Hepatitis B virus and HIV coinfection: relationship of different serological patterns to survival and liver disease

OBJECTIVES: Eighty per cent of HIV-positive patients show evidence of past or current infection with hepatitis B virus (HBV). The impact of chronic HBV infection or the presence of isolated HBV core antibody on survival in the era of highly active antiretroviral therapy (HAART) has not been well studied. METHODS: This retrospective analysis included patients from the HIV Atlanta Veterans Affairs Cohort Study (HAVACS). This cohort comprises 2818 HIV-positive patients followed since 1982. For this analysis, 1685 patients with available HBV serologies were included, based on laboratory records available since 1992. Adjusted survival analyses were performed for patients showing any of four serological patterns for HBV: (1) surface antigen positive (chronic HBV infection), (2) isolated core antibody, (3) surface antibody with or without core antibody (resolved/vaccinated) and (4) no HBV markers (negative group). Risk factors for liver disease were identified. RESULTS: A trend was seen for a lower survival rate from AIDS to death in the chronic HBV infection group compared with the negative group [hazard ratio (HR) 1.43; P=0.118]. The only independent predictor of lower survival rate was hepatitis C virus positivity (HR 1.62; P=0.008). Protective factors were use of HAART (HR 0.40; P=0.0003), use of lamivudine (HR 0.36; P<0.0001) and use of tenofovir (HR 0.23; P<0.0001). Survival from HIV diagnosis to death was not different among the HBV groups. Isolated core antibody patients did not have a lower survival rate compared with those with resolved HBV infection. Patients with chronic HBV infection were 3.5 times more likely to have liver disease than those with no HBV infection (P<0.02). CONCLUSIONS: There is a trend towards a lower survival rate in patients with HIV and chronic HBV infection, but the difference did not reach statistical significance. The presence of isolated core antibody was not associated with a lower survival rate.     

Antibodies to human T-cell leukemia virus type III in hemophiliacs from Spain

We tested serum samples from 50 hemophiliacs from Sevilla, Spain, for antibody to HTLV-III by indirect membrane immunofluorescence (IMI) and radioimmunoprecipitation with SDS polyacrylamide gel electrophoresis (RIP-SDS/PAGE). All had received commercial clotting factors from the United States with the exception of one hemophiliac who had never been transfused. Thirty-four (68%) reacted with HTLV-III-infected cells (H9/HTLV-III) by both methods, but not with the uninfected line (H9). Of 41 hemophilia-A patients tested, 28 (68%) were positive, and of nine hemophilia-B patients, six (66%) were positive. The nontransfused hemophilia-B patient was negative for antibody to HTLV-III by both methods. One patient with clinical AIDS tested positive as did six of seven with chronic unexplained lymphadenopathy. The eight individuals with AIDS or lymphadenopathy all had hemophilia A. We conclude that exposure to HTLV-III is widespread among asymptomatic hemophiliacs in Spain.     

HCV quasispecies evolution: association with progression to end-stage liver disease in hemophiliacs infected with HCV or HCV/HIV

Patients with inherited bleeding disorders who received clotting factor concentrates before 1987 have high rates of hepatitis C virus (HCV) or HCV/HIV infection. We evaluated HCV quasispecies evolution in longitudinally collected specimens comparing those from patients with progression to end-stage liver disease (ESLD; cases) to those with compensated chronic hepatitis (controls). Plasma samples were obtained from the National Cancer Institute Multicenter Hemophilia Cohort Study. Controls were matched for age, sex, infection duration, and presence/absence of HIV. Samples from early infection were compared to those obtained after onset of ESLD in the cases. The first hypervariable (HVR1) and core proteincoding regions were amplified, subcloned, and sequenced. Complexity and diversity were determined. More than 700 sub-clones from 10 pairs of patients (8 with HIV) followed over approximately 9.3 years were evaluated. HVR1 complexity narrowed over time in the cases, whereas it increased in controls (P = .01). Similar trends were observed for diversity within HVR1 and the core region (P = .04). HCV-infected patients with inherited bleeding disorders undergo quasispecies evolution over time. Evolution patterns differ for progressors and nonprogressors. Further understanding of these mechanisms may help identify factors related to progression rate and treatment response.     

