Secondary Logo

Journal Logo

Immune restoration disease after antiretroviral therapy

French, Martyn A; Price, Patricia; Stone, Shelley F

doi: 10.1097/01.aids.0000131375.21070.06

Suppression of HIV replication by highly active antiretroviral therapy (HAART) often restores protective pathogen-specific immune responses, but in some patients the restored immune response is immunopathological and causes disease [immune restoration disease (IRD)]. Infections by mycobacteria, cryptococci, herpesviruses, hepatitis B and C virus, and JC virus are the most common pathogens associated with infectious IRD. Sarcoid IRD and autoimmune IRD occur less commonly. Infectious IRD presenting during the first 3 months of therapy appears to reflect an immune response against an active (often quiescent) infection by opportunistic pathogens whereas late IRD may result from an immune response against the antigens of non-viable pathogens. Data on the immunopathogenesis of IRD is limited but it suggests that immunopathogenic mechanisms are determined by the pathogen. For example, mycobacterial IRD is associated with delayed-type hypersensitivity responses to mycobacterial antigens whereas there is evidence of a CD8 T-cell response in herpesvirus IRD. Furthermore, the association of different cytokine gene polymorphisms with mycobacterial or herpesvirus IRD provides evidence of different pathogenic mechanisms as well as indicating a genetic susceptibility to IRD. Differentiation of IRD from an opportunistic infection is important because IRD indicates a successful, albeit undesirable, effect of HAART. It is also important to differentiate IRD from drug toxicity to avoid unnecessary cessation of HAART. The management of IRD often requires the use of anti-microbial and/or anti-inflammatory therapy. Investigation of strategies to prevent IRD is a priority, particularly in developing countries, and requires the development of risk assessment methods and diagnostic criteria.

From the Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital and School of Surgery and Pathology, University of Western Australia, Perth, Australia.

Correspondence to Martyn French, Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Box X2213, GPO, Perth, WA 6001, Australia.


Received: 11 February 2004; revised: 15 April 2004; accepted: 17 May 2004.

Back to Top | Article Outline


Treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy (HAART) partially corrects the immune defects caused by chronic HIV infection. It was apparent that this included restoration of protective pathogen-specific immune responses shortly after the introduction of HAART because opportunistic infections were reported to resolve [1]. This has resulted in a sharp decline in the prevalence of opportunistic infections in HIV patients [2]. Furthermore, studies of the effect of HAART on cytomegalovirus (CMV) viraemia and CMV-specific CD4 T-cell responses [3,4] have provided direct evidence that HAART enhances protective pathogen-specific immune responses.

Suppression of HIV viraemia by antiretroviral therapy is accompanied by atypical ‘opportunistic infections’ or other inflammatory diseases in some patients. When these conditions were first reported, there was uncertainty about whether they were a consequence of the restoration of an immune response against opportunistic pathogens, or opportunistic infections resulting from residual defects of cell-mediated immunity [5–9]. Subsequently, there has been acceptance that they are a consequence of immune reconstitution in patients who experience a virological response to HAART. These conditions have previously been reviewed [10–15], although there has been a divergence of opinion about nomenclature and there continues to be uncertainty about pathogenic mechanisms and management. Here, we argue that atypical ‘opportunistic infections’ after commencing HAART are the consequence of restoring an immune response against the antigens of opportunistic pathogens that is immunopathological rather than protective. These conditions are therefore considered to be immune restoration disease (IRD) rather than immunodeficiency disease.

Sarcoid-like disease and autoimmune diseases are observed less frequently in patients responding to HAART and also appear to have an immunological basis. These conditions will also be considered as IRD. However, there is a need to differentiate the different types of IRD and we will consider them under the headings of infectious IRD, sarcoid IRD and autoimmune IRD.

As the use of HAART increases around the world, physicians managing patients with HIV infection will encounter increasing numbers of patients with IRD. Management of these conditions is often problematic, in particular their differentiation from opportunistic infections or drug toxicity. It is therefore important to understand the immunopathogenesis of IRD so that diagnostic criteria and prevention and treatment strategies can be developed.

Back to Top | Article Outline

Infectious immune restoration disease

Mycobacterial IRD

The observation of atypical presentations of Mycobacterium avium complex (MAC) disease in patients treated with zidovudine monotherapy was the first indication that restoring pathogen-specific immune responses can cause immunopathology [5]. MAC disease in this situation was localized rather than disseminated and was characterized by severe fever, painful lesions and a granulomatous inflammatory response or suppuration. Most importantly, it was associated with restoration of cutaneous delayed-type hypersensitivity (DTH) responses to mycobacterial antigens, whereas MAC disease before antiretroviral therapy had invariably been associated with anergy. Furthermore, subsequent loss of DTH responses to mycobacterial antigens was associated with the occurrence of disseminated MAC infection [16].

MAC IRD in patients responding to HAART presents with fever, lymphadenitis, pulmonary infiltrates or inflammatory masses [6,17–26]. Pyomyositis and cutaneous abscesses have also been described [27]. MAC IRD usually occurs during the first three months of therapy in patients with pre-therapy CD4 T-cell counts < 100 × 106 cells/l. Lymphadenitis is often painful and may suppurate. Inflammatory masses are usually endobronchial but may affect the abdominal cavity. Histological examination of lymph nodes or inflammatory masses often reveals granulomatous inflammation. MAC is usually cultured from lesions but not from the blood. Cutaneous DTH responses to mycobacterial antigens are a characteristic finding [6,19,25].

Restoration of cellular immune responses to Mycobacterium tuberculosis (MTB) antigens may also cause IRD in patients responding to HAART [28–36]. MTB IRD is associated with the restoration of a cutaneous DTH response to tuberculin [28,29,34]. It presents within the first 2 months of HAART, usually in the first 2–3 weeks. Common presenting features are severe fever, intra-thoracic and cervical lymphadenopathy and pulmonary infiltrates. Extra-thoracic disease is less common and includes focal cerebritis [6,30], pleural effusions, hepatosplenomegaly and ascites [31]. Pulmonary disease may be associated with hypercalcaemia [36].

Bacille Calmette-Guerin (BCG) lymphadenitis in a child, which was associated with a DTH response to tuberculin [37], and borderline tuberculoid leprosy [38] have also been described in patients responding to HAART.

Several lines of evidence indicate that mycobacterial IRD results from a DTH response to mycobacterial antigens. Granulomatous inflammation and tissue necrosis are typical of DTH responses [39]. Foudraine et al. [40] showed that MAC disease after HAART was associated with increased lymphoproliferation responses to mycobacterial antigens. The occurrence of MAC IRD and, to our knowledge, the lack of virus-associated IRD after zidovudine monotherapy supports the involvement of DTH because zidovudine monotherapy is sufficient to augment DTH responses [41]. Finally, a case study showed a correlation between MAC IRD and DTH responses to tuberculin in a patient who never had CD4 T-cell deficiency [25].

The basic elements of managing mycobacterial IRD are anti-mycobacterial and anti-inflammatory therapies. Corticosteroids are usually used but pentoxyphylline may be effective for MTB IRD [28].

Back to Top | Article Outline

Cryptococcal IRD

Soon after the introduction of HAART, it was observed that some patients presented with an initial or recurrent episode of cryptococcal meningitis during the first few weeks of therapy [42]. It occurred in patients with CD4 T-cell counts < 50 × 106 cells/l who had an immunological and virological response to HAART and was characterized by a more prominent inflammatory cell reaction in the CSF than in patients not receiving HAART. Cryptococci were usually cultured from CSF and/or blood. Subsequently, Jenny-Avital et al. reported that 50% of patients with cryptococcal infection who responded to HAART developed cryptococcal disease despite the use of fluconazole therapy [43]. However, cryptococcal disease in this series of patients presented 2 to 11 months after commencing HAART and was characterized by failure to culture cryptococci even though organisms were seen in lesions or cryptococcal antigen was detected in body fluids. Reports on other individuals or small series of patients have shown similar findings and a pattern of clinical presentation of late cryptococcal IRD is emerging.

