Thymic activity in late-stage HIV-1 infected individuals receiving highly active antiretroviral therapy: potential effect of steroid therapy

Objective Our objective was to monitor the effect of steroid therapy on the thymic output and function of late‐stage HIV‐1‐infected patients undergoing highly active antiretroviral therapy (HAART).
Design The indirect measurement of T cells that have recently emigrated from the thymus as a means of quantifying thymic output, and therefore thymic function, was achieved through use of the polymerase chain reaction‐based signal joint T cell receptor rearrangement excision circles (sjTREC) assay. Proliferative capacity and interleukin (IL)‐2 and IL‐4 production by T cells after antigenic, mitogenic and IL‐2 stimulation were also analysed.
Method Measurements were made of sjTREC levels in peripheral blood mononuclear cell DNA samples from five HIV‐1 infected patients (one on steroid therapy prior to and at the time of sample extraction) receiving HAART. IL‐2 and IL‐4 production and proliferative capacity were also measured in three patients, including the patient receiving steroids.
Result The sjTREC assay gave an extremely weak result for the patient on steroids but, under the same assay conditions, provided clear, positive readings for the four patients not on steroids. Comparison of the patients' cytokine profiles revealed that IL‐2 production was generally low or absent in all three patients tested but that IL‐4 production was significantly higher in the patient given steroids. Functional potential as revealed by proliferation assays showed very low or absent cellular proliferation.
Conclusion The thymic contribution to the restoration of T lymphocyte numbers, particularly during the treatment of HIV‐1 infection, may become compromised if thymic inhibitory factors such as steroids are used. Furthermore, the use of steroids may also favour the development of a T helper 2 response, which could prove particularly undesirable during HIV‐1 infection.     

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

This study compared plasma bioavailable interleukin (IL)-6 levels in 3 groups: human immunodeficiency virus (HIV)-infected patients who had a human herpesvirus (HHV)-associated immune restoration disease (IRD) during highly active antiretroviral therapy (HAART); patients who experienced an IRD initiated by Mycobacterium avium complex, hepatitis C virus, or human papillomavirus; and control patients who had uneventful immune reconstitution. Total IL-6, soluble IL-6 receptor (sIL-6R), and soluble gp130 were measured by ELISA, and levels of free IL-6 and sIL-6/IL-6R complex were modeled mathematically. Persons who had an HHV-associated IRD had increased plasma bioavailable IL-6 before HAART, compared with patients who experienced a non-HHV-associated IRD and with control patients, and their plasma bioavailable IL-6 increased progressively over 3-4 years of treatment. Increased IL-6 production may be a feature of HAART-induced restoration of immune responses to HHV infections and may have long-term immunopathologic consequences.     

Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy

Immune activation associated with HIV infection declines after highly active antiretroviral therapy (HAART), but may persist or recur in some patients. It is not clear whether this reflects a resurgence of HIV replication or another cause of immune activation, such as inflammatory reactions to opportunistic pathogens (immune restoration disease [IRD]). Here, we studied plasma and cellular immune activation markers in adult HIV-1 patients who had received HAART for >12 months and maintained plasma HIV RNA levels of <400 copies/ml for >6 months. Plasma interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels were similar in patients and HIV-negative control subjects, but the highest levels occurred mainly in patients with a history of IRD. In contrast, expression of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in patients than in control subjects. Thus, cellular markers of immune activation are abnormal in some patients with a good virological response to HAART, and abnormalities of plasma immune activation markers correlate with a history of IRD.     

Non-typhoidal Salmonella bacteraemia: clinical features and risk factors

A case control study was conducted to determine the risk factors of non‐typhoidal Salmonella bacteraemia. Eighty adult patients with non‐typhoidal Salmonella bacteraemia admitted to Siriraj Hospital from January to December 1993 served as the cases. The controls comprised 3 groups: group 1, 80 adult in‐patients with Escherichia coli bacteraemia; group 2, 80 adult in‐patients who did not have bacteraemia and had been admitted to the hospital during the same period as the cases; group 3, 80 in‐patients who did not have Salmonella bacteraemia and matched the cases in terms of gender, age, hospital services and admission date. AIDS and corticosteroid use were the major risk factors for acquiring non‐typhoidal Salmonella bacteraemia with an odds ratio of 7.27 to 12.31 (95% confidence interval of 3.39 to 29.40). Almost all patients with non‐typhoidal Salmonella bacteraemia presented with a fever for a median duration of 7 days. AIDS patients usually had concomitant opportunistic infections. Salmonella group D was the most common serogroup. Most patients were treated with co‐trimoxazole, quinolones, ceftriaxone and ampicillin. Localized suppurative complications were observed in 14% of the patients; the overall mortality rate was 36.3%, 12% of whom died prior to receiving appropriate antibiotics for Salmonella .     

