Comparison of Demographic, Epidemiological, Immunological, and Clinical Characteristics of Patients with HIV Mono-infection Versus Patients Co-infected with HCV or/and HBV: A Serbian Cohort Study.

OBJECTIVE: The study aimed to correlate the status of hepatitis C (HCV) and hepatitis B virus (HBV) co-infection in patients with human immunodeficiency virus (HIV) infection with clinical and demographic data prior to starting highly active antiretroviral therapy (HAART) and assess the impact of HCV and HBV co-infection on the natural history of HIV infection. PATIENTS AND METHODS: The study involved a total of 836 treatment-naive patients with available serological status for HBV and HCV at the point of therapy initiation. Patients were stratified into four groups: HIV mono-infection, HIV/HCV, HIV/HBV, and HIV/HCV/HBV co-infection. Demographic, epidemiological, immunological and clinical characteristics were analyzed in order to assess the possible impact of HCV and HBV co-infection on HIV - related immunodeficiency and progression to AIDS. RESULTS: The prevalence of HCV and HBV co-infection in our cohort was 25.7% and 6.3%, respectively. Triple HIV/HCV/HBV infection was recorded in 1.7% of the patients. In comparison with those co-infected with HCV, patients with HIV mono-infection had lower levels of serum liver enzymes activity and higher CD4 cell counts, and were less likely to have CD4 cell counts below100 cells/µL and clinical AIDS, with OR 0.556 and 0.561, respectively. No difference in the development of advanced immunodeficiency and/or AIDS was recorded between patients with HIV monoinfection and those co-infected with HBV, or both HCV/HBV. CONCLUSION: HIV/HCV co-infection was found to be more prevalent than HIV/HBV co-infection in a Serbian cohort. Co-infection with HCV was related to more profound immunodeficiency prior to therapy initiation, reflecting a possible unfavorable impact of HCV on the natural history of HIV infection.

The prevalence and risk of hepatitis flares in a Serbian cohort of HIV and HCV co-infected patients treated with HAART.

Despite substantial benefits of HAART treatment of HIV-infected patients, cumulative long-term toxicity, including drug-induced hepatotoxicity, has emerged as an important complication. Thus, to examine the prevalence and risk of developing severe hepatic injury during HAART, we conducted a retrospective study in a cohort of 364 HIV-infected patients treated with HAART between January 1998 and May 2006, for whom data on alanine aminotransferase activity were available both before and during HAART. HCV co-infection was recorded in 35.4% of the series, but was found not to influence either the efficacy of HAART or survival (P>0.05). Severe hepatotoxicity occurred in a total of 24 patients (6.6%). Multivariate logistic regression defined HCV co-infection (OR 16.6, 95% CI 3.8-46.0, P<0.0001), and the use of SQV/RTV and d4T (OR 3.1, 95% CI 1.2-8.16, P=0.02, and OR 7.1, 95% CI 1.0-54.5, P=0.05, respectively) as independent risk factors for aggravation of hepatitis. In addition, there was a significant increase in the probability of developing liver damage over years of treatment (Log rank, P<0.01). Conversely, the probability of developing hepatotoxicity was not associated with an increase in the CD4 cell count to values greater than 350/microL (Log rank, P=0.59). In conclusion, in the setting of chronic viral hepatitis, hepatotoxicity during HAART may be attributed to the cumulative toxicity of drugs that induce mitochondrial toxicity, along with particular PIs and/or NNRTIs. Furthermore, our data suggest prudent use of D-drugs, still common in resource-limited countries, in HCV co-infected patients.

Long-term survival of HIV-infected patients treated with highly active antiretroviral therapy in Serbia and Montenegro.

