Acquired Immunodeficiency Syndrome
Ariela Noy
Roy M. Gulick
HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND ACQUIRED IMMUNODEFICIENCY SYNDROME
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
Background
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.
Pathophysiology
HIV-1 is a retrovirus with a genome that contains the structural genes gag, pol, and env that code for viral core proteins that control viral replication (e.g., HIV reverse transcriptase, HIV integrase, and HIV protease), as well as the envelope glycoproteins, gp 160, 120, and 41.12 Additional regulatory genes, rev and tat, code for viral-specific proteins that control viral transcription and processing of viral messenger RNA. Other viral genes mediate infectivity and interactions with the host cell (nef, vif, vpr, vpu).
HIV entry is the first step in HIV-1 infection and consists of three substeps: CD4 receptor binding, co-receptor binding, and membrane fusion.13 In the first substep, the viral outer membrane glycoprotein, gp120, binds to the CD4 receptor on the surface of the target cell. Cells that express CD4 receptors include the CD4 lymphocyte, macrophages, and dendritic cells. Following binding of gp120 to the CD4 receptor, gp120 undergoes a conformational change and allows binding to a second co-receptor, the chemokine receptor, either CCR5 or CXCR4.14 Individuals who lack the gene that codes for the CCR5 receptor are relatively resistant to HIV infection; individuals who are heterozygotes for this gene demonstrate a slower progression of HIV disease.15 Following binding to the co-receptor, gp120 undergoes a second conformational change that allows a second HIV membrane glycoprotein, gp41, to bind and attach to the cell surface and then allows the viral membrane to fuse with the host cell membrane.
After HIV entry, the contents of the viral particle, including viral RNA and viral proteins, are extruded into the cytoplasm of the target cell. Viral RNA is transcribed to complementary viral DNA by the viral specific enzyme, HIV reverse transcriptase. The viral DNA forms a double-stranded complex that migrates to the nucleus of the cell where the viral-specific protein HIV integrase inserts the viral DNA randomly into the host cell genome. An HIV-infected CD4 lymphocyte may enter a latency period that can extend to 70 years, constituting a long-lived viral reservoir.16 The latently infected cell may be activated, and then genomic DNA along with incorporated viral DNA is transcribed to viral RNA that is translated to viral proteins, including gag and pol gene products that assemble at the surface of the cell and then bud off into new viral particles. Post-budding, precursor viral proteins are cleaved by another viral-specific enzyme, HIV protease, in a step that is required for viral maturation and infectiousness.17 A single latently infected cell can produce hundreds to thousands of virions. When enough viral particles have budded off from an infected cell, the membrane becomes compromised and cell death occurs.
The characteristic decrease in CD4 lymphocytes over the course of untreated HIV disease occurs from a combination of increased apoptosis and decreased lymphopoiesis, although this is not completely understood.18 An estimated one million latently infected CD4 lymphocytes exist in an HIV-infected individual with controlled infection on antiretroviral therapy.19 Although the relative number of latently infected CD4 cells is small, apoptosis may occur in uninfected CD4 cells. Untreated HIV infection also was recognized early on to be associated with immune activation, CD8 cell dysfunction, B-cell dysfunction and impaired antibody production and general immune dysregulation.20, 21
Diagnosis
The U.S. Centers for Disease Control currently recommend routine HIV testing for all individuals aged 13 to 64, not based on risk.22 Standard HIV testing detects HIV-1 antibody by using a screening test, a repeatedly positive enzyme-linked immunosorbent assay (ELISA), followed by a confirmatory test, a Western blot that demonstrates at least two among three major HIV-1-specific bands: p24, gp41, and gp120/160.23 False-positive ELISA may occur because of the low specificity of the test. False-negative HIV antibody tests can occur due to the window period (4 to 6 weeks), the
time between viral infection and the development of the detectable antibody response.
time between viral infection and the development of the detectable antibody response.
Newer rapid tests use a technology similar to the ELISA to detect HIV antibody in blood or oral fluids and results are available within 20 minutes. Although the rapid test is very specific (>99%) with a high positive predictive value (≥90%), a positive rapid test must be confirmed by a conventional confirmatory Western blot.24 Some rapid tests are now CLIA-waived and may be performed in nonhealth care settings (e.g., street fairs, mobile vans or even self-administered at home) allowing more widespread testing.
Another method of HIV testing detects the virus directly, either the viral p24 antigen or HIV RNA, and reduces the window period: p24 antigen testing was added to the standard HIV antibody ELISA test, the so-called 4th generation ELISA test, to detect HIV infections earlier.25 Nucleic-acid-based testing has been used both in individual cases and in blood bank screening programs.26 Using these newer tests along with pre-transfusion screening, the risk of acquiring HIV infection through a blood transfusion in the United States is less than 1 per 1.5 million units transfused and is decreasing.27
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
Treatment
In the 1980s and early 1990s, the average life expectancy of a patient with AIDS was less than 1 year. Today, it is estimated that an individual diagnosed with HIV infection and appropriately managed with antiretroviral treatment will live close to the average life expectancy of the general population.33 Antiretroviral therapy changes the natural history of HIV infection by inhibiting viral replication. Currently, there are 27 U.S. Food and Drug Administration-approved unique drugs for the treatment of HIV infection; combination regimens with 3 or more drugs are standard treatment. Current U.S. HIV treatment guidelines recommend starting antiretroviral therapy in all HIV-infected individuals, regardless of symptoms, HIV viral load, or CD4 cell count.6 The life cycle of the virus and the specific sites targeted by antiretroviral therapy are shown in Figure 64.1.
