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.     

Oral candidiasis and seborrheic dermatitis in HIV-infected patients on highly active antiretroviral therapy

Background

Mucocutaneous manifestations such as oral candidiasis (OC) and seborrheic dermatitis (SD) are very common HIV‐related opportunistic events and are usually initial markers of immunodeficiency.

Aim

The purpose of this study was to evaluate the efficacy of highly active antiretroviral therapy (HAART) in the regression of HIV‐associated OC and SD.

Methods

In a prospective study, 120 HIV‐infected patients with OC and SD were divided into two groups: HAART‐treated patients (group 1, n=76) and non‐HAART‐treated patients (group 2, n=44). Non‐HAART‐treated patients were given antimicrobial therapy. Study subjects were matched for sex, age, risk, and stage of HIV infection. The results were analysed by χ² test and the Kaplan‐Meier method.

Results

At baseline, OC was evident in 59 (77.7%) of the HAART‐treated patients and in 34 (77.3%) of the non‐HAART‐treated patients, while SD was present in 19 (25.0%) of the HAART‐treated patients and in 17 (38.6%) of the non‐HAART‐treated patients. After a median follow‐up period of 22 months, regression of OC and SD occurred in 49 (83.1%) and 16 (84.2%) of the HAART‐treated patients, respectively. In the control group, regression of OC and SD occurred in only five (14.7%) and seven (41.2%) patients, respectively, during the same period.

Conclusions

HAART showed greater efficacy than standard antimicrobial therapy for the treatment of OC and SD in HIV‐infected patients.

     

Evaluation of the impact of highly active antiretroviral therapy on immune recovery in antiretroviral naive patients

Objectives To examine the extent of immune reconstitution in treatment‐naive patients with CD4 T‐cell counts <500 cells/μL following 48 weeks of highly active antiretroviral therapy (HAART). Methods Thirteen antiretroviral naive patients were evaluated longitudinally for 48 weeks on HAART utilizing immune functional and lymphocyte phenotyping assays, including lymphocyte proliferation assay, flow cytometric evaluation of cell surface markers, and delayed type hypersensitivity skin tests. Virologic responses were monitored using commercially available viral load assays and gag/pol mRNA quantification using simultaneous immunophenotyping/UltraSensitive fluorescence in situ hybridization (ViroTect In Cell HIV‐1 Detection Kit; Invirion, Frankfort, MI). Thymic function was evaluated for a subset of four patients using real‐time polymerase chain reaction (PCR) for T‐cell receptor excision circle (TREC) quantification and thymic scans using computerized axial tomography (CT) of the thymus. Results HAART initiation resulted in a significant decline in plasma viremia and percentage of infected peripheral blood cells, and a rise in CD4 T cells from a baseline median of 207 cells/μL to a week‐48 median of 617 cells/μL. The rise was predominately in CD4 memory cells. Naive T cells also increased in number, but at a slower rate. Activated (HLA‐DR CD38) CD4 and CD8 T cells were elevated at baseline (24 and 62%, respectively) and declined by week 48 (17 and 36%, respectively) but did not reach normal levels. The number of Fas CD4 T cells increased from a baseline median of 169 to 381 cells/μL at week 48. Both soluble interleukin (IL)‐2 and tumour necrosis factor (TNF) II receptors declined by week 48. HIV p24 lymphocyte proliferation assay responses were transiently detected in three patients. TREC values increased from a median 6400 copies/μg at baseline to a week‐48 median value of 26 697 copies/μg. Conclusion Immune functional reconstitution was not achieved in these HAART naive patients.     

A significant proportion of HIV-infected patients admitted to hospital have immunosuppression as a result of failure of highly active antiretroviral therapy

OBJECTIVES: To investigate the immunological and virological features of patients on highly active antiretroviral therapy (HAART) admitted to a tertiary centre. METHODS: A retrospective study was carried out on HIV-infected patients on HAART admitted to the Regional Infectious Disease Unit in Edinburgh between June 2002 and July 2003. RESULTS: A total of 125 patients who had been on HAART for at least 6 months were admitted during the study period. The frequencies of hepatitis C virus (HCV) and hepatitis B virus (HBV) coinfection were 52% (78 of 150 patients) and 48% (72 of 150 patients), respectively (P>0.05 for comparison of frequencies of hepatitis B and C). Of patients who had been on HAART for at least 6 months, 50% (63 of 125 patients) were immuno-suppressed and had significantly higher bed-days 6 (3-12) compared with those with CD4>200 cells/microL (P<0.002). Amongst immuno-suppressed patients, 38% (24 of 63) had undetectable viral load after at least 6 months of therapy. Those patients were mostly (67%) intravenous drug users and had a significantly higher median age (43 years; range 38-47 years) than other patients (P<0.001). CONCLUSIONS: Earlier start of HAART and addition of interleukin (IL)-2 to the treatment regimens of patients at risk of slow CD4 T-cell count recovery may reduce the duration of their subsequent hospital admissions.     

