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Intravenous Gammaglobulin Treatment in HIV-1 Infection
I ntravenous Gammaglobulin Treatment in HIV -1 I nfe c tion Avi Deener, MDa, Ami Mehra, MDa, Larry Bernstein, MDa, Jenny Shliozberg, MDa, Arye Rubinstein, MD, PhDa,b,* KEYWORDS Immunodeficiency B cells T cells Highly active antiretroviral therapy (HAART) HIV-1 AIDS Thrombocytopenia Opportunistic infections
HISTORICAL BACKGROUND OF GAMMAGLOBULIN REPLACEMENT IN HIV/AIDS
In 1978–1979, children with an unusual clinical and immunologic profile were observed at Albert Einstein College of Medicine.1–3 These children presented with recurrent bacterial infections; several had multiple septic episodes with the same organism that failed to respond to specific antibodies.1,4 Their clinical presentation appeared typical for a B-cell deficiency such as Bruton’s agammaglobulinemia. In contrast to parents of children with congenital B-cell deficiencies, parents of these children also presented with immune aberrations, including cell-mediated immunity and B-cell immunity, which suggested that a transmittable infectious agent may be involved. Researchers soon recognized that the children’s B-cell deficiency was unique in its immunologic and histopathologic profile. They had a prominent generalized lymphadenopathy, and their lymph node biopsies revealed a marked proliferation of B cells. They also exhibited a pan-hypergammaglobulinemia that encompassed all three immunoglobulin classes: IgA, IgM, and IgG.1–3 Despite the hypergammaglobulinemia, they failed to mount specific antibody responses to various antigens.5 Most prominent was their inability to mount specific antibodies to polysaccharide antigens.
This work was supported by Grant No.AI051519 from the National Institutes of Health. a Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461, USA b Department of Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461, USA * Corresponding author. Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461. E-mail address: [email protected] (A. Rubinstein). Immunol Allergy Clin N Am 28 (2008) 851–859 doi:10.1016/j.iac.2008.06.001 immunology.theclinics.com 0889-8561/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Treatment of these children, who were later identified as being infected with HIV-1, with intravenous immunoglobulin (IVIG) not only abolished the recurrent bacterial infections 6–8 but also induced previously unexpected immunomodulatory effects.8–14 The introduction of antiretroviral therapies had an effect on immune functions in pediatric and adult patients infected with HIV-1, in most instances deviating the need for IVIG. USE OF INTRAVENOUS GAMMAGLOBULIN IN THE PRE-ANTIRETROVIRAL ERA
The B-cell immune system in children infected with HIV-1 is more compromised than that of adults who have HIV-1. Maturation of the B-cell compartment is physiologically incomplete at birth, and protection against common pathogens is provided by passive transplacental transfer of maternal IgG. Even babies with Bruton’s agammaglobulinemia usually enjoy an infection-free interval of 6 to 9 months through passive immunity. This is not always the case in infants who are infected with HIV-1. Because humoral (B-cell) and cellular (T-cell) immune defects are noted in pregnant women who are infected with HIV-1, the protection of their infants through passive immunity is incomplete. This finding explains the often earlier onset of bacterial and septic infections in individuals who are infected with HIV-1. The maturation of B cells in infants who are infected with HIV-1 is further compromised by the inadequate interaction provided by dysfunctional T cells and by abnormal thymic epithelium function. Decreased levels of circulating thymulin, a marker of thymic dysplasia, have been noted in infants infected with HIV-1.15 In 1979, our rationale for the introduction of IVIG in children infected with HIV-1 was based on documents of in vivo defective primary and secondary antibody responses to a T-cell–dependent bacteriophage neoantigen (4X174), tetanus toxoid, and a B-cell–dependent pneumococcal polysaccharide antigen.5,16 The poor secondary responses to these antigens included abnormal class switches from IgM to IgG.16 Further in vitro evidence of B-cell dysfunction was the poor lymphocyte proliferative response to Pokeweed mitogen and Staphylococcal aureus, a T-cell–independent B-cell mitogen.1–3 Pokeweed mitogen also failed to induce in vitro B-cell secretion of IgG in the presence of normal T lymphocytes.12 The IVIG regimen used between 1979 and 1982 was the same as that used for patients who had agammaglobulinemia (200–300 mg/kg monthly). In 1982, evidence emerged for an associated multitude of immune aberrations, including markedly elevated circulating immune complexes,9,13 elevated serum neopterin levels,10 elevated serum tumor necrosis factor a,11 elevated serum b2-microglobulin,14 isomorphic elevation of serum lactate dehydrogenase,17 and T-cell dysregulation of humoral immunity.12 The IVIG regimen was subsequently modified to address the additional factors. The dose was increased to 300 mg/kg every 2 weeks (instead of every 4 weeks). The following account details the clinical and immune alterations by IVIG in a 10-year follow-up of 112 children aged 9 months to 6 years who were treated by the latter intensified protocol. Infectious Complications
Only mild upper respiratory infections occurred. No additional episodes of sepsis were noted at 300 mg/kg biweekly as compared with 13 serious bacterial infections in children who received 200 to 300 mg/kg monthly. Immunomodulatory Effects
Serum IgG levels did not increase over baseline in IVIG-treated patients, whereas a progressive increase in serum IgG was noted in most untreated infants. After IVIG
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treatment there was a statistically significant decrease in b2-microglobulin and lactate dehydrogenase levels. As markers of immune activation, neopterin10 and tumor necrosis factor a also decreased or normalized.11 Circulating immune complexes levels decreased in 77% of patients on the intensified IVIG protocol but in none of 24 untreated patients and in 10 patients who received the monthly IVIG dose of 200 mg/kg.9,13 In children infected with HIV-1, the CD81 T-cell compartment is markedly increased, but these cells are of poor function, as documented by the failure of CD81 T cells to suppress in vitro Pokeweed mitogen–driven IgG secretion.12 The reduced Pokeweed mitogen–driven IgG secretion normalized in 80% of studied subjects after IVIG treatment. The absent in vitro Concanavalin A generation of suppressor T cells was restored in IVIG-treated patients.12 Statistically significant increases in percentage and absolute T-cell counts were observed in 43% of treated patients. This trend persisted in most patients for up to 10 years until highly active antiretroviral therapy (HAART) was introduced.6–8 In vitro lymphocyte mitogenic responses to phytohemagglutinin increased transiently