Acquired Immunodeficiency Syndrome

Acquired Immunodeficiency Syndrome

Ariela Noy

Roy M. Gulick


Human immunodeficiency virus (HIV) infection is a true pandemic, an infection that affects individuals in every country of the world.1 A diagnosis of acquired immunodeficiency syndrome (AIDS) is made when a person with HIV infection progresses to develop severe immunodeficiency as demonstrated by a CD4 lymphocyte count of less than 200/µl or the development of specific AIDS-associated diseases.2 The first cases of AIDS were described in 1981 in five young gay men in Los Angeles.3 Since the beginning of the HIV pandemic, an estimated 70 million people worldwide acquired HIV infection and over half of them died.1 Currently, an estimated 34 million people are living with HIV infection, with over two thirds of them living in sub-Saharan Africa. There are an estimated 1.1 million people currently living with HIV infection in the United States.4 The development of effective antiretroviral treatment in 1996 changed the natural history and clinical course of HIV infection dramatically, with remarkable decreases in HIV-associated illnesses and deaths.5 In parallel, many of the hematologic complications of HIV infection also occur much less commonly today. Cytopenias due to HIV disease or its treatment occurred frequently in the past, but now are uncommon. Coagulation abnormalities occur occasionally. Hematologic malignancies remain an important challenge, even in the setting of effective HIV treatment. This chapter discusses HIV infection and the diagnosis and management of associated hematologic complications. A complete discussion of antiretroviral therapy and opportunistic diseases can be found elsewhere.6, 7, 8


HIV-1 was discovered by two independent groups in 1983 to 1984.9 A related virus, HIV-2, was discovered in 1986, but remains localized to Western Africa and countries with historic ties to Western African countries.10 HIV is transmitted most commonly worldwide by sexual contact and also by intravenous drug use, transfusion of infected blood or blood products, and perinatally from an infected mother to her child. HIV may be transmitted by infected blood, blood products, bloody fluids, or genital secretions, but not by saliva, sweat, urine, other nonbloody fluids, or feces. In the absence of HIV treatment, the time from initial HIV infection to the development of severe immunodeficiency and AIDS is approximately 10 years.11 The U.S. Centers for Disease Control and Prevention define AIDS in individuals who are HIV-1 antibody positive with a CD4 cell count <200/µL (regardless of symptoms) or have one of ˜25 AIDS-defining illnesses, including opportunistic infections and malignancies.2 Effective antiretroviral therapy changes the natural history of the disease and prevents HIV disease progression and prolongs survival.

Clinical Features of Hiv-1 Infection

Acute HIV infection can present as a nonspecific illness characterized by fever, oral ulcers, and maculopapular rash28; however, at least 50% of newly infected individuals may be completely asymptomatic. The clinical illness will subside over several weeks and then the patient enters an asymptomatic phase, often with nonspecific generalized lymphadenopathy, that may last years as the CD4 lymphocyte count gradually declines over time. HIV-related diseases occurring at higher CD4 counts (>300/µL) include those caused by more aggressive pathogens (e.g., tuberculosis, herpes zoster, and pneumococcal pneumonia) as well as Kaposi’s sarcoma. As the CD4 cell count declines below 300, other HIV-related illnesses also occur, including oral hairy leukoplakia, oral thrush, and seborrheic dermatitis. As the CD4 cell count declines below 200, the case definition of AIDS is met and AIDS-defining illnesses may also occur including Pneumocystis jiroveci (formerly carinii) pneumonia, central nervous system (CNS) toxoplasmosis, and cryptococcal meningitis. Multiple opportunistic illnesses can occur simultaneously in a single patient.

Hematologic disorders such as leucopenia, anemia, immune and thrombotic thrombocytopenia, bone marrow failure, coagulation disorders including thrombosis, and malignancies all occurred commonly in HIV-infected individuals.29, 30 Some of these complications were due to viremia and immune dysregulation, and others were due to toxicity from HIV therapies.31 With the development of effective antiretroviral therapy, hematologic disorders and HIV-associated malignancies have decreased markedly.32



Anemia is the most frequent cytopenia observed in HIV-1 infection. Striking anemia with transfusion dependence was common early in the epidemic when high doses of zidovudine (ZDV) were in use, but severe depression of hemoglobin levels are now rarely observed, except in patients with advanced disease.40 In several large multicenter studies, persistent anemia was associated with shorter survival, independent of the degree of immunosuppression.41, 42

As in other persons, anemia occurs due to one of three major factors: either ineffective hematopoiesis; blood loss due to involvement of the intestines by infection such as cytomegalovirus (CMV) or Kaposis’s sarcoma; or red blood cell destruction.

