Elevated Viral Load Research Articles

Factors involved in treatment durability and immunological recovery in a cohort of HIV-positive patients receiving atazanavir-based regimens.

IntroductionSince antiretroviral therapy must be taken lifelong, persistence and safety have become the goals to achieve. Protease inhibitors, in particular atazanavir (ATV) with or without ritonavir (r), represent a highly prescribed class in real life long-term treatment.MethodsWe conducted a retrospective cohort study in HIV-1-positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan. Data regarding viral load, CD4 lymphocytes and the mean blood chemistry parameters were collected at baseline, first, third, sixth months from the beginning of therapy and then every six months. Factors related to persistence of therapy with ATV and time-dependent probability to reach a CD4 cells count >500 cells/µL were evaluated with Kaplan-Meier curve and Cox model.ResultsA total of 1030 patients were evaluated: 183 received therapy with ATV/r as naïve, 653 switched to ATV/r as a second or following line and 194 switched to unboosted ATV from previous ATV-free regimens. A total of 138 patients shifted to unboosted ATV from a previous ATV/r regimen (17 from naïve ATV/r and 121 from experienced ATV/r). The median duration of therapy was 38 months (95% CI 29–73) in ATV/r naïve patients, 36 months (95% CI 23–53) in unboosted ATV group and 35 months (95% CI 31–43) in patients switched to ATV/r. We observed no significant difference in the persistence of the three regimens (p=0.149). Female (HR=1.317; 95% CI 1.073–1.616 p=0.008) and patients with CD4<200 cells/µL at baseline (HR=1.433 95% CI 1.086–1.892 p=0.011) were at increased risk of regimen interruption, whereas starting therapy with a backbone containing abacavir (HR=0.725; 95% CI 0.533–0.987 p=0.041) resulted protective. In multivariate analysis no significant difference between the three regimens was observed regarding reaching a count of CD4 cells >500 cells/µL. Factors associated to a poor CD4 gain were each extra Log of viral load at baseline (HR=0.915; 95% CI 0.852–0.982 p=0.014) and CD4<200 cells/µL at ATV start (HR=0.197; 95%CI 0.138–0.281 p<0.0001); conversely, females (HR=1.262; 95%CI 1.032–1.543 p=0.023) had a higher probability of CD4 recovery.ConclusionsAntiretroviral regimens containing atazanavir with or without ritonavir were durable and well tolerated, an elevated viral load and CD4 <200 cells/µL at baseline resulted related to regimen discontinuation and reduced CD4 recovery.

Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications.

Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood-brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1ß, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in HAND pathogenesis. By these diverse mechanisms, HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection.

Lymphoprolifération systémique T liée à l’EBV chez l’enfant

Systemic EBV+ T-cell lymphoproliferative disease of childhood is a recent entity described in the 2008 World Health Organisation tumours of haematopoietic system and lymphoid tissues as a clonal T-cell EBV+ systemic proliferation. It occurs after acute or chronic active EBV infection. We report the case of a caucasian, immunocompetent 12-year-old girl, with no particular history, who presented with hemophagocytic lymphohistiocytosis in the aftermath of an infectious mononucleosis. Main symptoms were multiple organ failure, hepatosplenomegaly and pancytopenia. Histopathology of peripheral lymph node and bone marrow revealed a T-cell, CD8+, EBV+ lymphoproliferation. An elevated viral load was detected in blood by PCR. The patient died within 3 weeks. Since most of the cases have been reported in Asia and South America, few cases still have been described in Europe. Unlike B-cell lymphoproliferation in immunocompromised individuals, T-cell EBV+ lymphoproliferation occurs in immunocompetent patients and seems to be the consequence of a proliferative disorder of EBV-infected T-cells, attributed to a cytotoxic T-cell response deficiency. These T-cell proliferations are more frequently immunoreactive for CD8 than CD4. A key feature of the diagnosis might be EBV viral load.

