Loss Of Virologic Control Research Articles

Use of next-generation sequencing on HIV-1 DNA to assess archived resistance in highly treatment-experienced people with multidrug-resistant HIV under virological control: data from the PRESTIGIO Registry.

To clarify whether next-generation sequencing (NGS) can be useful for resistance assessment in virologically suppressed highly treatment-experienced (HTE) individuals with MDR HIV. Ninety-one participants from the PRESTIGIO Registry were included. NGS was performed on HIV-DNA at 1%, 5% and 20% cut-offs; major drug resistance mutations (DRMs) were evaluated and compared with those detected in historical plasma genotypic resistance testing (h-GRT). APOBEC editing was also characterized. Participants had a complex and long treatment history [median 23 (IQR 21-25) years of ART exposure) and had been virologically suppressed since a median of 3 (IQR 2-5) years. Among all major DRMs detected by HIV-DNA NGS and/or h-GRT, 30% were exclusively found through NGS. The highest detection rate of historical major DRMs was reached with NGS set at 1%, but unusual substitutions and extensive APOBEC hypermutations suggest technical issues and poor clinical relevance in the 1%-5% interval. At NGS set at 5%, 67.2% of historical major DRMs were detected. The number of major DRMs detected exclusively by DNA-NGS as minority variants (frequency 5%-20%) was significantly higher in individuals who later experienced virological rebound compared with those who maintained virological control [median 2 (IQR 1-3) versus 1 (0-2), P = 0.030] and positively correlated with viraemia levels at rebound (rho = 0.474, P = 0.030). In non-viraemic people with an MDR virus, HIV-1 DNA NGS set at 5% is an acceptable technical cut-off that might help to reveal mutations with a potential clinical relevance. Moreover, the number of minority resistance mutations additionally detected by NGS might be associated with loss of virological control.

Highlights from the Inaugural HIV Reservoirs and Immune Control Conference, October 1st-4th 2023, Malahide Ireland.

The inaugural FASEB HIV Reservoirs and Immune Control Conference brought researchers together from across the globe to discuss reservoir dynamics in clinical cohorts. It extended over 4 days in the seaside town of Malahide, Ireland. The scientific sessions covered a broad range of topics, including: 1) HIV pathogenesis and control, 2) reservoirs and viral expression, 3) pediatric reservoirs, 4) innate immunity and B cell responses, 5) environmental factors affecting pathogenesis, 6) loss of virologic control, and 7) HIV-2. The following article provides a brief summary of the meeting proceedings and includes a supplementary document with the meeting abstracts.

The Immunoregulatory Role of CMKLR1 within the CNS During WNV Encephalitis

Abstract West Nile Virus (WNV)-induced neuroinvasive disease (WNND) has been a public health concern in North America since its introduction in 1999. In recent years, severe neurological illness has been reported much more frequently, together with neuromuscular manifestations. Previous studies have shown that dendritic cells (DCs) within the central nervous system (CNS) are required to restrict WNV replication and immunopathology by regulating anti-viral T-cell responses. In this study, we examined the role of CMKLR1 within the CNS during WNV encephalitis. CMKLR1-expressing microglial cells and CNS-infiltrating myeloid DCs have been shown to have an inflammatory role during autoimmune neurological disorders, yet their contribution to WNND remains unknown. In addition, chemerin, the ligand for CMKLR1, was upregulated in the CNS of WNV-infected mice. To evaluate the role of CMKLR1, we infected CMKLR1-deficient (CMKLR1−/−) and wild-type (WT) mice with WNV. WNV-infected CMKLR1−/− mice exhibited increased susceptibility to WNV, loss of virologic control, and more severe clinical signs of disease. Proinflammatory chemokine expression, including CCL5, CXCL9, and CXCL10, was significantly decreased in the absence of CMKLR1 suggesting reduced leukocyte trafficking into the CNS. For future studies, we will determine the numbers and type of infiltrating leukocytes and their role in virologic control within the WNV-infected CNS. Taken together, these data will help clarify the immunoregulatory role of CMKLR1 during WNV encephalitis. NIH-SC3GM130472

In the absence of DEC-205, Enhanced inflammation in the CNS is Associated with Reduced numbers of IL-10-producing CD4+ T-cells During WNV encephalitis.