Revelations of HIV-infected patients treated with highly active antiretroviral therapy (HAART) in rural Uganda

The purpose of this qualitative study was to explore the psychosocial changes revealed by persons living with HIV/AIDS (PLWHA) in western Uganda as a result of the introduction of highly active antiretroviral therapy (HAART). Fourteen participants were interviewed on two occasions. Two focus groups discussions were also conducted. Patients experienced important personal benefits as a result of HAART and the resulting clinical improvement. These benefits included a restoration of hope, self-esteem and personal agency. Patients were also relieved of the great fear which they had about the conditions of their death. The financial and social struggles introduced by AIDS illness continued after the introduction of HAART. The conclusion is that the HAART programs should provide more holistic care to patients to address the persistent family issues identified in this study.     

Longitudinal changes in serum lipids among HIV-infected men on highly active antiretroviral therapy

OBJECTIVE: The aim of the study was to describe longitudinal changes in serum lipids among HIV-infected men receiving highly active antiretroviral therapy (HAART) with long-term follow-up. METHODS: A total of 304 HIV-infected men who initiated HAART and who had serum lipid measurements prior to and for up to 7 years after HAART initiation were identified from the Multicenter AIDS Cohort Study (MACS). Mean levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were examined at biannual time-points. RESULTS: Significant lipid changes were seen within 0.5 years of HAART initiation but increases in TC (+1.09 mmol/L), LDL-C (+0.57 mmol/L), HDL-C (+0.16 mmol/L) and non-HDL-C (+0.91 mmol/L) reached peak levels 2-3 years after HAART initiation. Declines in serum TC, LDL-C and non-HDL-C in subsequent years occurred concurrently with a substantial increase in use of lipid-lowering medications (from 1% usage pre-HAART to 43% 6-7 years after HAART initiation) but the proportion of men who either were treated with cholesterol-lowering medication or had elevated cholesterol levels (>5.18 mmol/L) did not change during the 2-7-year interval after HAART. Mean HDL-C also decreased after 2-3 years and was low (<1.04 mmol/L) in 55% of HIV-infected men 6-7 years after HAART initiation. CONCLUSIONS: Atherogenic serum lipids increased early after the initiation of HAART, peaked at 2-3 years and remained high or required treatment thereafter. Low HDL-C levels persisted in the majority of men. The long-term effects of lipid abnormalities on cardiovascular risk and the effectiveness and toxicity of prolonged use of lipid-lowering medications in combination with HAART are not known.     

Dyspepsia in HIV-infected patients under highly active antiretroviral therapy

BACKGROUND AND AIM: Upper gastrointestinal symptoms, mainly dyspepsia, are common adverse effects in patients under highly active antiretroviral therapy (HAART). Whether it is worthwhile to perform endoscopy early in their treatment is a matter of debate. We have done a prospective study of the prevalence and the etiology of endoscopic lesions in a large cohort of dyspeptic adult HIV-infected patients under HAART, according to their immunological status. METHODS: 528 (334 men and 194 women, mean age 38) HIV-infected patients under HAART with epigastric pain and/or nausea and vomiting underwent upper endoscopy. Patients were classified in two groups, according to CD4 cells counting (>200 cells/mm(3) or < or =200 cells/mm(3)). Gastric and duodenal biopsies were taken from normal mucosa and any lesion found. RESULTS: Gastric mucosa alterations were seen in 61.74% of patients (40.71% erythema, 18.38% erosion and 2.65% ulcer). Duodenum mucosa alterations were seen in 25.37% of patients, mainly erosions (19.50%) and ulcer (3.59%). There was no difference in endoscopic findings according to CD4 cell count groups. Chronic active gastritis was shown in 459 patients (86.93%). H. pylori infection was seen in 32.38%, and it was more prevalent in the group with CD4 > 200 (p < 0.01). Opportunistic infections and malignancies were seen exclusively in patients with CD4 < or = 200. CONCLUSIONS: Most of the endoscopic lesions in dyspeptic HIV-infected patients under HAART were not related to AIDS. Upper endoscopy was more helpful in dictating clinical treatment in patients with low CD4 counts (< or =200) and should be done earlier in this group.     

