Amy Nelson

Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial

IMPORTANCE The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations. OBJECTIVE To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics. DESIGN, SETTING, AND PATIENTS Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012). INTERVENTIONS In the studys first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks. MAIN OUTCOMES AND MEASURES The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]). RESULTS In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events. CONCLUSION AND RELEVANCE In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01441180.

Virologic Response Following Combined Ledipasvir and Sofosbuvir Administration in Patients With HCV Genotype 1 and HIV Co-infection

IMPORTANCE There is an unmet need for interferon- and ribavirin-free treatment for chronic hepatitis C virus (HCV) infection in patients co-infected with human immunodeficiency virus (HIV). OBJECTIVE To evaluate the rates of sustained virologic response (SVR) and adverse events in previously untreated patients with HCV genotype 1 and HIV co-infection following a 12-week treatment of the fixed-dose combination of ledipasvir and sofosbuvir. DESIGN, SETTING, AND PARTICIPANTS Open-label, single-center, phase 2b pilot study of previously untreated, noncirrhotic patients with HCV genotype 1 and HIV co-infection conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from June 2013 to September 2014. Patients included those receiving antiretroviral therapy with HIV RNA values of 50 copies/mL or fewer and a CD4 T-lymphocyte count of 100 cells/mL or greater or patients with untreated HIV infection with a CD4 T-lymphocyte count of 500 cells/mL or greater. Serial measurements of safety parameters, virologic and host immune correlates, and adherence were performed. INTERVENTIONS Fifty patients with HCV genotype 1 never before treated for HCV were prescribed a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily for 12 weeks. MAIN OUTCOMES AND MEASURES The primary study outcome was the proportion of patients with sustained viral response (plasma HCV RNA level <12 IU/mL) 12 weeks after end of treatment. RESULTS Forty-nine of 50 participants (98% [95% CI, 89% to 100%]) achieved SVR 12 weeks after end of treatment, whereas 1 patient experienced relapse at week 4 following treatment. In the patient with relapse, deep sequencing revealed a resistance associated mutation in the NS5A region conferring resistance to NS5A inhibitors, such as ledipasvir. The most common adverse events were nasal congestion (16% of patients) and myalgia (14%). There were no discontinuations or serious adverse events attributable to study drug. CONCLUSIONS AND RELEVANCE In this open-label, uncontrolled, pilot study enrolling patients co-infected with HCV genotype 1 and HIV, administration of an oral combination of ledipasvir and sofosbuvir for 12 weeks was associated with high rates of SVR after treatment completion. Larger studies that also include patients with cirrhosis and lower CD4 T-cell counts are required to understand if the results of this study generalize to all patients co-infected with HCV and HIV. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT01878799.

Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study

BACKGROUND Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration. METHODS In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov, number NCT01805882. FINDINGS Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs. INTERPRETATION In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis. FUNDING National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.

Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study

BACKGROUND Worldwide, although predominantly in low-income countries in the Middle East and Africa, up to 13% of hepatitis C virus (HCV) infections are caused by HCV genotype 4. For patients with HCV genotype 1, the combination of ledipasvir and sofosbuvir has been shown to cure high proportions of patients with excellent tolerability, but this regimen has not been assessed for the treatment of HCV genotype 4. We assessed the efficacy, safety, and tolerability of 12 weeks of combination therapy with ledipasvir and sofosbuvir for patients with chronic HCV genotype 4 infections. METHODS In this single-centre, open-label cohort, phase 2a trial, patients with HCV genotype 4 who were treatment naive or interferon treatment experienced (HIV-negative) were sequentially enrolled at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA. We gave patients 12 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) as a single combination tablet once per day. The primary efficacy endpoint was sustained viral response at 12 weeks (SVR12), as measured by the proportion of patients with HCV RNA concentrations less than the lower limit of quantification (COBAS TaqMan HCV test, version 1.0, 43 IU/mL). The primary safety endpoint was the frequency and severity of adverse events. We did our analyses on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01805882. FINDINGS Between Sept 16, 2013, and Nov 2, 2014, we recruited 21 patients. 20 (95%) of 21 patients completed 12 weeks of treatment and achieved SVR12 (95% CI 76-100), including seven patients with cirrhosis. One patient was non-adherent to study drugs and withdrew from the study, but was included in the intention-to-treat analysis. No patients discontinued treatment because of adverse events and no grade 3 or 4 adverse events occurred that were related to study medications. The most common adverse events were diarrhoea (two patients), fatigue (three patients), nausea (two patients), and upper respiratory infections (two patients). INTERPRETATION Ledipasvir and sofosbuvir treatment for 12 weeks was well tolerated by patients with HCV genotype 4 and resulted in 100% SVR for all patients who received all 12 weeks of study drugs, irrespective of previous treatment status and underlying liver fibrosis. This is the first report of a single-pill, all-oral, interferon-free, ribavirin-free treatment for patients with HCV genotype 4. FUNDING NIAID, National Cancer Institute and Clinical Center Intramural Program. The study was also supported in part by a Cooperative Research and Development Agreement between NIH and Gilead Sciences.