Incidence of congenital toxoplasmosis among infants born to HIV-coinfected mothers: case series and literature review

IntroductionThere is a paucity of data on the occurrence of congenital toxoplasmosis in children born to mothers dually infected with HIV and Toxoplasma gondii. ObjectiveTo evaluate aspects of the mother–infant pairs associated with vertical transmission of toxoplasmosis in women co-infected with HIV in a referral center for perinatally acquired infections in Belo Horizonte, Brazil. MethodsDescriptive study of HIV vertically exposed children, with congenital toxoplasmosis, followed at a referral center (cohort/Belo Horizonte). Prenatal and post-natal variables for the mother–infant pairs were evaluated. A literature review with no filtering for time and language was performed to identify reports of congenital toxoplasmosis in HIV vertically exposed children. ResultsAmong 2007 HIV vertically exposed children evaluated in the period from 1998 to 2011, 10 cases of congenital toxoplasmosis were identified (incidence: 0.5%, 95% confidence interval: 0.24–0.91). In searching the literature 22 additional cases in 17 reports were found. Combining the findings of our cohort with other reported cases, 50% (16/32) of congenital toxoplasmosis in HIV vertically exposed children were from Brazil. The cases of congenital toxoplasmosis in HIV vertically exposed children identified in Brazil occurred mainly in the post-Highly Active Antiretroviral Therapy era (p=0.002) and presented a lower death rate (p=0.003) than those from other countries. In the cohort/Belo Horizonte, HIV infection was identified mainly during gestation; T. gondii vertical transmission was observed in pregnant women with CD4+>500cells/mm3 and latent toxoplasmosis. High rates of ocular lesions (87.5%) and central nervous system involvement (70%) were detected. ConclusionsThe risk of vertical transmission of T. gondii in HIV-infected women is low and has been usually associated with maternal immunosuppression and elevated viral load. However, our findings of congenital toxoplasmosis in children born to HIV-infected mothers with latent toxoplasmosis and not immunosuppressed emphasize the need for careful follow-up in these cases.

Reactivation of multiple viruses in patients with sepsis.

A current controversy is whether patients with sepsis progress to an immunosuppressed state. We hypothesized that reactivation of latent viruses occurred with prolonged sepsis thereby providing evidence of clinically-relevant immunosuppression and potentially providing a means to serially-monitor patients' immune status. Secondly, if viral loads are markedly elevated, they may contribute to morbidity and mortality. This study determined if reactivation of herpesviruses, polyomaviruses, and the anellovirus TTV occurred in sepsis and correlated with severity. Serial whole blood and plasma samples from 560 critically-ill septic, 161 critically-ill non-septic, and 164 healthy age-matched patients were analyzed by quantitative-polymerase-chain-reaction for cytomegalovirus (CMV), Epstein-Barr (EBV), herpes-simplex (HSV), human herpes virus-6 (HHV-6), and TTV. Polyomaviruses BK and JC were quantitated in urine. Detectable virus was analyzed with respect to secondary fungal and opportunistic bacterial infections, ICU duration, severity of illness, and survival. Patients with protracted sepsis had markedly increased frequency of detectable virus. Cumulative viral DNA detection rates in blood were: CMV (24.2%), EBV (53.2%), HSV (14.1%), HHV-6 (10.4%), and TTV (77.5%). 42.7% of septic patients had presence of two or more viruses. The 50% detection rate for herpesviruses was 5–8 days after sepsis onset. A small subgroup of septic patients had markedly elevated viral loads (>104–106 DNA copies/ml blood) for CMV, EBV, and HSV. Excluding TTV, DNAemia was uncommon in critically-ill non-septic patients and in age-matched healthy controls. Compared to septic patients without DNAemia, septic patients with viremia had increased fungal and opportunistic bacterial infections. Patients with detectable CMV in plasma had higher 90-day mortality compared to CMV-negative patients; p<0.05. Reactivation of latent viruses is common with prolonged sepsis, with frequencies similar to those occurring in transplant patients on immunosuppressive therapy and consistent with development of an immunosuppressive state. Whether reactivated latent viruses contribute to morbidity and mortality in sepsis remains unknown.