in 71% of patients who received IVIG.6 A large National Institute of Child Health and Human Development (NICHD) randomized double-blind placebo controlled multicenter IVIG study on children infected with HIV-1 was conducted 10 years later. This study corroborated most of the earlier findings, although the benefits achieved were not as robust. The IVIG regimen used was different in that 400 mg/kg were administered every 4 weeks.18–21 In this trial, children who had a baseline CD41T-cell count of more than 200/mL remained free from serious laboratory-proven and clinical diagnosed bacterial infections.18–20 In contrast to our studies with the higher IVIG dose, no statistically significant benefit was noted in children with fewer than 200 CD41T-cells/mL. This difference is probably due to the less intensive IVIG regimen. The NICHD study confirmed the immunomodulatory effect on CD41 T cells with a statistically significant slower decline in CD41 T-cell counts.21 IVIG also was used to treat several autoimmune manifestations, most prominently thrombocytopenia, which is a frequent complication of several conditions, including pediatric HIV-1 infection,22 sepsis,23 and conditions that involve antiplatelet IgG.24 The incidence of thrombocytopenia in children infected with HIV-1 who were on prophylactic IVIG was lower than in untreated patients. Thrombocytopenia, including septic thrombocytopenia, responded promptly with increased platelet counts after high-dose IVIG at 1 g/kg.22–24 The numeric platelet responses were not always associated with a favorable clinical outcome, however. In contrast to adults with HIV-1–associated thrombocytopenia, children may have antiplatelet antibodies and autoantibody-mediated vasculitis or clotting factor abnormalities.25 As a result, they have more frequent episodes of bleeding and a poorer prognosis. Intravenous Gammaglobulin in Adults Who Have HIV-1 Infection
Questions have been raised as to whether IVIG plays a role in adults who are infected with HIV-1.26 HIV-1 infected adults may retain their full complement of B cells, including anamnestic antibody responses, for a while because they were formed before their HIV-1 infection. As a result, adults who have HIV-1 infection are less susceptible to infections with common pathogens. HIV-1 can, however, profoundly affect humoral immunity in a subset of infected adults. Polsky and colleagues27 and Selwyn and colleagues28 reported a marked increase in the number of bacterial pneumonias, mainly caused by Staphylococcus pneumoniae and Haemophilus influenza, in adults who have AIDS, most of whom were substance abusers. Janoff and colleagues29
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estimated that the rate of pneumococcal bacteremia among patients who have AIDS was 100-fold higher than in age-matched controls. These findings formed the rationale for use of IVIG in adults. Several uncontrolled clinical trials have not shown conclusive benefits to routine IVIG prophylaxis. There was also no evidence that IVIG delayed progression of HIV-1–related disease or had immunomodulatory effects as noted in children who were infected with HIV-1. In a small randomized IVIG trial, Schrappe-Bacher and colleagues30 showed no changes in CD41 cell counts or other clinical and immunologic parameters. These studies should not exclude the use of IVIG for adults who are infected with HIV-1 with recurrent bacterial infections that are not well controlled with antibiotics. In this subset of patients, the use of bacterial vaccines was first studied. Because initial uncontrolled studies suggested an acceptable immunogenicity of polysaccharide vaccines, pneumococcal vaccines were recommended as a standard of care for adults who are infected with HIV-1 in North America and the United Kingdom. Unfortunately, a meta-analysis of prospective randomized pneumococcal vaccine trials did not show efficacy among the subgroup of North American adults infected with HIV-1.31 A second clinical trial with a pneumococcal vaccine was evaluated in Africa, where invasive pneumococcal disease was particularly prevalent in adults who are HIV-1 infected. The study showed not only lack of efficacy but also evidence of vaccine harm,32 probably caused by immune activation. We have shown in an animal model that HIV-1 was enhanced by the capsular polysaccharide of Cryptococcus neoformans.33 Brichachek and colleagues34 noted an increased plasma HIV-1 burden after challenge with a pneumococcal vaccine. We reported transient up-regulation of HIV-1 transcription after a phage FX174 vaccine16 and pneumococcal immunizations. After bacteriophage immunization, a transient decline in CD41 cells was noted. It was recommended that vaccination should preferably be administered only in tandem with antiretroviral therapy. Because it is unclear what level of antibodies is protective in HIV-1 infected patients and the finding that bacterial vaccines may be ineffective or harmful, prophylactic IVIG may be an option in patients with documented recurrent bacterial infections and absent or marginal bacterial vaccine responses. There is evidence for the use of IVIG in adults with autoimmune thrombocytopenia. The incidence of thrombocytopenia in adult patients who have HIV-1 is estimated at 65 per 10,000 persons, whereas the incidence of thrombocytopenia in HIV-1–negative patients is estimated at 1.5 per 10,000 individuals.35,36 The introduction of HAART has been effective in mitigating thrombocytopenias, but no studies are available on the incidence of autoimmune thrombocytopenia for patients treated with HAART. The two most common treatments, steroids and splenectomy, remain undesirable for patients who have thrombocytopenia and HIV-1, regardless of whether they are on HAART. In a study by Cai and colleagues,37 the use of steroids was associated with an increased risk of developing Kaposi’s sarcoma. Splenectomy was associated with an increased susceptibility to infections with encapsulated organisms. In a recent study by Gyongyossy-Issa and colleagues,38 the thrombopoietic responses to IVIG treatment were evaluated in patients who were uninfected with HIV-1 and had immune thrombocytopenic purpura and patients who had HIV-1–associated autoimmune thrombocytopenia. The initial response to IVIG in HIV-1 autoimmune patients who had thrombocytopenia was similar to that seen in patients who were not infected with HIV-1. Often-repeated doses were required to maintain an adequate response, however.39 As a result, the question was raised as
