Blood Disorders (Anemia etc.)

“The incidence of first severe anemia was assessed among HIV-uninfected infants in…MTCT [mother-to-child transmission] prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding and 1 month of postnatal zidovudine (HAART-BF); infants exposed to maternal zidovudine (ZDV [AZT]) in utero, 6 months of postnatal ZDV, and breastfeeding (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF)…A total of 1719 infants were analyzed- 691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF and 2.5% of ZDV-FF infants [which is amazing because one of the most notorious side effects of ZDV [AZT] is anemia. Note that there was no comparison with a group whose mothers were not given any AIDS drugs during pregnancy]”

“High early mortality was observed in this cohort of Kenyan children receiving HAART, and low baseline hemoglobin was an independent risk factor for death [This does not mean that AIDS drugs are absolved from responsibility. Some children might have been on only one or two AIDS drugs (notably AZT) which does not count as HAART or it might be that children with low hemoglobin to start with are less able to withstand the additional blood toxicity of HAART]”

“Macrocytosis, generally defined as a mean corpuscular volume [MCV] greater than 100 fL, is frequently encountered when a complete blood count is performed. The most common etiologies are alcoholism, vitamin B12 and folate deficiencies, and medications…Treatment of HIV with reverse transcriptase inhibitors (e.g., stavudine [Zerit], lamivudine [Epivir], zidovudine [Retrovir/AZT]) will cause macrocytosis because they interfere with DNA production, which may lead to megaloblastic changes. Most patients with HIV who are being treated with reverse transcriptase inhibitors will display macrocytosis without anemia. This indicates medication compliance by the patient, and no treatment is necessary [except that anemia is one of the leading side effects of these drugs, so this is clearly not true]”

“The most common side effects attributed to abacavir [a nucleoside analog AIDS drug] are gastrointestinal signs and symptoms (loss of appetite, nausea, vomiting, and diarrhoea), headache, malaise, and asthenia. These untoward events usually appear in the first few weeks of therapy, tend to resolve spontaneously, and are usually mild-to-moderate in severity [which could be because the body adapts to the drug or because patients lose patience and stop taking it]…The most serious adverse event caused by abacavir is the hypersensitivity reaction, a severe allergic reaction that has been estimated to occur in around 8% of persons who begin abacavir therapy, usually within the first 6 weeks of treatment. Its multiform clinical manifestations include fever, rash, gastrointestinal, or respiratory symptoms, and may lead to life-threatening hypotension, renal failure and death, especially in the event of rechallenge with abacavir after a prior episode of hypersensitivity…In our patient, a potentially life-threatening neutropenia occurred 4 weeks after the start of abacavir therapy and was associated with fever, skin rash, and anaemia. The neutrophil count started to increase and themajority of clinical signs and symptoms resolved within 3–4 days after stopping abacavir, whereas absolute neutrophil count and haemoglobin level became normal after 10 days. Consistent clinical manifestations, a positive HLA-B 5701 testing, and the rapid recovery of our patient suggest that these adverse events may be immune mediated, probably due to the secretion of drug-related antibodies.”

“The hemophagocytic syndrome is characterized by an association of fever, hepato-splenomegaly [liver and spleen enlargement] and hemophagocytosis in organs such as the bone marrow and a high ferritin level…We describe two cases of hemophagocytic syndrome occurring after highly active antiretroviral therapy (HAART) initiation. Both patients were antiretroviral therapy naive, starting HAART with a low CD4 count, and, within 1 week, developed a severe hemophagocytic syndrome revealing Hodgkin’s lymphoma in bone marrow biopsy [both developed severe pancytopenia, a major reduction in all major blood cell types]”

“Boehringer Ingelheim has identified 14 cases of intracranial hemorrhage (ICH) (bleeding into the brain), including 8 deaths, in 6,840 HIV-1 infected patients receiving APTIVUS [a protease inhibitor also known as Tipranavir] in clinical trials [note that it is estimated that only 1% to 10% of adverse reactions are reported, although this may be higher for patients participating in clinical trials]”

“A 42-year-old HIV patient was hospitalized in July 2003 after his HIV specialist doctor noted advanced anaemia in a routine blood count (haemoglobin 0.71 g/l, normal range 1.4–1.8) and elevated lactate dehydrogenase…In February 2003, a salvage regimen with two boosted protease inhibitors, lopinavir/ ritonavir and indinavir, was started…The review of the routine blood parameters during the past few weeks showed that both the anaemia and lactate dehydrogenase increase started after the failing antiretroviral therapy (ART) had been changed in February 2003.”