The most common presentation of late cryptococcal IRD is lymphadenitis, particularly mediastinal lymphadenitis [43–46]. It is reported to present up to 15 months after commencing HAART [44]. Histological examination of nodes may reveal granulomatous inflammation, necrosis or suppuration. Granulomatous inflammation may be associated with hypercalcaemia [43]. Cryptococcal IRD of the central nervous system (CNS) has also been described. Aseptic meningitis is associated with high intracranial pressure [43,47] and localized inflammatory lesions may occur in the spinal cord [48] or brain [49].

There are no known data showing that cryptococcal disease in patients responding to HAART is associated with increased immune responses to cryptoccocal antigens. However, an interpretation of the available clinical data suggests that effective HAART may result in two types of inflammatory reaction to cryptoccoci. Firstly, an acute inflammatory reaction to subclinical meningeal infection during the first few weeks of therapy and secondly, a chronic inflammatory reaction in lymph nodes or the CNS, possibly initiated by a T-cell response to the antigens of non-viable cryptoccoci.

The optimal management of cryptococcal IRD has not been defined. Anti-inflammatory therapy has been used [44] but many cases resolve spontaneously.

Back to Top | Article Outline

Pneumocystis IRD

Pneumocystis carinii pneumonitis that has improved on anti-Pneumocystis therapy may relapse following the introduction of HAART [50–52]. Commencement of HAART within 18 days of commencing anti-Pneumocystis therapy and/or cessation of corticosteroid therapy appear to be risk factors, but only a limited amount of data are available.

Back to Top | Article Outline

Hepatitis B and C virus IRD

Hepatotoxicity is an adverse effect of HAART in up to 18% of patients. This is a direct effect of antiretroviral drugs, particularly nevirapine and high-dose ritonavir, in some patients but hepatotoxicity occurs most often in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection (for example see [53–55]). The pathogenesis of hepatotoxicity in HIV/HCV or HIV/HBV co-infected patients has not been defined, but early clinical studies suggested IRD might be a cause [56,57].

Liver biopsies in HIV/HCV co-infected patients with HAART-associated hepatotoxicity show changes of viral hepatitis [54,57], suggesting that there has been an immune response against the HCV. However, the association of hepatotoxicity with increased blood CD4 T-cell counts is controversial [54,55,58] and there are no known data on HCV-specific T-cell responses. Studies of pathogenic mechanisms may require the use of liver biopsy samples or serological markers to demonstrate the role of HCV-specific immune responses because the cellular immune response in HCV-associated hepatitis is compartmentalized to the liver [59]. For example, HAART-associated hepatotoxicity is associated with increased plasma levels of HCV antibodies [57,60,61] and dipeptidyl dipeptidase IV [DPP IV, soluble (s) CD26] activity [61]. sCD26 (DPP IV) is an aminopeptidase which down-regulates CXCR3 [62], a major homing molecule expressed by Th1 cells in the HCV-infected liver [63].

Although HAART-associated hepatotoxicity in HIV/HCV co-infected patients may result in fulminant hepatitis and sometimes cirrhosis [64,65], this is very uncommon [54]. The outcome for most patients appears to be similar to patients who do not experience hepatotoxicity [66,67]. However, the long- term effect of hepatotoxicity on liver fibrosis is currently unknown and it has been argued that HCV infection should be treated before commencing HAART to reduce the probability of hepatotoxicity [68].

HAART-associated hepatotoxicity in HIV/HBV co-infected patients is associated with a decreased plasma HIV RNA level and increased CD4 T-cell count, and liver biopsies show changes of viral hepatitis [56,69–73]. In some patients, hepatotoxicity was associated with clearance of HBeAg and HBV DNA and increased anti-HBc and anti-HBe [56,70,73] whereas in others it was associated with increased plasma levels of HBV DNA, reappearance of HBsAg, loss of anti-HBs and appearance of anti-HBcIgM [69,71,72]. An explanation for the dichotomous immunological and virological effects of HAART in HIV/HBV co-infected patients with hepatotoxicity is not available. Clearly, further studies are needed to elucidate pathogenic mechanisms.

Back to Top | Article Outline

Cytomegalovirus IRD

Eye disease is the most common presentation of CMV IRD. It presents as retinitis in the first 3 months of HAART or as uveitis, usually much later than retinitis. CMV retinitis IRD may be the first indication of CMV infection [74,75], or present as a relapse of established CMV retinitis that is in remission on anti-CMV therapy [6,76] and subsequently resolves without relapse when anti-CMV therapy is ceased [77]. It occurs in patients with CD4 T-cell counts < 100 × 106 cells/l who experience an increased CD4 T-cell count in response to HAART. A positive plasma CMV polymerase chain reaction was a strong predictor of CMV retinitis in a prospective study of patients commencing protease inhibitor therapy [75].

Immune recovery uveitis (IRU) is an inflammatory disorder that affects eyes with inactive CMV retinitis in patients who have experienced an increased CD4 T-cell count on HAART [78–81]. It presents with floaters and/or impaired visual acuity and can result in permanent visual impairment. The inflammatory changes may include vitritis, papillitis, cystoid macular oedema and epiretinal membranes. Fibrovascular membranes resulting from the inflammation may be misdiagnosed as recurrent CMV retinitis [82]. Karavellas et al. [81] reported that IRU presents 2–84 (median 20) weeks after an increase in the CD4 T-cell count. Eyes with an average CMV retinitis area of > 30% had a 4.5-fold increased risk of developing IRU. The incidence was estimated to be 0.83/person-year. However, this is much greater than the rate of 0.109/person-year reported in another study [80]. IRU can cause severe inflammatory eye disease and, therefore, patients on HAART with a previous history of CMV retinitis who develop visual symptoms must be assessed by an ophthalmologist. Topical or systemic corticosteroid therapy is usually effective.

First presentations or relapses of CMV retinitis after commencing HAART appear to represent the effects of an immune response against retinal CMV infection that eventually controls the infection. However, Hsieh et al. [83] showed that CMV-specific CD4 T-cell responses were lower in patients who developed CMV retinitis after commencing HAART compared with patients without retinitis. We and others [84,85] have shown that CD4 T-cell responses to CMV antigens remain low in all patients with nadir CD4 T-cell counts of < 50 × 106 cells/l during the first year of HAART. However, we have also shown that CMV retinitis after HAART is associated with increased plasma levels of IgG anti-CMV antibody and soluble (s) CD30 [86] and with increased bioavailable interleukin (IL)-6 [87]. Our interpretation of these findings is that the immune response restored against CMV antigens in patients with CMV retinitis IRD is immunopathological and characterized by a Th2 bias and/or a CD8 T-cell response because CD30 is expressed by Th2 cells and has a regulatory function in CD8 cytolytic T cells [88]. With regard to this, Hsieh et al. [83] showed that CMV-specific CD8 T-cell responses in patients with CMV retinitis after HAART are similar to patients without retinitis, indicating that there is a relative predominance of CD8 over CD4 CMV-specific T-cell responses in patients who develop retinitis.

Examination of epiretinal membranes from eyes with IRU demonstrated the presence of chronic inflammatory cells consisting predominantly of T cells [81]. Preliminary evidence suggests that the inflammation represents a CMV-specific CD8 T-cell response. Thus, cloning of T cells from the vitreous fluid of a single patient demonstrated a predominance of CMV-specific CD8 T cells [89] and the severity of IRU is not related to the magnitude of the increase in blood CD4 T cells [81].