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to whether low-dose IVIG is effective. In 13 patients treated with low-dose IVIG (400 mg/kg/wk for 5 weeks), Majluf-Cruz and colleagues40 demonstrated a sustained response 3 months after the end of treatment. Anti-D therapy has been studied in the treatment of HIV-1–associated thrombocytopenia as an alternative to IVIG. In a prospective study, 14 Rh1 patients who had HIV-1 received 12 to 25 mg/kg of anti-D IgG intravenously on 2 consecutive days. Nine patients had a rapid and significant increase in their platelet counts. These data suggested that anti-Rh IgG is effective and safe in HIV-1–related thrombocytopenic purpura.40 A small, prospective, randomized study by Scaradavou and colleagues41 compared anti-D therapy with IVIG. Nine patients who were Rh1 and had HIV-1 were treated with IVIG or anti-D for 3 months. Patients who were treated with anti-D demonstrated higher mean peak platelet counts and longer duration of response. Anti-D resulted in a mean peak platelet count of 77,000/mL compared with only 29,000/mL after IVIG (P 5 .07). The mean duration of response was significantly longer in patients treated with anti-D (41 days) compared with IVIG (19 days; P 5 .01). This study may support the use of anti-D as first-line therapy in patients who are Rh1 and have HIV-1 and need urgent treatment for thrombocytopenia. In a retrospective study, Lesprit and colleagues42 compared the cost of anti-D therapy to high-dose IVIG. The cost of IVIG per treated episode was $4269, compared with $2716 for anti-D therapy. Overall, based on the evaluation of incidence, treatment patterns, and hospital care required, anti-D therapy was associated with significantly lower costs. Because lower doses of IVIG also were found to be effective, however,40 it remains more cost effective than anti-D therapy. Rheumatic manifestations may develop at any time during the clinical spectrum of HIV-1 infection, but they are usually seen more often in late stages. Various disorders may be seen, particularly Reiter’s syndrome and undifferentiated spondyloarthropathy. Most patients do well with conventional anti-inflammatory therapy, but some patients require immunosuppressive-cytotoxic therapy. IVIG has not been studied in these situations, except for in cases of polymyositis, in which patients who received high-dose IVIG showed dramatic improvement.43 USE OF INTRAVENOUS GAMMAGLOBULIN IN THE ERA OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPIES
Recent advances with HAART have dramatically reduced mortality and morbidity and prolonged life expectancy. Immune restoration is an important component of HAART. There is an initial increase in CD41 and CD81 T cells and B cells followed by improved in vitro lymphocyte proliferative responses and the return of delayed-type skin hypersensitivity reactions.44 Not all patients demonstrate a substantial T-cell reconstitution, and no controlled studies evaluated the restoration of the functional integrity of the humoral immune responses. Most studies on the restoration of B-cell function or the lack thereof were performed in children with HIV-1 infection and may not reflect the situation in adults. Questions that were raised discussed whether HAART restores the humoral immune system in children who are infected with HIV-1 to function in a relatively normal way; that is, to recognize an antigen, produce antibodies to that antigen, and create and sustain memory B cells for quick production of protective antibodies in the event of re-exposure. One of the first studies that examined this issue was published in 1996. In the face of a measles epidemic in New York City, Arpadi and colleagues45 studied measles antibody titers among children aged 9 to 168
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months who had HIV-1. They correlated measles titers with CD41 cell counts along with other parameters, including age of first measles immunization and the number of immunizations. They found that CD41 T-cell counts had a positive correlation with one’s ability to maintain measles antibodies. Among children who had no T-cell immunosuppression, 82% maintained immunity, whereas among the most severely compromised (CD41 T-cell counts % 600/mL) only 53% had positive measles antibody titers. Overall, 72% of previously vaccinated children maintained immunity compared with 95% of healthy children. Treatment with zidovudine at the time of vaccination was significantly associated with the children testing seropositive to measles. Moir and colleagues46 studied the mechanisms by which uncontrolled HIV-1 infection may compromise B-cell function. They showed that in viremic patients (patients who were either on HAART-resistant regimens or were noncompliant with HAART) compared with aviremic patients who had HIV-1, B cells were less responsive to CD41 T cells. This finding was still true when controlling for CD41 T-cell numbers. Their studies showed that this B-cell dysfunction was likely related to B cells’ inability to up-regulate CD25 (interleukin-2 receptor) in response to appropriate CD41 T-cell signaling in the presence of HIV-1 viremia. Thus, HIV-1 viremia may cause an inherent B-cell dysfunction independent of T-cell function. Bekker and colleagues47 documented that even after immune reconstitution with effective HAART, B-cell memory was not restored to vaccination (MMR) and naturally occurring viral pathogens (VZV, CMV, EBV). The most imperative of B-cell functions— providing specific antibodies to previously exposed antigens—was not restored. Overall, 40% of the patients lost immunity to measles, 38% lost immunity to mumps, and 11% lost immunity to rubella. Only 43% maintained immunity to all three pathogens, and 20% lost varicella zoster virus titers after being followed longitudinally on HAART. B-cell reconstitution by HAART was also studied by Rosenblatt and colleagues48 in children aged 4 months to 17 years who were HIV-1 infected and lost their titers to tetanus and then underwent HAART therapy. These children had only mild to moderate impairment in their immune status before enrolling in this study; their percentage of CD41 cells was more than 15% with a median absolute count of 976 cells. After reimmunization with tetanus, most (74%) had a good response 4 weeks later; however, the percentage of patients with a positive titer dropped to 67% at 8 weeks, 53% at 18 weeks, and 38% at 32 weeks. In a study that compared patients who had common variable immune deficiency, patients who underwent splenectomy, and patients who had HIV-1 infection, Hart and colleagues49 reported a decreased response to Pneumovax among individuals who had HIV-1 infection and were on HAART. They showed that this poor response was caused by a relative deficiency in IgM memory B cells. This finding provided an explanation for the increased risk of invasive pneumococcal disease among people who have HIV-1 infection. These data suggested that a segment of patients who have HIV-1 who exhibit poor B-cell functions, respond poorly to bacterial vaccines, and have recurrent bacterial infections may be candidates for prophylactic IVIG treatment. No controlled studies have documented the immunomodulatory effect of IVIG on patients who are infected with HIV-1 and are on HAART; nor have studies examined the effect that IVIG may have on reducing morbidity and mortality. The use of IVIG for autoimmune manifestations on HAART remains controversial and an unchartered field. It plays a role in autoimmune thrombocytopenia for the preHAART era.
