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PubMed2003

Viral load detectability profiles for HIV infection.

The introduction of potent antiretroviral therapies for treatment of HIV infection typically results in a dramatic reduction in plasma HIV RNA concentration, often to levels undetectable by current measurement practices. However, although a high proportion of patients achieve 'undetectability', many then experience a return to a state of detectability at a later date. As evaluation of virologic response provides a useful measure of therapy efficacy, it is of interest to estimate the proportions of cases with undetectable viral load over time following commencement of treatment. These proportions depend on the rates of transition from detectability to undetectability and subsequent return to detectability, and may be related to covariates or risk factors, possibly differing in both transitions. We consider construction of detectability profiles as estimates of these proportions, based on parametric modelling of the component survival distributions. The method is applied to an examination of the effects of baseline CD4 T-cell lymphocyte counts on virologic response to therapy amongst patients of the Western Australian HIV Cohort Study.

Anti-HIV Agents↗

PubMed2006

Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.

Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.

Adolescent↗

PubMed2000

Analysis and design issues for studies using censored biomarker measurements with an example of viral load measurements in HIV clinical trials.

For many biomarkers, the range (L,R) over which they can be quantified is restricted by technical limitations, leading to some measurements that are left or right censored. However, despite the widespread availability of statistical methods for the analysis of censored data, many studies use an imputed value for censored measurements (for example, replacing a value <L by L, or by L/2). Commonly, an analysis that ignores such imputation is then used. In clinical trials, this leads to bias and a loss of power in evaluating treatment effects. In this paper, a review of appropriate statistical methods for parametric and non-parametric analysis of such measurements is presented. This includes methods for situations in which baseline measurements are available. New results concerning design issues such as sample size determination are also presented. The paper is illustrated using two examples of studies that included censored measurements of viral load in HIV-infected subjects.

Biomarkers↗

PubMed1998

A preliminary study to determine the effect of an infusion of cryopreserved autologous lymphocytes on immunocompetence and viral load in HIV-infected patients.

Therapeutic measures aimed at boosting the immunity of HIV-infected patients are a critical component of strategies for effective therapy of HIV and AIDS. To improve immunocompetence in patients with progressive disease, autologous lymphocytes that were collected and cryopreserved earlier in the course of HIV-infection were reinfused. None of the 12 patients receiving cell infusions experienced any adverse effects. Improvements in immunologic parameters (CD4+ counts, CD8+ counts, or both; HIV-specific cytotoxic T-lymphocyte (CTL) activity; or viral load) were seen in seven patients. Restoration of the CD4+ count to the level recorded at the time of cell harvest was achieved in two patients with less advanced disease. Plasma HIV RNA was reduced by >0.5 logs in two of the four patients tested. These preliminary results suggest that cellular immunotherapy using cryopreserved autologous lymphocytes has the potential to improve some measures of immunity in patients with HIV/AIDS and warrants further investigation.

Adult↗

PubMed2002

Analysis of virological efficacy in trials of antiretroviral regimens: drawbacks of not including viral load measurements after premature discontinuation of therapy.

OBJECTIVES: To compare two analytic approaches to assess the virological effect of HAART according to the intention-to-treat (ITT) principle. MATERIAL: Data from 2318 patients enrolled in 10 randomised clinical trials (RCTs) and from 3091 patients followed in an observation cohort (EuroSIDA) starting their first HAART regimen. METHODS: Two classifications of defining virological response 48 weeks after starting the therapy to be evaluated were compared: 1) only patients remaining on the therapy and having a plasma viral load (pVL) below a given cut-off level at week 48 were classified as responders (ITT/s=f); and 2) patients with a pVL below a given cut-off at week 48 whether they remained on initial assigned therapy or switched therapy were responders (ITT/s incl). In both analyses, patients with missing data at week 48 were classified as failures (i.e., non-responders). RESULTS: According to ITT/s=f, 22-70% of the patients starting a HAART regimen in a RCT experienced a virological response at week 48. Only two RCTs had complete follow-up data (n=424): between 29 and 62% achieved a virological response at week 48 in the six treatment arms evaluated in the studies according to ITT/s=f, and 41-72% according to ITT/s incl. Among those who discontinued the therapy to be evaluated in these two trials, 13-45% (cohort: 39-74%) subsequently experienced a virological response at week 48. The subsequent response rates were associated with the reason for discontinuation (toxicity versus confirmed virological failure: 63 vs 33%), varied largely across regimens and were not associated with the discontinuation rate. CONCLUSIONS: Discontinuation of follow-up at switch from the therapy to be evaluated remains common in antiretroviral treatment trials, but leads to an imprecise and incomplete assessment of the intrinsic effect of a given regimen. Complete follow-up of all patients should be encouraged strongly as this will allow for several complementary analytic approaches and a focus on optimal treatment strategies rather than specific regimens.