Back to Top | Article Outline

Varicella zoster virus IRD

Rates of varicella zoster virus (VZV) disease are increased in patients responding to HAART. Dermatomal VZV disease occurs in 6–8% of patients at a rate of 6.2–9.0 episodes per 100 patient years [6,90–92]. The rate has been estimated to be five times higher than expected [90]. The majority of cases present during the first 4 months of HAART but some cases present much later.

Studies by two Spanish groups have identified a greater increase in CD8 T-cell counts as a risk factor for dermatomal VZV disease after HAART [91,92], suggesting that CD8 T cells may be mediating an immune response against VZV antigens. A case study of transverse myelitis resulting from VZV IRD demonstrated that NK cells as well as CD8 T cells may be mediating a response to VZV antigens [93]. Of note, the immune response in that case was compartmentalized to the CNS, indicating that IRD may occur in the absence of immune reconstitution in the blood.

VZV IRD responds to acyclovir therapy [6,91,92] suggesting that the immune response is against active VZV infection. However, VZV stromal keratitis has also been reported as an IRD in a patient receiving prophylactic acyclovir therapy [94].

Back to Top | Article Outline

Herpes simplex virus IRD

Data from an observational study suggests that mucocutaneous herpes simplex virus (HSV) disease may occur more frequently and be more severe in patients responding to HAART [6]. In addition, Fox et al. [95] reported chronic penile ulceration related to HSV infection in black African men. Of note, all three affected patients carried HLA-B72, -Cw0202 and -DRB4, suggesting that there is a genetic susceptibility to this condition. Presumptive HSV infection has been associated with encephalomyelitis after HAART [6].

Back to Top | Article Outline

JC virus IRD

HAART is the only effective therapy for progressive multifocal leukoencephalopathy (PML) in HIV patients [96], probably because it augments CD4 T-cell responses to JC virus (JCV) antigens [97]. However, in some patients who commence HAART, PML may become worse or present for the first time [96,98–103]. Cinque et al. [96] reported that 18% of patients with PML experienced an exacerbation within 9 weeks of commencing HAART associated with a reduction of the plasma HIV RNA level and an increased CD4 T-cell count. Antiretroviral-naive patients responding to HAART had the worst outcome with 50% experiencing progression of PML lesions. Histopathology examination of lesions demonstrates more inflammation than in lesions from patients not receiving HAART. In particular, perivascular infiltrations of lymphocytes, monocytes and plasma cells have been observed [99,101–103]. The lymphocytes are predominantly CD8 T cells [99,101], suggesting that CD8 T cells may mediate an immunopathological response to JCV antigens. Supporting evidence has been provided by a case study of a patient who developed PML after responding to HAART without an increase in the blood CD4 T-cell count [103].

Evidence-based guidelines for the prevention and management of JCV IRD are not available. However, there is preliminary evidence that modification of the antiretroviral regimen might have a beneficial effect. In the series of patients reported by Cinque et al. [96], a better outcome was observed in patients who interrupted therapy or used a drug regimen that resulted in slower immune reconstitution. Corticosteroid therapy has been used to treat JCV IRD but may be ineffective [101,102].

Back to Top | Article Outline

Uncommon infectious IRD

There are several case reports of IRD associated with uncommon opportunistic pathogens. These are listed in Table 1.

Table 1

Table 1

Back to Top | Article Outline

Disease in patients responding to HAART that might be infectious IRD

Other diseases associated with an infection by an opportunistic viral pathogen are reported to present atypically or more frequently in patients responding to HAART. The evidence that they are IRD is not as strong as for the conditions discussed so far, but they are discussed to promote further study of their pathogenesis because an immunopathological response to the virus might be involved.

Two publications documenting an increase in the prevalence of oral warts in the context of a decrease in Candida stomatitis, hairy leukoplakia and Kaposi's sarcoma of the mouth in patients on HAART [111,112] raise the possibility of human papillomavirus IRD. Non-Hodgkin's lymphoma (NHL) after commencing HAART [113] might be related to an immunopathological response to Epstein Barr virus (EBV) infection, as T-cell responses to some EBV antigens induce IL-10 production [114] and increased IL-10 production is associated with HIV-associated NHL [115]. Finally, reports that Kaposi's sarcoma [116] or multicentric Castleman's disease [117] develop after commencing HAART suggest a possible immunopathological response to human herpes virus-8.

Back to Top | Article Outline

Risk factors for infectious IRD

Collation of the clinical, immunological and immunogenetic data presented over the last 12 years has identified risk factors for infectious IRD that could be used in a risk assessment for patients commencing HAART (Fig. 1). Firstly, an active or subclinical infection by opportunistic pathogens [16], or the antigens of non-viable micro-organisms (eg. cryptococci and CMV) are all possible targets for an immunopathological response. This may explain why prophylactic anti-MAC therapy may not prevent MAC IRD [118]. Secondly, a CD4 T-cell count below 50 × 106 cells/l is a major risk factor for IRD [6]. It may be a marker of a high pathogen load and/or an increased susceptibility to immune dysregulation during immune reconstitution. Finally, there are disease susceptibility genes for some IRD. The first indication of this was that some patients with CMV retinitis presenting as IRD also experienced neurological disease associated with definitive or presumptive infection by other herpes viruses [6]. This suggested a genetic susceptibility to an immunopathological response against herpes viruses. Supportive evidence has been provided by our studies showing that HLA-B44 and the major histocompatibility complex (MHC) ancestral haplotype HLA-A2, -B44, -DR4 [119], and allele 1 at a single nucleotide polymorphism (SNP) in the 3′UTR of the IL12B gene encoding IL-12 p40 [120] are associated with herpes virus IRD. The significance of these findings was strengthened by the observation that alleles of other cytokines genes (TNFA-308*2 and IL6-174*G) were not associated with herpesvirus IRD but were associated with mycobacterial IRD.

Fig. 1. Risk factors for infectious immune restoration disease (IRD).

Fig. 1. Risk factors for infectious immune restoration disease (IRD).

Back to Top | Article Outline

Diagnosis of infectious IRD

If advances are to be made in the diagnosis and management of infectious IRD, it is essential that diagnostic criteria are formulated and tested in clinical practice. Proposed diagnostic criteria are outlined in Table 2. These are based on the findings of a retrospective study [6] and the many clinical studies referred to in this review. A diagnosis of IRD would require both major criteria or criterion A and two minor criteria.

Table 2

Table 2

Back to Top | Article Outline

Sarcoid immune restoration disease

Granulomatous inflammation of the lungs, which has the characteristics of sarcoidosis, has been described in patients responding to HAART [121–127]. Granulomatous inflammation of other organs has also been described, including the skin [122,128,129; and Fig. 2a], kidneys, liver and duodenum [130]. In a study undertaken on patients presenting to five pneumonology departments, Foulon et al. [127] reported that cases presented from 3 to 43 months after commencing HAART. HIV-associated sarcoidosis has been reported in patients not receiving HAART [125] but this is characterized by a CD8 T-cell alveolitis whereas sarcoid IRD is associated with an intense CD4 T-cell alveolitis and a CD4 T-cell infiltrate in granulomas [121,127]. The involvement of CD4 T cells in the pathogenesis of sarcoid IRD may explain the occurrence of this disorder after the addition of interleukin-2 therapy to HAART [121,124,127]. It is important to exclude infectious IRD as a cause of granulomatous inflammation because this may occur in patients infected by mycobacteria, cryptococci (see above) and histoplasma (Fig. 2b).

Fig. 2. Different causes of granulomatous inflammation in HIV patients with immune restoration disease (IRD).

Fig. 2. Different causes of granulomatous inflammation in HIV patients with immune restoration disease (IRD).

Sarcoid IRD may resolve spontaneously with continuation of HAART but corticosteroid therapy is sometimes necessary [127].