Abstract West Nile Virus (WNV), a mosquito-borne single-stranded RNA flavivirus, can cause significant human morbidity and mortality. Previous studies have shown that dendritic cells (DCs) within the central nervous system (CNS) are required to reactivate antiviral effector T-cell responses that restrict WNV replication and limit immunopathology within the CNS. Among these DCs, one subset expressing DEC-205 accumulates within the CNS during WNV encephalitis. DEC-205, an endocytic receptor highly expressed on conventional DCs (cDCs), mediates the efficient processing and presentation of antigens in vivo, leading to either tolerance or immunity depending on DC maturation status, suggesting that DEC-205+ DCs play an immunoregulatory role in the CNS during WNV infection. However, the contributions of CNS-localized DEC-205+ DCs in programming WNV-specific T-cell immunity remains poorly understood. In preliminary experiments, WNV-infected DEC-205 −/−mice exhibited increased susceptibility to WNV infection, more severe clinical signs of disease, and loss of virologic control with early entry into the CNS despite the increased trafficking, activation, and effector response of CD4+ and CD8+ T cells. We found that this uncontrolled inflammatory response was associated with a lack of IL-10-expressing CD4+ T regulatory cell (T reg) expansion that occurs typically during acute WNV infection. Thus, the enhanced inflammatory response in the absence of DEC-205 was coupled with a failure to protect against WNV infection and neuroinvasive disease. Taken together, DEC-205-expressing DCs regulate the degree and balance of the antiviral immune response to WNV infection within the CNS by activating T regs. NIH SC3GM130472

Differential miRNA plasma profiles associated with the spontaneous loss of HIV‐1 control: miR‐199a‐3p and its potential role as a biomarker for quick screening of elite controllers

Differential miRNA plasma profiles associated with the spontaneous loss of HIV‐1 control: miR‐199a‐3p and its potential role as a biomarker for quick screening of elite controllers

Antiretroviral therapy for HIV controllers: Reasons for initiation and outcomes in the French ANRS-CO21 CODEX cohort.

BackgroundLess than 1% of Human Immunodeficiency Virus (HIV)-infected individuals are able to achieve spontaneous viral control without requiring antiretroviral therapy (ART). Whether these HIV controllers (HIC) are at risk of HIV-associated comorbidities and could benefit from ART is debated, but recent studies reported decreased T-cell activation upon ART initiation. We report the frequency of ART initiation, reasons to treat, treatment outcome on immunovirological parameters, and rate of side-effects and treatment discontinuation in the French cohort of HIC.MethodsParticipants included in the French multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites (ANRS) Cohorte des extremes (CODEX) cohort of HIC between July 6, 2007 and January 3, 2018 were prospectively followed. ART initiation, indication, discontinuation, non-Acquired ImmunoDeficiency Syndrome (AIDS)-defining events, side-effects, and immunovirological parameters were recorded. Undetectable HIC (u-HIC) were defined as participants with strictly undetectable viral loads based on routinely used assays throughout the follow-up and blipper HIC (b-HIC) as participants with possible detectable viral loads above the detection threshold during follow-up.FindingsAmong 302 HIC followed for a median of 14.8 years [10.3–20.2], 90 (30%) received ART (7 u-HIC and 83 b-HIC). The main reasons for ART initiation were decreased CD4 T-cell counts (n = 36, 40%), loss of virological control (n = 13, 14%), and non-AIDS-defining events (n = 12, 13%). Sixteen (18%) participants experienced 17 grade 1–2 adverse events. In b-HIC, ART slightly increased the CD4/CD8 ratio (median +0.19, p < 0.0001) and decreased the frequency of circulating CD38+ HLA-DR.+ CD4 and CD8 lymphocytes (median -0.75%, p = 0.003, and -2%, p < 0.0001, respectively), but these changes were not observed for treated u-HIC. Thirteen (14%) participants discontinued ART (5 (38%) because of side-effects, and 10 remained HIC after treatment cessation (median follow-up: 305 days [235–728]).InterpretationOnly 30% of participants in this large cohort of HIC required ART during a median follow-up of 14.8 years. These results show that HIC status is very stable and vouch for a patient-centered treatment decision based on the individual benefit/risk balance.

Late-Onset Cytokine Release Syndrome (CRS) in HIV Patient with Relapsed Classical Hodgkin Lymphoma on Nivolumab and Non-Compliance with Anti-Retroviral Therapy