Antiretroviral Therapy, Highly Active↗

PubMed2006

Effects on gene expression and viral load of a medicinal extract from Agaricus blazei in patients with chronic hepatitis C infection.

Extracts from the mushroom Agaricus blazei Murill (AbM) are used extensively as a non-prescription remedy against cancer and infections, including hepatitis. We previously demonstrated a potent immunomodulating effect of a particular preparation on monocytes in vitro, and a protective effect on bacterial infections in mice. Here we report the effect on gene expression in peripheral blood cells from four chronic hepatitis C patients, using global (29 k) oligo-based, single channel microarrays. The viral load was slightly, but not significantly, decreased after 1 week of AbM treatment. The cytokine genes most strongly induced in vitro were not induced in vivo. The more notable changes in mRNA levels were related to genes involved in the G-protein coupled receptor signalling pathway, in cell cycling, and in transcriptional regulation. The results suggest that the beta-glucans of the extract, which presumably are responsible for cytokine induction, did not readily enter the blood, while other components, such as substances proposed to have anticancer effects, were active in the blood.

Administration, Oral↗

PubMed2004

Fluoroquinolone antibiotics in a hospital sewage line; occurrence, distribution and impact on bacterial resistance.

In hospital sewage lines, human faecal bacteria are exposed to antibiotics, posing a risk for selection of antibiotic resistant microorganisms. We constructed a system for continuous sampling in a hospital sewage line that allowed us to study longitudinal establishment of bacteria, concentrations of antibiotics, and selection of bacterial resistance in waste water, sediment and biofilm. The focus in this study was on fluoroquinolones, a widely used group of antibiotics with increasing resistance problems. We found low levels of ciprofloxacin and ofloxacin in waste water but high concentrations in sediment. Despite the high levels of fluoroquinolones bound to sediment, we did not find any development of resistance against fluoroquinolones in Enterobacteriacae spp. and faecal enterococci isolated from sediment.

Drug Resistance, Bacterial↗

PubMed1997

Impact of transfusion on viral load in human immunodeficiency virus infection.

Recent research has shown that anemia and transfusion are associated with accelerated mortality in patients with human immunodeficiency virus type 1 (HIV-1) infection. It appears that blood transfusions may directly accelerate HIV-1 disease progression through activation of HIV-1 expression and/or transfusion related immunosuppression. In vitro and in vivo evidence suggests that immunization with common recall antigens (eg, tetanus toxoid) can significantly increase plasma HIV viremia, as well as the in vitro susceptibility of peripheral blood mononuclear cells to acute infection. Allogeneic leukocytes also present an antigenic challenge to HIV-infected mononuclear cells, which may cause them to proliferate and increase viral production. In vitro incubation of HIV-infected mononuclear cells with allogeneic blood components (mainly leukocytes) results in increased viral replication. Whether the effects of transfusion on HIV viral load are due to a reduced immune response and/or activation of the virus itself remains to be determined. An ongoing study is evaluating the effects of depleting leukocytes from blood prior to transfusion in HIV-infected patients. Patients are randomized to receive standard of leukocyte-depleted red blood cell (RBC) transfusions and the effect of transfusion on HIV replication is measured. Preliminary data suggest that leukocyte depletion prior to RBC transfusion does not alter viral replication compared with standard packed RBC transfusions.

Adult↗

PubMed2005

Plasma RNA viral load in HIV-1 group O infection by real-time PCR.