Clinical implications of elevated HIV-1 viral load results obtained from samples stored frozen in vacutainer plasma preparation tubes

Studies have demonstrated that plasma samples collected and stored frozen using vacutainer plasma preparation tubes (PPT) may result in falsely elevated viral load (VL) values with the Roche COBAS TaqMan HIV-1 v1.0 test. At the University of Connecticut Health Center, a total of 349 samples from HIV-1-infected patients on HAART were collected and stored frozen in PPT. Viral load (VL) results were obtained using the Roche COBAS TaqMan HIV-1 v2.0 test (CTM v2.0) and Abbott RealTime HIV-1 assay (RealTime HIV-1). Of the 349 samples, 260 (74.5%) had VL values that differed by >0.5log10copies/mL; 64 of these were quantified by both assays. The remaining 196 samples were detected by CTM v2.0 but not detected in RealTime HIV-1: 62 of the most discordant samples in this category (CTM v2.0 detected/RealTime HIV-1 not detected) were further analyzed using two nested RT-PCR assays targeting pol integrase: full-length (864nt) and a highly conserved subregion (134nt). No HIV-1 RNA was detected in the discordant samples, confirming RealTime HIV-1 results. The increase in VL reactivity with the CTM v2.0 assay was presumably due to proviral DNA captured by the CTM total nucleic acid extraction chemistry but not the RNA-specific extraction procedure used in RealTime HIV-1. These results suggest that using CTM v2.0 with samples frozen in PPT could have significant clinical implications for HIV-1 patient management.

Bees under stress: sublethal doses of a neonicotinoid pesticide and pathogens interact to elevate honey bee mortality across the life cycle.

Microbial pathogens are thought to have a profound impact on insect populations. Honey bees are suffering from elevated colony losses in the northern hemisphere possibly because of a variety of emergent microbial pathogens, with which pesticides may interact to exacerbate their impacts. To reveal such potential interactions, we administered at sublethal and field realistic doses one neonicotinoid pesticide (thiacloprid) and two common microbial pathogens, the invasive microsporidian Nosema ceranae and black queen cell virus (BQCV), individually to larval and adult honey bees in the laboratory. Through fully crossed experiments in which treatments were administered singly or in combination, we found an additive interaction between BQCV and thiacloprid on host larval survival likely because the pesticide significantly elevated viral loads. In adult bees, two synergistic interactions increased individual mortality: between N. ceranae and BQCV, and between N. ceranae and thiacloprid. The combination of two pathogens had a more profound effect on elevating adult mortality than N. ceranae plus thiacloprid. Common microbial pathogens appear to be major threats to honey bees, while sublethal doses of pesticide may enhance their deleterious effects on honey bee larvae and adults. It remains an open question as to whether these interactions can affect colony survival.

Vertical transmission of hepatitis C virus: Current knowledge and perspectives.

Hepatitis C virus (HCV) infection is a major global health issue. Infection by the HCV can cause acute and chronic liver diseases and may lead to cirrhosis, hepatocellular carcinoma or liver failure. The World Health Organization estimates that approximately 3% of the world population have been infected with HCV and the worldwide prevalence is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Following the introduction of blood product screening, vertical transmission becomes the leading cause of childhood HCV infection. The prevalence of pediatric HCV infection varies from 0.05% to 0.36% in developed countries and between 1.8% and 5% in the developing world. All children born to women with anti-HCV antibodies should be checked for HCV infection. Though universal screening is controversial, selective antenatal HCV screening on high-risk populations is highly recommended and should be tested probably. Multiple risk factors were shown to increase the possibility of HCV vertical transmission, including coinfections with human immunodeficiency virus, intravenous drug use and elevated maternal HCV viral load, while breastfeeding and HCV genotypes have been studied to have little impact. At present, no clinical intervention has been clearly studied and proved to reduce the HCV vertical transmission risk. Cesarean section should not be recommended as a procedure to prevent vertical transmission, however, breastfeeding is generally not forbidden. The high prevalence of global HCV infection necessitates renewed efforts in primary prevention, including vaccine development, as well as new approaches to reduce the burden of chronic liver disease. Future researches should focus on the interruption of vertical transmission, developments of HCV vaccine and direct-acting antivirals in infancy and early childhood.

