Harmful Effects on Blood and Bone Marrow

“Reversible pure red cell aplasia is a recognized complication of both zidovudine and lamivudine, typically occurring within the first 3 months of therapy [1,2]. We report the case of a 29-year-old man with HIV, severe haemophilia A and hepatitis C, who developed reversible pure red cell aplasia 4 years after commencing zidovudine.”

“For this study, 1278 patient charts were screened, and 758 were included in the study…Of [these], 30.3% (230) were anemic (Hb [hemoglobin] level of 12.5 g/dL or less) at some time during the study…The majority of the ever-anemic patients (67%; 154 of 230) had a nadir [lowest] Hb level of 12.0 to 12.5 g/dL, which was considered mild to moderate anemia…Anemia was significantly more prevalent in patients who were currently being treated with HAART regimens containing zidovudine [AZT]…The presence of an AIDS diagnosis was not an independent risk factor for anemia in multivariate logistic regression analysis, although markers of disease progression, such as decreasing CD4+ cell count and increasing viral load, remain independent predictors of risk.”

“Zidovudine [AZT] was generally well tolerated in this high-risk population…[from Table II: 32%-Anemia grade >=2; 11%-Neutropenia; 13%-Thrombocytopenia; 45%-Received transfusion; 26%-Received erythropoetin; 11%-HIV infection; 8%-Died]…Slightly more than half of the subjects had anemia severe enough to require a transfusion [giving new meaning to the term 'well tolerated']”

“Recent epidemiologic studies of HIV-related anemia have strongly and repeatedly associated low hemoglobin level with disease progression and mortality. Patients who are at greater risk for anemia may include those of African-American ancestry, and those with low CD4 cell counts, high virus load, and low mean corpuscular volume and those receiving zidovudine [AZT]…[in one study] for patients without anemia, 3.1% died by 12 months. In contrast, for patients with mild anemia, 15.9% had died, and for patients with severe anemia, 40.8% had died [this association remained even after controlling for CD4/viral load measurements]”

“We conducted a longitudinal study of 797 human immunodeficiency virus (HIV) positive women (7732 visits) and 389 HIV-negative women (3651 visits) to characterize anemia...Risk factors for anemia [included] zidovudine use [1.14 times more likely]. Anemia was common and associated with an increased risk of death (hazards ratio, 1.64; 95% CI, 1.21 2.23) among HIV-positive women...the mortality rate during the follow-up period was 37% in those who were anemic at enrollment and 22% in those who were not anemic at enrollment”

“1 patient [out of a grand total of 10 in this clinical trial] suffered from severe anemia resulting from ZDV [AZT] therapy”

“In a retrospective evaluation of medical records of 32,867 HIV-infected persons followed in nine cities in the United States, the 1-year incidence of anemia, defined as a hemoglobin level <10 g/dl or a physician’s diagnosis of anemia, was approximately 37% for patients with a clinical AIDS-defining condition; 12% for those with immunologic AIDS, defined as a CD4 count <200; and 3% for persons without either of these conditions…Use of ZDV either currently or in the past 6 months was associated with anemia…A total of 41.5% of those with a history of ZDV in the past 6 months and 27.7% of those without such history were anemic at baseline…The strong statistical associations between worsening parameters of HIV disease and increased likelihood of anemia…suggest that effective antiretroviral therapy may be associated with improvement in Hb [hemoglobin] levels [!]”

“Of variables related to HIV infection, low CD4+ cell count, AIDS diagnosis and receiving zidovudine [AZT] therapy were predictive for prevalent anemia”

“We found that 78.2% of the patients with mild or severe anaemia at baseline had received zidovudine [AZT]”

“While effective [effective at what?] drug therapy is continued in zidovudine[AZT]-treated HIV-infected patients…PROCRIT Reduces Transfusion Requirements and Helps Lift the Burden of Anemia. PROCRIT enables physicians to effectively: 1) Manage anemia with an easily administered, well-tolerated theerapy that allows continuation of zidovudine [AZT]-based regimens for HIV infection. 2) Help mildly anemic patients…3) Eliminate transfusion complications and inconvenience in patients who become transfusion-independent.

PROCRIT increases HCT [hematocrit, percentage of blood that is composed of red cells] significantly during myelosuppressive [bone marrow destroying] zidovudine therapy.”

“Anemia occurred in 22% of the infants who received zidovudine”

“A third possible cause of excessive tissue iron is the use of zidovudine [AZT]. The drug interferes with heme synthesis and, in an animal model, has been shown to upregulate iron acquisition. Although may of the reports of iron-loading cited herein involved patients in the first half of the 1980s, before the routine use of zidovudine.”

“Toxicity studies of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) were conducted in F344/N rats and B6C3F1 mice…AZT and ddC produced dose-related, poorly regenerative, macrocytic anemias as evidenced by decreases in erythrocyte counts, hematocrits, and hemoglobin concentrations and increases in mean corpuscular hemoglobin and mean corpuscular volume. Bone marrow samples in rats treated with AZT were hyperplastic whereas those in mice treated with AZT and rats and mice treated with ddC were hypoplastic. The hematologic toxicity of AZT was more severe than that of ddC. Generally, toxic effects of either chemical were greater in mice than in rats and more pronounced in female than in male animals. After 30 days without dosing, hematologic effects either resolved or dramatically improved…These studies demonstrated the early and progressive time course of toxicity of AZT and ddC”

“the drug [AZT] has some serious side effects, the most important of which is myelosuppression [damage to the ability of the bone marrow to produce new white blood cells]”

“The majority of patients had a macrocytic anemia (70%); however, all of these patients were also receiving zidovudine”