HIV neutralizing antibodies: development and association with HIV related disease

Serum neutralization was measured in 72 sera collected during a 5.5-year period from 10 HIV infected individuals. Neutralizing antibodies (NA) were present in all sera. NA titers ranging from greater than 40 to greater than 640 were detected in sera from 4 patients, who all remained healthy and further an increase with time of NA was observed in these 4 patients. Progression to disease was observed in 3 persons with NA titers less than or equal to 40 who also lacked or lost anti-gag antibodies. Two of these patients were HIV antigenaemic prior to development of disease, whereas antigen was not detected in the remaining 7 healthy persons. A weak positive correlation (R(S) = +0.643, p less than 0.001) was found between titers of NA and whole virus antibody (WVA), with the ratios between titers (NA titer/WVA titer) varying a 100-fold. The results suggest that the presence of NA in some cases might be related to a healthy carrier state and that a combination of low titer NA with decline of anti-gag antibodies and/or HIV antigenaemia is associated with progression to clinical disease.     

The relationship between atypical lymphocytosis and serological tests in infectious mononucleosis

The relationship between serological tests for infectious mononucleosis was compared with atypical lymphocytosis in one hundred cases with clinical features of the disease. All blood samples showed atypical lymphocytosis greater than 20 per cent of the total leucocyte count. Positive serological tests were obtained in 69 of these patients, whereas in patients with more than 40 per cent atypical lymphocytosis all had positive serology. Of the 31 patients with negative serological tests for infectious mononucleosis, significant antibody titres to Toxoplasma gondii were obtained in five and to cytomegalovirus in two. Twenty-four patients remained undiagnosed. The Paul-Bunnell-Davidsohn positive patients had a significantly higher white cell count, lymphocyte count and atypical lymphocyte count than the toxoplasmosis group or the undiagnosed group.     

ANCA seropositivity in HIV: a serological pitfall

In systemic vasculitis, cytoplasmic staining in ethanol-fixed neutrophilic granulocytes, i.e. cytoplasmic antineutrophilic cytoplasmic antibody (c-ANCA), is generally considered a highly significant serological marker. When a patient presents with upper airway or renal symptomatology and seropositivity to c-ANCA, a Wegener's granulomatosis is usually easily diagnosed by performing a biopsy of the diseased organ. However, not every ANCA-positive patient with pulmonary inflammation is suffering from Wegener's disease. In some cases of upper airway or pulmonary symptomatology, the a priori chance of having Wegener's disease is low despite a positive ANCA. A coincidental positivity of ANCA may then lead to clinicians jumping to conclusions. We present a 40-year-old man who was falsely suspected of having Wegener's disease because of upper airway symptomatology and c-ANCA positivity. Specificity analysis revealed that he was negative to antibodies for proteinase-3, but positive to myeloperoxidase. The potential serological pitfall of the supposedly specific c-ANCA is discussed.     

Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study

We have previously observed an increased frequency of liver failure in human immunodeficiency virus (HIV)-infected hemophiliacs. The purpose of this study was to quantitate hepatitis C virus (HCV) RNA levels in serial samples from HIV-seropositive (HIV+) and HIV-seronegative (HIV-) hemophiliacs before and after HIV seroconversion, and to examine the relationship of HCV RNA levels to CD4 cell counts and to hepatic dysfunction over time. HCV RNA levels were measured on serial samples of serum stored frozen from 17 HCV+/HIV+ and 17 HCV+/HIV- subjects matched within 5 years of their birth dates. All were HCV+ before study entry. HCV RNA levels were quantitated by a branched DNA-enhanced label amplification (bDNA) assay. For samples less than the cut off, HCV RNA was measured by the nested polymerase chain reaction. Individual changes over time, clinical groups, and mean values within predetermined time windows were compared with Wilcoxon rank sum tests. Mean HCV RNA levels increased from 2.76 (standard error [SE] 1.33) x 10(5) to 2.84 (SE 1.39) x 10(6) eq/mL during the first 2 years after HIV seroconversion (P = .006). Baseline HCV RNA levels in the pre-HIV seroconversion group were not significantly different from the baseline levels in those who remained HIV (P = .79). Over the entire period of study, HCV RNA levels increased nearly threefold in those who remained HIV- (mean 9.47 [SE 4.78] x 10(5) to 2.81 [SE 1.13] x 10(6)/mL; P = .02). Among those who became HIV+, HCV RNA levels increased 58-fold (mean 2.85 [SE 1.26] x 10(5) to 1.66 [SE 0.57] x 10(7) eq/mL; P = .0001). The rate of increase in HCV RNA levels was eightfold faster for HIV+ subjects than for subjects who remained HIV- (P = .009). HCV RNA levels increased twofold higher in 5 subjects who developed liver failure compared with the 12 who did not (P = .43). HCV RNA levels correlated significantly with CD4 counts (R = -.33, P = .01) and serum aspartate aminotransferase levels (AST) (R = .36, P = .007). We conclude that HCV RNA levels are significantly higher in HIV+ than in HIV- multitransfused hemophiliacs. HCV load increases over time, is enhanced by HIV, and further increases as immune deficiency progresses. HCV RNA levels are directly associated with high AST levels. These findings suggest that HIV-induced immune deficiency may promote increased HCV replication.     