Hepatitis C and human immune deficiency coinfection at the era of highly active antiretroviral therapy

Interactions between human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have been widely studied before the introduction of highly active antiretroviral therapies (HAART). We reviewed the potential impact of HAART on hepatitis C as well as the interactions between HIV and HCV therapies. Physicians should be aware of the potential risk of: (i) symptomatic liver disease in HCV-HIV-coinfected patients at the era of triple antiretroviral therapy; (ii) potential liver deterioration paralleling immune restoration; (iii) lack of impact of triple antiretroviral therapy on HCV load; and (iv) potential drug-related hepatitis which may modify the natural history of HCV-related liver disease. Liver biopsies should be performed regularly in these patients in order to identify patients with severe liver disease who require early initiation of anti-HCV therapy under close monitoring of their immune status. Treatment is, to date, based on the combination of ribavirin and interferon with an expected sustained response rate around 25%. An important unresolved issue is to better delineate the temporal place of anti-HCV and anti-HIV antiviral therapies. At least in coinfected patients with significant liver disease, namely necro-inflammatory activity and/or fibrosis ≥ 2, we believe that anti-HCV therapy is the priority since it lessens the risk of drug-induced hepatitis and of hepatitis due to immune restoration.     

Dysregulation of CD28 and CTLA-4 expression by CD4 T cells from previously immunodeficient HIV-infected patients with sustained virological responses to highly active antiretroviral therapy

OBJECTIVES: Current guidelines recommend commencing highly active antiretroviral therapy (HAART) in HIV-infected patients when CD4 T-cell counts reach 350 cells/microL. However, late-presenting HIV-infected patients with CD4 T-cell counts<50 cells/microL are still common. The ability of long-term HAART to normalize immune dysregulation in severely immunodeficient HIV-infected patients remains unclear. Here we address indices of immune dysregulation in previously severely immunocompromised HIV-infected patients treated with long-term HAART who had achieved increased CD4 T-cell counts and complete suppression of HIV viraemia. METHODS: We examined expression of CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and intracellular perforin by CD4 and CD8 lymphocytes from 25 highly selected HIV-infected patients [nadir CD4 T-cell counts <50 cells/microL, >4 years on HAART and >6 months of complete viral suppression (<50 HIV-1 RNA copies/mL)] and 18 HIV-seronegative age- and sex-matched controls. RESULTS: HIV-infected patients had lower percentages of CD28-expressing CD4 lymphocytes and higher percentages of CTLA-4-expressing CD4 lymphocytes than controls. The percentage of CTLA-4-expressing CD4 lymphocytes correlated inversely with that of CD28-expressing CD4 lymphocytes. The proportion of CD4 lymphocytes expressing perforin was generally low. However, more HIV-infected patients than controls had >1% of CD4 lymphocytes expressing perforin [11 of 25 (44%) vs. one of 18 (5.5%)]. The percentage of CD8 lymphocytes expressing perforin did not differ between HIV-infected patients and controls. Amongst HIV-infected patients, the percentage of perforin-expressing CD8 lymphocytes correlated inversely with nadir but not current CD4 T-cell count. CONCLUSIONS: Expression of CD28, CTLA-4 and perforin by CD4 lymphocytes remain dysregulated in HIV-infected patients with previous severe immunodeficiency, despite increased CD4 T-cell counts and control of HIV viraemia by HAART.     