PD-1 inhibitors have emerged as an important class of immunotherapy drugs and several agents, such as nivolumab, are now FDA approved for the treatment of various malignancies, including classical Hodgkin lymphoma (cHL). By blocking the interaction of PD-1 with its ligands, PD-1 inhibitors unleash T-cells to attack neoplastic cells, but also interfere with immune self-recognition of healthy tissue. PD-1 inhibitors can thus lead to toxicity by immune attack of several organ systems. Less frequently, an exaggerated immunological response known as cytokine release syndrome (CRS) can develop. Unhindered T-cell activation leads to activation of bystander immune (dendritic cells, macrophages) and non-immune cells (endothelial cells) and ultimately massive release of a range of cytokines . CRS can be life-threatening, leading to hemodynamic instability, liver dysfunction, DIC and multiorgan failure. A limited number of CRS cases in patients treated with immune checkpoint inhibitors (ICIs) have been reported to date. Almost all cases have early-onset CRS with a median of 4 weeks from treatment initiation. Late-onset CRS has been documented in only one case of a patient with melanoma treated with nivolumab. No obvious risk factors for CRS have yet been identified in the context of ICIs, although high burden of disease has been linked to higher rates and severity with other immunotherapies, such as bispecific antibodies and CAR-T cells, which can explain the early-onset of the syndrome. We now report another case of late-onset CRS with nivolumab, this time in a patient with cHL and HIV. CRS coincided with loss of HIV control due to a period of non-compliance with anti-retroviral therapy (ART), which likely contributed to the development of cytokine storm. A 28-year-old female with HIV infection on ART and chemotherapy-refractory stage IV cHL on cycle 11 of nivolumab, with a favorable response, was admitted with worsening fatigue, subjective fevers, diarrhea and mild headaches. She was febrile, hypotensive and tachycardic (Figure 1). Physical exam was essentially normal. Laboratory work-up showed new transaminitis, elevated LDH and slightly prolonged PT; she was not neutropenic. She was hypothyroid due to non-compliance with levothyroxine for nivolumab-related hypothyroidism. Newly elevated HIV VL along with dropping CD4 count and CD4/CD8 ratio were noted (Table 1). She reported recent non-compliance with ART. She continued to have unremitting high fevers with persistent hypotension after 24 hours of IV hydration, anti-pyretics and broad-spectrum antibiotics. CRS was suspected. Adrenal insufficiency and hypophysitis were ruled out. CRP was elevated to 9mg/dl. She was started on methylprednisolone 1 mg/kg/day. She clinically improved within 5 hours of first steroid dose (Figure 1) and was discharged 2 days later on a 2-week-long steroid taper. Re-challenge with nivolumab approximately 1 month later, with undetectable HIV viral load, led to no recurrent events. She remains on treatment and in complete metabolic remission after 2.5 years of therapy. HIV infection leads to disturbed T-cell homeostasis, generating a systemic inflammatory environment and shifted profiles of inflammatory markers. Untreated infection leads to massive depletion of both HIV-infected and uninfected bystander CD4 cells, inverted CD4/CD8 ratio, impaired CD8 T cell function with increased expression of immune checkpoint proteins (such as PD-1) and elevated plasma levels of cytokines including INF-g, TNF and IL-6. It is possible that loss of HIV control in our case, promoted an evolving state of immune dysregulation with low CD4/CD8 ratio, increased PD-1 expression and elevated cytokines, which under the pressure of PD-1 inhibition led to an uncontrolled immune stimulation, culminating in a cytokine storm. Initial ICI cancer trials have largely excluded HIV patients, but their safety is increasingly recognized in this population. Our case highlights the nuances around safety and efficacy of immunotherapy in HIV. Nivolumab was highly efficacious and well-tolerated while ART maintained viral suppression. CRS coincided with loss of virologic control and did not recur upon re-challenge, once HIV infection was controlled. We conclude that continuous viral suppression may be key for the safe implementation of ICIs, and likely other forms of immunotherapy, in patients with cancer and HIV. Disclosures No relevant conflicts of interest to declare.

Outcomes of donor-derived superinfection screening in HIV-positive to HIV-positive kidney and liver transplantation: a multicentre, prospective, observational study