HIV-1 group O strains are highly divergent, and are found mainly in central Africa. The clinical course of group O infection is identical to that of HIV-1 group M infection, with rapid onset of immunodeficiency. The important divergence of the HIV-1 group O strains lead to high limitations of the commercial tests. We describe here a method based on real-time polymerase chain reaction (PCR) to quantify plasma HIV-1 group O RNA. Primers amplify both HIV-1 group O and HIV-1 group M strains. Conversely, the probe is HIV-1 group O-specific. The standard used to quantify the clinical samples is an RNA solution resulting from the transcription of a plasmid including the amplified fragment of PCR. Our technique is capable of amplifying a wide range of HIV-1 group O strains belonging to the three current clades. This technique can be used to monitor HIV-1 group O viral load, which has previously been difficult.

Base Sequence↗

PubMed2004

Plasma interleukin-18 is associated with viral load and disease progression in HIV-1-infected patients.

Recent studies demonstrate persistent elevation of interleukin-18 (IL-18) concentration in human immunodeficiency virus type 1 (HIV-1)-infected patients. Due to pleiotropic action of IL-18 on the immune system, dysregulation of its synthesis may lead to inappropriate immune activation. The aim of this study was to determine possible correlation between IL-18 levels and the natural stages of HIV-1 infection. IL-18 plasma concentrations were determined in 42 patients in different stages of an HIV-1 infection and in 15 healthy controls. HIV infection resulted in a more than fourfold increase of plasma IL-18 concentration compared to healthy individuals (865 +/- 87 vs. 206 +/- 32 pg/ml, P < 0.001). Moreover, a positive correlation between plasma IL-18 concentration and HIV viral load was found (r = 0.44, P < 0.01). Further analysis showed marked elevation of IL-18 levels in late-stage symptomatic patients. Plasma IL-18 concentrations in patients receiving high-activity antiretroviral treatment (HAART) were significantly lower than in those not undergoing antiretroviral treatment. Individuals who did not reach viral suppression showed higher IL-18 plasma concentration than the group with achieved viral suppression. Excessive production of IL-18 observed in our study may promote viral replication and disease progression in advanced, especially late-stage HIV-infected patients. Furthermore, reduction of IL-18 concentration can be an important step in HAART-related immune restoration.

Adult↗

PubMedDate not supplied

[Oral manifestations, CD4+ T-lymphocytes count and viral load in Brazilian and North-American HIV-infected children].

Oral manifestations related to HIV infection were evaluated in 184 children of both genders, aging 0-13 years. The oral exams were carried out at the Ambulatory of Pediatric AIDS, São Lucas Hospital and at the Clinics Hospital, both in Porto Alegre, RS, Brazil, and at the University Hospital and School of Dentistry, State University of New York, Stony Brook, NY, USA, from January 1999 to May 2000. A high prevalence of oral manifestations was observed both in Brazilian (72.73%) and American (53.66%) children. The most frequent manifestations were cervical lymphadenopathy, swelling of the parotids, erythematous candidiasis, petechia, gingivitis, xerostomia and angular cheilitis. Children with oral manifestations had almost normal counts of CD4+ T lymphocytes and high viral load.

Adolescent↗

PubMed2001

Oromucosal interferon therapy: relationship between antiviral activity and viral load.

Intraperitoneal (i.p.) administration of 20,000 IU recombinant murine IFN-alpha (rMuIFN-alpha) was highly effective in protecting mice challenged i.p. with doses of encephalomyocarditis virus (EMCV) ranging from 44 to 440 LD(50) (p<0.001). Oromucosal (o.m.) IFN therapy was also found to be effective in protecting mice challenged with a lethal dose of EMCV. Thus, 40% of animals infected with 44 LD(50) of EMCV and treated o.m. with 20,000 IU rMuIFN-alpha survived infection with a mean survival time of 12.0 +/- 2.46 days relative to a mean of 6.11 +/- 0.38 days in the control group (p<0.05). Oromucosal IFN therapy was found to be ineffective, however, in animals infected with higher doses of EMCV (88-440 LD(50)), even though intraperitoneal administration of the same dose of rMuIFN-alpha resulted in the survival of 90%, 50%, and 60% of animals infected with 88, 220, and 440 LD(50) of EMCV, respectively. These results suggest that oromucosal IFN therapy is effective at relatively low viral load only and that the mechanism of action of oromucosal IFN therapy may be different from that of parenterally administered IFN. Our results suggest that oromucosal IFN therapy may be most effective in chronic viral infections as an alternative to parenterally administered IFN, which is clinically effective but poorly tolerated.