Immune restoration in human immunodeficiency virus and hepatitis C virus coinfected patients after highly active antiretroviral therapy

ObjectiveTo evaluate the influence of hepatitis C virus on immunological and virological responses after highly active antiretroviral therapy initiation in human immunodeficiency virus/hepatitis C virus coinfected patients compared to monoinfected human immunodeficiency virus-infected patients.MethodsThe study enrolled 65 human immunodeficiency virus-1-infected subjects who initiated highly active antiretroviral therapy and attended follow-up visits over 48 weeks from 2008 to 2010. They were grouped based on hepatitis C virus-RNA results. Virological and immunological responses were monitored at baseline and at the end of weeks 12, 24, 36, and 48.ResultsThere were 35 human immunodeficiency virus monoinfected and 30 human immunodeficiency virus/hepatitis C virus coinfected patients. In the present study human immunodeficiency virus/hepatitis C virus coinfection did not seem to influence CD4 T-lymphocytes recovery. There was no difference between the curves of CD4 T-lymphocytes raise of coinfected and monoinfected groups.ConclusionThis prospective study confirms that hepatitis C virus infection does not seem to be associated with impaired CD4 T-lymphocytes recovery after HAART.     

HAART预防艾滋病母婴传播的可行性和有效性

目的总结和分析在云南省边远的农村地区,对孕妇实施高效反转录病毒治疗（HAART）以预防艾滋病病毒（HIV）母婴传播（PMTCT）的有效性和可行性。方法梳理和定量分析2005—2012年,云南省与美国艾伦戴蒙德艾滋病研究中心开展的预防艾滋病母婴传播项目的效果。结果在1861名HIV阳性孕妇中,1353名孕妇（72．7％）采用了HAART阻断方案。在1584名有HIV检测结果的婴儿中,阳性25人,阳性率为1．58％;其中1168名采用HAART妇女所生的婴儿中,仅有9人阳性,阳性率为0．8％;在孕28周前开始HAART的妇女所生婴儿中,HIV阳性率为0．2％（2／899）。结论HAART对于阻断HIV母婴传播效果非常显著,如果在孕28周前开始HAART,婴儿HIV感染率已经非常接近“零感染”的目标,可以推广和实施。     

HAART后HIV感染者免疫重建炎症综合征的口腔表征

艾滋病病毒(HIV)感染者经高效抗反转录病毒治疗(HAART)后,能够恢复对病原体的免疫反应,并大大降低感染者的死亡率。然而,一些HIV感染者接受HAART后,重建的免疫系统又导致了新的病理性炎症反应,称为免疫重建炎症综合征(IRIS),它可导致大量的患者在短期内发病甚至死亡。文章对免疫重建炎症综合征的发病机制和口腔临床表现等方面的最新进展进行了综述。     

Assessing baseline religious practices and beliefs to predict adherence to highly active antiretroviral therapy among HIV-infected persons

The efficacy of highly active antiretroviral therapy (HAART) is dependent upon moderately high levels of adherence; however, predicting adherence before HAART initiation can be difficult. We conducted a prospective, longitudinal study among 350 HIV-infected adults attending a HIV clinic in San Diego, CA (USA) from January 2010 to December 2011 to examine both established and novel predictors of adherence, including religious practices and beliefs. Statistically significant (p < .05) variables identified in bivariate analyses were included in multivariate analyses predicting ≥90% adherence. Higher annual household income (p = .004) and religious affiliation (p = .031) were predictive of greater adherence. Participants who said their beliefs gave meaning to their lives, made them feel they had a connection with a higher being, were influential during their recovery, and helped them feel connected to humanity were more likely to be ≥90% adherent (p < .015). Conversely, participants who believed God created all things in the universe; that God will not turn his back on them; and those who regularly attended religious services, participated in religious rituals, and prayed and meditated to get in touch with God were less likely to be ≥90% adherent (p ≤ .025). Results indicate that a patient's religious beliefs and practices may predict medication adherence. Interventions should be designed to emphasize the use of positive religious coping strategies and address the adverse implications of religious fatalism.     

Prevalence,severity, and duration of thrombocytopenia among HIV patients in the era of highly active antiretroviral therapy