Post-natal incidence of HIV-1 infection among children in a rural Ugandan population: no evidence for transmission other than mother to child

We conducted a prospective cohort study to determine the post‐natal incidence of and possible transmission routes for HIV‐1 infection in rural Ugandan children. The cohort consisted of the population of a cluster of 15 villages in Masaka District, south‐west Uganda, and was enrolled in 1989–1990 through a demographic and serological survey. During the period 1991–1993 the population was resurveyed annually. A total of 5492 children aged 0–12 years were enrolled; of these, 41 (0.7%) were seropositive infants. A total of 3941 (72%) children were HIV‐negative on enrolment and had at least one follow‐up specimen. During 8596 person‐years of observation only 1 seroconversion was observed, an incidence rate of 0.12 (95% CI 0.00–0.35) per 1000 years of observation. The transmission of HIV was most probably through breast milk. The case corresponds to a rate of 1.1 per 1000 in households with one or more HIV‐positive adults (874 years of observation); no incident case was observed in households with only seronegative adults (6423 years of observation). Thus, HIV infection among children aged 0–12 years in this population is virtually exclusively the result of mother‐to‐child transmission. No infections were observed attributable to parenteral exposure, non‐sexual casual or household contact, or insects.     

Enhanced production of interleukin-6 (IL-6), oncostatin M and soluble IL-6 receptor by cultured peripheral blood mononuclear cells from patients with systemic sclerosis.

OBJECTIVES: To determine whether the spontaneous production of interleukin 6 (IL-6), oncostatin M (OSM), soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130) from peripheral blood mononuclear cells (PBMC) is increased in patients with systemic sclerosis (SSc). METHODS: The culture supernatants of PBMC from patients with SSc (n = 33) and healthy controls (n = 20) were examined by enzyme-linked immunosorbent assay. RESULTS: The production levels of IL-6, OSM and sIL-6R were significantly higher in patients with SSc than in controls. However, sgp130 levels in supernatants from patients with SSc were not significantly elevated when compared with those from controls. Soluble IL-6R levels correlated significantly with the severity of pulmonary fibrosis in patients with SSc. CONCLUSIONS: The enhanced production of IL-6, OSM and sIL-6R from PBMC may cooperatively contribute to the disease process in SSc. In particular, enhanced sIL-6R production from PBMC may be related to the development of pulmonary fibrosis via enhancement of IL-6 signal transduction in SSc, since sIL-6R can act as an agonist of IL-6.     

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

Plasma levels of cytomegalovirus (CMV)-specific immunoglobulin G (IgG), soluble (s) CD30, sCD26 (dipeptidyl peptidase IV [DPP IV]) enzyme activity, and tumor necrosis factor receptor-I (TNFR-I) were assessed in human immunodeficiency virus (HIV)-infected patients who experienced CMV retinitis (CMVR) as an immune restoration disease (IRD) during their first 6 months of highly active antiretroviral therapy (HAART) and in CMV-seropositive, HIV-infected patients with similar baseline CD4(+) T cell counts who had uneventful immune reconstitution. Patients who experienced CMVR IRD had a significant increase in CMV-specific IgG during their first 12 months of HAART, indicating restored CMV-specific immune responses. They also had significantly higher levels of sCD30 both before HAART and for up to 12 months after start of treatment. sCD30 levels remained elevated during 48 months of HAART, suggesting persistence of a predominant Th2 cytokine environment. Levels of sCD26 (DPP IV) enzyme activity and TNFR-I did not differ significantly between the 2 groups at any time point.     

Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy

Background To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log₁₀ copies/mL).
Methods Baseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients.
Results Thirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses.
Conclusions We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens.     