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REFERENCES
1. Rubinstein A, Sicklick M, Gupta A, et al. Acquired immunodeficiency with reversed T4/T8 ratios in infants born to promiscuous and drug-addicted mothers. JAMA 1983;249:2345–9. 2. Rubinstein A. Acquired immunodeficiency syndrome in infants [editorial]. Am J Dis Child 1983;137:825–6. 3. Rubinstein A, Bernstein L, Small C. Autoantibodies to AIDS-T cells. Ann N Y Acad Sci 1985;437:508–9. 4. Bernstein L, Krieger BZ, Novick B, et al. Bacterial infection in the acquired immunodeficiency syndrome of children. Pediatr Infect Dis 1985;4:472–5. 5. Bernstein L, Ochs H, Wedgewood R, et al. Defective humoral immunity in children with AIDS. J Pediatr 1985;107:352–7. 6. Rubinstein A, Calvelli T, Rubinstein R. Intravenous gammaglobulin for pediatric HIV-1 infection: effects on infectious complications, circulating immune complexes and CD4 cell decline. Ann N Y Acad Sci 1993;693:151–7. 7. Calvelli T, Rubinstein A. Immunodeficiency: pediatric AIDS. In: Rosen FS, editor. Clinical aspects of immunology. 5th edition. Oxford, England: Blackwell Scientific Publication, Ltd; 1993. p. 1341–68. 8. Calvelli TA, Rubinstein A. Intravenous gamma-globulin in infant acquired immunodeficiency syndrome. Pediatr Infect Dis 1986;5:S207–8. 9. Ellaurie M, Calvelli T, Rubinstein A. Human immunodeficiency virus (HIV) circulating immune complexes in infected children. AIDS Res Hum Retroviruses 1990;6:1437–44. 10. Ellaurie M, Calvelli T, Rubinstein A. Neopterin levels in pediatric HIV infection as predictor of disease activity. Pediatr Infect Dis J 1992;11:286–9. 11. Ellaurie M, Rubinstein A. Tumor necrosis factor in pediatric HIV-1 infection. AIDS 1992;6:1265–8. 12. Gupta A, Novick ME, Rubinstein A. Restoration of suppressor T-cell functions in children with AIDS following intravenous gamma globulin treatment. Am J Dis Child 1986;140:143–6. 13. Ellaurie M, Calvelli T, Rubinstein A. Immune complexes in pediatric HIV infection. Am J Dis Child 1990;144:1207–9. 14. Ellaurie M, Rubinstein A. Beta-2-microglobulin concentrations in pediatric human immunodeficiency virus infection. Pediatr Infect Dis 1990;9:807–9. 15. Rubinstein A, Novick BE, Sicklick MJ, et al. Circulating thymulin and thymosin a1 activity in pediatric acquired immunodeficiency ayndrome (in vivo and in vitro studies). J Pediatr 1986;109:422–7. 16. Rubinstein A, Mizrachi Y, Bernstein L, et al. Progressive specific immune attrition after primary, secondary and tertiary immunizations with bacteriophage 4X174 in asymptomatic HIV-1 infected patients. AIDS 2000;14:F55–62. 17. Silverman B, Rubinstein A. Serum lactate dehydrogenase in adults and children with AIDS and ARC: possible indicator of B cell proliferation and disease activity. Am J Med 1985;78:728–36. 18. The NCHD Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic HIV infection. N Engl J Med 1991;325:73–80. 19. Mofenson LM, Moye J Jr, Bethel J, et al. Prophylactic intravenous gammaglobulin in HIV-infected children with CD41 counts of 0.20/L or more. JAMA 1992;268:483–8. 20. Mofenson LM, Moye J Jr, Korelitz J, et al. Crossover of placebo patients to intravenous immunoglobulin confirms efficacy for prophylaxis of bacterial infections
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n S, et al. Usefulness of a low-dose 40. Majluf-Cruz A, Luna-Castan˜os G, Huitro intravenous immunoglobulin regimen for the treatment of thrombocytopenia associated with AIDS. Blood 1993;82(5):1415–21. 41. Scaradavou A, Cunningham-Rundles S, Ho JL, et al. Superior effect of intravenous anti-D compared with IV gammaglobulin in the treatment of HIVthrombocytopenia: results of a small, randomized prospective comparison. Am J Hematol 2007;82(5):335–41. drono G, Molina JM, et al. ANRS 114-Pneumovac Study Group. Im42. Lesprit P, Pe munological efficacy of a prime-boost pneumococcal vaccination in HIV-infected adults. AIDS 2007;21(18):2425–34. 43. Viard JP, Vittecog D, Lacroix C, et al. Response of HIV-1 associated polymyositis to intravenous gammaglobulin. Am J Med 1992;92:580–1. 44. Smith KY, Valdez H, Landay A, et al. Thymic size and lymphocyte restoration in HIV infected patients following 48 weeks of therapy with zidovudine, lamivudine and ritonavir. J infect Dis 2000;181:141–7. 45. Arpadi SM, Markowitz LE, Baughman AL, et al. Measles antibody in vaccinated human immunodeficiency virus type 1-infected children. Pediatrics 1996;97(5): 653–7. 46. Moir S, Ogwaro KM, Malaspina A, et al. Perturbations in B cell responsiveness to CD41 T cell help in HIV-infected individuals. Proc Natl Acad Sci USA 2003;10: 6057–62. 47. Bekker V, Scherpbier H, Pajkrt D, et al. Persistent humoral immune defect in highly active antiretroviral therapy-treated children with HIV-1 infection: loss of specific antibodies against attenuated vaccine strains and natural viral infection. Pediatrics 2006;118(2):e315–22. 48. Rosenblatt HM, Song LY, Nachman SA, et al. Tetanus immunity after diphtheria, tetanus toxoids, and acellular pertussis vaccination in children with clinically stable HIV infection. J Allergy Clin Immunol 2005;116:698–703. 49. Hart M, Steel A, Clark SA, et al. Loss of discrete memory B cell subsets is associated with impaired immunization responses in HIV-1 infection and may be a risk factor for invasive pneumococcal disease. J Immunol 2007;178:8212–20.
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HISTORICAL BACKGROUND OF GAMMAGLOBULIN REPLACEMENT IN HIV/AIDS