The oldest mechanistic classes of drugs are the HIV reverse transcriptase inhibitors of two kinds, the nucleoside analogs and the nonnucleoside analogs. The nucleoside analogs mimic the structures of the four DNA bases and when bound to the active site and incorporated into the elongating viral DNA, result in chain termination: adenosine analogs, didanosine (ddI) and tenofovir (TDF); cytosine analogs, emtricitabine (FTC), lamivudine (3TC), zalcitabine (ddC); guanine analog, abacavir (ABC); and thymidine analogs, stavudine (d4T) and zidovudine (AZT, ZDV). The nonnucleoside analogs also inhibit the HIV reverse transcriptase enzyme, but do so by binding a site remote to the active site and include delavirdine (DLV), efavirenz (EFV), etravirine (ETR), nevirapine (NVP), and rilpivirine (RPV).
In the mid-1990s, the third antiretroviral drug class was approved, the HIV protease inhibitors that target a step late in the viral life cycle. Following budding of the viral particles from the infected cell, viral precursor proteins must be chemically cleaved by the viral-specific enzyme, HIV protease. These compounds were the most potent known against HIV and when used in combination regimens resulted in suppression of HIV RNA levels and dramatic decreases in morbidity and mortality.5 The 10 approved protease inhibitors bind in the active site of the protease and block this cleavage: amprenavir (APV) and its prodrug fosamprenavir (FPV), atazanavir (ATV), darunavir (DRV), indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), ritonavir (RTV), saquinavir (SQV), and tipranavir (TPV).
The three newer mechanistic classes of approved HIV drugs are two different HIV entry inhibitors and the HIV integrase inhibitors. The approved chemokine receptor antagonist is maraviroc (MVC) that binds to the host cell CCR5 receptor and prevents viral binding. The approved HIV fusion inhibitor is a small peptide, enfuvirtide (ENF, T-20) that targets the viral glycoprotein gp41 and prevents fusion of the viral and cellular membranes; as a
peptide it requires twice-daily subcutaneous dosing and is used uncommonly. Raltegravir (RAL) and elvitegravir (EVG) inhibits the viral-specific enzyme HIV integrase that inserts the viral DNA into the host cell DNA.
peptide it requires twice-daily subcutaneous dosing and is used uncommonly. Raltegravir (RAL) and elvitegravir (EVG) inhibits the viral-specific enzyme HIV integrase that inserts the viral DNA into the host cell DNA.
 FIGURE 64.1. The human immunodeficiency virus (HIV) life cycle, deciphered with the help of genomic analyses, is unusually complex in its details, but all viruses undergo the same basic steps to infect cells and reproduce. Points at which antiretrovirals act are marked. |
Current treatment guidelines recommend four preferred combination antiretroviral regimens on the basis of potency, tolerability, and convenience6: (1) tenofovir/emtricitabine/efavirenz (co-formulated as a single pill taken once daily); (2) tenofovir/emtricitabine (co-formulated) + atazanavir and ritonavir (given as a low-dose pharmacologic booster; 3 pills once daily); (3) tenofovir/emtricitabine (co-formulated) + darunavir and ritonavir (booster; 3 pills once daily); and (4) tenofovir/emtricitabine (co-formulated) + raltegravir (3 pills divided twice daily). The goal of current HIV treatment is maximal virologic suppression; current virologic suppression rates on initial therapy regimens approach 90%. CD4 cell counts typically increase 100/µL over baseline in the first weeks or months following initiation of therapy and then continue to increase at a slower rate.34 The reconstituted CD4 cells generally are of the memory type (CD45RO+ or CD34RA+), with naïve cells increasing more slowly; thymic function also improves. Immune reconstitution may result in IRIS, the immune-related inflammatory syndrome that is usually managed symptomatically.35 Appropriate increases in CD4 cell counts allow discontinuation of opportunistic maintenance therapy and prophylaxes. Specific immune-based therapies, including interleukin-2, have failed to demonstrate additional clinical benefits and are not recommended currently.36
An HIV-infected individual who is stable taking antiretroviral therapy will typically see the treating physician every 3 to 6 months to check for side effects and monitor the HIV RNA and CD4 cell count.6 In the case of virologic failure, drug resistance testing is performed and a new regimen selected on the basis of treatment history, drug resistance testing results, and available drug options. The goal is to construct a regimen with 2 to 3 fully active drugs and this will result in resuppression of HIV RNA in the majority of patients. HIV therapy currently is lifelong. Treatment interruptions are associated with clinical events37 and should be avoided.