“Long-term tolerance of zidovudine [AZT] treatment was retrospectively analysed in 97 patients with AIDS or AIDS-related complex. After one year of treatment 68% and after two years 87% of the patients had had at least one dose adjustment during their course of therapy. Myelotoxicity [damage to the blood forming tissues] was the most common cause (58% of all cases) of dose reductions and therapy interruptions (dose adjustments). At the time of the first dose adjustment 33 patients (34%) were suffering from anaemia ([hemoglobin] less than 6.0 g/dl), 20 patients (21%) from leukopenia (leukocytes less than 1.5 x 10^9], and 10 patients (10%) from thrombocytopenia (thrombocytes less than 75 x 10^9]. 56 patients (57%) needed one or more blood transfusions during therapy. The median time from the start of therapy to the time of the first dose adjustment was 14 weeks in patients who had a first dose adjustment because of anaemia without co-existing leukopenia or thrombocytopenia…only a minority of patients with severe symptomatic HIV-1-related diseases can tolerate full-dose zidovudine regimens for prolonged periods [AZT doses are now generally much lower, but adherence still remains a challenge for people taking this drug or other nucleoside analogs]”

“178 subjects (34%) had a hemoglobin concentration below 5 mmol per liter [anemia]...A greater proportion of subjects in the standard-treatment [high dose AZT] group had a first episode of severe anemia earlier in the study, as compared with the proportion in the low-dose group. 134 subjects (26%) received red-cell transfusions (65 in the standard-treatment group and 69 in the low-dose group)...230 subjects(44%) had a [low] neutrophil [infection fighting white blood cells] count...134 (51%) in the standard-treatment group and 96 (37%) in the low-dose group...22 subjects (4%) had a [low] platelet [blood clotting cells] count.”

“[in mice] AZT had a profound effect on the number of erythrocytes [mature red blood cells] and a small effect on the number of leukocytes [white blood cells]…anemia was seen in all the mice tested at 1,000 mg/kg per day”

“The occurrence of severe anemia, although more common in the 500-mg[per day] zidovudine [AZT] group than the placebo groiup (5 cases vs. 1 case), was rare in both grouips. The subjects in the 1500-mg group, however, had higher rates of anemia (6.3%) and neutropenia (6.3%).”

“One or more transfusions were reported for 19.7% of patients [taking AZT], but anemia was reported as a serious adverse event in only 11.4% of patients. The mean time to first transfusion was 98 days after beginning therapy.”

“Zidovudine is well known to produce haematological toxicity in vitro and in some patients...It is worrying that bone marrow changes in patients on zidovudine seem not to be readily reversed when the drug is withdrawn…These findings have serious implications for the use of zidovudine in HIV positive but symptom-free individuals.”

“Between 10% and 25% of patients experienced decreases in granulocyte counts to less than 750/cubic-mm during each month of therapy…The incidence of anemia remained relatively constant over time. Approximately 10% of patients per month reported with hemoglobin levels less than 7.5 g/dl, and fewer than 5% were reported with levels less than 6.5 g/dl…At the physicians’ discretion, transfusions with packed red blood cells were used to manage hemoglobin levels in patients with anemia [Figure 4 shows that 20-25% of patients required transfusions during the main portion of the trial (12-52 weeks)]…Anemia and granulocytopenia remained the major reasons for dose reductions or discontinuation of zidovudine treatment.”

“Blood transfusion is often necessary in patients with AIDS, especially in those receiving AZT, a drug which produces severe anaemia in a proportion of recipients. Forty nine (36%) of 138 patients treated with AZT … required blood transfusion at least once.”

“In the current study, transfusion-dependent anemia occurred in 6 of 15 patients with AIDS and Kaposi sarcoma who were receiving zidovudine therapy. All 6 affected patients required their first blood transfusion between 3 and 9 weeks after starting zidovudine therapy, and each required 4 to 14 units of packed erythrocytes to maintain a hemoglobin level above 100 g/L over a 12-week study.”

“The hematocrit [red blood cell count] decreased in the same patients...with three of eight patients requiring red-cell transfusion by the fourth week of treatment.”

“Four patients with [AIDS], and a history of Pneumocystis carinii pneumonia developed severe pancytopenia [marked decrease in all types of blood cells]…12 to 17 weeks after the initiation of azidothymidine (AZT) therapy…Partial bone marrow recovery was documented within 4 to 5 weeks in three patients, but no marrow recovery has yet occurred in one patient during the more than 6 months since AZT treatment was discontinued.”

“Anemia…developed in 24% of AZT recipients and 4% of placebo recipients (P<0.001). 21% of AZT recipients and 4% of placebo recipients required multiple red-cell transfusions (P<0.001). Neutropenia (<500 cells per cubic millimeter) occurred in 16% of AZT recipients, as compared with 2% of placebo recipients (P<0.001).”

“31% of the AZT recipients and 11% of the placebo recipients were given red-cell transfusions during the study. Transfusions were required on more than one occasion by 21% of the AZT recipients and 4% of the placebo recipients…Anemia developed as early as week 4 of therapy but most frequently occurred during weeks 6 and 8. Hemoglobin levels fell suddenly in some patients…Red-cell transfusions were required to continue therapy in many of the AZT recipients. Despite stabilization of anemia by dose reduction or transfusion, neutropenia often ensued. These manifestations of drug toxicity are potentially life-threatening”

“more than half of all AIDS patients may not benefit from the drug because it is more toxic for them than their AIDS infection. The most serious side effect of AZT is to suppress the bone marrow, leaving patients highly vulnerable to bacterial infections”

“nearly one half of patients treated with AZT for [HIV]-associated disease develop transfusion-dependent anaemia due to bone marrow depression”