In 1978–1979, children with an unusual clinical and immunologic profile were observed at Albert Einstein College of Medicine.1–3 These children presented with recurrent bacterial infections; several had multiple septic episodes with the same organism that failed to respond to specific antibodies.1,4 Their clinical presentation appeared typical for a B-cell deficiency such as Bruton’s agammaglobulinemia. In contrast to parents of children with congenital B-cell deficiencies, parents of these children also presented with immune aberrations, including cell-mediated immunity and B-cell immunity, which suggested that a transmittable infectious agent may be involved. Researchers soon recognized that the children’s B-cell deficiency was unique in its immunologic and histopathologic profile. They had a prominent generalized lymphadenopathy, and their lymph node biopsies revealed a marked proliferation of B cells. They also exhibited a pan-hypergammaglobulinemia that encompassed all three immunoglobulin classes: IgA, IgM, and IgG.1–3 Despite the hypergammaglobulinemia, they failed to mount specific antibody responses to various antigens.5 Most prominent was their inability to mount specific antibodies to polysaccharide antigens.
This work was supported by Grant No.AI051519 from the National Institutes of Health. a Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461, USA b Department of Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461, USA * Corresponding author. Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine and Montefiore Hospital Medical Center, 1525 Blondell Avenue, Bronx, NY 10461. E-mail address: [email protected] (A. Rubinstein). Immunol Allergy Clin N Am 28 (2008) 851–859 doi:10.1016/j.iac.2008.06.001 immunology.theclinics.com 0889-8561/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Treatment of these children, who were later identified as being infected with HIV-1, with intravenous immunoglobulin (IVIG) not only abolished the recurrent bacterial infections 6–8 but also induced previously unexpected immunomodulatory effects.8–14 The introduction of antiretroviral therapies had an effect on immune functions in pediatric and adult patients infected with HIV-1, in most instances deviating the need for IVIG. USE OF INTRAVENOUS GAMMAGLOBULIN IN THE PRE-ANTIRETROVIRAL ERA
The B-cell immune system in children infected with HIV-1 is more compromised than that of adults who have HIV-1. Maturation of the B-cell compartment is physiologically incomplete at birth, and protection against common pathogens is provided by passive transplacental transfer of maternal IgG. Even babies with Bruton’s agammaglobulinemia usually enjoy an infection-free interval of 6 to 9 months through passive immunity. This is not always the case in infants who are infected with HIV-1. Because humoral (B-cell) and cellular (T-cell) immune defects are noted in pregnant women who are infected with HIV-1, the protection of their infants through passive immunity is incomplete. This finding explains the often earlier onset of bacterial and septic infections in individuals who are infected with HIV-1. The maturation of B cells in infants who are infected with HIV-1 is further compromised by the inadequate interaction provided by dysfunctional T cells and by abnormal thymic epithelium function. Decreased levels of circulating thymulin, a marker of thymic dysplasia, have been noted in infants infected with HIV-1.15 In 1979, our rationale for the introduction of IVIG in children infected with HIV-1 was based on documents of in vivo defective primary and secondary antibody responses to a T-cell–dependent bacteriophage neoantigen (4X174), tetanus toxoid, and a B-cell–dependent pneumococcal polysaccharide antigen.5,16 The poor secondary responses to these antigens included abnormal class switches from IgM to IgG.16 Further in vitro evidence of B-cell dysfunction was the poor lymphocyte proliferative response to Pokeweed mitogen and Staphylococcal aureus, a T-cell–independent B-cell mitogen.1–3 Pokeweed mitogen also failed to induce in vitro B-cell secretion of IgG in the presence of normal T lymphocytes.12 The IVIG regimen used between 1979 and 1982 was the same as that used for patients who had agammaglobulinemia (200–300 mg/kg monthly). In 1982, evidence emerged for an associated multitude of immune aberrations, including markedly elevated circulating immune complexes,9,13 elevated serum neopterin levels,10 elevated serum tumor necrosis factor a,11 elevated serum b2-microglobulin,14 isomorphic elevation of serum lactate dehydrogenase,17 and T-cell dysregulation of humoral immunity.12 The IVIG regimen was subsequently modified to address the additional factors. The dose was increased to 300 mg/kg every 2 weeks (instead of every 4 weeks). The following account details the clinical and immune alterations by IVIG in a 10-year follow-up of 112 children aged 9 months to 6 years who were treated by the latter intensified protocol. Infectious Complications
Only mild upper respiratory infections occurred. No additional episodes of sepsis were noted at 300 mg/kg biweekly as compared with 13 serious bacterial infections in children who received 200 to 300 mg/kg monthly. Immunomodulatory Effects
Serum IgG levels did not increase over baseline in IVIG-treated patients, whereas a progressive increase in serum IgG was noted in most untreated infants. After IVIG