Administration, Intranasal↗

PubMed2001

Development of a real-time PCR procedure including an internal control for the measurement of HCMV viral load.

Human cytomegalovirus (HCMV) infections are frequent in immuno-compromised patients. The recent development of real-time PCR procedures that allow the rapid quantification of genome load will be helpful for accurate monitoring of these infections. Two extraction procedures were evaluated using 30 blood samples that were processed pure and diluted (1/10). Repeatability and reproducibility of the quantitative PCR procedure using an internal control for amplification were analysed, and its sensitivity compared to a qualitative PCR procedure using 50 HCMV culture positive blood samples. The real-time PCR and qualitative PCR procedures were positive in 46 and 48 of the samples tested, respectively. Discrepancies were observed for samples with a low viral load. The sensitivity of the real-time PCR procedure was evaluated at 500 HCMV DNA copies per ml of sera. The use of an internal control concomitantly processed during the HCMV quantification did not alter the sensitivity of the procedure, and was relevant for the detection of putative PCR inhibitors that may interfere with the amplification process. This procedure was used to measure genome load in two bone marrow transplant patients with HCMV disease, confirming that this new PCR procedure should be used widely for diagnosing and monitoring HCMV infections in transplant patients.

Bone Marrow Transplantation↗

PubMed2000

Higher prevalence and viral load of TT virus in saliva than in the corresponding serum: another possible transmission route and replication site of TT virus.

Although TT virus (TTV) is transmissible by blood or blood products, many patients with no history of transfusion of blood and blood products have been shown to be infected, suggesting other possible routes of transmission. To investigate the transmission routes and replication sites of TTV, 85 paired saliva and serum samples were studied by semi-nested polymerase chain reaction. The prevalence of TTV DNA was 38% (32/85 samples) and 21% (18/85) in saliva and serum, respectively. Fifteen patients had TTV DNA both in saliva and serum. Six out of fifteen patients had significantly higher viral titers in saliva than in serum, but none had higher titer in serum than in saliva. When the 222 base-pair nucleotide sequences of PCR products amplified from the samples were analyzed, 12 patients had the same genotype/subtype in saliva and serum and exhibited high homology (96-100%). The other 3 had different genotypes/subtypes in saliva and serum, and the homology was 61.9-87.2%. Mixed infection was observed both in saliva and serum. Further studies are required to determine if a subgroup of TTV has tropism to saliva. The high prevalence and viral load of TTV in saliva suggest that salivary fluid may be a possible route of transmission of TTV and that TTV might replicate not only in liver tissue but also in other tissues such as oropharyngeal tissues and/or salivary glands.

Aged↗

PubMed2004

High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy.

Hepatitis B virus (HBV) reactivation during cytotoxic chemotherapy for cancer may complicate treatment and cause liver damage. The complication has been reported to occur in 10% to over 50% of HBV carriers, but the factors that determine which patients will develop reactivation remain unclear. The objective of the study is to test the hypothesis that the prechemotherapy HBV DNA level is a risk factor for the development of HBV reactivation. We studied 41 women undergoing cytotoxic chemotherapy for breast cancer, 17 of whom developed reactivation and 24 who did not. We developed a novel, ultra-sensitive, real-time polymerase chain reaction assay for the measurement of HBV DNA. The sera of 37 patients (16 who developed reactivation and 21 who did not) were available for measurement of HBV DNA using this technique. The results showed that patients in the reactivation group had a significantly higher median HBV DNA load (1.03 x 10(6) copies/mL; range <2.9 x 10(3) to 8.723 x 10(7)) than did the nonreactivation group (<2.9 x 10(3) copies/ml; range <2.9 x 10(3) to 6.331 x 10(7)) (P < 0.001). The optimal cut-off between the two groups was found to be at serum HBV DNA level of 3 x 10(5), which gave a sensitivity of 81.0% and a specificity of 85.0%. In conclusion, for breast cancer patients receiving standard cytotoxic chemotherapy, a high HBV viral load prior to the administration of cytotoxic chemotherapy is a significant predictive factor for the development of HBV reactivation. Such information may be useful in determining which patients would benefit most from prophylactic antiviral therapy during cytotoxic chemotherapy.