Red blood cell production can be affected by HIV itself due to cytokines that interfere with hematopoiesis,43, 44, 45 highly active antiretroviral therapy (HAART) and medications used to treat HIV-associated infections (Table 64.1 including high-dose trimethoprim-sulfamethoxazole (TMP-SMX) for P. carinii pneumonia and ganciclovir for CMV), HIV-associated cancers such as lymphomatous infiltration of the marrow, low erythropoietin, or HIV-associated hypogonadism.46

The Effect of HAART on Anemia

Nucleoside analogs other than ZDV are not associated with anemia. Zidovudine is commonly associated with marrow toxicity, particularly with long-term administration. Use of lower ZDV doses in combination with other nonmyelosuppressive antiviral drugs (such as the protease inhibitors or other nucleoside analogs) has significantly decreased the frequency of anemia, although patients with advanced disease on doses of ZDV of <500 mg/day still demonstrate significantly decreased hemoglobin levels when compared to similarly immunosuppressed HIV-infected patients not taking the drug.47 Although the mechanism responsible for ZDV-associated anemia, inhibition of thymidine kinase, and DNA chain termination should theoretically also affect cells of other lineages, neutropenia is less frequent a toxicity and thrombocytopenia is very uncommon. In contradistinction to zidovudine, protease inhibitors, such as indinavir, ritonavir, crixivan, and nelfinavir, alone or in combination with ZDV or other nucleoside
analogs, have little or no effect on hematopoiesis.31, 48 It is important to note that HAART itself improves anemia as shown in a single center retrospective series in the HAART era. HAART was associated with hemoglobin levels >140 g/L in 42% of patients, irrespective of use of zidovudine as part of HAART regimen, compared with 31% of patients who did not use HAART.49



Type of Activity

Hematologic Toxicity


Nucleoside analogs, antiviral

Anemia, neutropenia (dose dependent)


Nucleoside analogs, antiviral

Anemia, neutropenia (dose dependent)


Cytomegalovirus infection

Leukopenia, thrombocytopenia


Antibiotic, Pneumocystis pneumonia

Dose-related neutropenia, anemia; methemoglobinemia especially in persons with G6PD deficiency


Antibiotic, Pneumocystis pneumonia

Rare agranulocytosis, thrombocytopenia; methemoglobinemia especially in G6PD deficiency


Pneumocystis pneumonia

Infrequent anemia, leukopenia, thrombocytopenia



Leukopenia in 40%; thrombocytopenia in 12%



Cytopenias in 31%

Amphotericin B

Antifungal, cryptococcal meningitis


G6PD, glucose-6-phosphate dehydrogenase.

Treatable causes of anemia include nutritional/vitamin deficiency, gastrointestinal losses, parvovirus B19 infection,50, 51 HIV related kidney disease, and low erythropoietin levels independent of normal renal function. In HIV infection, erythropoietin levels are low in some patients, in part because tumor necrosis factor-α (TNF-α) acts to block erythropoietin release in response to low hemoglobin levels.52 Patients with low erythropoietin levels respond better to its administration than do patients with normal or elevated levels of the hormone. In one meta-analysis, patients with erythropoietin levels below 500 IU/L demonstrated significant increases in hemoglobin levels, decreases in transfusion requirements, and improvement in quality of life, whereas replacement was ineffective in patients with high erythropoietin levels.53

Some patients with HIV infection have significant anemia, requiring frequent transfusion. Clinical and experimental evidence suggests transfusion may be associated with substantial morbidity in HIV-infected patients. In one study, transfused patients with advanced disease had an increased incidence of CMV infection and death.54 Laboratory data suggest transfusion may be associated with HIV viral activation. Allogeneic lymphocytes present in transfused blood components activate viral production by HIV-infected lymphocytes in vitro.55 When quantitative polymerase chain reaction (PCR) was used to measure circulating HIV, viral load was increased in HIV-infected patents 5 days after transfusion.56 However when leuko-depleted blood components were used, no significant differences in viremia or infectious complications occurred.57

Red Blood Cell Destruction

Red blood cells can be destroyed in the setting of HIV infection through a variety of mechanisms. This includes autoimmune disease,58 hemophagocytic syndrome, disseminated intravascular coagulation typically seen with infection or cancer, sulfa use in the setting of 6-GPD deficiency, or thrombotic thrombocytopenic purpura (TTP) (dealt with separately below). Drugs can also cause hemolysis.