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treatment there was a statistically significant decrease in b2-microglobulin and lactate dehydrogenase levels. As markers of immune activation, neopterin10 and tumor necrosis factor a also decreased or normalized.11 Circulating immune complexes levels decreased in 77% of patients on the intensified IVIG protocol but in none of 24 untreated patients and in 10 patients who received the monthly IVIG dose of 200 mg/kg.9,13 In children infected with HIV-1, the CD81 T-cell compartment is markedly increased, but these cells are of poor function, as documented by the failure of CD81 T cells to suppress in vitro Pokeweed mitogen–driven IgG secretion.12 The reduced Pokeweed mitogen–driven IgG secretion normalized in 80% of studied subjects after IVIG treatment. The absent in vitro Concanavalin A generation of suppressor T cells was restored in IVIG-treated patients.12 Statistically significant increases in percentage and absolute T-cell counts were observed in 43% of treated patients. This trend persisted in most patients for up to 10 years until highly active antiretroviral therapy (HAART) was introduced.6–8 In vitro lymphocyte mitogenic responses to phytohemagglutinin increased transiently in 71% of patients who received IVIG.6 A large National Institute of Child Health and Human Development (NICHD) randomized double-blind placebo controlled multicenter IVIG study on children infected with HIV-1 was conducted 10 years later. This study corroborated most of the earlier findings, although the benefits achieved were not as robust. The IVIG regimen used was different in that 400 mg/kg were administered every 4 weeks.18–21 In this trial, children who had a baseline CD41T-cell count of more than 200/mL remained free from serious laboratory-proven and clinical diagnosed bacterial infections.18–20 In contrast to our studies with the higher IVIG dose, no statistically significant benefit was noted in children with fewer than 200 CD41T-cells/mL. This difference is probably due to the less intensive IVIG regimen. The NICHD study confirmed the immunomodulatory effect on CD41 T cells with a statistically significant slower decline in CD41 T-cell counts.21 IVIG also was used to treat several autoimmune manifestations, most prominently thrombocytopenia, which is a frequent complication of several conditions, including pediatric HIV-1 infection,22 sepsis,23 and conditions that involve antiplatelet IgG.24 The incidence of thrombocytopenia in children infected with HIV-1 who were on prophylactic IVIG was lower than in untreated patients. Thrombocytopenia, including septic thrombocytopenia, responded promptly with increased platelet counts after high-dose IVIG at 1 g/kg.22–24 The numeric platelet responses were not always associated with a favorable clinical outcome, however. In contrast to adults with HIV-1–associated thrombocytopenia, children may have antiplatelet antibodies and autoantibody-mediated vasculitis or clotting factor abnormalities.25 As a result, they have more frequent episodes of bleeding and a poorer prognosis. Intravenous Gammaglobulin in Adults Who Have HIV-1 Infection
Questions have been raised as to whether IVIG plays a role in adults who are infected with HIV-1.26 HIV-1 infected adults may retain their full complement of B cells, including anamnestic antibody responses, for a while because they were formed before their HIV-1 infection. As a result, adults who have HIV-1 infection are less susceptible to infections with common pathogens. HIV-1 can, however, profoundly affect humoral immunity in a subset of infected adults. Polsky and colleagues27 and Selwyn and colleagues28 reported a marked increase in the number of bacterial pneumonias, mainly caused by Staphylococcus pneumoniae and Haemophilus influenza, in adults who have AIDS, most of whom were substance abusers. Janoff and colleagues29
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estimated that the rate of pneumococcal bacteremia among patients who have AIDS was 100-fold higher than in age-matched controls. These findings formed the rationale for use of IVIG in adults. Several uncontrolled clinical trials have not shown conclusive benefits to routine IVIG prophylaxis. There was also no evidence that IVIG delayed progression of HIV-1–related disease or had immunomodulatory effects as noted in children who were infected with HIV-1. In a small randomized IVIG trial, Schrappe-Bacher and colleagues30 showed no changes in CD41 cell counts or other clinical and immunologic parameters. These studies should not exclude the use of IVIG for adults who are infected with HIV-1 with recurrent bacterial infections that are not well controlled with antibiotics. In this subset of patients, the use of bacterial vaccines was first studied. Because initial uncontrolled studies suggested an acceptable immunogenicity of polysaccharide vaccines, pneumococcal vaccines were recommended as a standard of care for adults who are infected with HIV-1 in North America and the United Kingdom. Unfortunately, a meta-analysis of prospective randomized pneumococcal vaccine trials did not show efficacy among the subgroup of North American adults infected with HIV-1.31 A second clinical trial with a pneumococcal vaccine was evaluated in Africa, where invasive pneumococcal disease was particularly prevalent in adults who are HIV-1 infected. The study showed not only lack of efficacy but also evidence of vaccine harm,32 probably caused by immune activation. We have shown in an animal model that HIV-1 was enhanced by the capsular polysaccharide of Cryptococcus neoformans.33 Brichachek and colleagues34 noted an increased plasma HIV-1 burden after challenge with a pneumococcal vaccine. We reported transient up-regulation of HIV-1 transcription after a phage FX174 vaccine16 and pneumococcal immunizations. After bacteriophage immunization, a transient decline in CD41 cells was noted. It was recommended that vaccination should preferably be administered only in tandem with antiretroviral therapy. Because it is unclear what level of antibodies is protective in HIV-1 infected patients and the finding that bacterial