Immune restoration disease: a consequence of dysregulated immune responses after HAART

Immune Restoration Diseases (IRD) are a collection of atypical 'opportunistic infections' and inflammatory diseases seen in human immunodeficiency virus (HIV) patients after HIV viraemia is suppressed by highly active antiretroviral therapy (HAART). IRD probably reflect dysregulated immune responses against pre-existing infections by opportunistic pathogens, with different immunopathological mechanisms for different pathogens. For example, mycobacterial IRD are associated with delayed type hypersensitivity (DTH) responses to mycobacterial antigens, whereas patients who experience cytomegalovirus (CMV) IRD have elevated plasma levels of soluble CD30, a marker of a T2 cytokine environment expressed by activated CD8 T-cells. As IRD are often compartmentalised to organs, monitoring serological markers such as pathogen-specific IgG antibody, may be informative, as demonstrated for CMV and hepatitis C virus (HCV)-associated IRD. Genetic studies have provided evidence of distinct immunopathological mechanisms and inherited susceptibility to IRD associated with mycobacterial and herpesviridae infections. The expansion of HAART in the developing world where many HIV patients have low CD4+ T-cell counts and high rates of concomitant infections will place a large number of patients at-risk of developing IRD. It is therefore important to understand the immunopathology so that prevention, diagnosis and treatment can be improved.     

获得性免疫缺陷综合征患者胃黏膜组织人类免疫缺陷病毒感染分析

目的 探讨获得性免疫缺陷综合征(AIDS)患者胃黏膜组织中人类免疫缺陷病毒(HIV)感染的分布、数量及高效抗逆转录病毒治疗(HAART)前、后的变化.方法 选取伴有消化道症状的AIDS患者35例,对照组为HIV-1阴性者10例,均进行胃镜检查.PCR法制备地高辛标记HIV-1 LTR、gag基因的双链cDNA探针,对胃黏膜组织冰冻切片采取核酸原位杂交法观察HIV感染情况,并与外周血单个核细胞(PBMC)涂片对比.结果 ①AIDS患者胃镜下多表现为不同程度的慢性浅表性胃炎(CSG)和慢性萎缩性胃炎(CAG),AIDS患者临床消化道症状、胃镜下表现及病理结果未见明显特征性.②AIDS患者胃黏膜组织内HIV阳性显色多见于单个核细胞(MMC)中,胃黏膜上皮、腺上皮细胞和问质细胞中亦有阳性杂交信号.③胃窦黏膜组织与胃体黏膜组织HIV阳性率差异无统计学意义(P>0.05).④AIDS患者胃黏膜HIV阳性率为(1.97±3.25)%,AIDS未治疗组与HAART治疗组各组间胃窦和胃体部HIV阳性率差异均无统计学意义(P值均>0.05).PBMC中HIV总阳性细胞率为(12.38±9.17)%;AIDS未治疗组PBMC中HIV阳性细胞率为(19.37±9.23)%,AIDS治疗1～4年组为(4.25±3.47)%,两组间差异有统计学意义(P<0.05).结论 胃黏膜是HIV感染的靶部位之一,HAART治疗对AIDS患者胃黏膜感染收效甚微.     

Immune restoration disease in HIV-infected individuals receiving highly active antiretroviral therapy: clinical and immunological characteristics

BACKGROUND: HIV-infected patients responding to HAART can show a diverse spectrum of symptoms caused by inflammatory reaction. The pathogenesis of this phenomenon, called immune restoration disease (IRD), is unclear. This study describes the spectrum of IRD and analyses the immunological and clinical parameters that could be related to its development. METHODS: In a retrospective, matched case-control study, 17 HIV-infected individuals who developed inflammatory symptoms < 12 months after initiation of HAART were included. HIV-infected controls were matched for age, gender and CDC classification. Factors included in the analysis were: CD4+ and CD8+ cell counts, deltaCD4+ and deltaCD8+, CD4/CD8 ratios, HIV-1-RNA load (VL), AVL and the number of CDC events prior to HAART. RESULTS: The median time after initiation of HAART and developing IRD (n = 17) was 72 days (range 2-319). In nine cases (53%) a mycobacterial infection was identified as the underlying cause. HAART was started at a mean CD4+ count (+/- SD) of 55 x 10(6) /l (+/- 59) and 85 x 10(6) /l (+/- 78.0) for cases and controls, respectively (p = 0.13). After initiation of HAART, the CD4+ count showed a 10.6 fold increase at the onset of IRD in the cases and a 2.7 fold increase in the controls in an equal period of time (p = 0.020). The other parameters analysed did not differ significantly between cases and controls. CONCLUSION: We conclude that the risk of developing IRD is associated with a high-fold increase in CD4+ lymphocytes. In this study, mycobacteria are the pathogens most frequently associated with IRD.     