Effect of Histone Deacetylase Inhibitors on HIV Production in Latently Infected, Resting CD4+ T Cells From Infected Individuals Receiving Effective Antiretroviral Therapy

Persistence of the latent viral reservoir has been recognized as a major obstacle to eradicating human immunodeficiency virus (HIV) in infected individuals receiving antiretroviral therapy. It has been suggested that histone deacetylase inhibitors (HDACis) may purge HIV in the latent viral reservoir. However, the effect of HDACis on the degree and extent of HIV expression in the latent viral reservoir has not been fully delineated. Here we demonstrate that HDACis do not induce HIV production in the latent viral reservoir of aviremic individuals. Therefore, alternative therapeutic strategies may be necessary to eliminate HIV in the latent viral reservoir.

Utility of Hepatitis C Viral Load Monitoring on Direct-Acting Antiviral Therapy

BACKGROUND Hepatitis C virus (HCV) RNA loads serve as predictors of treatment response during interferon-based therapy. We evaluated the predictive ability of HCV RNA levels at end of treatment (EOT) for sustained virologic response (SVR12) during interferon-sparing direct-acting antiviral therapies. METHODS HCV genotype 1-infected, treatment-naive patients were treated with sofosbuvir and ribavirin for 24 weeks (n = 55), sofosbuvir and ledipasvir for 12 weeks (n = 20), sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (n = 20), or sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (n = 19). Measurements of HCV RNA were performed using the Roche COBAS TaqMan HCV test and the Abbott RealTime HCV assay. Positive predictive value (PPV) and negative predictive value (NPV) of HCV RNA less than the lower limit of quantification (<LLOQ) at EOT for SVR12 were calculated. RESULTS All 55 patients treated with sofosbuvir and ribavirin had HCV RNA <LLOQ at EOT by the Roche and Abbott assays, but only 38 achieved SVR12 (PPV, 69%). Among patients treated with sofosbuvir and ledipasvir with or without GS-9669 or GS-9451, 100% (59/59) had HCV RNA <LLOQ by the Roche assay and 1 relapsed (PPV, 98%). By the Abbott assay, 90% (53/59) had HCV RNA <LLOQ, of whom 1 patient relapsed (PPV, 98%). Notably, 6 patients with HCV RNA ≥LLOQ at EOT (range, 14-64 IU/mL) achieved SVR12 (NPV, 0%). Quantifiable HCV RNA (range, 15-57 IU/mL) was measured 2 weeks posttreatment in 4 individuals, and 4 weeks posttreatment in 1 patient (14 IU/mL). CONCLUSIONS Contrary to past experience with interferon-containing treatments, low levels of quantifiable HCV RNA at EOT do not preclude treatment success.

Re-treatment of chronic hepatitis C virus genotype 1 infection after relapse: an open-label pilot study.