vaccines may be ineffective or harmful, prophylactic IVIG may be an option in patients with documented recurrent bacterial infections and absent or marginal bacterial vaccine responses. There is evidence for the use of IVIG in adults with autoimmune thrombocytopenia. The incidence of thrombocytopenia in adult patients who have HIV-1 is estimated at 65 per 10,000 persons, whereas the incidence of thrombocytopenia in HIV-1–negative patients is estimated at 1.5 per 10,000 individuals.35,36 The introduction of HAART has been effective in mitigating thrombocytopenias, but no studies are available on the incidence of autoimmune thrombocytopenia for patients treated with HAART. The two most common treatments, steroids and splenectomy, remain undesirable for patients who have thrombocytopenia and HIV-1, regardless of whether they are on HAART. In a study by Cai and colleagues,37 the use of steroids was associated with an increased risk of developing Kaposi’s sarcoma. Splenectomy was associated with an increased susceptibility to infections with encapsulated organisms. In a recent study by Gyongyossy-Issa and colleagues,38 the thrombopoietic responses to IVIG treatment were evaluated in patients who were uninfected with HIV-1 and had immune thrombocytopenic purpura and patients who had HIV-1–associated autoimmune thrombocytopenia. The initial response to IVIG in HIV-1 autoimmune patients who had thrombocytopenia was similar to that seen in patients who were not infected with HIV-1. Often-repeated doses were required to maintain an adequate response, however.39 As a result, the question was raised as
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to whether low-dose IVIG is effective. In 13 patients treated with low-dose IVIG (400 mg/kg/wk for 5 weeks), Majluf-Cruz and colleagues40 demonstrated a sustained response 3 months after the end of treatment. Anti-D therapy has been studied in the treatment of HIV-1–associated thrombocytopenia as an alternative to IVIG. In a prospective study, 14 Rh1 patients who had HIV-1 received 12 to 25 mg/kg of anti-D IgG intravenously on 2 consecutive days. Nine patients had a rapid and significant increase in their platelet counts. These data suggested that anti-Rh IgG is effective and safe in HIV-1–related thrombocytopenic purpura.40 A small, prospective, randomized study by Scaradavou and colleagues41 compared anti-D therapy with IVIG. Nine patients who were Rh1 and had HIV-1 were treated with IVIG or anti-D for 3 months. Patients who were treated with anti-D demonstrated higher mean peak platelet counts and longer duration of response. Anti-D resulted in a mean peak platelet count of 77,000/mL compared with only 29,000/mL after IVIG (P 5 .07). The mean duration of response was significantly longer in patients treated with anti-D (41 days) compared with IVIG (19 days; P 5 .01). This study may support the use of anti-D as first-line therapy in patients who are Rh1 and have HIV-1 and need urgent treatment for thrombocytopenia. In a retrospective study, Lesprit and colleagues42 compared the cost of anti-D therapy to high-dose IVIG. The cost of IVIG per treated episode was $4269, compared with $2716 for anti-D therapy. Overall, based on the evaluation of incidence, treatment patterns, and hospital care required, anti-D therapy was associated with significantly lower costs. Because lower doses of IVIG also were found to be effective, however,40 it remains more cost effective than anti-D therapy. Rheumatic manifestations may develop at any time during the clinical spectrum of HIV-1 infection, but they are usually seen more often in late stages. Various disorders may be seen, particularly Reiter’s syndrome and undifferentiated spondyloarthropathy. Most patients do well with conventional anti-inflammatory therapy, but some patients require immunosuppressive-cytotoxic therapy. IVIG has not been studied in these situations, except for in cases of polymyositis, in which patients who received high-dose IVIG showed dramatic improvement.43 USE OF INTRAVENOUS GAMMAGLOBULIN IN THE ERA OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPIES
Recent advances with HAART have dramatically reduced mortality and morbidity and prolonged life expectancy. Immune restoration is an important component of HAART. There is an initial increase in CD41 and CD81 T cells and B cells followed by improved in vitro lymphocyte proliferative responses and the return of delayed-type skin hypersensitivity reactions.44 Not all patients demonstrate a substantial T-cell reconstitution, and no controlled studies evaluated the restoration of the functional integrity of the humoral immune responses. Most studies on the restoration of B-cell function or the lack thereof were performed in children with HIV-1 infection and may not reflect the situation in adults. Questions that were raised discussed whether HAART restores the humoral immune system in children who are infected with HIV-1 to function in a relatively normal way; that is, to recognize an antigen, produce antibodies to that antigen, and create and sustain memory B cells for quick production of protective antibodies in the event of re-exposure. One of the first studies that examined this issue was published in 1996. In the face of a measles epidemic in New York City, Arpadi and colleagues45 studied measles antibody titers among children aged 9 to 168
