viral load for demonstrating
treatment failure is essential as disease progression
itself is associated with the development of anaemia.
In the meantime, what should be the strategies
to deal with this type of problem in resource-limited
settings ? First, AZT is not too expensive and is
affordable to be used in the first-line combination
drugs by most resource constrained nations as a public
health approach. Therefore, one can continue with the
current guidelines to use it in those patients who have
haemoglobin level >8g/dl and these patients should
have a detailed haematological work-up at baseline
and close monitoring of haematological profile
during follow up, and change to other nucleoside
analogue such as tenofovir or emtricitabine in case
haemoglobin level falls below 8 g/dl. Second, AZT
should not be used as the first-line drug and instead
use d4T as the first drug and use AZT as a switch
therapy after sometime and while on AZT patients
should be carefully and closely monitored. While
doing so one has to keep in mind the current World
Health Organization Guidelines (2009) to phase out
the use of d4T in combination therapy because of
mitochondrial toxicity17. Third, the use of tenofovir
(TDF) or emtricitabine (FTC) as the first-line drug in
combination therapy should be considered if country
programmes for HIV/AIDS have enough budget to
afford the cost on a long-term basis.
In conclusion, we should first try to determine
the exact magnitude and predictors of AZT-induced
anaemia in HIV/AIDS patients in properly planned and
well-conducted prospective studies. Meanwhile, we
should continue to use AZT in the first-line combination
therapy in HIV/AIDS patients with haemoglobin levels
>8g/dl as a public health approach since the drug is
cheaper and should do a continuous surveillance for
development of haematological toxicity.
Surendra K. Sharma
Department of Internal Medicine
All India Institute of Medical Sciences
New Delhi 110 029, India
surensk@gmail.com
sksharma@aiims.ac.in
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