Síndrome de opsoclonia-mioclonia-ataxia em paciente com AIDS

ABSTRACTWe report the case of a 38-year-old woman with AIDS who developed opsoclonus-myoclonus-ataxia syndrome during a period different from other cases reported in literature. Opsoclonus-myoclonus-ataxia syndrome had already been reported as the initial neurological presentation of AIDS, as well as at the time of HIV-seroconversion and immune reconstitution syndrome. Our case is unique since the patient had an elevated CD4 count and negative viral load in the period when the opsoclonus-myoclonus-ataxia syndrome occurred.

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Introduction: Background: Disseminated herpes simplex virus (HSV) infection in neonates represents a devastating entity which yields high mortality despite treatment with high dose acyclovir. We present the pharmacokinetics (PK) of acyclovir in an infant with disseminated HSV-1 infection progressing to fulminant hepatic and renal failure necessitating the use of extracorporeal membrane oxygenation (ECMO) for hemodynamic support and to facilitate continuous veno-venous hemofiltration (CVVH) as a treatment modality for hepatic and renal failure. Current literature demonstrates increased survival and decreased long term morbidity in patients treated with high dose acyclovir with a dose of 60mg/kg/day divided every 8 hours. Currently, no data exists regarding the PK of acyclovir in ECMO or in the setting of CVVH coupled with ECMO for intermittent or continuous infusion (CI) dosing modalities. Methods: This is a single case report describing the PK of acyclovir on ECMO with concurrent CVVH. Acyclovir was initially started at 30 mg/kg/dose IV q8h to account for the extra volume of distribution (Vd) of the ECMO circuit and the efficiency of the CCVH circuit. After 24 hours of therapy, blood samples were collected at 0.25, 2 and 4 h from the end of 0.5h acyclovir infusion. The patient specific acyclovir serum concentrations were plotted against time, and individual PK parameters were determined by a one-compartmental analysis. After obtaining an elevated quantitative HSV viral load, the patient was then transitioned to a continuous infusion of acyclovir via the replacement solution for CVVH, at a concentration of 5.5 mg/L. Acyclovir serum concentration was obtained on day 3 of CI acyclovir. Results: The initial acyclovir levels were 17 and 16 mcg/mL, respectively, representing a Vd of 1.4 L/kg, a t1/2 of 11.4 h, and a peak of 19.8 mcg/mL which was below the target peak of ~45 mcg/mL and a trough of 12.1 mcg/mL. After starting the CI, the levels on day 3 were 8.8 mcg/mL which was within the target range for CI acyclovir. Conclusions: These are the first PK data of acyclovir on ECMO with or without CVVH. This data suggests that adding acyclovir to the replacement fluid during CVVH is effective in achieving therapeutic drug levels despite the complications of adding ECMO and CVVH circuits to a small patient.

Alterations in the Levels of Vesicular Trafficking Proteins Involved in HIV Replication in the Brains and CSF of Patients with HIV-associated Neurocognitive Disorders

Human immunodeficiency virus (HIV) associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral therapies. A HAND-specific biomarker indicative of neuropsychological impairment (NPI) would give insight into disease progression and aid clinicians in designing therapy. Endosomal sorting complex required for transport (ESCRT) proteins such as tumor susceptibility gene (TSG)-101, vacuolar protein sorting (VPS)-4 and LIP-5 are important for HIV replication and recently antiviral interferon stimulated gene (ISG)-15 was proposed as a biomarker for CNS injury. Here, we analyzed a well-characterized cohort of HIV+ cerebral spinal fluid (CSF) and postmortem brain specimens for multiple vesicular trafficking proteins and a related innate immune protein, ISG-15, TSG-101, VPS-4 and LIP-5. All protein levels trended higher with increased NPI and neuropathology. ISG-15 CSF levels were increased in HIV encephalitis (HIVE) compared to normal cases, and three quarters of HIVE samples had above average CSF ISG-15 levels. VPS-4 CSF levels were increased in NPI/NPI-O compared to normal patients. VPS-4 CSF levels in HIV-associated dementia were equivalent to that of normal patients. LIP-5 CSF levels positively correlate with ISG-15 levels, and higher than average ISG-15 levels indicate elevated viral load. Immunoblot and immunohistochemical analyses show increased expression of ISG-15, VPS-4 and LIP-5 in neuronal cell bodies and astroglial cells. ESCRT protein CSF levels analyzed in conjunction with viral load may be indicative of NPI stage, and may aid in the diagnosis and design of therapies for HIV patients. Further studies on the ESCRT protein expression during HIV infection may lead to a promising biomarker for predicting progression of NPI.