Antineoplastic Agents↗

PubMed1998

The sequential occurrence of pol 215 and pol 41 zidovudine resistance mutations is associated in an additive fashion with low CD4 cell counts and high plasma and cellular HIV viral load.

We report on a cross-sectional study of virological and immunological surrogate markers of HIV infection in 115 patients for whom a determination of the pol 215 and pol 41 zidovudine (ZDV) resistance mutations had been described between January 1995 and February 1996. The patients received ZDV alone or a combination of ZDV and zalcitabine or didanosine. A total of 55, 15 and 45 patients exhibited a wild (W), a mixed (MIX) or a mutant (M) genotype at codon pol 215, respectively; 85, 10 and 20 patients exhibited a W, a MIX or a M genotype at codon pol 41, respectively. Patients exhibiting the pol 215 M genotype had lower CD4 cells, higher plasma viral load and higher proviral burden than patients exhibiting the pol 215 W genotype. Patients who had variants exhibiting both pol 215 M and pol 41 M or MIX genotypes had significantly worsened surrogate marker values than patients having variants only carrying the pol 215 M genotype. These observations demonstrate that the two mutations additively associate with pejorative surrogate markers.

Adult↗

PubMed2002

Correlation between breadth of memory HIV-specific cytotoxic T cells, viral load and disease progression in HIV infection.

BACKGROUND: Memory cytotoxic T lymphocytes (CTL) should play a key role in controlling HIV infection. The correlations between the breadth and specificities of memory CTL and virus production and disease progression are still unknown, but are of major importance for vaccine strategies. METHODS AND DESIGN: One-hundred and forty-eight chronically-infected patients, enrolled before the advent of highly active antiretroviral therapy, were followed-up prospectively over 5 years. Memory CTL were tested in vitro against autologous target cells expressing Env, Gag, Pol, Nef, Vif, Rev or Tat HIV-LAI sequences. RESULTS: At entry, an HIV-specific CTL response was detected against at least one viral protein in 77% cases, with Pol and Gag recognized in 57% each, Env and Nef in 36% and 30%, Vif, Rev and Tat in 14%, 10% and 5% of cases respectively. The same pattern was observed over time with some individual variations in responder status. Multivariate analysis of longitudinal data showed that the average number of recognized proteins of two at entry significantly decreased over time with the average loss of one protein per 7 years. The number of recognized proteins was negatively associated with viral load (P < 0.05), and with occurrence of opportunistic infection (P < 0.01), and significantly correlated with CD8 cell counts (P < 0.05) but not with CD4 cell counts. CONCLUSION: The breadth of HIV antigens recognized by memory CTL is a major correlate of immune control of HIV-replication and disease progression.

Adult↗

PubMed1998

Cerebrospinal fluid viral load in HIV-1-infected patients without antiretroviral treatment: a longitudinal study.

HIV-1 RNA and neopterin levels were observed longitudinally for 20 to 68 months (mean, 37.5 months) in cerebrospinal fluid (CSF) and serum in 15 HIV-1-infected patients not receiving antiretroviral treatment. During the course of infection the HIV-1 RNA levels increased significantly in CSF, from a mean of 3.08 to 3.51 log10 copies RNA/ml (p < .01). A significant positive correlation was found between the CSF levels of HIV-I RNA and neopterin (rs = 0.54; p < .001), which increased from 13.6 to 19.6 nmol/L (p < .01). No significant changes in HIV-1 RNA or neopterin levels were found in serum. We suggest that the increase of CSF viral load with time in HIV-1 infection triggers an intrathecal immune activation reflected by increased CSF levels of neopterin. These results are in accordance with the theory that a chronic immune stimulation within the central nervous system (CNS) is involved in the pathogenesis of neurologic HIV-1 disease.

Adult↗