Several ongoing challenges remain in the management of HIV disease. Despite suppression of virologic replication, some patients experience ongoing inflammation and immune activation and this has been linked to nontraditional HIV illnesses such as cardiac, hepatic, renal, neurologic, and non-AIDS malignancies. In addition, despite dramatic improvements in life expectancy, cure of HIV disease remains elusive. The unique case of a man with HIV disease virologically controlled on antiretroviral therapy who developed acute myelogenous leukemia necessitating totalbody irradiation, cytotoxic chemotherapy, and bone marrow transplant from a donor with a deletion in the gene coding for the CCR5-receptor who ultimately experienced a course complicated by rejection and a second transplant is thought to be the only patient cured successfully of HIV disease.38 Cure, or complete eradication of HIV, remains challenging because of the long-lived latently infected CD4 cell reservoir; much current research is focused on this goal.39
HEMATOLOGIC COMPLICATIONS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Anemia
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
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
TABLE 64.1 HEMATOLOGIC TOXICITIES OF ANTIRETROVIRAL DRUGS | |||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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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
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
Treatment
Generally, patients with modest thrombocytopenia (platelet count >50 × 109/L) require no treatment. For others with clinically significant thrombocytopenia, short-term steroids produce rapid responses in 60% to 80% of patients. However, steroids are immunosuppressive and are associated with long-term infectious complications and can accelerate the development of Kaposi’s sarcoma. HIV-specific antiretroviral therapy will result in improvements of platelet counts in most patients. Although most of the original work was done with ZDV, other antiretrovirals are effective. Both antiretroviral agents and steroids improve thrombocytopenia by increasing platelet production, without significantly affecting platelet survival.68, 69 Splenectomy will increase platelet counts in those not responding to antiretroviral therapy and does not appear to accelerate the underlying HIV disease.70 Intravenous immune globulin also is effective but its high cost, limited availability, and short duration of action make this a less attractive treatment. Anti-Rh immune globulin has the advantages of wide availability and cheaper cost, but is also limited by its short duration of action71 and is associated with a mild hemolysis which can be clinically problematic in patients with pre-existing anemia, requiring transfusion prior to administration of anti-Rh immune globulin. Vincristine is effective when given monthly, although its administration is complicated by neuropathy. IL-11, a cytokine that promotes megakaryocyte maturation, is licensed for treatment of chemotherapy-related thrombocytopenia, but no studies have reported efficacy in HIV-infected patients. Rituximab is effective in some patients with idiopathic thrombocytopenic purpura (ITP) without HIV but has not been studied extensively in patients with HIV infection72 for this indication. Three newer treatments for ITP in the general population include the anti-B cell antibody rituximab, effective in 60% of patients, and the thrombopoietin mimetics, romiplostim and eltrombopag, each associated with a 60% to 85% response.73 Remarkably, these drugs have not been systematically studied in HIV-associated ITP.
Neutropenia
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.
Treatment
Neutropenic (absolute neutrophil count, <1.0 × 109/L) HIV-positive patients may experience increased frequency of significant bacterial infections. In a case-controlled study, Tumbarello et al.75 compared the neutrophil counts of groups of HIV-infected patients with and without bacteremia. An absolute neutrophil count of <1.0 × 109/L as present in 38% of bacteremic patients was compared with 19% of asymptomatic patients. A matched cohort study76 found the frequency of bacteremia increased in neutropenic patients to 12.60 events per 100 patient months compared with 0.87 events per 100 patient months in the nonneutropenia controls. In another study of 1,645 patients with an absolute neutrophil count of <0.5 × 109/L the risk of Gramnegative infection increased eightfold.77
A number of studies have looked at the effect of recombinant growth factors on the incidence of infection and number of hospitalizations. Granulocyte colony-stimulating factor (G-CSF) enhances the proliferation and differentiation of neutrophils and improves neutrophil function, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the proliferation and differentiation of a variety of myeloid progenitor cells and inhibits migration of neutrophils, enhancing the function of mature neutrophils and macrophages.71, 78 G-CSF is the most widely used hematopoietic growth factor in HIV-infected patients, has fewer side effects, and increases the neutrophil count more rapidly. Although GM-CSF has been associated with an increase in HIV-1 replication in vitro, no consistent observation of acceleration of disease progression or increase in p24 antigen levels in patients receiving the drug has been demonstrated. GCSF is primarily used to increase the tolerance of patients undergoing chemotherapy.
HIV-infected patients can also have a number of defects in neutrophil function. These include reduced L-selectin shedding and decreased H2O2 production79 as well as defects in leukocyte migration, chemotaxis, and chemiluminescence during phagocytosis. These defects were more prominent in patients with advanced disease.80 G-CSF and GM-CSF both improve leukocyte function in vitro. A number of studies have looked at potential benefits of these cytokines in animal models of immunosuppression. In a murine model of Pneumocystis jiroveci pneumonia, CD4+-depleted immunosuppressed mice that received G-CSF after experiential pulmonary infection with P. jiroveci demonstrated improved survival when compared with control mice receiving placebo. Similar benefits were demonstrated using mouse models of disseminated Mycobacterium avium infection, systemic candidiasis, and streptococcal pneumonia.81 No clinical study using either G-CSF or GM-CSF to enhance leukocyte function has been performed.
Lymphopenia
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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