BACKGROUND: Highly active antiretroviral therapy (HAART) has dramatically changed the prognosis of HIV disease, even in terminally ill patients. Although these patients may survive many years after the diagnosis of AIDS if treated with HAART, some still die during treatment. METHODS: A retrospective study in a cohort of 481 HIV-infected patients treated with HAART between January 1998 and December 2005 was conducted to compare subgroups of long-term survivors (LTSs) and patients who died during treatment. RESULTS: A total of 48 patients survived for more than 72 months (mean 83.8+/-standard deviation 5.6 months). Thirty patients died during treatment (mean 35.3+/-25.0 months), of whom nine died from non-AIDS-related causes, 18 died from AIDS-related causes, and three died as a result of HAART toxicity. Although LTSs were significantly (P=0.015) younger at HAART initiation, age below 40 years was not a predictor of long-term survival. The subgroups did not differ in the proportion of clinical AIDS cases at HAART initiation, in the prevalence of hepatitic C virus (HCV) coinfection, or in pretreatment and end-of-follow-up CD4 cell counts. In contrast, the viral load achieved during treatment was lower in the survivors (P=0.03), as was the prevalence of hepatitis B virus (HBV) coinfection (P=0.03). Usage of either protease inhibitor (PI)-containing regimens [odds ratio (OR) 9.0, 95% confidence interval (CI) 2.2-35.98, P<0.001] or all three drug classes simultaneously (OR 7.4, 95% CI 2.2-25.1, P<0.001) was associated with long-term survival. Drug holidays incorporated in structured treatment interruption (STI) were also associated with a good prognosis (OR 14.9, 95% CI 2.9-75.6, P<0.001). CONCLUSIONS: Long-term survival was associated with PI-based HAART regimens and lower viraemia, but not with the immunological status either at baseline or at the end of follow up. STI when CD4 counts reach 350 cells/microL, along with undetectable viraemia, was a strong predictor of long-term survival.

The dissociation between virological and immunological responses to HAART.

While HAART allows for the reconstitution of immune functions in most treated HIV patients, discrepant responses including failure to achieve a significant increase in circulating CD4+ T cells despite undetectable plasma viral loads (pVL), or a good immunological response while not reaching undetectable viremia, may occur. Thus, to evaluate the incidence of and risk factors for discrepant responses to HAART, we conducted a retrospective study of all 446 patients treated with HAART between 1 January 1998 and 31 August 2004 in our HIV unit. CD4+ T cell counts and pVL values at baseline and end of study were parameters of the type of response. Within a mean follow-up period of 33 months, discrepant immunological and virological responses occurred in even 50% patients. Of these, 174 (39%) did not have a rise in CD4+ T cells to above 400 per microl despite a good virological response (type 1 dissociation), while 49 (11.0%) had a rise in the CD4+ T cell count to at least 200 per microl but their pVL was not undetectable (type 2 dissociation). The risk factors for immunological failure despite an undetectable pVL were baseline CD4+ T cells below 100 per microl (OR 1.44, 95%CI 1.02-2.03) and HAART composed of three NRTIs (OR 1.92, 95%CI 1.35-2.73), while usage of two NRTIs in combination with PI(s) (OR 0.36, 95%CI 0.26-0.49), as well as simultaneous usage of all three drug classes (OR 0.37, 95%CI 0.26-0.53) were shown to be protective. The usage of PI-containing HAART regimens was protective against type 2 dissociation (OR=0.40, 95%CI 0.19-0.83). Importantly, there were no differences in the survival of HAART-treated patients irrespective of the type of response.

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.

HBsAg as the antigen component of circulating immune complexes in HIV-infected patients.

Seeing the same transmission pattern of HIV and HBV coinfection by these two agents is not an uncommon feature. Immunity impairment due to HIV infection can be the cause of a higher rate of HBV replication with less intensive liver damage and less effective immune response to HBV, while the pathological course in both infections involves elevated levels of circulating immune complexes (CIC). These were the reasons for us to examine the frequency of HBsAg involvement as the antigen component of circulating immune complexes formed in sera of HIV-infected patients in different stages of HIV disease. We tested 67 sera of HIV-positive patients in different stages of HIV disease for the presence of HBsAg and HIV antigen p24 (with and without acid dissociation of immune complexes), for the presence of anti-Hbc antibodies and circulating immune complexes. HBsAg was positive in 13.8% sera prior to and 33.8% after acid pretreatment. Anti-HBc antibodies were present in 76.9% serum samples tested. Fifty percent of sera were positive for both HBsAg and p24 antigen after dissociation of immune complexes. The level of CIC was elevated in 65.9% of sera. Our results suggest that HBsAg is commonly associated in immune complexes formed in the sera of HIV-infected patients and that they may simultaneously contain HIV and HBsAg in patients coinfected with both agents. This may contribute to their mutual interaction and influence the diagnosis and follow-up of patients.

Distribution of HCV genotypes among risk groups in Serbia.