“A 59-year-old nurse of Korean origin from our HIV ward sustained a needle-stick injury with an HIV-contaminated needle. A potent PEP [post-exposure prophylaxis] regimen comprising ZDV[AZT]/3TC (Combivir) 300/150 mg twice a day (bid) and LPV/r (Kaletra [Lopinavir]) 400/100 mg bid was instituted 2 h after exposure. The following day, she experienced weakness and nausea, followed by acute deterioration of her condition. On admission, the patient was somnolent but rousable. She was unable to communicate appropriately but could open her eyes on command…Under initial therapy comprising vasopressors and fluid substitution her cardiovascular situation stabilized temporarily, before she developed acute renal [kidney] failure with anuria and hypoxaemic respiratory failure several hours after admission…The patient experienced a delayed recovery, suffering from sustained severe vertigo and weakness. Renal function also recovered after a polyuric phase of about 2 weeks’ duration. After 6 weeks of hospitalization, and a further 5 weeks in a neurological rehabilitation centre, she was finally discharged. At that time, she was still suffering from vertigo, concentration difficulties and neuropsychological cognition disorder. Other organ systems recovered completely and were unremarkable. Six months after the incident, she was still unable to resume her work. …Although the exact cause and mechanism of this incident remain unclear, the timely coincidence with PEP initiation suggests a primarily drug-induced cardiovascular failure leading to severe hypotension, shock and subsequent effects on pulmonary, renal and neurological function.”

“In this retrospective study, performed on 16 HIV-infected patients with congenital coagulation disorders [hemophilia]…the incidence rate of bleeding with a lopinavir–ritonavir-containing regimen was almost 4 times the rate with other protease inhibitor-containing regimens. Lopinavir–ritonavir also appeared to be associated with exceptionally severe haemorrhagic events.”

“We describe a patient in whom disseminated intravascular coagulation (DIC) developed within 6 days after starting abacavir for the treatment of HIV infection [resulting in kidney failure and liver abnormalities]”

“Didanosine appears associated with an increased risk of hyperlactataemia [elevated levels of lactic acid]”

“We report the case of a child who was diagnosed with a vertical HIV infection at the age of 11 months. Before diagnosis the boy had been repeatedly admitted with thrombocytopenia [lack of platelets that allow blood to clot], hepatosplenomegaly and lymphadenopathy…HAART was initiated with lamivudine (4 mg/kg twice a day), stavudine (1 mg/kg twice a day) and nelfinavir (55 mg/kg twice a day). A reduction in the size of lymph nodes, liver and spleen occurred over a period of 2 months. The HIV-RNA viral load was 1495 copies/ml 2 weeks after the initiation of HAART, and reached undetectable levels (detection limit 50 copies/ml) within 5 months…While on therapy the patient has been repeatedly admitted to our hospital with petechiae [blood blister] and platelet counts below 10 000/microliter. Intravenous gammaglobulin led to a prompt increase of the platelet count above 150 000/microliter, followed by a gradual decrease to counts below 10 000 within 4 weeks on all occasions. Thrombocytopenia has now persisted for more than 9 months despite [or perhaps because of] HAART.”