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months who had HIV-1. They correlated measles titers with CD41 cell counts along with other parameters, including age of first measles immunization and the number of immunizations. They found that CD41 T-cell counts had a positive correlation with one’s ability to maintain measles antibodies. Among children who had no T-cell immunosuppression, 82% maintained immunity, whereas among the most severely compromised (CD41 T-cell counts % 600/mL) only 53% had positive measles antibody titers. Overall, 72% of previously vaccinated children maintained immunity compared with 95% of healthy children. Treatment with zidovudine at the time of vaccination was significantly associated with the children testing seropositive to measles. Moir and colleagues46 studied the mechanisms by which uncontrolled HIV-1 infection may compromise B-cell function. They showed that in viremic patients (patients who were either on HAART-resistant regimens or were noncompliant with HAART) compared with aviremic patients who had HIV-1, B cells were less responsive to CD41 T cells. This finding was still true when controlling for CD41 T-cell numbers. Their studies showed that this B-cell dysfunction was likely related to B cells’ inability to up-regulate CD25 (interleukin-2 receptor) in response to appropriate CD41 T-cell signaling in the presence of HIV-1 viremia. Thus, HIV-1 viremia may cause an inherent B-cell dysfunction independent of T-cell function. Bekker and colleagues47 documented that even after immune reconstitution with effective HAART, B-cell memory was not restored to vaccination (MMR) and naturally occurring viral pathogens (VZV, CMV, EBV). The most imperative of B-cell functions— providing specific antibodies to previously exposed antigens—was not restored. Overall, 40% of the patients lost immunity to measles, 38% lost immunity to mumps, and 11% lost immunity to rubella. Only 43% maintained immunity to all three pathogens, and 20% lost varicella zoster virus titers after being followed longitudinally on HAART. B-cell reconstitution by HAART was also studied by Rosenblatt and colleagues48 in children aged 4 months to 17 years who were HIV-1 infected and lost their titers to tetanus and then underwent HAART therapy. These children had only mild to moderate impairment in their immune status before enrolling in this study; their percentage of CD41 cells was more than 15% with a median absolute count of 976 cells. After reimmunization with tetanus, most (74%) had a good response 4 weeks later; however, the percentage of patients with a positive titer dropped to 67% at 8 weeks, 53% at 18 weeks, and 38% at 32 weeks. In a study that compared patients who had common variable immune deficiency, patients who underwent splenectomy, and patients who had HIV-1 infection, Hart and colleagues49 reported a decreased response to Pneumovax among individuals who had HIV-1 infection and were on HAART. They showed that this poor response was caused by a relative deficiency in IgM memory B cells. This finding provided an explanation for the increased risk of invasive pneumococcal disease among people who have HIV-1 infection. These data suggested that a segment of patients who have HIV-1 who exhibit poor B-cell functions, respond poorly to bacterial vaccines, and have recurrent bacterial infections may be candidates for prophylactic IVIG treatment. No controlled studies have documented the immunomodulatory effect of IVIG on patients who are infected with HIV-1 and are on HAART; nor have studies examined the effect that IVIG may have on reducing morbidity and mortality. The use of IVIG for autoimmune manifestations on HAART remains controversial and an unchartered field. It plays a role in autoimmune thrombocytopenia for the preHAART era.
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n S, et al. Usefulness of a low-dose 40. Majluf-Cruz A, Luna-Castan˜os G, Huitro intravenous immunoglobulin regimen for the treatment of thrombocytopenia associated with AIDS. Blood 1993;82(5):1415–21. 41. Scaradavou A, Cunningham-Rundles S, Ho JL, et al. Superior effect of intravenous anti-D compared with IV gammaglobulin in the treatment of HIVthrombocytopenia: results of a small, randomized prospective comparison. Am J Hematol 2007;82(5):335–41. drono G, Molina JM, et al. ANRS 114-Pneumovac Study Group. Im42. Lesprit P, Pe munological efficacy of a prime-boost pneumococcal vaccination in HIV-infected adults. AIDS 2007;21(18):2425–34. 43. Viard JP, Vittecog D, Lacroix C, et al. Response of HIV-1 associated polymyositis to intravenous gammaglobulin. Am J Med 1992;92:580–1. 44. Smith KY, Valdez H, Landay A, et al. Thymic size and lymphocyte restoration in HIV infected patients following 48 weeks of therapy with zidovudine, lamivudine and ritonavir. J infect Dis 2000;181:141–7. 45. Arpadi SM, Markowitz LE, Baughman AL, et al. Measles antibody in vaccinated human immunodeficiency virus type 1-infected children. Pediatrics 1996;97(5): 653–7. 46. Moir S, Ogwaro KM, Malaspina A, et al. Perturbations in B cell responsiveness to CD41 T cell help in HIV-infected individuals. Proc Natl Acad Sci USA 2003;10: 6057–62. 47. Bekker V, Scherpbier H, Pajkrt D, et al. Persistent humoral immune defect in highly active antiretroviral therapy-treated children with HIV-1 infection: loss of specific antibodies against attenuated vaccine strains and natural viral infection. Pediatrics 2006;118(2):e315–22. 48. Rosenblatt HM, Song LY, Nachman SA, et al. Tetanus immunity after diphtheria, tetanus toxoids, and acellular pertussis vaccination in children with clinically stable HIV infection. J Allergy Clin Immunol 2005;116:698–703. 49. Hart M, Steel A, Clark SA, et al. Loss of discrete memory B cell subsets is associated with impaired immunization responses in HIV-1 infection and may be a risk factor for invasive pneumococcal disease. J Immunol 2007;178:8212–20.
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