Blood samples from 190 patients that were anti-hepatitis C virus (HCV) positive were genotyped and 165 were found to contain HCV-RNA. Genotyping was performed by PCR based on type-specific primers (117 isolates) and LiPA test (48 isolates) and verifying by sequencing. In Serbia, the most frequent genotype was 1b (49.1%), followed by genotype 3 (21.2%) and genotype 1a (8.5%). The frequency of genotypes 2 and 4 was below 5% and mixed infections were encountered in 9.1% of cases. Distribution of genotypes was monitored in different risk groups: intravenous drug abusers, patients under blood transfusion, patients with previous history of surgery, patients undergoing hemodialysis and those with unknown risk factors. Genotype distribution is essentially the same in all the groups, except for the patients undergoing hemodialysis and those with previous history of surgery where significant difference exists compared with the group with unknown route of transmission (p < 0.001 and p < 0.05, respectively). There exists significant age-dependent genotype 3 distribution in Serbian population (p < 0.01).

Drug utilization patterns and outcomes associated with in-hospital treatment with risperidone or olanzapine.

This study compared the drug-utilization costs and indicators of clinical outcomes associated with the use of risperidone and olanzapine in a hospital setting. We conducted a nonrandomized, retrospective chart review of consecutive patients identified as presenting with psychotic symptoms on inpatient wards at Riverview Hospital in British Columbia and given either risperidone or olanzapine as their first new drug after reassessment (n = 30 per treatment group). Data were collected for up to 120 days. No significant differences were observed between groups in terms of sex, age, duration of illness, or diagnosis. The mean dosage of risperidone for responders was 4.89 +/- 2.56 mg/d, whereas that for olanzapine was 17.19 +/- 3.88 mg/d. The associated daily drug-acquisition costs were significantly different, at CA$4.69 for risperidone and CA$11.52 for olanzapine. Notes in patient charts indicated that a significantly greater proportion of risperidone-treated patients (60.0%) than olanzapine-treated patients (26.7%) responded to therapy, as indicated by improvement in at least one target symptom (P < 0.01). Forty percent of patients initially treated with risperidone were discharged on their original therapy, compared with 13.3% of patients treated with olanzapine (P < 0.05). These results were not substantially affected by correction for markers of illness severity or treatment resistance. Overall, no significant differences in side effects were recorded in the patient records of the two groups. Within this cohort of patients, risperidone treatment was associated with lower drug-acquisition cost and better treatment outcomes than olanzapine.

[Neural manifestations in Lyme disease (Lyme borreliosis of the nervous system)]. / Nervne pojave u Lajmskoj bolesti (Lajm-borelioza nervnog sistema).

The involvement of the nervous system is common during Lyme's disease, and the term neuroborreliosis has been established. All structures of the nervous system, from meninges to periferial nerves, can be involved. Neurological manifestations are most common in the second stage (dissemination). The article deals with the most important neurological manifestations, as well as with the contemporary pathogenetic considerations and therapy. Eleven patients with neuroborreliosis who were treated at Dr. Kosta Todorovitsh Institute of Infectious and Tropical Diseases, are reviewed. Five of them had acute meningoencephalitis, of whom two had concurrent neuritis; one patient had Banawart's syndrome with arthralgias, arthritis and fatigue syndrome; two patients had neuritis; one had bilateral facial palsy; two had chronic fatigue syndrome.

Antigen/antibody content of circulating immune complexes in HIV-infected patients.

Dual infection with HIV and hepatitis B virus (HBV) is not an uncommon feature. Immunity impairment due to HIV infection can be the cause of a higher rate of HBV replication with less intensive liver damage and less effective immune response to HBV. Many HIV-infected patients have an elevated level of circulating immune complexes (CIC) in serum, throughout all stages of illness evolution. The aim of our study was to estimate p24 and HBsAg content of CIC in dually infected patients, and the prevalence of major classes of complexed antibodies (IgM and IgG). We examined 146 samples of sera from 105 HIV positive patients of the Institute for Infectious and Tropical Diseases during 1992 and 1993. On those sera we performed p24Ag and HbsAg detection, with and without prior dissociation of CIC, we determined serum level of CIC and immunoglobulin classes IgM and IgG level in sera and in polyethilenglycol (PEG) precipitates of sera. Acid dissociation of immune complexes revealed a high proportion of HIV antigen positive sera in all stages of HIV disease progression. HbsAg in serum of HIV positive patients was also found coupled in immune complexes much more frequently than in the HIV negative control group. In many instances both antigens were simultaneously found coupled in CIC. Immune complexes detected have been shown to contain both IgM and IgG immunoglobulins, while IgM antibodies were associated to immune complexes in higher proportion than IgG, compared to total serum immunoglobulins.