心理行为因素与心血管疾病的发生发展

心理社会因素,如A型行为通过激活神经、内分泌系统等机制与心血管疾病的发生、发展密切相关.A型行为的心理特征可以表现为好胜心强、匆匆忙忙、固执等.大量研究阐明具有A型行为的人群冠心病的患病率和严重的心血管事件发生几率明显高于非A型行为的人群.通过焦虑自评表的测定也发现在具有A型行为的原发性高血压患者中的焦虑情绪表现十分常见.在心血管疾病患者中焦虑和惊恐的躯体的主要表现有以下几点胸痛、高血压、气急、QT离散度增加与猝死.通过心理行为治疗如针对"匆忙症"和"好胜心强"的训练可以很好地矫正A型行为中的AIAI反应(即烦恼、激动、发怒和不耐烦),从而可以有效地阻止心血管疾病的发生和发展.     

Long-term immunogenicity of a plasma-derived hepatitis B vaccine in HIV seropositive and HIV seronegative hemophiliacs

Short-term studies indicate that hepatitis B vaccines are safe and satisfactorily immunogenic in hemophiliacs. The duration of immunity in these immunocompromised patients, however, is not known. To determine this, we studied 78 hemophiliacs prospectively 2, 3, and 4 years after the initial vaccination with a plasma-derived vaccine given as three monthly injections followed by a fourth booster injection at month 14. The duration of immunity clearly depended on whether the patients were infected with the human immunodeficiency virus (HIV). In HIV seronegative hemophiliacs (n = 67), there was a progressive decline in titers of antibody to the hepatitis B surface antigen (anti-HBs), but antibody was still detectable 4 years later in all of them. From the curves of decline of antibody titers, it appears that there is no need to revaccinate patients for at least 5 to 6 years. The HIV seropositive hemophiliacs (n = 11) not only started from much lower anti-HBs titers, but 5 of 11 lost anti-HBs. None of the 45 patients treated with concentrates during the postvaccination period developed serologic signs of hepatitis B, even though 6 of them had come into contact with live or inactivated hepatitis B virus as shown by the occurrence of spontaneous anamnestic antibody responses. This vaccine and schedule of vaccination afford a prolonged duration of immunity in HIV seronegative hemophiliacs, but HIV seropositive hemophiliacs have a risk of losing immunity early.     

The relationship between HIV infection and atopic dermatitis

Patients with HIV infection exhibit a wide range of skin pathology, including bacterial, fungal, and viral infections, skin tumors, inflammatory and eczematous eruptions, and drug rashes. HIV-infected adults commonly develop a condition that strongly resembles atopic dermatitis and is sometimes called “atopic-like dermatitis”; moreover, atopic dermatitis and other atopic disorders have been described as common manifestations of pediatric HIV infection. Conditions such as sinusitis, asthma, and hyper-IgE syndrome, and laboratory abnormalities, eg, elevated IgE levels, eosinophilia, and possible Th1-Th2 imbalances, suggest a predilection for atopic disorders in these patients. It is of interest to examine the immune perturbations intrinsic to HIV infection, and their possible role in triggering atopic dermatitis, and to consider whether other abnormalities, such as xerosis, bacterial or viral superantigens, or epidermal barrier disruption with altered presentation of cutaneous aeroallergens, might play a significant role.     

Spectrum of HIV infection and AIDS in a cohort of Italian hemophiliacs

A group of 173 subjects affected by congenital clotting factor deficiencies was evaluated with regard to the impact of HIV infection. On the whole, 78 patients (45%) were found to be HIV Ab-positive. As of March, 1988, of the seropositive patients, 63 (80.8%) had an asymptomatic HIV infection (Group II/CDC), three (3.8%) had a persistent generalized lymphadenopathy (Group III/CDC). The 12 (15.4%) remaining patients could be classified in Group IV of the CDC classification due to their symptoms and signs; in particular, 10 came under surveillance case definition for AIDS. Assay for the HIV antigen was positive in 14 (17.9%) seropositive hemophiliacs. With regard to the immunological features, our data clearly show that a sharp decline in the number of CD4+ cells was associated with symptomatic forms of the disease. An evaluation of the time elapsed from seroconversion to the appearance of the symptomatic clinical condition showed an average incubation of 37 months.     