Central Nervous System vasculitis associated with Hepatitis C virus infection: A brain MRI-supported diagnosis

BackgroundThe Hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, being the Central Nervous System (CNS) rarely involved. Case reportWe report a case of a 54year-old black man with arterial hypertension who presented with progressively worsening headaches, apathy, somnolence and left hemiparesis. Brain MRI showed an acute ischemic lesion in the left anterior cerebral artery (ACA) and an old ischemic infarct in the right ACA territory. Brain MRI with gadolinium revealed mural thickening and contrast enhancement of the A1 and A2 segments of the ACAs, of the middle and distal basilar artery and of the P1 segment of the left posterior cerebral artery, suggesting active vasculitis. Digital angiography confirmed those irregularities and stenosis. Laboratory evaluation revealed ESR (73mm/h), transaminase elevation, elevated HCV viral load genotype 2, positive IGRA, negative cryoglobulins, CSF protein elevation with oligoclonal bands (mirror pattern) and no pleocytosis; investigation excluded other infectious causes. Pegylated interferon alpha-2a and ribavirin, corticotherapy and tuberculosis prophylaxis were started with clinical and imagiological improvement. ConclusionThe typical inflammation signs of the vascular wall demonstrated by the gadolinium-enhanced MRI strengthened the hypothesis of CNS vasculitis. The association with HCV infection is rare but should be investigated once specific therapeutic is required.

Chronic Progressive HIV-1 Infection Is Associated With Elevated Levels of Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSC) consist of a heterogeneous population of progenitor cells and immature myeloid cells that are potent suppressors of T-cell function in many tumor models. The purpose of this study was to evaluate the possibility that MDSC play a role in HIV-induced immunosuppression.Ninety-seven patients participated in this study: 16 healthy controls; 20 HIV-infected individuals with suppressed viral loads; 49 HIV-infected treatment-naive individuals; 2 individuals with hepatitis C co-infection; 4 HIV-infected individuals failing to respond to treatment; and 8 individuals with lung cancer as positive controls.Flow cytometry analysis was performed on freshly isolated peripheral blood mononuclear cells. MDSC were defined as CD11b+CD14-CD33+CD15+. CD4+CD25+, FoxP3+ regulatory T cells were also analyzed. Mixed lymphocyte reactions and proliferation assays were used to measure suppressor function.Subjects with progressive or chronic uncontrolled HIV infection had significantly higher levels of MDSC than healthy controls. Subjects with lung cancer, as expected, had elevated MDSC. In HIV-infected individuals, percent MDSC correlated positively with elevated viral load (>50 000/mL) and low CD4 count (<250/mm3). In addition, effective antiretroviral therapy was associated with normalization of MDSC number; individuals with elevated MDSC before antiviral therapy had significant reductions in MDSC after initiation of therapy. MDSC number was correlated with generation of CD4+CD25+FoxP3+ regulatory T cells. Finally, MDSC directly impaired the proliferative capacity of T cells of healthy donors and HIV controllers.Uncontrolled HIV infection is associated with elevated levels of MDSC. These cells potentially contribute to the impaired T-cell responses characteristic of progressive HIV disease.The variety of hematopoietic cells seems endless, and as new cell types are defined, they routinely seem to be affected by HIV infection. MDSC are a case in point. The relevance of these cells in tumor biology has recently been better defined. It has long been known that chronic inflammation creates a tumor-inducing environment. It is now speculated that infiltrating MDSC inhibits effective immunologic control of evolving malignant cells. The current study suggests that MDSC may contribute to the immunopathogenesis of HIV. Are these cells contributing to the immunologic suppression associated with HIV, or are they a regulatory response to HIV-associated persistent immune activation? As described in an accompanying Editorial Comment (Macatangay BJ, et al. AIDS. 2012;26[12]:1567–1569), dampening the effects of MDSC could be important in purging latent HIV reservoirs in approaches aimed at curing HIV disease. However, understanding the immunoregulatory networks involved in HIV pathogenesis is likely critical for the design of effective HIV immune-based therapies.