Context The treatment of hepatitis C virus is changing rapidly with the introduction of interferon-free regimens that include direct-acting antiviral drugs, such as sofosbuvir. Although treatment generally results in sustained viral response, some patients have relapse after initial treatment. Contribution In a small, nonrandomized study, 14 patients who had relapse after treatment with sofosbuvir plus ribavirin were re-treated with sofosbuvir plus ledipasvir for 12 weeks. All patients, including those with advanced liver disease, achieved a sustained virologic response. The combination was generally well-tolerated. Implication Treatment with sofosbuvir plus ledipasvir may be efficacious in patients who have relapse after initial therapy for hepatitis C virus. Larger randomized studies of this promising combination are warranted. The Editors Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma and the leading indication for liver transplantation in Western countries (1, 2). Until recently, HCV treatment consisted of combination therapy with pegylated interferon (IFN) and ribavirin, with the addition of an HCV protease inhibitor (boceprevir or telaprevir) in recent years. In 2013, the U.S. Food and Drug Administration approved sofosbuvir plus ribavirin as the first IFN-free treatment of HCV genotype 2 or 3 and for patients with genotype 1 (GT-1) who are IFN-ineligible (37). Although sofosbuvir (an NS5B inhibitor) plus ribavirin is well-tolerated and effective with sustained virologic response (SVR) rates from 68% to 76% in patients with HCV GT-1 (8, 9), modest rates of relapse in patients with advanced liver disease and transplant recipients have been seen (8, 10, 11). Recent studies using sofosbuvir combined with ledipasvir (an NS5A inhibitor) for 12 weeks demonstrated high SVR rates (95% to 99%) in treatment-naive patients with HCV GT-1 (1215). Ledipasvir has potent antiviral activity against the S282T resistance-associated variant, known to reduce susceptibility to sofosbuvir in vitro (16). As previously reported, 17 of 54 patients treated with sofosbuvir plus ribavirin for 24 weeks in the National Institute of Allergy and Infectious Diseases (NIAID) SPARE study had relapse after treatment (8). We hypothesized that the combination of a second potent direct-acting antiviral agent (DAA) with sofosbuvir could result in SVR, even in patients with relapse after sofosbuvir plus ribavirin therapy and who may harbor the S282T mutation. To test this hypothesis, we re-treated those patients with sofosbuvir plus ledipasvir for 12 weeks. Methods Design Overview All patients who had relapse after 24 weeks of treatment with sofosbuvir plus ribavirin in the NIAID SPARE study (8) were offered re-treatment with sofosbuvir plus ledipasvir in the ongoing, phase 2a, open-label NIAID SYNERGY study (ClinicalTrials.gov: NCT01805882). Of the 17 eligible patients, 3 did not participate in the study. Fourteen patients enrolled and were treated with 400 mg of sofosbuvir and 90 mg of ledipasvir, administered daily as a single combination tablet, for 12 weeks. Setting and Patients The trial was conducted at the National Institutes of Health (NIH) in Bethesda, Maryland, and at community clinics that are part of the District of Columbia Partnership for HIV/AIDS Progress in Washington, DC. Written informed consent, which was approved by the NIAID Institutional Review Board, was obtained from all study patients. Eligibility criteria included documented HCV GT-1 infection and relapse in the NIAID SPARE study (8). Liver fibrosis stage was determined by biopsy within 3 years of enrollment in the NIAID SPARE study. The study was approved by the NIAID Institutional Review Board. It was conducted in adherence to the Good Clinical Practice guidelines and with regulatory requirements consistent with the Declaration of Helsinki. Outcomes and Follow-up Efficacy Assessments Plasma HCV RNA levels were measured using the Abbott RealTime HCV assay, with a lower limit of quantification of 12 IU/mL and a lower limit of detection of 3 IU/mL, or the Roche Cobas TaqMan HCV assay, version 2.0, with a lower limit of quantification of 43 IU/mL and a lower limit of detection of 15 IU/mL. Safety Assessments Patients were closely monitored for adverse events. Clinical laboratory results were assessed while receiving therapy (4, 8, and 12 weeks) and afterward (2, 4, 8, and 12 weeks after treatment). Adverse events were graded from 1 (mild) to 4 (severe), according to the NIAID Division of AIDS Toxicity Table (version 1.0). Interleukin-28B Genotyping Interleukin-28B genotype (rs12979860) was determined as previously described (8). Clinical End Points The primary end point was the proportion of patients with unquantifiable plasma HCV viral load 12 weeks after treatment completion. Safety end points included frequency and severity of adverse events, discontinuations due to adverse events, and safety laboratory changes. Statistical Analysis Primary safety and efficacy data were analyzed by intention-to-treat (all patients who initiated study medication). Missing virologic data were imputed if data from preceding and