Back to Top | Article Outline

Autoimmune immune restoration disease

Autoimmune diseases presenting for the first time, or as an exacerbation of established disease, have also been reported in HIV patients responding to HAART. Patients with systemic lupus erythematosus, polymyositis or rheumatoid arthritis usually present during the first few months therapy [131–134]. A patient with relapsing polychondritis and sarcoidosis presented after 2 years [126]. It is presumed that the immune dysregulation underlying the autoimmune disease is precipitated or exacerbated by the immunological changes that occur after suppression of HIV replication. Guillain–Barre syndrome may also present in the first few weeks of HAART [135,136]. CD8 T cells were demonstrated in the endoneurium of brachial plexus nerves in one patient [136].

Graves’ disease is an uncommon but well-recognized complication of immune reconstitution in severely immunodeficient HIV patients [137,138]. It presents later than other autoimmune diseases in patients on HAART and probably has a different pathogenic mechanism. A case study has provided evidence that it may result from thymic dysfunction during immune reconstitution [139].

Back to Top | Article Outline

Miscellaneous immune restoration diseases

The pathogenesis of several disparate disorders in patients responding to HAART is unclear but immunological mechanisms appear be involved (Table 3).

Table 3

Table 3

Back to Top | Article Outline

Immune restoration disease in developing countries

Antiretroviral therapy is gradually being introduced into developing countries through the activities of agencies such as Medecins Sans Frontieres (MSF) and the Global Fund to Fight AIDS, Tuberculosis and Malaria. In one report on 743 patients in a MSF programme, all patients had baseline CD4 T-cell counts of < 200 × 106 cells/l and the median count was 48 × 106 cells/l [146]. There were therefore many patients at risk of developing infectious IRD. During an observation period of between 1.7 and 6.9 months, 8.2% of patients died, of whom 42.6% died during the first 30 days of therapy. While this may have reflected opportunistic infections complicating residual immunodeficiency, the findings of another study suggest that it may have been IRD. In a prospective study of 60 Thai patients with treated cryptococcal meningitis commencing HAART with CD4 T-cell counts between 0 and 147 × 106 cells/l, 20 episodes of ‘opportunistic infection’ occurred in 14 (23%) patients [147]. These occurred between 4 and 32 (median 16) weeks after commencing HAART and were associated with increased CD4 T cell counts. Disease was associated with infections by MTB, MAC, cryptococci, Toxoplasma, VZV and HSV and there were two deaths.

Back to Top | Article Outline


The increasing use of HAART in developing countries and late presentation of HIV patients in some developed countries [148] will inevitably result in a large number of severely immunodeficient patients being given HAART. There will therefore be many patients at-risk of developing IRD. Although some IRD are short-lived or cause minor clinical problems, others may result in significant morbidity and sometimes death. Infectious IRD of the central nervous system is of particular concern because it may result in permanent neurological disability or death [6,93,96,102,104].

Strategies should therefore be devised to prevent IRD. In patients about to commence a new HAART regimen, these might include identification of patients with risk-factors for infectious IRD (see Fig. 1) so that subclinical infection by opportunistic pathogens can be excluded, or measures taken to reduce pathogen load in patients with an opportunistic infection. However, the potential benefits of delaying HAART to prevent IRD in patients receiving treatment for an opportunistic infection might be outweighed by the risk of developing another opportunistic infection if HAART is delayed. This issue should be examined in prospective clinical studies.

The development of new therapeutic approaches for IRD requires a better understanding of pathogenic mechanisms. It has become clear that infectious IRD has two patterns of presentation. Early IRD presents during the first 3 months of HAART and appears to result from an immune response against viable opportunistic pathogens, which are often present as a subclinical infection. An exception may be VZV IRD, which sometimes presents later than 3 months because VZV infection reactivates infrequently [6]. Late IRD presents month to years after commencing HAART and appears to result from an immune response against the antigens of non-viable opportunistic pathogens. Cryptococcal lymphadenitis and CMV IRU are good examples of this. Anti-microbial therapy is unlikely to be effective. Late IRD would appear to be different to the opportunistic infections, such as localized MAC infection [149,150], that occur infrequently in patients who had nadir CD4 T-cell counts of < 50 × 106 cells/l and cease prophylaxis because their CD4 T-cell count has increased on HAART. This type of disease is characterized by isolation of viable pathogens and is probably the result of an immune defect that has not been corrected by HAART, which might include deficiency of type 1 cytokines [151].

Finally, it has become clear that the immunopathological response to different pathogens has different pathogenic mechanisms. Mycobacterial and fungal IRD appear to be the result of a DTH response whereas IRD associated with viruses, such as herpes viruses and JCV, appear to result from a CD8 T-cell response. The association of mycobacterial and herpes virus IRD with polymorphisms in the genes encoding different cytokines [120] provides further evidence of different types of immune response. The long-term effect of these immunopathological responses is unclear. The increase in plasma bioavailable IL-6 in patients with CMV retinitis IRD persists for at least 4 years [87], which may partly explain the elevation of plasma IL-6 levels in patients with a previous history of IRD [152]. Mycobacterial IRD may also increase the plasma IL-6 level [153] but the effect is transient. The immunological and metabolic consequences of increased IL-6 production deserve further attention as it might contribute to persistent immune activation in patients with well-controlled HIV replication on HAART [154] or to the pathogenesis of type 2 diabetes [155], which is increasingly being recognized as a long-term complication of HAART [156].

Back to Top | Article Outline


We are grateful to Dr Kate Clezy and Dr Jeffrey Post for contributions to Table 2 and to Dr Cecily Metcalf for providing Fig. 2b.