Have the explosive HIV epidemics in sub-Saharan Africa been driven by higher community viral load?

The HIV epidemic has carved contrasting trajectories around the world with sub-Saharan Africa (SSA) being most affected. We hypothesized that mean HIV-1 plasma RNA viral loads are higher in SSA than other areas, and that these elevated levels may contribute to the scale of epidemics in this region.To evaluate this hypothesis, we constructed a database of means of 71,668 viral load measurements from 44 cohorts in seven regions of the world. We used linear regression statistical models to estimate differences in viral load between regions. We also constructed and analyzed a mathematical model to describe the impact of the regional viral load differences on HIV epidemic trajectory.We found substantial regional viral load heterogeneity. The mean viral load in SSA was 0.58 log(10) copies/ml higher than in North America (95% confidence interval 0.45-0.71); this represents about a four-fold increase. The highest mean viral loads were found in Southern and East Africa, whereas in Asia, Europe, North America, and South America, mean viral loads were comparable. Mathematical modeling indicated that conservatively 14% of HIV infections in a representative population in Kenya could be attributed to the enhanced infectiousness of patients with heightened viral load.We conclude that community viral load appears to be higher in SSA than in other regions and this may be a central driver of the massive HIV epidemics in this region. The elevated viral loads in SSA may reflect, among other factors, the high burden of co-infections or the preponderance of HIV-1 subtype C infection.

HIV-1 Disease Progression During Highly Active Antiretroviral Therapy

Accurately estimating rates of disease progression is of central importance in developing mathematical models used to project outcomes and guide resource allocation decisions. Our objective was to specify a multivariate regression model to estimate changes in disease progression among individuals on highly active antiretroviral treatment in British Columbia, Canada, 1996-2011. We used population-level data on disease progression and antiretroviral treatment utilization from the BC HIV Drug Treatment Program. Disease progression was captured using longitudinal CD4 and plasma viral load testing data, linked with data on antiretroviral treatment. The study outcome was categorized into (CD4 count ≥ 500, 500-350, 350-200, <200 cells/mm, and mortality). A 5-state continuous-time Markov model was used to estimate covariate-specific probabilities of CD4 progression, focusing on temporal changes during the study period. A total of 210,083 CD4 measurements among 7421 individuals with HIV/AIDS were included in the study. Results of the multivariate model suggested that current highly active antiretroviral treatment at baseline, lower baseline CD4 (<200 cells/mm), and extended durations of elevated plasma viral load were each associated with accelerated progression. Immunological improvement was accelerated significantly from 2004 onward, with 23% and 46% increases in the probability of CD4 improvement from the fourth CD4 stratum (CD4 < 200) in 2004-2008 and 2008-2011, respectively. Our results demonstrate the impact of innovations in antiretroviral treatment and treatment delivery at the population level. These results can be used to estimate a transition probability matrix flexible to changes in the observed mix of clients in different clinical stages and treatment regimens over time.

THU0217 Safety of Infliximab Therapy in HbsAg Carriers with Rheumatoid Arthritis: A Prospective Study

BackgroundPrevalence rate of hepatitis B virus (HBV) infection in China (13%) and many other developing countries are much higher than that in developed countries. When anti-TNF agents are more available...

AB0898 Biomarker for spondyloarthritis: Autoantibodies against class II-associated invariant chain peptide (clip)

BackgroundSpondyloarthritis (SpA) is relatively common inflammatory disorder with a frequency of 1-2% in the European population (1). Establishing the diagnosis however may be difficult, since abnormalities in conventional X-ray develop...