Long-term efficacy and safety of ritonavir/indinavir at 400/400 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors as first line antiretroviral therapy

Objective To determine the long‐term antiretroviral efficacy and tolerability of dual protease inhibitor (PI) therapy with indinavir (IDV)/ritonavir (RTV) at 400/400 mg twice a day (BID) in combination with two nucleoside reverse trancriptase inhibitors (NRTIs).
Design and methods In an open‐label, uncontrolled multicentre clinical trial, antiretroviral therapy naive patients ( n  = 93) with a high median baseline HIV‐1 RNA level of 210 000 copies/mL (range 17 000–2 943 000) and a median CD4 cell count of 195 copies/µL (range 4–656 copies/µL) were started on a regimen of either zidovudine (ZDV)/lamivudine (3TC) (49%), stavudine (d4T)/3TC (38%) or d4T/didanosine (ddI) (14%) plus RTV and IDV, each at 400 mg BID. CD4 cell counts and HIV RNA were determined at 4‐week intervals for a duration of 72 weeks. Statistical analysis was performed on treatment as well as by intent to treat, where missing values were counted as failures.
Results HIV RNA levels below the limit of detection were achieved in 59.5% (< 80 copies/mL) and 63% (< 500 copies/mL) of patients according to the intent to treat analysis at week 72. In the on treatment analysis, the proportion of patients reaching an undetectable viral load was 94.5% (< 80 copies/mL) and 100% (< 500 copies/mL), respectively. Apart from diarrhoea and nausea, serum lipid abnormalities were identified as the most prominent adverse reaction. No cases of nephrotoxicity occurred during the entire observation period of 72 weeks.
Conclusions Our results demonstrate that quadruple therapy with RTV/IDV and two NRTIs induces potent, durable and safe HIV suppression and might be particularly beneficial as a first line therapy for patients with a high baseline viral load.     

HAART后血液及精液中HIV水平的比较研究

目的高效抗逆转录病毒治疗(highly active antiretroviral therapy,HAART)6个月后,对HIV感染者血浆及精浆中的HIV RNA水平进行比较研究,对外周血单个核细胞(peripheral blood mononuclear cell,PBMC)及精液细胞中的HIV DNA水平进行比较研究。方法收集HAART 6个月后血液中HIV RNA下降到检测不出的16例患者的精液和血液样本,采用实时定量PCR的方法检测其血浆及精浆中的HIV RNA水平,PBMC及精液细胞中的HIV DNA水平。结果 16例患者的精浆中有15例可检测到HIV RNA,在PBMC及精液细胞中均可检测到HIV DNA,且二者HIV DNA水平差异无统计学意义。结论 HAART 6个月后,大多数患者精液中仍可检测到HIV RNA及HIV DNA。     

Immune restoration disease after antiretroviral therapy

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.     

Impact of immune interventions on proviral HIV-1 DNA decay in patients receiving highly active antiretroviral therapy

Objective   To measure the evolution of proviral HIV-1 DNA levels in patients receiving highly active antiretroviral therapy (HAART) compared to those treated with HAART plus interleukin-2 (IL-2) and hydroxyurea.
Design   Prospective randomised trial.
Methods   Twenty-two HIV-1 infected patients were randomly assigned to a five-drug antiretroviral regimen for 72 weeks, with or without IL-2, followed by a three-drug regimen up to week 120 with additional hydroxyurea in patients having received IL-2. HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were measured regularly using the Amplicor Monitor kit from Roche Diagnostics (Meylan, France). Potentially infectious HIV-1 was cultured in enhanced conditions from circulating CD4 T cells at week 120.
Results   During the study period of 120 weeks, HIV-1 DNA levels in PBMC decreased by −1.1 log in patients treated with HAART only compared with −1.8 log in patients with additional IL-2 and hydroxyurea. A two-phase decay rate was observed, with an inflexion point at 12 weeks. The second decay was slow, with mean half-lives of 130.1 ± 21.3 weeks and 95.1 ± 26.3 weeks for patients on HAART and those receiving additional IL-2 and hydroxyurea, respectively. At week 120, one out of 11 patients with HAART alone compared to six out of 11 in the group with IL-2 and hydroxyurea had undetectable proviral DNA levels and three of them had unsuccessful recovery of replication-competent HIV-1 from blood CD4 T cells.
Conclusion   Therapeutic strategies combining HAART and immune interventions have higher potency to decrease the number of infected cells than HAART alone.     