Parvovirus is a rare, but treatable cause of anemia. Parvovirus affects erythroid lineage cells. In immunocompetent patients this is a self-limited infection, but is serious in patients who cannot clear the infection, or have other hemolytic problems. For parvovirus infection, commercial immune globulin infusion (400 mg/kg/day for 5 to 10 days) is almost always associated with marked improvement in hemoglobin levels with resolution of anemia.51, 59 HIV-infected patients frequently develop repeated episodes of B19 infection and need repeated treatments with intravenous immune globulin.60


Thrombocytopenia occurs in the setting of HIV infection due to decreased production, increased destruction, or splenic sequestration secondary to other causes such as lymphoma or hepatitis C. Although mild to moderate thrombocytopenia is common in patients with HIV, it is rarely associated with bleeding. Thrombocytopenia is generally associated with decreased platelet survival, except in patients with advanced disease where bone marrow failure is more prominent.61 Opportunistic infection, splenomegaly, and fever all decrease platelet survival.

Autoimmune thrombocytopenia (ITP) is a feature of HIV infection and is a diagnosis of exclusion. Notably, patients can present in advance of other symptoms of HIV. Consequently, HIV should be ruled out in new cases of ITP. CD4+ lymphocyte counts in reported series of patients with HIV-ITP have averaged between 0.3 and 0.6 × 109/L.

Although platelet-associated antibodies increase in prevalence with HIV disease progression, it is not clear if they play a major role in most patients. Technical difficulties in detecting platelet-associated antibody have led to a very high false-positive rate.62 Furthermore, for any condition (including sepsis and TTP) associated with platelet injury, antibody can be detected on the platelet surface. Specific platelet-associated antibody has nonetheless been carefully characterized in a limited number of patients. One study demonstrated that platelet-associated immune complexes are made up of antiplatelet integrin, glycoprotein IIIa (β3), antibody (Ab), and its anti-idiotype blocking Ab.63 Some of the antibodies also bound epitopes with homology to HIV-1 proteins nef, gag, env, and pol, suggesting molecular mimicry. The presence of this Ab was associated with thrombocytopenia and produced thrombocytopenia when infused into mice.64 The associated platelet fragmentation was due to generation of the membrane-damaging peroxide and other reactive oxygen species. Antibodies to a cleavage product of talin, which can be generated by platelet activation or exposure to HIV-1 protease, have also been characterized. These may result from an immune response to talin-H, a neoantigen that may have been created by platelet fragmentation.65

Defective megakaryocytopoiesis may also contribute to thrombocytopenia, particularly in patients with advanced disease. Megakaryocytes can be infected with certain strains of HIV, some of which can be cytopathic for the megakaryocytes.66 In addition, megakaryocytes arising from HIV-1-infected CD34+ progenitor cells are defective in their ability to produce platelets.67


Mild neutropenia is relatively common in patients with HIV infection. Although generally not of clinical significance, a deficiency in bone marrow reserve may become clinically apparent when administration of cytotoxic chemotherapy or other marrowsuppressive drugs becomes necessary. In fact it is generally held that most cytotoxic chemotherapy requires prophylactic use of hematopoietic growth factors. Antineutrophil antibodies can frequently be seen,62 but their presence does not correlate with the degree of neutropenia. Progenitor cell numbers are generally normal except in patients with advanced disease when they are modestly decreased.74 Parenteral treatment with ganciclovir (GCV) or cytotoxic chemotherapy results in leukopenia in the majority of patients, frequently necessitating dose reduction and cytokine treatment.


Increases in both CD4 and CD8 cell death and impairment in function are the sine qua non of HIV infection. IL-2 partially corrects the impaired lymphocyte proliferation and cytotoxicity seen in HIV infection in vitro. It also can partially block the enhanced tendency of lymphocytes obtained from HIV-infected patients to undergo programmed cell death (apoptosis).38 In phase I trials of IL-2 in HIV-infected patients, it increased CD4 cell number and improved lymphocyte function.82 The development of a longacting polyethylene glycol-modified IL-2, which increases the half-life by 10- to 15-fold, allows for intermittent administration of the drug. Administration of doses of 1 to 5 million U/m2, two to three times weekly, resulted in modest but sustained increases in CD4 counts and improvement in natural killer activity in a patient with CD4 counts >0.4 × 109/L83 in 3 to 6 months. Fever, rash, and capillary leak are the most common toxicities.84 More recently, administration of very high doses of IL-2 (7.5 million IU twice daily to patients with early HIV infection) resulted in substantial increases in CD4 counts, compared with those seen in the group administered lower doses (1.5 million IU twice daily).85 Of greater importance is the suggestion that intermittent administration of IL-2 in combination with HAART may lead to reduction in CD4+ T-lymphocyte cells that contain replication-competent HIV.86 None of these approaches is currently standard of care.

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Oct 21, 2016 | Posted by in HEMATOLOGY | Comments Off on Acquired Immunodeficiency Syndrome
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