succeeding time points were obtained. Baseline demographics were described using frequency statistics. Comparisons were calculated using either nonparametric tests or t tests with GraphPad Prism, version 6.0 (GraphPad Software). Role of the Funding Source This study was funded in part by the National Cancer Institute, the intramural programs of the NIH Clinical Center and NIAID, and a Collaborative Research and Development Agreement between the NIH and Gilead Sciences. The study sponsor was the Regulatory Compliance and Human Participants Protection Branch of the NIAID. The sponsor reviewed the study and provided oversight. However, it did not play a role in designing the study; collecting, analyzing, or interpreting the data; or the preparation, review, approval, or submission of the manuscript for publication. All study medications were provided by Gilead Sciences, which did not have a role in the design or conduct of the study, writing of the manuscript, or the decision to submit the manuscript for publication. Results Baseline Characteristics of Patients Most study patients were black men with an unfavorable interleukin-28B non-CC genotype (Table 1). There was a high representation of patients with HCV GT-1a infection, increased baseline HCV viral load (>800000 IU/mL), increased body mass index (>30 kg/m2), and advanced liver disease (Knodell Histology Activity Index score of 3 or 4) (17). Table 1. Baseline Characteristics of Study Patients Presence of S282T Mutation At the time of relapse after sofosbuvir plus ribavirin treatment in the SPARE trial, 13 of 14 patients had wild-type virus by population sequencing (Supplement). The 1 exception achieved unquantifiable HCV RNA levels by week 2 of therapy in SPARE and the virus remained undetectable through the end of treatment. He missed his visit at 26 weeks (2 weeks after treatment), but at 28 weeks (4 weeks after treatment), his HCV viral load was 374 IU/mL and the S282T mutation was readily detected by population sequencing. By 36 weeks (12 weeks after treatment), his HCV viral load was 81286 IU/mL and the S282T mutation was no longer detectable. He initiated sofosbuvir plus ledipasvir treatment 50 weeks after relapse. Supplement. HCV Resistance Mutations Virologic Response Each of the 14 patients treated with sofosbuvir plus ledipasvir had HCV RNA levels below the lower limit of quantification by 4 weeks (Roche Cobas TaqMan HCV Assay, version 2.0), which was maintained through the end of treatment (12 weeks). All patients achieved SVR 12 weeks after completion of treatment. Changes in Hemoglobin Levels No significant change in hemoglobin levels during sofosbuvir plus ledipasvir treatment was seen, in contrast to the decrease seen with sofosbuvir plus ribavirin. The mean hemoglobin level change was 0.07 g/L versus 11.70 g/L at 4 weeks (P=0.01), 0.5 g/L versus 12.6 g/L at 8 weeks (P=0.01), and 3.1 g/L versus 12.1 g/L at 12 weeks (P=0.06) with sofosbuvir plus ledipasvir and sofosbuvir plus ribavirin, respectively. No participant had a decrease in hemoglobin level of 15.0 g/L or greater with sofosbuvir plus ledipasvir compared with 8 of 14 (57%) with sofosbuvir plus ribavirin. Changes in Renal Function Renal variables did not change significantly over the course of treatment, although a single participant with grade 2 renal insufficiency at baseline (estimated glomerular filtration rate, 54 mL/min/1.73 m2) developed a grade 3 event. After 6 weeks of receiving study medications, he had received amoxicillin in the context of a dental procedure and continued preenrollment medications (benazepril, telmisartan, and simvastatin). In this context, his estimated glomerular filtration rate decreased to 29 mL/min/1.73 m2 (grade 3 toxicity); however, it improved (grade 2) within 1 week of withdrawing amoxicillin, returned to baseline within 3 weeks, and remained stable thereafter. He received study drugs without interruption. Safety All patients completed treatment, and no grade 4 adverse events or laboratory abnormalities occurred. The most common adverse events were myalgia and hypophosphatemia, and most adverse events were mild (Table 2). Four grade 3 events occurred (increased creatinine levels described above [n=1], hypercholesterolemia [n=1], and hypophosphatemia [n=2]). Table 2. Treatment Discontinuations, Adverse Events, and Laboratory Abnormalities Discussion In this study, we demonstrate that patients with HCV GT-1 who have viral relapse after sofosbuvir plus ribavirin therapy can be successfully re-treated with sofosbuvir plus ledipasvir. Seven (50%) of the patients in this study had advanced liver disease, which has been shown to be associated with relapse after sofosbuvir plus ribavirin therapy (8, 10, 11). In addition to having a high prevalencBackground The interferon (IFN)-free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV), genotype-1 (GT-1) infection for interferon-ineligible patients . However, sofosbuvir/ribavirin therapy is associated with treatment relapse in 15-30% of HCV GT-1 study subjects. Neither the mechanism of relapse nor the optimal retreatment strategy for these subjects is defined.

Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals

Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. Despite extensive evidence of B cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, we used HIV envelope gp140 and CD4 or coreceptor (CoR) binding site (bs) mutant probes to evaluate HIV-specific responses in peripheral blood B cells of HIV-infected individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs, which is a poorly neutralizing epitope, arose early, whereas those against the well-characterized neutralizing epitope CD4bs were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. The distribution of HIV-specific responses among memory B cell subsets was corroborated by transcriptional analyses. Taken together, our findings provide valuable insight into virus-specific B cell responses in HIV infection and demonstrate that memory B cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals.

Paucity of HIV DNA Methylation in Latently Infected, Resting CD4+ T Cells from Infected Individuals Receiving Antiretroviral Therapy

ABSTRACT Maintenance of HIV latency in vitro has been linked to methylation of HIV DNA. However, examinations of the degree of methylation of HIV DNA in the latently infected, resting CD4+ T cells of infected individuals receiving antiretroviral therapy have been limited. Here, we show that methylation of the HIV 5′ long terminal repeat (LTR) in the latent viral reservoir of HIV-infected aviremic individuals receiving therapy is rare, suggesting that other mechanisms are likely involved in the persistence of viral latency.

Characterization of Plasmablasts in the Blood of HIV-Infected Viremic Individuals: Evidence for Nonspecific Immune Activation

ABSTRACT Terminal differentiation of B cells and hypergammaglobulinemia are hallmarks of B-cell hyperactivity in HIV disease. Plasmablasts are terminally differentiating B cells that circulate transiently in the blood following infection or vaccination; however, in HIV infection, they arise early and are maintained at abnormally high levels in viremic individuals. Here we show that only a small fraction of plasmablasts in the blood of viremic individuals is HIV specific. Assessment of plasmablast immunoglobulin isotype distribution revealed increased IgG+ plasmablasts in early and most prominently during chronic HIV viremia, contrasting with a predominantly IgA+ plasmablast profile in HIV-negative individuals or in aviremic HIV-infected individuals on treatment. Of note, IgG is the predominant immunoglobulin isotype of plasmablasts that arise transiently in the blood following parenteral immunization. Serum immunoglobulin levels were also elevated in HIV-infected viremic individuals, especially IgG, and correlated with levels of IgG+ plasmablasts. Several soluble factors associated with immune activation were also increased in the sera of HIV-infected individuals, especially in viremic individuals, and correlated with serum immunoglobulin levels, particularly IgG. Thus, our data suggest that while plasmablasts in the blood may contribute to the HIV-specific immune response, the majority of these cells are not HIV specific and arise early, likely from indirect immune-activating effects of HIV replication, and reflect over time the effects of chronic antigenic stimulation. Such B-cell dysregulation may help explain why the antibody response is inadequate in HIV-infected individuals, even during early infection.