艾滋病的高效抗逆转录病毒治疗、疗效观察及其对免疫功能的影响

目的 为探讨艾滋病高效抗逆转录病毒治疗、疗效观察及其对免疫功能的影响.方法 应用HAART疗法对4例有严重免疫功能低下的HIV/AIDS病人进行治疗.结果 所有病人在治疗4周HIV复制被明显抑制,血浆病毒载量平均下降1.99log/ml(0.73～2.46log/ml),CD_8~ 、CD_4~ 细胞和血浆IL-2浓度在4～12周后持续性显著增高,上升幅度分别为67.2%,103.0%,255.1%,而血浆sIL-2R、IL-6、TNF-α、sTNFR-I、Neopterin浓度在治疗4～12周后持续下降至正常水平或以下.HAART治疗后各因素变化间的相关性分析显示,CD_4~ 细胞数与CD_8~ 、CD_3~ 细胞和血浆IL-2浓度之间,血浆病毒载量与sIL-2R、IL-6、TNF-α、sTNFR-I、Neopterin之间,sTNFR-I和Neopterin与sIL-2R、IL-6、TNF-α之间均存在明显正直线相关性;而CD_4~ 细胞数与血浆病毒载量、sIL-2R、sTNFR-I、Neopterin之间.以及IL-2和sIL-2R之间则有明显负直线相关性.结论 抗病毒治疗效果、病毒复制和免疫活化间具有密切关系,HAART治疗能快速有效地抑制HIV-1的复制,纠正机体免疫功能紊乱和重建免疫功能;外周血CD_4~ 细胞数、血浆病毒载量、IL-2、sIL-2R、TNF-α、sTNFR-I、Neopterin的浓度变化可以作为HAART治疗效果评价的重要指标.     

艾滋病患者胃黏膜与外周血中人类免疫缺陷病毒感染和CD4~+T淋巴细胞数量的区室性差异的探讨

目的 探讨AIDS患者胃黏膜与外周血中HIV感染和CD4~+T淋巴细胞数量的区室性差异.方法 选取AIDS患者35例,对照组为HIV抗体阴性者10例,均进行胃镜检查并收集外周血.PCR法制备地高辛标记HIV-1长末端重复序列(LTR)、gag基因的双链cDNA探针,核酸原位杂交方法观察胃黏膜组织冰冻切片和外周血单个核细胞(PBMC)涂片H1V感染情况,免疫组织化学方法检测CD41T淋巴细胞,数据结果行t检验.结果 AIDS未治疗组胃黏膜中HIV阳性率为(1.67±1.48)%,PBMC中为(19.37±9.23)%.AIDS未治疗组与高效抗反转录病毒治疗(HAART)组各组间的胃黏膜HIV阳性率差异尤统计学意义(t=-0.996,t=-0.794,t=-0.461;P＞0.05).PBMC涂片中,治疗1～4年组HIV阳性率为(4.25±3.47)%,明显低于未治疗组的(19.37±9.23)%(t=3.000,P＜0.05).AIDS未治疗组胃黏膜单个核细胞(MMC)中CD4+T淋巴细胞阳性率为(12.53±8.14)%,PBMC中CD4+T淋巴细胞阳性率为(19.00±9.55)%,HAART1～4年组胃黏膜MMC中CD4~+T淋巴细胞计数为(37.44±18.00)%,仍低于对照组的(50.35±3.41)%(t=-4.620,P＜0.01),但PBMC中CD4+T淋巴细胞计数与对照组比较,差异无统计学意义(t=-2.094,P＞0.05).结论 胃黏膜与外周血中HIV感染和CD4~+T淋巴细胞数量存在区室性差异.     

Is acute appendicitis another inflammatory condition associated with highly active antiretroviral therapy (HAART)?