Thrombocytopenia is a clinically relevant outcome in HIV. However, the epidemiology of this condition, including frequency, severity, and duration, has not been well-characterized in the era of highly active antiretroviral therapy (HAART). In this study, we describe the epidemiology of thrombocytopenia using two methods. We conducted a systematic review of the literature published between 1997 and 2009 to characterize the frequency of thrombocytopenia in different populations in the HAART era. Secondly, we examined the frequency, severity, and duration of thrombocytopenia among HIV patients in the Collaborations in HIV Outcomes Research/US (CHORUS) Cohort from 1997 to 2006 and among HIV patients participating in GlaxoSmithKline HIV Clinical Trials between 1996 and 2004. Prevalence estimates of thrombocytopenia (<150?000 platelets/µl) in the literature varied greatly but were generally above 10%. The thrombocytopenia prevalence estimates in the CHORUS Cohort and the HIV Clinical Trials were both 14%. In the CHORUS Cohort, the platelet count was ≤50?000/µl among 3.1% and ≤30?000/µl among 1.7%; in the HIV clinical trials database, the platelet count was ≤50?000/µl among 1.3% and ≤30?000/µl among 0.67%. Duration of severe thrombocytopenia varied greatly, with the medium duration to ≥75?000 platelets/µl taking 147 days in the CHORUS Cohort and 33 days in the HIV clinical trials database. Among 111 patients with severe thrombocytopenia in the CHORUS Cohort, 23% never achieved a higher platelet count over follow-up. In conclusion, while the prevalence of severe thrombocytopenia was low, it occurred at levels associated with bleeding and was persistent among a small proportion of patients despite receipt of HAART.     

Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART

Objectives We have previously described immune restoration diseases (IRD) associated with asymptomatic opportunistic infections presenting in immunodeficient HIV patients responding to highly active antiretroviral therapy (HAART). Here we address the question of whether patients with a history of IRD exhibit persistent immune activation, shown by elevated levels of interleukin‐(IL)‐6 and soluble IL‐6 receptor (sIL‐6R).
Methods Peripheral blood mononuclear cells (PBMCs) and plasma were collected from HIV patients with nadir CD4 T cell counts of < 80/µL and who had achieved immune reconstitution after HAART with ( n =14) or without ( n =15) experiencing IRD, severely immunodeficient (SID) patients with < 80 CD4 T cells/µL ( n =8) and HIV seronegative controls ( n =15). PBMC production and plasma levels of IL‐6, sIL‐6R and interferon (IFN)‐γ (PBMC only) were measured by enzyme linked immunosorbent assay (ELISA). Intracellular flow cytometry was used to determine the predominant cellular source of IL‐6 in HIV patients and controls.
Results Unstimulated PBMC from IRD patients produced significantly higher amounts of IL‐6 and sIL‐6R than non‐IRD patients and HIV seronegative controls. The sIL‐6R concentration was also significantly higher in supernatants from mitogen‐stimulated PBMC from IRD patients compared to non‐IRD patients. The production of IFN‐γ did not differ between IRD and non‐IRD patients. IRD patients had significantly higher plasma levels of IL‐6 compared to non‐IRD patients, SID patients and controls. Monocytes were the predominant source of IL‐6 in both HIV patients and controls.
Conclusions Patients with a history of IRD after HAART have elevated levels of IL‐6 and sIL‐6R.     

Appendicitis in HIV-infected patients during the era of highly active antiretroviral therapy

Background

Limited studies have suggested increased incidence rates and unusual clinical presentations of appendicitis among HIV‐infected patients during the pre‐highly active antiretroviral therapy (HAART) era. Data in the HAART era are sparse, and no study has evaluated potential HIV‐related risk factors for the development of appendicitis.

Methods

We retrospectively studied 449 HIV‐infected patients receiving care at a US Naval hospital involving 4750 person‐years (PY) of follow‐up. We also evaluated the rates of appendicitis among HIV‐negative persons at our medical facility. We compared demographics, HIV‐specific data, and HAART use in HIV‐infected patients with and without appendicitis.

Results

Sixteen (3.6%) of 449 patients developed appendicitis after HIV seroconversion. The incidence rate was 337 cases/100 000 PY, more than fourfold higher than among HIV‐negative persons. Eighty‐eight per cent of cases among HIV‐infected patients had an elevated white blood count at presentation, 39% were complicated, and 64% required hospitalization. HIV‐infected patients with appendicitis compared with those who did not develop appendicitis were less likely to be receiving HAART (25 vs. 71%, P<0.001), had higher viral loads (3.5 vs. 1.7 log₁₀ HIV‐1 RNA copies/mL, P=0.005), and were younger (median age of 30 vs. 41 years, P<0.002). In the multivariate model, receipt of HAART remained protective [odds ratio (OR) 0.21, P=0.012] for appendicitis, while younger age was positively associated (OR 1.08, P=0.048) with appendicitis.

Conclusion

Acute appendicitis occurs at higher incidence rates among HIV‐infected patients compared with the general population. Our study demonstrates that the lack of HAART may be a risk factor for appendicitis among HIV‐infected patients; further studies are needed.