One of the primary risks of HIV-positive to HIV-positive organ transplantation is loss of virological control because of donor-derived HIV superinfection, which occurs when an HIV-positive individual becomes infected with a new distinct HIV strain. In this study, as part of the larger HIV Organ Policy Equity pilot study, HIV-positive to HIV-positive kidney and liver transplant recipients in the USA were examined for evidence of sustained donor-derived HIV superinfection. In this multicentre, prospective, observational study, HIV-positive to HIV-positive kidney and liver transplant recipients were followed in three hospitals in the USA. Candidates with well controlled HIV infection on ART, no active opportunistic infections, and minimum CD4 T-cell counts (>100 cells per μL for liver and >200 cells per μL for kidney per federal guidelines) were eligible to receive a kidney or liver from deceased HIV-positive donors without active infections or neoplasm. Peripheral blood mononuclear cells were collected from donor-recipient pairs at the time of transplantation, and from recipients at several timepoints up to 3 years after transplantation. Donor samples were assessed for HIV RNA viral load, CD4 cell count, and antiretroviral drug-resistant mutations. Donor and recipient HIV proviral DNA, and viral RNA from the viraemic timepoint were sequenced using a site-directed next-generation sequencing assay for the reverse transcriptase and gp41 genes. Neighbour-joining phylogenetic trees and direct sequence comparison were used to detect the presence of HIV superinfection. This study is registered with ClinicalTrials.gov, NCT02602262. 14 HIV-positive to HIV-positive kidney and eight liver transplant recipients were followed from March, 2016, to July, 2019. 17 recipients had adequate viral sequences allowing for HIV superinfection assessment. Eight donors were suppressed (viral load <400 copies per mL), and none had multiclass drug-resistant mutations detected. None of the recipients examined had evidence of HIV superinfection. One recipient had a viraemic episode (viral load of 2 080 000 copies per mL) 3 years after transplantation as a result of non-adherence to ART. Only recipient viral sequences were detected during the viraemic episode, suggesting that the donor virus, if present, was not reactivated despite temporary withdrawal of ART. These findings suggest that loss of HIV suppression due to donor-derived HIV superinfection might not be a significant clinical concern in carefully monitored ART suppressed HIV-positive organ recipients. US National Institute of Allergy and Infectious Diseases and National Cancer Institute.

Approaches to Objectively Measure Antiretroviral Medication Adherence and Drive Adherence Interventions.

Traditional methods to assess antiretroviral adherence, such as self-report, pill counts, and pharmacy refill data, may be inaccurate in determining actual pill-taking to both antiretroviral therapy (ART) or pre-exposure prophylaxis (PrEP). HIV viral loads serve as surrogates of adherence on ART, but loss of virologic control may occur well after decreases in adherence and viral loads are not relevant to PrEP. Pharmacologic measures of adherence, electronic adherence monitors, and ingestible electronic pills all serve as more objective metrics of adherence, surpassing self-report in predicting outcomes. Pharmacologic metrics can identify either recent adherence or cumulative adherence. Recent dosing measures include antiretroviral levels in plasma or urine, as well as emtricitabine-triphosphate in dried blood spots (DBS) for those on tenofovir-emtricitabine-based therapy. A urine tenofovir test has recently been developed into a point-of-care test for bedside adherence monitoring. Cumulative adherence metrics assess adherence over weeks to months and include measurement of tenofovir-diphosphate in peripheral blood mononuclear cells or DBS, as well as ART levels in hair. Electronic adherence monitors and ingestible electronic pills can track pill bottle openings or medication ingestion, respectively. New and objective approaches in adherence monitoring can be used to detect nonadherence prior to loss of prevention efficacy or virologic control with PrEP or ART, respectively.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study

Treatment with tenofovir disoproxil fumarate has been associated with renal toxicity or reductions in bone mineral density, or both, in some patients with chronic hepatitis B virus (HBV) infection. Tenofovir alafenamide is a tenofovir prodrug with high intrahepatic concentrations of active drug and reduced systemic tenofovir exposures compared with tenofovir disoproxil fumarate. In patients with chronic HBV, tenofovir alafenamide has shown efficacy non-inferior to that of tenofovir disoproxil fumarate with improved renal and bone safety. With this non-inferiority study, we aimed to evaluate the efficacy and safety of tenofovir alafenamide in patients with HBV infection switching from tenofovir disoproxil fumarate who are virally suppressed. Patients with chronic HBV infection who had been receiving tenofovir disoproxil fumarate for 48 weeks or more and who had HBV DNA less than the lower limit of quantification (LLOQ) for at least 12 weeks were recruited to this randomised, multicentre, double-blind, phase 3 non-inferiority study. Patients were randomly assigned in a 1:1 ratio to receive tenofovir alafenamide 25 mg once a day or to continue tenofovir disoproxil fumarate 300 mg once a day. The primary efficacy endpoint was loss of virological control, defined as the proportion of patients who received at least one dose of study drug who had HBV DNA of at least 20 IU/mL at week 48 by the modified US Food and Drug Administration (FDA) snapshot algorithm. Key safety endpoints were changes in hip and spine bone mineral density, estimated creatinine clearance by Cockcroft-Gault, and markers of bone turnover and renal tubular function. The study was powered for non-inferiority in efficacy of tenofovir alafenamide versus tenofovir disoproxil fumarate with a 4% margin. Investigators and patients were unaware of treatment allocation and on-treatment results. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02979613. Participants in this study were enrolled between Dec 29, 2016, and Oct 20, 2017. 541 patients were screened and 490 patients were randomly assigned to switch to tenofovir alafenamide or to stay on tenofovir disoproxil fumarate. Two patients assigned to receive tenofovir alafenamide did not receive treatment; thus the full analysis set for efficacy and safety analyses consisted of 243 patients in the tenofovir alafenamide group and 245 in the tenofovir disoproxil fumarate group. At week 48, one patient from each treatment group (both <1%) had HBV DNA of at least 20 IU/mL (difference in proportion 0·0%, 95% CI -1·9 to 2·0), thereby showing non-inferior efficacy of tenofovir alafenamide to tenofovir disoproxil fumarate. Patients who received tenofovir alafenamide had significantly increased bone mineral density at hip (mean change 0·66% [SD 2·08] vs -0·51% [SD 1·91]; difference in least square means 1·17% [95% CI 0·80 to 1·54; p<0·0001]) and at spine (mean change 1·74% [3·46] vs -0·11% [3·13]; difference in least square means 1·85% [1·24 to 2·46; p<0·0001]), creatinine clearance by Cockcroft-Gault relative to tenofovir disoproxil fumarate (median change 0·94 mL/min [IQR -4·47 to 6·24] vs -2·74 mL/min [-7·89 to 1·88]; p <0·0001), and improved markers of bone turnover and tubular function at week 48. The most common treatment-emergent adverse events were upper respiratory tract infection (18 [7%] of 243 patients in the tenofovir alafenamide group and 16 [7%] of 245 patients in the tenofovir disoproxil fumarate group) and nasopharyngitis (13 [5%] of 243 patients in the tenofovir alafenamide group and 12 [5%] of 245 patients in the tenofovir disoproxil fumarate group). The incidence of grade 3 and above adverse events and serious adverse events was low and similar between groups. No viral resistance was observed in patients who qualified for viral sequencing. These findings suggest that tenofovir alafenamide can be substituted for tenofovir disoproxil fumarate in patients with HBV infection for improved safety without a loss of efficacy. Gilead Sciences.