  ¹ Department of Genitourinary Medicine, St George's Hospital, London, UK,   ² Department of Infectious Diseases, Cork University Hospital, Cork, Ireland,   ³ Department of Infectious Diseases and   ⁴ Department of Histopathology, St George's Hospital, London, UK
Objective   To report the occurrence of acute appendicitis as a possible manifestation of the immune restoration inflammatory syndrome (IRIS) following the commencement of highly active antiretroviral therapy (HAART) in HIV patients.
Design   Case-note review of HIV patients on HAART with acute appendicitis.
Methods   Review of HIV markers, antiretroviral therapy and abdominal ultrasound results of four HIV patients with acute appendicitis and the histopathology reports on the appendix in two of the patients.
Results   From a population of approximately 350 HIV patients on HAART, we found four patients who developed acute appendicitis within 6 months of commencing or changing HAART.
Conclusion   Acute appendicitis occurring in HIV patients on HAART may represent a variant of IRIS. Further immunohistopathological and epidemiological evaluation will be needed to define this relationship fully.     

Alleles of the gene encoding IL-1alpha may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy

OBJECTIVE: Some HIV patients treated with highly active antiretroviral therapy (HAART) do not resolve their plasma viraemia or HIV RNA can reappear after a period of virological control. We investigate whether polymorphisms in cytokine genes affect the control of plasma HIV RNA over 5 years on HAART. DESIGN: The study utilized adult HIV-infected patients in Western Australia. Plasma HIV-RNA levels were assessed from commencement of HAART in patients who had a CD4 T-cell count less than 100 cells/microl before HAART and achieved immune reconstitution assessed by CD4 T-cell counts. RESULTS: Control of plasma viraemia could be predicted from carriage of allele 2 at position -889 in the IL1A gene (IL1A-889*2). This was significant when assessed by the proportion of patients with a plasma HIV-RNA level of 400 copies/ml or less (P = 0.002). At 48 months post-HAART, proportions were approximately 0.76, 0.51 and 0.32 for IL1A (1,1), (1,2) and (2,2) patients, respectively. The outcome was independent of the patients' CD4 T-cell counts before or on therapy, drug regimen or age. Polymorphisms in IL6, TNFA, IL1B or IL12B had less significant effects, which became marginal when IL1A was included in the statistical model. IL1A-889 was in linkage disequilibrium with a non-synonymous polymorphism at IL1A+4845. CONCLUSION: Alleles carried at IL1A-889 or IL1A+4845 may predict the control of HIV replication in previously immunodeficient patients responding to HAART.     

The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy

BACKGROUND: It is becoming increasingly clear that, during successful highly active antiretroviral therapy (HAART), a proportion of treated patients develop opportunistic infections (OIs), referred to in this setting as immune restoration disease (IRD). We examined the risk of developing IRD in HAART-treated HIV-infected patients. METHODS: A retrospective study of a cohort including all 389 patients treated with HAART between 1 January 1998 and 31 May 2004 in our HIV unit was performed to evaluate the occurrence of and risk factors for IRD during HAART. Baseline and follow-up values of CD4 T-cell counts and plasma viral loads (pVLs) were compared to assess the success of HAART. RESULTS: During successful HAART (significant increase in CD4 T-cell counts and decrease in pVL), at least one IRD episode occurred in 65 patients (16.7%). The median time to IRD was 4.6 months (range 2-12 months). IRDs included dermatomal herpes zoster (26 patients), pulmonary tuberculosis (four patients), tuberculous exudative pericarditis (two patients), tuberculous lymphadenitis (two patients), cerebral toxoplasmosis (one patient), progressive multifocal leucoencephalopathy (PML) (one patient), inflamed molluscum (one patient), inflamed Candida albicans angular cheilitis (three patients), genital herpes simplex (two patients), tinea corporis (two patients), cytomegalovirus (CMV) retinitis (two patients), CMV vitritis (one patient) and hepatitis B (three patients) or C (fifteen patients). A baseline CD4 T-cell count below 100 cells/microL was shown to be the single predictor [odds ratio (OR) 2.5, 95% confidence interval (CI) 0.9-6.4] of IRD, while a CD4 T-cell count increase to >400 cells/microL, but not undetectable pVL, was a negative predictor of IRD (OR 0.3, 95% CI 0.1-0.8). CONCLUSIONS: To avoid IRD in advanced patients, HAART should be initiated before the CD4 T-cell count falls below 100 cells/microL.