Back to Top | Article Outline


1. Jacobson M, French M. Altered natural history of AIDS-related opportunistic infections in the era of potent combination anti-retroviral therapy.AIDS - A year in Review 1998; 12: S157–S163.
2. Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d'Arminio Monforte A, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study.Lancet 2003; 362: 22–29.
3. Deayton J, Mocroft A, Wilson P, Emery VC, Johnson MA, Griffiths PD. Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy.AIDS 1999; 13:1203–1206.
4. Weinberg A, Wohl DA, MaWhinney S, Barrett RJ, Brown DG, Glomb N, et al. Cytomegalovirus-specific IFN-gamma production is associated with protection against cytomegalovirus reactivation in HIV-infected patients on highly active antiretroviral therapy.AIDS 2003; 17:2445–2450.
5. French MAH, Mallal SA, Dawkins RL. Zidovudine induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients.AIDS 1992; 6: 1293-1297.
6. French MA, Lenzo N, John M, Mallal SA, McKinnon EJ, James IR, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy.HIV Med 2000; 1:107–115.
7. Behrens GM, Meyer D, Stoll M, Schmidt RE. Immune reconstitution syndromes in human immuno-deficiency virus infection following effective antiretroviral therapy.Immunobiology 2000; 202:186–193.
8. Rodriguez-Rosado R, Soriano V, Dona C, Gonzalez-Lahoz J. Opportunistic infections shortly after beginning highly active antiretroviral therapy.Antivir Ther 1998; 3:229–231.
9. Michelet C, Arvieux C, Francois C, Besnier JM, Rogez JP, Breux JP, et al. Opportunistic infections occurring during highly active antiretroviral treatment.AIDS 1998; 12:1815–1822.
10. French MAH. Immune restoration disease in HIV-infected patients on HAART.The AIDS Reader 1999; 9:548–562.
11. DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1 infected persons after initiation of highly active antiretroviral therapy.Ann Intern Med 2000; 133:447–454.
12. Cheng VC, Yuen KY, Chan WM, Wong SS, Ma ES, Chan RM. Immunorestitution disease involving the innate and adaptive response.Clin Infect Dis 2000; 30:882–892.
13. Shelburne SA, III, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy.Medicine (Baltimore) 2002; 81:213–227.
14. Stoll M, Schmidt RE. Immune restoration inflammatory syndromes: the dark side of successful antiretroviral treatment.Curr Infect Dis Rep 2003; 5:266–276.
15. Shelburne SA III, Hamill RJ. The immune reconstitution inflammatory syndrome.AIDS Rev 2003; 5:67–79.
16. Mallal SA, James IR, French MAH. Detection of subclinicalMycobacterium avium intracellulare complex infection in immunodeficient HIV-infected patients treated with zidovudine.AIDS 1994; 8:1263–1269.
17. Race EM, Adelson-Mitty J, Kriegel GR, Barlam TF, Reimann KA, Letvin NL, et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease.Lancet 1998; 351:252–255.
18. Dworkin MS, Fratkin MD. Mycobacterium avium complex lymph node abscess after use of highly active antiretroviral therapy in a patient with AIDS.Arch Intern Med 1998; 158:1828–1828.
19. Cabie A, Abel S, Brebion A, Desbois N, Sobesky G. Mycobacterial lymphadenitis after initiation of highly active antiretroviral therapy.Eur J Clin Microbiol Infect Dis 1998; 17:812–813.
20. Phillips P, Kwiatkowski MB, Copland M, Craib K, Montaner J. Mycobacterial lymphadenitis associated with the initiation of combination antiretroviral therapy.J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20:122–128.
21. del Giudice P, Durant J, Counillon E, Mondain V, Bernard E, Roger PM, et al. Mycobacterial cutaneous manifestations: a new sign of immune restoration syndrome in patients with acquired immunodeficiency syndrome.Arch Dermatol 1999; 135:1129–1130.
22. Schwietert M, Battegay M. Focal mycobacterial lymphadenitis after starting highly active antiretroviral treatment.Dtsch med Wschr 1999; 124:45–48.
23. Bartley PB, Allworth AM, Eisen DP. Mycobacterium aviumcomplex causing endobronchial disease in AIDS patients after partial immune restoration.Int J Tuberculosis Lung Dis 1999; 3:1132–1136.
24. Price LM, O'Mahoney C. Focal adenitis developing after immune reconstitution with HAART.Int J STD AIDS 2000; 11:685–686.
25. Hassell M, French MA. Mycobacterium aviuminfection and immune restoration disease after highly active antiretroviral therapy in a patient with HIV and normal CD4+ counts.Eur J Clin Microbiol Infect Dis 2001; 20:889–891.
26. Salama C, Policar M, Venkataraman M. Isolated pulmonary Mycobacterium avium complex infection in patients with human immunodeficiency virus infection: case reports and literature review.Clin Infect Dis 2003; 37:e35–e40.
27. Lawn SD, Bicanic TA, Macallan DC. Pyomyositis and cutaneous abscesses due toMycobacterium avium: an immune reconstitution manifestation in a patient with AIDS.Clin Infect Dis 2004; 38:461–463.
28. John M, French MAH. Exacerbation of the inflammatory response toMycobacterium tuberculosisafter antiretroviral therapy.Med J Aust 1998; 169:473–474.
29. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS.Am J Respir Crit Care Med 1998; 158: 157–161.
30. Crump JA, Tyrer MJ, Lloyd-Owen SJ. Miliary tuberculosis with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy.Clin Infect Dis 1998; 26:1008–1009.
31. Furrer H-J, Malinverni R. Systemic inflammatory reaction after starting highly active antiretroviral therapy in AIDS patients treated for extrapulmonary tuberculosis.Am J Med 1999; 106:371–372.
32. Kunimoto DY, Chui L, Nobert E, Houston S. Immune mediated ‘HAART’ attack during treatment for tuberculosis. Highly active antiretroviral therapy.Int J Tuberc Lung Dis 1999; 3:944–947.
33. Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB.Chest 1998; 114:933–936.
34. Fishman JE, Saraf-Lavi E, Narita M, Hollender ES, Ramsinghani R, Ashkin D. Pulmonary tuberculosis in AIDS patients: transient chest radiographic worsening after initiation of antiretroviral therapy.Am J Roentgenol 2000; 174:43–49.
35. Navas E, Martin-Davila P, Moreno L, Pintado V, Casado JL, Fortun J, et al. Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy.Arch Intern Med 2002; 162:97–99.
36. Lawn SD, Macallan DC. Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person.Clin Infect Dis 2004; 38:154–155.
37. Sharp MJ, Mallon DFJ. Regional Bacillus Calmette-Guerin lymphadenitis after initiating anti-retroviral therapy in an infant with human immunodeficiency virus type 1 infection.Ped Infect Dis J 1998; 17:660–662.
38. Lawn SD, Wood C, Lockwood DN. Borderline tuberculoid leprosy: an immune reconstitution phenomenon in a human immunodeficiency virus-infected person.Clin Infect Dis 2003; 36:e5–e6.
39. Dannenberg Jr AM. Delayed-type hypersensitivity and cell-mediated immunity in the pathogenesis of tuberculosis.Immunol Today 1991; 12:228–233.
40. Foudraine NA, Hovenkamp E, Notermans DW, Meenhorst PL, Klein MR, Lange JM, et al. Immunopathology as a result of highly active anti-retroviral therapy in HIV-1 infected patients.AIDS 1999; 13:177–184.
41. French MAH, Cameron PU, Grimsley G, Smyth LA, Dawkins RL. Correction of human immunodeficiency virus-associated depression of delayed-type hypersensitivity (DTH) after zidovudine therapy: DTH, CD4+ T-cell numbers, and epidermal Langerhans cell density are independent variables.Clin Immunol Immunopathol 1990; 55 :86–96.
42. Woods ML, MacGinley R, Eisen D, Allworth AM HIV combination therapy: partial immune reconstitution unmasking latent cryptococcal infection.AIDS 1998; 12:1491–1494.
43. Jenny-Avital ER, Abadi M. Immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy.Clin Infect Dis 2002; 35:e128–e133.