B109 Vacc-4x and Vacc-C5

Immune-based interventions for HIV-1 infection need to achieve both the induction of effective anti-viral responses as well as a reduction in HIV-associated hyperactivation of the immune system. Vacc-4x is a peptide-based therapeutic vaccine designed to induce cytotoxic T-cell-based killing of HIV-infected cells. Vacc-4x has recently completed a large phase II study in Europe and the USA enrolling 135 subjects (www.clinicaltrials.gov identifier NCT00659789). Vacc-4x Subjects that achieved a 6 month ART-free period showed a statistically significant reduction in viral load set point (64%) compared to placebo subjects that were similarly ART-free for 6 months (p=0.04). Immunological data suggest that in contrast to placebo, the quality of immune responses in subjects that received Vacc-4x influenced viral load in a manner that was independent of human leukocyte antigen (HLA) status. Vacc-C5 is a peptide-based therapeutic vaccine candidate designed to induce non-neutralizing antibodies to the 5th constant domain (C5) on the HIV-1 envelope glycoprotein gp120. This product is currently being evaluated in a phase I clinical study (www.clinicaltrials.gov identifier NCT01627678). Recent results from analysis of serum samples from a number of different cohorts of treatment naïve subjects in Norway and the United States support previous observations that the presence of anti-C5 antibodies is associated with low/moderate viral load in natural viral suppressor subjects whereas anti-C5 antibody levels are significantly reduced in subjects with elevated viral load that show disease progression. Vacc-4x and Vacc-C5 are being considered for use in combination as a therapeutic vaccine and ultimately as a preventive vaccine.

Have the explosive HIV epidemics in sub-Saharan Africa been driven by higher community viral load?

The HIV epidemic has carved contrasting trajectories around the world with sub-Saharan Africa (SSA) being most affected. We hypothesized that mean HIV-1 plasma RNA viral loads are higher in SSA than other areas, and that these elevated levels may contribute to the scale of epidemics in this region. To evaluate this hypothesis, we constructed a database of means of 71,668 viral load measurements from 44 cohorts in seven regions of the world. We used linear regression statistical models to estimate differences in viral load between regions. We also constructed and analyzed a mathematical model to describe the impact of the regional viral load differences on HIV epidemic trajectory. We found substantial regional viral load heterogeneity. The mean viral load in SSA was 0.58 log(10) copies/ml higher than in North America (95% confidence interval 0.45-0.71); this represents about a four-fold increase. The highest mean viral loads were found in Southern and East Africa, whereas in Asia, Europe, North America, and South America, mean viral loads were comparable. Mathematical modeling indicated that conservatively 14% of HIV infections in a representative population in Kenya could be attributed to the enhanced infectiousness of patients with heightened viral load. We conclude that community viral load appears to be higher in SSA than in other regions and this may be a central driver of the massive HIV epidemics in this region. The elevated viral loads in SSA may reflect, among other factors, the high burden of co-infections or the preponderance of HIV-1 subtype C infection.

Risk factors associated with elevated blood cytomegalovirus pp65 antigen levels in patients with autoimmune diseases

Objectives To further assess the relationship between elevated levels of cytomegalovirus (CMV) pp65 antigen in blood, as indicative of viral load, during treatment-free follow-up and CMV diseases in patients with autoimmune diseases and to identify any risk factors associated with elevated viral loads.Methods This was a retrospective review of the electronic medical charts of 148 patients with autoimmune diseases who tested positive for CMV pp65 antigen in the blood.Results A total of 106 patients were analyzed. During follow-up, elevated viral loads were detected in 35 patients who were not on antiviral therapy, of whom five developed CMV diseases. Elevated viral load was significantly associated with CMV diseases [5/35 vs. 0/71 (no elevated viral load); P = 0.001). Multivariate analysis revealed that lymphopenia [lymphocyte numbers < 700/mm3, odds ratio (OR) 34.44, 95 % confidence interval (CI), 7.82–151.66; P < 0.001], systemic lupus erythematosus (SLE) (OR 6.71, 95 % CI, 1.23–36.49; P = 0.028), and polymyositis/dermatomyositis (PM/DM) (OR 10.62, 95 % CI 1.41–79.77; P = 0.022) were significantly associated with elevated viral load.Conclusions Elevated viral load was significantly associated with CMV diseases. Patients with SLE or PM/DM and lymphopenia would therefore benefit from a detailed viral load follow-up and careful physical examination.