Antibodies to platelet glycoproteins in haemophiliacs infected with HIV

Summary The techniques of Western blotting and the monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay were used to detect antibodies to platelet glycoproteins in 43 samples of serum from 23 anti-HIV positive haemophiliacs (8 with severe thrombocytopenia, 6 with moderate thrombocytopenia, and 9 with a normal platelet count), six anti-HIV negative haemophiliacs and ten controls. Antibodies were present in the majority of anti-HIV positive patients' sera even before the onset of thrombocytopenia. Thrombocytopenia was associated with an increase in the incidence of antibodies to GPIIIa and GPIb, whereas the antigen most frequently recognized in patients without thrombocytopenia was GPIIb. Anti-GPIIb and/or GPIIIa reactivity was also seen in three out of the six anti-HIV negative patients. There was no correlation between the absolute platelet count and the detection of antibodies in either assay. Effective therapy for thrombocytopenia with zidovudine, interferon or splenectomy did not influence the presence of antibody. Eight of nine patients with AIDS were negative in the MAIPA assay, consistent with their depressed immune status. It is concluded that the production of antibodies to platelet membrane glycoprotein in anti-HIV positive haemophiliacs is influenced by factors other than HIV. The presence of such antibodies is independent of the platelet count and is therefore unlikely to play a causative role in HIV-related thrombocytopenia.     

50例乙型肝炎病毒携带者肝组织病理与血清学指标关系的探讨

目的探讨乙型肝炎病毒（HBV）携带者肝组织病理与血清学指标的关系。方法对50例HBV携带者进行肝穿刺取肝组织送病理,研究病理结果与血清学指标的关系。结果 26例HBeAg阳性患者中,全部为HB-VDNA阳性,其中肝组织病理显示6例为G3S1,全为40岁以上的患者,12例G2S1,有1例40岁以上患者,8例为G2S0。18例抗HBe阳性患者中,有12例HBVDNA阳性患者,其中肝组织病理显示6例为G2S1,（有2例40岁以上）,6例为G2S0,有6例HBVDNA阴性患者,其中5例为G2S0,1例为G1S0。6例HBeAg与抗HBe均阴性的患者中,有HBVDNA阳性4例,其中2例为G2S1,2例为G2S0。HBVDNA阴性2例,其中1例为G2S1,1例为G2S0。结论 40岁以下的HBV携带者肝穿均指示有程度不等的炎症和有或无肝纤维化,且炎症程度和肝纤维化程度与HB-VDNA高低不成正比,无明确关系,与HBeAg是否阳性也无正比关系。     

心理行为因素与心血管疾病的发生发展

心理社会因素,如A型行为通过激活神经,内分泌系统等机制与心血管疾病的发生,发展密切相关,A型行为的心理特征可以表现为：好胜心强,匆匆忙忙,固执等。大量研究阐明具有A型行为的人群冠心病的患病率和严重的心血管事件发生几率明显高于非A型行为的人群,通过焦虑自评表的测定也发现在具有A型行为的原发性高血压患中的焦虑情绪表现十分常见,在心血管疾病患中焦虑和惊恐的躯体的主要表现有以下几点：胸痛,高血压,气急,QT离散度增加与猝死,通过心理行为治疗如：针对“匆针症”和“好胜心强”的训练可以很好地矫正A型行为中的AIAI反应（即：烦恼,激动,发怒和不耐烦）,从而可以有效地阻止心血管疾病的发生和发展。     

DNA amplification of HIV genome in hemophiliacs and in newborns from seropositive mothers

Summary We evaluated the validity of DNA enzymatic amplification (PCR) in a population at risk for HIV-1 infection, consisting of hemophiliacs and children born to seropositive mothers. All but one of the seropositive hemophiliacs and controls were found positive with the three sets of primers. All the seronegative patients and controls were found negative in PCR. No correlation with the anti-nef serology was found, one seropositive being anti-nef negative and three seronegative anti-nef positive. The results obtained with PCR are in good agreement with classical serology, and this would suggest that the possible period of latency may not be as long as suspected. No seroconversion has been described in hemophiliacs since solvent-detergent inactivated blood products have been in use, and seronegative hemophiliacs no longer constitute a population at risk. Studies on seronegative sexual partners of seropositive patients would be of great interest. For newborns from seropositive mothers, PCR is the only possible technique in early age before seronegativation of the healthy children. Further studies will be required to determine the fiability and sensitivity of the test.The study was supported by a grant from CNAMTS-INSERM (Biologie moléculaire des maladies hémorragiques et thrombotiques héréditaires).