44. Blanche P, Gombert B, Ginsburg C, Passeron A, Stubei I, Rigolet A, et al. HIV combination therapy: immune restitution causing cryptococcal lymphadenitis dramatically improved by anti-inflammatory therapy.Scand J Infect Dis 1998; 30:615–616.
45. Lanzafame M, Trevenzoli M, Carretta G, Lazzarini L, Vento S, Concia E. Mediastinal lymphadenitis due to cryptococcal infection in HIV-positive patients on highly active antiretroviral therapy.Chest 1999; 116:848–849.
46. Trevenzoli M, Cattelan AM, Rea F, Sasset L, Semisa M, Lanzafame M, et al. Mediastinitis due to cryptococcal infection: a new clinical entity in the HAART era.J Infect 2002; 45:173–179.
47. Cinti SK, Armstrong WS, Kauffman CA. Case report. Recurrence of increased intracranial pressure with antiretroviral therapy in an AIDS patient with cryptococcal meningitis.Mycoses 2001; 44:497–501.
48. Rambeloarisoa J, Batisse D, Thiebaut JB, Mikol J, Mrejen S, Karmochkine M, et al. Intramedullary abscess resulting from disseminated cryptococcosis despite immune restoration in a patient with AIDS.J Infect 2002; 44:185–188.
49. Breton G, Seilhean D, Cherin P, Herson S, Benveniste O. Paradoxical intracranial cryptococcoma in a human immunodeficiency virus-infected man being treated with combination antiretroviral therapy.Am J Med 2002; 113:155–157.
50. Wislez M, Bergot E, Antoine M, Parrot A, Carette MF, Mayaud C, et al. Acute respiratory failure following HAART introduction in patients treated forPneumocystis cariniipneumonia.Am J Respir Crit Care Med 2001; 164:847–851.
51. Dean GL, Williams DI, Churchill DR, Fisher MJ. Transient clinical deterioration in HIV patients with Pneumocystis carinii pneumonia after starting highly active antiretroviral therapy: another case of immune restoration inflammatory syndrome.Am J Respir Crit Care Med 2002; 165:1670.
52. Koval CE, Gigliotti F, Nevins D, Demeter LM. Immune reconstitution syndrome after successful treatment of Pneumocystis carinii pneumonia in a man with human immunodeficiency virus type 1 infection.Clin Infect Dis 2002; 35:491–493.
53. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy.J Infect Dis 2002; 186: 23–31.
54. Puoti M, Torti C, Ripamonti D, Castelli F, Zaltron S, Zanini B, et al. Severe hepatotoxicity during combination antiretroviral treatment: incidence, liver histology, and outcome.J Acquir Immune Defic Syndr 2003; 32:259–267.
55. Law WP, Dore GJ, Duncombe CJ, Mahanontharit A, Boyd MA, Ruxrungtham K, et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996–2001.AIDS 2003; 17:2191–2199.
56. Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patients on protease inhibitors.Lancet 1997; 349:995–996.
57. John M, Flexman J, French M. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an ‘immune restoration disease'?AIDS 1998; 12:2289–2293.
58. Martin-Carbonero L, Nunez M, Rios P, Perez-Olmeda M, Gonzalez-Lahoz J, Soriano V. Liver injury after beginning antiretroviral therapy in HIV/hepatitis C virus co-infected patients is not related to immune reconstitution.AIDS 2002; 16:1423–1425.
59. Valiante NM, D'Andrea A, Crotta S, Lechner F, Klenerman P, Nuti S, et al. Life, activation and death of intrahepatic lymphocytes in chronic hepatitis C.Immunol Rev 2000; 174:77–89.
60. Michelet C, Chapplain JM, Petsaris O, Arvieux C, Ruffault A, Lotteau V, et al. Differential effect of ritonavir and indinavir on immune response to hepatitis C virus in HIV-1 infected patients.AIDS 1999; 13:1995–1996.
61. Stone SF, Lee S, Keane NM, Price P, French MA. Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26 dipeptidyl peptidase IV enzyme activity with hepatotoxicity after highly active antiretroviral therapy in human immunodeficiency virus-HCV-coinfected patients.J Infect Dis 2002; 186:1498–1502.
62. Proost P, Schutyser E, Menten P, Struyf S, Wuyts A, Opdenakker G, et al. Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties.Blood 2001; 98:3554–3561.
63. Harvey CE, Post JJ, Palladinetti P, Freeman AJ, Ffrench RA, Kumar RK, et al. Expression of the chemokine IP-10 (CXCL10) by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation.J Leukoc Biol 2003; 74:360–369.
64. Zylberberg H, Pialoux G, Carnot F, Landau A, Brechot C, Pol S. Rapidly evolving hepatitis C virus - related cirrhosis in a human immunodeficiency virus-infected patient receiving triple antiretroviral therapy.Clin Infect Dis 1998; 27:1255–1258.
65. Murcia JM, Boix V, Merino E, Manso MI, Portilla J. Drug toxicity or syndrome of immune restoration causing fulminant cirrhosis after HAART-induced immune recovery.Eur J Clin Microbiol Infect Dis 2002; 21:153–155.
66. Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sauerbruch T, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection.Lancet 2003; 362:1708–1713.
67. Martin-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Quereda C, et al. Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European collaborative study.Clin Infect Dis 2004; 38:128–133.
68. Uberti-Foppa C, De Bona A, Morsica G, Galli L, Gallotta G, Boeri E, et al. Pretreatment of chronic active hepatitis C in patients coinfected with HIV and hepatitis C virus reduces the hepatotoxicity associated with subsequent antiretroviral therapy.J Acquir Immune Defic Syndr 2003; 33:146–152.
69. Mastroianni CM, Trinchieri V, Santopadre P, Lichtner M, Forcina G, D'Agostino C, et al. Acute clinical hepatitis in an HIV-seropositive hepatitis B carrier receiving protease inhibitor therapy.AIDS 1998; 12:1939–1940.
70. Velasco M, Moran A, Tellez MJ. Resolution of chronic hepatitis B after ritonavir treatment in an HIV-infected patient.N Engl J Med 1999; 340:1765–1766.
71. Proia LA, Ngui SL, Kaur S, Kessler HA, Trenholme GM. Reactivation of hepatitis B in patients with human immunodeficiency virus infection treated with combination antiretroviral therapy.Am J Med 2000; 108:249–251.
72. Manegold C, Hannoun C, Wywiol A, Dietrich M, Polywka S, Chiwakata CB, et al. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy.Clin Infect Dis 2001; 32:144–148.
73. Rouanet I, Peyriere H, Mauboussin JM, Terrail N, Vincent D. Acute clinical hepatitis by immune restoration in a human immunodeficiency virus/hepatitis B virus co-infected patient receiving antiretroviral therapy.Eur J Gastroenterol Hepatol 2003; 15:95–97.
74. Jacobson MA, Zegans M, Pavan PR, O'Donnell JJ, Sattler F, Rao N, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy.Lancet 1997; 349:1443–1445.
75. Casado JL, Arrizabalaga J, Montes M, Marti-Belda P, Tural C, Pinilla J, et al. Incidence and risk factors for developing cytomegalovirus retinitis in HIV-infected patients receiving protease inhibitor therapy. Spanish CMV-AIDS Study Group.AIDS 1999; 13:1497–1502.
76. Casado JL, Perez-Elias MJ, Marti-Belda P, Antela A, Suarez M, Ciancas E, et al. Improved outcome of cytomegalovirus retinitis in AIDS patients after introduction of protease inhibitors.J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19:130–134.
77. Tay-Kearney ML, French MAH, Mallal S. CMV retinitis in transition.Aust NZ J Ophthalmol 1999; 27:89–89.
78. Karavellas MP, Lowder CY, Macdonald C, Avila CP, Jr., Freeman WR. Immune recovery vitritis associated with inactive cytomegalovirus retinitis: a new syndrome.Arch Ophthalmol 1998; 116:169–175.
79. Zegans ME, Walton RC, Holland GN, O'Donnell JJ, Jacobson MA, Margolis TP. Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis.Am J Ophthalmol 1998; 125:292–300.
80. Nguyen QD, Kempen JH, Bolton SG, Dunn JP, Jabs DA. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy.Am J Ophthalmol 2000; 129:634–639.