The analysis of virus-caused alterations of cellular and humoral immunoresponsiveness during the first days of morbilli rush in the young adult population.

The parameters of cellular and humoral immune responsiveness were studied during the first days of morbilli rush in the group of 34 young adult patients. The analysis of cell-mediated immune response included T cell relative and absolute numbers, mitogen-induced T cell proliferative response, as well as the relative and absolute numbers of mononuclear phagocytes. The tested parameters of humoral immune response included B cell relative and absolute numbers, serum concentrations of immunoglobulins IgG, IgA and IgM, and serum level of immune complexes (IC). The reduction of total leukocyte number, T cell and B cell relative and absolute numbers, as well as diminished mitogen-induced T cell proliferative response, associated with the elevation of IgM and IC serum levels were found in the majority of analyzed patients. Moreover, the subsequent analysis revealed positive correlations between T cell percentage and T cell proliferative response, as well as between serum concentrations of IgM and IC. These data confirmed the presence of acute morbilli infection-caused disturbances of patients' immunocompetence.

Epidemiology of hepatitis D virus (delta) infection in Yugoslavia.

In 614 HBsAg-positive Yugoslavian patients, radioimmunoassay testing for anti-delta showed the presence of this antibody in serum in 11.2%. Of the patients, 213 belonged to a risk group (i.v. drug users, hemophiliacs, hemodialysed patients and patients with posttransfusion hepatitis); a significant number of these patients (63; 29.6%) were found to have anti-delta. A second group was composed of 401 HBsAg-positive patients from the general population (patients with acute hepatitis B, with fulminant hepatitis B and patients with chronic HBV infection); delta infection was found only in six (1.5%). Immunohistochemical methods failed to demonstrate the delta antigen in the livers of 73 patients with chronic HBV infection. Testing the liver of 36 patients with fulminant hepatitis B for delta antigen demonstrated this reactivity in only one (2.8%) liver sample. Delta antigen was also found in the liver of a female patient who underwent biopsy in 1972. The results of this study suggest the HDV is not endemic in Yugoslavia; however, it is frequently found in patients at risk of blood exposure, primarily i.v. drug users.

[Clinico-laboratory diagnosis of Lyme borreliosis--personal experience]. / Klinicko-laboratorijska dijagnoza Lyme borreliosis--nasa iskustva.

Between May 1992 and February (second half) 1993 two hundred patients with the history of tick bite have been examined at the Institute for Infectious and Tropical Diseases "Dr Kosta Todorovic". Of the above 200 persons, 103 of them have had clinical/epidemiological evidence of Lyme disease (i.e. Erythema migrans). In order to establish the degree of seroconversion in this stage of Lyme disease, blood of each patient has been tested by PHA and IFA methods. Blood from each patient has been drawn in pairs, immediately before and after the treatment. By method of PHA we have analyzed 186 sera and found 23 positive results. By method of IFA we have analyzed 10 sera and found one positive result. By Comparative testing we have analyzed 10 sera, obtaining 5 positive results by PHA and 3 positive results ba IFA.

[Human immunodeficiency virus type 1 (HIV) and laboratory tests for detection of HIV infection]. / Virus humane imunodeficijencije (HIV) i testovi za detekciju HIV infekcije.

Human immunodeficiency virus type 1 (HIV) has been identified as the primary cause of the acquired immunodeficiency syndrome (AIDS). HIV-1 is a prototypical member of the laentivirinae subfamily of human retroviruses. The infections with HIV are notable for involvement of the nervous system, long periods of clinical latency and weak humoral immune responses complicated by persistent viraemia. HIV is spread by sexual contact, exposure to infected blood or blood products, and perinatal transmission from mother to child. The most important feature of HIV is a remarkable complexity of its viral genome. Besides T cells and monocytes, HIV may also infect other types of cells, including glial cells, gut epithelium, and bone marrow progenitors. It has become increasingly important to have sensitive and specific methods to establish the presence of absence of HIV infection. The diagnosis of HIV infection depends on detection of specific antibodies to HIV, detection of circulating viral antigens, isolation of the virus from clinical specimens of detection of genetic material in infected cells and plasma. The most widely used are ELISA as a screening test and Western blot as a confirmatory test.