“73 (8.3%) of 880 [Swiss HIV] patients presented an increase in serum lactate of >1.1 times the upper normal limit (UNL). For 9 patients (1%), lactate elevation was moderate or severe (>2.2 times the UNL). Patients who presented with hyperlactatemia were more likely to be receiving stavudine with or without didanosine, as compared with patients who received zidovudine[AZT]-based regimens…Hyperlactatemia was associated with lipoatrophy [fat loss], hyperlipidemia [high blood lipid levels], and hyperglycemia [high blood sugar levels]. Age, sex, or stage of infection with human immunodeficiency virus were not predictive of hyperlactatemia”

“Severe lactic acidosis has been increasingly reported as a potentially fatal complication of HIV treatment…A 39-year-old HIV-positive woman was admitted…on February 2000 because of progressive dyspnoea [difficulty breathing], peripheral oedema [accumulation of fluid under the skin], ascites [accumulation of fluid within the abdominal cavity] and cyanosis [blue tinge to the skin due to lack of oxygen in the blood]. She was on her first anti-HIV combination regimen with stavudine, lamivudine and indinavir since January 1999…The patient was asymptomatic [at the time drugs were prescribed]…Anti-HIV therapy was well tolerated [whatever this means] with good virological (HIV-DNA <50 copies/ml) and immunological response (CD4: 326 cells/cubic mm) after 52 weeks…On December 1999 she developed mild dyspnoea and peripheral oedema, and she was started on frusemide [a diuretic] 12.6 mg daily…On February 2000, the patient was hospitalized because her condition had worsened…Highly active antiretroviral therapy was discontinued the same day…Over the following 16 h[ours], her clinical condition worsened dramatically and she developed severe acidosis [buildup of lactic acid in the blood]…An empirical approach with thiamine was started and, after a few hours, the patient had a dramatic improvement…All the metabolic abnormalities normalized within 7 days…It is noteworthy that similar events always took time to develop, occurring several months after starting antiretroviral medication…Several cases of lactic acidosis resolved spontaneously after stopping HIV treatment.”

“In 516 patient-years of observation, 2 patients experienced severe fulminant lactic acidosis (lactate >5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further 5 patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia”

“High-grade B-cell non-Hodgkin lymphoma (NHL) has been classified as an AIDS-defining illness (ADI) since 1985, following the description of NHL in a group of 90 HIV-1 seropositive men…HIV-associated NHL consequently accounted for up to 16% of all deaths attributable to AIDS [in 1994]…During [the 1990’s], potent therapies for the treatment of HIV infection have become available, and morbidity and mortality have plummeted. Despite this, the incidence of NHL remains largely unchanged-a finding confirmed by other studies [so, if NHL is caused by HIV, and HAART attacks HIV, why is this the case? Could it be that NHL is not caused by HIV, but by drugs, including antiretroviral drugs? Or, is it that HAART does not attack HIV, but simply acts as a potent, although toxic, antibiotic? Or, both?]”

“Further study is needed to characterize the association between indinavir and thrombosis [2.4 times the risk of blood clots inside blood vessels]…physicians should be alert for thrombosis in recently hospitalized HIV-infected patients, those with AIDS-defining opportunistic illnesses and those receiving indinavir [a Protease Inhibitor] or megestrol acetate.”

“In HIV-infected individuals, serum parameters of iron status can resemble those seen in chronic disease anemia, associated with immunologically altered iron metabolism…Frequent findings are: elevated concentrations of serum ferritin, decreased values of serum iron; decreased levels of total transferrin [there is no mention of the possibility that the increased iron may be from blood cells destroyed by nucleoside analogs or other anemia-inducing drugs]”

“Hydroxyurea has become an important drug in the treatment of HIV disease...One of the side effects...is [bone] marrow suppression, which is seen commonly as pancytopenia [deficiency in all types of blood cells], although different cell lineages can be affected individually. Conventional thinking is that stopping hydroxyurea administration will result in quick reconstitution of the suppressed cell lines. We describe two cases of prolonged hydroxyurea-induced marrow suppression in HIV-infected patients...Our patients became transfusion dependent [one for 2-1/2 months, one longer]”

“Toxicity studies of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC [a nucleoside analog similar to AZT]) 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”

“d4T [a nucleoside analog] significantly inhibited erythroid [red blood cell] progenitor cell colonies [the cells in the bone marrow that produce red blood cells]”