81. Karavellas MP, Azen SP, Macdonald JC, Shufelt CL, Lowder CY, Plummer DJ, et al. Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes.Retina 2001; 21:1–9.
82. Robinson MR, Csaky KG, Lee SS, Masur H, Polis MA. Fibrovascular changes misdiagnosed as cytomegalovirus retinitis reactivation in a patient with immune recovery.Clin Infect Dis 2004; 38:139–141.
83. Hsieh S-M, Pan S-C, Hung C-C, Tsai H-C, Chen M-Y, Chang S-C. Association between cytomegalovirus-specific reactivity of T cell subsets and development of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome.J Infect Dis 2001; 184:1386–1391.
84. Gerna G, Piccinini G, Genini E, Percivalle E, Zavattoni M, Lilleri D, et al. Declining levels of rescued lymphoproliferative response to human cytomegalovirus (HCMV) in AIDS patients with or without HCMV disease following long-term HAART.J Acquir Immune Defic Syndr 2001; 28:320–331.
85. Keane NM, Price P, Lee S, Almeida C-A, Stone SF, James I, et al. Restoration of CD4 T-cell responses to cytomegalovirus is short-lived in severely immunodeficient HIV patients responding to highly active antiretroviral therapy.HIV Med (in press).
86. Stone SF, Price P, Tay-Kearney M-L, French MA. Cytomegalovirus (CMV) retinitis immune restoration disease occurs during highly active antiretroviral therapy-induced restoration of CMV-specific immune responses within a predominant Th2 cytokine environment.J Infect Dis 2002; 185:1813–1817.
87. Stone SF, Price P, Brochier J, French MA. Plasma bioavailable interleukin-6 is elevated in human immunodeficiency virus-infected patients who experience herpesvirus-associated immune restoration disease after start of highly active antiretroviral therapy.J Infect Dis 2001; 184:1073–1077.
88. Podack ER, Strbo N, Sotosec V, Muta H. CD30-governor of memory T cells?Ann NY Acad Sci 2002; 975:101–113.
89. Mutimer HP, Akatsuka Y, Manley T, Chuang EL, Boeckh M, Harrington R, et al. Association between immune recovery uveitis and a diverse intraocular cytomegalovirus-specific cytotoxic T cell response.J Infect Dis 2002; 186:701–705.
90. Aldeen T, Hay P, Davidson F, Lau R. Herpes zoster infection in HIV-seropositive patients associated with highly active anti-retroviral therapy.AIDS 1998; 12:1719–1720.
91. Martinez E, Gatell J, Moran Y, Aznar E, Buira E, Guelar A, et al. High incidence of herpes zoster in patients with AIDS soon after therapy with protease inhibitors.Clin Infect Dis 1998; 27:1510–1513.
92. Domingo P, Torres OH, Ris J, Vazquez G. Herpes zoster as an immune reconstitution disease after initiation of combination antiretroviral therapy in patients with human immunodeficiency virus type-1 infection.Am J Med 2001; 110: 605–609.
93. Clark BM, Krueger RG, Price P, French MAH. Compartmentalisation of the immune response in varicella zoster virus immune restoration disease causing transverse myelitis.AIDS 2004; 18: 1218–1221.
94. Naseri A,Margolis TP. Varicella zoster virus immune recovery stromal keratitis in a patient with AIDS.Br J Ophthalmol 2001; 85:1390–1391.
95. Fox PA, Barton SE, Francis N, Youle M, Henderson DC, Pillay D, et al. Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease.HIV Med 1999; 1:10–18.
96. Cinque P, Pierotti C, Vigano MG, Bestetti A, Fausti C, Bertelli D, et al. The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy.J Neurovirol 2001; 7: 358–363.
97. Gasnault J, Kahraman M, de Goer de Herve MG, Durali D, Delfraissy JF, Taoufik Y. Critical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy.AIDS 2003; 17:1443–1449.
98. Mayo H, Collazos J, Martinez E. Progressive multifocal leukoencephalopathy following initiation of highly active anti-retroviral therapy.AIDS 1998; 12:1720–1722.
99. Kotecha N, George MJ, Smith TW, Corvi F, Litofsky NS. Enhancing progressive multifocal leukoencephalopathy: an indicator of improved immune status?Am J Med 1998; 105:541–543.
100. Tantisiriwat W, Tebas P, Clifford DB, Powderly WG, Fichtenbaum CJ. Progressive multifocal leukoencephalopathy in patients with AIDS receiving highly active antiretroviral therapy.Clin Infect Dis 1999; 28:1152–1154.
101. Miralles P, Berenguer J, Lacruz C, Cosin J, Lopez JC, Padilla B, et al. Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy.AIDS 2001; 15:1900–1902.
102. Safdar A, Rubocki RJ, Horvath JA, Narayan KK, Waldron RL. Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution.Clin Infect Dis 2002; 35: 1250–1257.
103. Hoffmann C, Horst HA, Albrecht H, Schlote W. Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment.J Neurol Neurosurg Psychiatry 2003; 74:1142–1144.
104. Nolan RC, Chidlow G, French MA. Parvovirus B19 encephalitis presenting as immune restoration disease after highly active antiretroviral therapy for human immunodeficiency virus infection.Clin Infect Dis 2003; 36:1191–1194.
105. Bouscarat F, Maubec E, Matheron S, Descamps V. Immune recovery inflammatory folliculitis.AIDS 2000; 14:617–618.
106. Blanche P, Gombert B, Rivoal O, Abad S, Salmon D, Brezin A. Uveitis due to Leishmania major as part of HAART-induced immune restitution syndrome in a patient with AIDS.Clin Infect Dis 2002; 34:1279–1280.
107. Ridolfo AL, Gervasoni C, Antinori S, Pizzuto M, Santambrogio S, Trabattoni D, et al. Post-kala-azar dermal leishmaniasis during highly active antiretroviral therapy in an AIDS patient infected with Leishmania infantum.J Infect 2000; 40:199–202.
108. Abino JF, Peraldi R, Lepidi H, Luciani M, Girard PM. Bacillary splenitis (Bartonella henselae) during immune restoration in an HIV-infected patient.AIDS 2002; 16:1429–1430.
109. Gajdatsy AD,Tay-Kearney ML. Microsporidial keratoconjunctivitis after HAART.Clin Exp Ophthalmol 2001; 29:327–329.
    110. Neumann S, Kreth F, Schubert S, Mossner J, Caca K. Reiter's syndrome as a manifestation of an immune reconstitution syndrome in an HIV-infected patient: successful treatment with doxycycline.Clin Infect Dis 2003; 36:1628–1629.
    111. Greenspan D, Canchola AJ, MacPhail LA, Cheikh B, Greenspan JS. Effect of highly active antiretroviral therapy on frequency of oral warts.Lancet 2001; 357:1411–1412.
    112. King MD, Reznik DA, O'Daniels CM, Larsen NM, Osterholt D, Blumberg HM. Human papillomavirus-associated oral warts among human immunodeficiency virus-seropositive patients in the era of highly active antiretroviral therapy: an emerging infection.Clin Infect Dis 2002; 34:641–648.
    113. Collazos J, Ojanguren J, Mayo J, Martinez E, Ibarra S. Lymphoma developing shortly after the onset of highly active antiretroviral therapy in HIV-infected patients.AIDS 2002; 16: 1304–1306.
    114. Marshall NA, Vickers MA, Barker RN. Regulatory T cells secreting IL-10 dominate the immune response to EBV latent membrane protein 1.J Immunol 2003; 170:6183–6189.
    115. Breen EC, Boscardin WJ, Detels R, Jacobson LP, Smith MW, O'Brien SJ, et al. Non-Hodgkin's B cell lymphoma in persons with acquired immunodeficiency syndrome is associated with increased serum levels of IL10, or the IL10 promoter -592 C/C genotype.Clin Immunol 2003; 109:119–129.
    116. Weir A, Wansbrough-Jones M. Mucosal Kaposi's sarcoma following protease inhibitor therapy in an HIV-infected patient.AIDS 1997; 11:1895–1896.
    117. Zietz C, Bogner JR, Goebel FD, Lohrs U. An unusual cluster of cases of Castleman's disease during highly active antiretroviral therapy for AIDS.N Engl J Med 1999; 340:1923–1924.
    118. Phillips P, Chan K, Hogg R, Bessuille E, Black W, Talbot J, et al. Azithromycin prophylaxis forMycobacterium aviumcomplex during the era of highly active antiretroviral therapy: evaluation of a provincial program.Clin Infect Dis 2002; 34: 371–378.