[Correlation between immunological markers and clinical course of HIV infection]. / Klinicko-imunoloske odlike razvoja HIV infekcije.

The interaction of human immunodeficiency virus (HIV) with CD4 molecule, which is expressed on various human cells is the crtical event in the pathogenesis of HIV infection. Decreased number and functional anergy of CD4+ T cells, which are the most important immunoregulatory cells, cause severe immunodeficiency. Having in mind that there is a significant correlation between clinical course of HIV infection and laboratory markers it is possible to predict progression of HIV infection toward acquired immunodeficiency syndrome (AIDS). These markers can be divided into four categories: (1) measures of viral production; (2) the specific immune response to HIV; (3) nonspecific immune system activation; (4) measurements of immune system damage. In addition, the use of these predictors can improve clinical management of HIV-infected individuals.

[Neurological disorders associated with HIV infection]. / Neuroloske komplikacije HIV infekcije.

Neurological diseases occur frequently in patients infected with human immunodeficiency virus (HIV). There are three main groups of central nervous system (CNS) dysfunction: (1) direct effects of HIV; (2) opportunistic infections; (3) opportunistic neoplasms. On the basis of clinical characteristics it is possible to differentiate focal and diffuse pathologic alterations of CNS. The starting point of evaluation of CNS dysfunction is computed tomography (CT). If the focal lesions are not present on CT scan, it is necessary to carry out cerebrospinal fluid (CSF) examination.

[Diseases of digestive system in patients with AIDS]. / Oboljenja digestivnog sistema u bolesnika sa AIDS-om.

Human immunodeficiency virus infection can affect the entire gastrointestinal tract and hepatobiliary system. Gastrointestinal abnormalities in acquired immunodeficiency syndrome are common and may relate to opportunistic inections and tumors, diseases which are usual in the anti-HIV negative population also, and disease of unknown aethiology, such as wasting syndrome and recurrent diarrhoeal illness. Diarrhoea and weight loss are found in more than 50% of patients with AIDS. Gastrointestinal manifestations range in severity from the discomfort of oral and perianal infections, through life threatening diarrhoea due to intestinal cryptosporidiosis. The approach to the patient with AIDS and gastrointestinal or hepatobiliary disorders is oriented toward diagnosing treatable aethiologies and avoiding unnecessary invasive procedures. Although the final prognosis of full developed AIDS is poor, management of gastrointestinal disease may be improved by accurate diagnosis.

[Antiretroviral therapy of acquired immunodeficiency syndrome (AIDS)]. / Antiretrovirusna terapija sindroma stecene imunodeficijencije (AIDS-om).

The unique nature of the replication cycle of the retroviruses, including HIV, offera number of possible targets for chemotherapeutic agents. These are RNA viruses which have the capacity to make DNA copies through their characteristic enzyme, reverse transcriptase, encoded in the pole region of the viral genoma. Reverse transcription is an attractive target for therapeutic intervention as this event is uniquelly associated with retroviruses. Dideoxynucleoside analogues can compete with endogenous nucleosides that are the natural substrate for reverse transcriptase or may be incorporated intro the growing chain of proviral DNA and terminate elongation. Reverse transcriptase inhibition is the principal mechanism of action of zidovudine (AZT) and related nucleosides, dideoxyinosine (ddl) and dideoxycitidine (ddC), which all attach to reverse transcriptase to the same site. This review will discuss current approaches to the antiretroviral therapy in AIDS patients. Several well controlled clinical trials have established both the efficacy and toxicity of AZT in patients with AIDS and severe ARC and it was shown that this drug decreased the incidence and severity of opportunistic infections, with the highly significant reduction in early mortality. The efficacy of newer reverse transcriptase-inhibiting nucleoside derivatives will be discussed too, as well as the issue of combination therapies.

No interference of rheumatoid factor(s) with toxoplasmosis IgM determination in infancy.

Sera from 263 newborns and infants suspected of congenital toxoplasmosis were tested for the presence of rheumatoid factor (RF) by the latex agglutination test, of which 40 were also tested by the enzyme-linked immunosorbent assay (ELISA). RF was detected in only one serum sample (0.38%), suggesting that false-positive results of the IgM-indirect fluorescent antibody test and the IgM-ELISA due to RF is most unusual in infancy.