    119. Price P, Keane NM, Stone SF, Cheong KYM, French MA. MHC haplotypes affect the expression of opportunistic infections in HIV patients.Hum Immunol 2001; 62:157–164.
    120. Price P, Morahan G, Huang D, Stone E, Cheong KY, Castley A, et al. Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases.AIDS 2002; 16:2043–2047.
    121. Naccache JM, Antoine M, Wislez M, Fleury-Feith J, Oksenhendler E, Mayaud C, et al. Sarcoid-like pulmonary disorder in human immunodeficiency virus-infected patients receiving antiretroviral therapy.Am J Respir Crit Care Med 1999; 159:2009–2013.
    122. Mirmirani P, Maurer TA, Herndier B, McGrath M, Weinstein MD, Berger TG. Sarcoidosis in a patient with AIDS: a manifestation of immune restoration syndrome.J Am Acad Dermatol 1999; 41:285–286.
    123. Gomez V, Smith PR, Burack J, Daley R, Rosa U. Sarcoidosis after antiretroviral therapy in a patient with acquired immunodeficiency syndrome.Clin Infect Dis 2000; 31:1278–1280.
    124. Blanche P, Gombert B, Rollot F, Salmon D, Sicard D. Sarcoidosis in a patient with acquired immunodeficiency syndrome treated with interleukin-2.Clin Infect Dis 2000; 31:1493–1494.
    125. Haramati LB, Lee G, Singh A, Molina PL, White CS. Newly diagnosed pulmonary sarcoidosis in HIV-infected patients.Radiology 2001; 218:242–246.
    126. Zandman-Goddard G, Peeva E, Barland P. Combined autoimmune disease in a patient with AIDS.Clin Rheumatol 2002; 21:70–72.
    127. Foulon G, Wislez M, Naccache JM, Blanc FX, Rabbat A, Israel-Biet D, et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy.Clin Infect Dis 2004; 38: 418–425.
    128. Blanche P, Passeron A, Gombert B, Ginsburg C, Salmon D, Sicard D. Sarcoidosis and HIV infection: influence of highly active antiretroviral therapy.Br J Dermatol 1999; 140:1185
    129. Trevenzoli M, Cattelan AM, Marino F, Marchioro U, Cadrobbi P. Sarcoidosis and HIV infection: a case report and a review of the literature.Postgrad Med J 2003; 79:535–538.
    130. Viani RM. Sarcoidosis and interstitial nephritis in a child with acquired immunodeficiency syndrome: implications of immune reconstitution syndrome with an indinavir-based regimen.Pediatr Infect Dis J 2002; 21:435–438.
    131. Behrens G, Knuth C, Schedel I, Mendila M, Schmidt RE. Highly active antiretroviral therapy.Lancet 1998; 351:1057–1058.
    132. Diri E, Lipsky PE, Berggren RE. Emergence of systemic lupus erythematosus after initiation of highly active antiretroviral therapy for human immunodeficiency virus infection.J Rheumatol 2000; 27:2711–2714.
    133. Sellier P, Monsuez JJ, Evans J, Minozzi C, Passeron J, Vittecoq D, et al. Human immunodeficiency virus-associated polymyositis during immune restoration with combination antiretroviral therapy.Am J Med 2000; 109:510–512.
    134. Bell C, Nelson M, Kaye S. A case of immune reconstitution rheumatoid arthritis.Int J STD AIDS 2002; 13:580–581.
    135. Makela P, Howe L, Glover S, Ferguson I, Pinto A, Gompels M. Recurrent Guillain–Barre syndrome as a complication of immune reconstitution in HIV.J Infect 2002; 44:47–49.
    136. Piliero PJ, Fish DG, Preston S, Cunningham D, Kinchelow T, Salgo M, et al. Guillain–Barre syndrome associated with immune reconstitution.Clin Infect Dis 2003; 36:e111–e114.
    137. Jubault V, Penfornis A, Schillo F, Hoen B, Izembart M, Timsit J, et al. Sequential occurrence of thyroid autoantibodies and Graves’ disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients.J Clin Endocrinol Metab 2000; 85: 4254–4257.
    138. Sereti I, Sarlis NJ, Arioglu E, Turner ML, Mican JM. Alopecia universalis and Graves’ disease in the setting of immune restoration after highly active antiretroviral therapy.AIDS 2001; 15:138–140.
    139. French MA, Lewin SR, Dykstra C, Krueger R, Price P, Leedman PJ. Graves’ disease during immune reconstitution after highly active antiretroviral therapy for HIV infection: evidence of thymic dysfunction.AIDS Res Hum Retroviruses 2004; 20: 157–162.
    140. Silvestre JF, Albares MP, Ramon R, Botella R. Cutaneous intolerance to tattoos in a patient with human immunodeficiency virus: a manifestation of the immune restoration syndrome.Arch Dermatol 2001; 137:669–670.
    141. Wimalasundera RC, Larbalestier N, Smith JH, de Ruiter A, McG Thom SA, Hughes AD, et al. Pre-eclampsia, antiretroviral therapy, and immune reconstitution.Lancet 2002; 360: 1152–1154.
    142. van der Ven AJ, van Oostenbrugge RJ, Kubat B, Tervaert JW. Cerebral vasculitis after initiation of antiretroviral therapy.AIDS 2002; 16:2362–2364.
    143. Rogers GD, French MAH. Peyronie's disease in men with HIV responding to highly active antiretroviral therapy.HIV Med 2004; 5:185–186.
    144. Bachmeyer C, Cordier F, Blum L, Cazier A, Verola O, Aractingi S. Multiple eruptive dermatofibromas after highly active antiretroviral therapy.Br J Dermatol 2000; 143:1336–1337.
    145. Casariego Z, Pombo T, Perez H, Patterson P. Eruptive cheilitis: a new adverse effect in reactive HIV-positive patients subjected to high activity antiretroviral therapy (HAART). Presentation of six clinical cases.Med Oral 2001; 6:19–30.
    146. Tassie JM, Szumilin E, Calmy A, Goemaere E. Highly active antiretroviral therapy in resource-poor settings: the experience of Medecins Sans Frontieres.AIDS 2003; 17:1995–1997.
    147. Sungkanuparph S, Vibhagool A, Mootsikapun P, Chetchotisakd P, Tansuphaswaswadikul S, Bowonwatanuwong C. Opportunistic infections after the initiation of highly active antiretroviral therapy in advanced AIDS patients in an area with a high prevalence of tuberculosis.AIDS 2003; 17:2129–2131.
    148. Klein D, Hurley LB, Merrill D, Quesenberry CP, Jr. Review of medical encounters in the 5 years before a diagnosis of HIV-1 infection: implications for early detection.J Acquir Immune Defic Syndr 2003; 32:143–152.
    149. Murray R, Mallal S, Heath C, French M. CerebralMycobacterium aviuminfection in an HIV-infected patient following immune reconstitution and cessation of therapy for disseminatedMycobacterium aviumcomplex infection.Eur J Clin Microbiol Infect Dis 2001; 20:199–201.
    150. Aberg JA, Chin-Hong PV, McCutchan A, Koletar SL, Currier JS. Localized osteomyelitis due to Mycobacterium avium complex in patients with Human Immunodeficiency Virus receiving highly active antiretroviral therapy.Clin Infect Dis 2002; 35:E8–E13.
    151. Lee S, French MAH, Price P. Interleukin-23 and interferon-gamma deficiency in immunodeficient HIV patients who achieved a long-term increase in CD4 T-cell counts on HAART.AIDS 2004; 18:1337–1340.
    152. Stone SF, Price P, Keane NM, Murray RJ, French MA. Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART.HIV Med 2002; 3.21–27.
    153. Morlese JF, Orkin CM, Abbas R, Burton C, Qazi NA, Nelson MR, et al. Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection.AIDS 2003; 17: 1411–1413.
    154. Almeida CA, Price P, French MA. Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy.AIDS Res Hum Retroviruses 2002; 18:1351–1355.
    155. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes.Trends Immunol 2004; 25:4–7.
    156. Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, et al. Prevalence and incidence of pre-diabetes and diabetes in the Multicentre AIDS Cohort Study.XI Conference on Retroviruses and Opportunistic Infections, San Francisco, February 2004 [abstract no. 73].

    HIV; antiretroviral therapy; immune reconstitution; immune restoration disease

    © 2004 Lippincott Williams & Wilkins, Inc.