Factors Leading to the Loss of Natural Elite Control of HIV-1 Infection.

HIV-1 elite controllers (EC) maintain undetectable viral loads (VL) in the absence of antiretroviral treatment. However, these subjects have heterogeneous clinical outcomes, including a proportion that loses HIV-1 control over time. In this work, we compared, in a longitudinal design, transient EC, analyzed before and after the loss of virological control, with persistent EC. The aim was to identify factors leading to the loss of natural virological control of HIV-1 infection with a longitudinal retrospective study design. Gag-specific T-cell responses were assessed by in vitro intracellular polycytokine production quantified by flow cytometry. Viral diversity determinations and sequence dating were performed in proviral DNA by PCR amplification at limiting dilution of env and gag genes. The expression profile of 70 serum cytokines and chemokines was assessed by multiplex immunoassays. We identified transient EC as subjects with low Gag-specific T-cell polyfunctionality, high viral diversity, and high proinflammatory cytokine levels before the loss of control. Gag-specific T-cell polyfunctionality was inversely associated with viral diversity in transient controllers before the loss of control (r = -0.8; P = 0.02). RANTES was a potential biomarker of transient control. This study identified virological and immunological factors, including inflammatory biomarkers associated with two different phenotypes within EC. These results may allow a more accurate definition of EC, which could help in better clinical management of these individuals and in the development of future curative approaches.IMPORTANCE There is a rare group of HIV-infected patients who have the extraordinary capacity to maintain undetectable viral load levels in the absence of antiretroviral treatment, the so-called HIV-1 elite controllers (EC). However, there is a proportion within these subjects that eventually loses this capability. In this work, we found differences in virological and immune factors, including soluble inflammatory biomarkers, between subjects with persistent control of viral replication and EC that will lose virological control. The identification of these factors could be a key point for a right medical care of those EC who are going to lose natural control of viral replication and for the design of future immunotherapeutic strategies using as a model the natural persistent control of HIV infection.

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers.

ObjectiveHIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control.MethodsHICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models.ResultsWe identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds.DiscussionExpansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.

CD8+ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles.

The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P = 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8(+) T cell responses against Gag and enhanced ability of CD8(+) T cells to suppress viral replication ex vivo In some cases, loss of virological control was associated with reduction in the total breadth of CD8(+) T cell responses in the absence of differences in HIV-1-specific CD8(+) T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8(+) T cell responses characterized by reduced ability to suppress viral replication ex vivo These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8(+) T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8(+) T cell-independent mechanisms. Host mechanisms of natural HIV-1 control are not fully understood. In a longitudinal study of antiretroviral therapy (ART)-naive individuals, we show that those with protective HLA class I alleles subsequently experienced virologic failure compared to those without protective alleles. Among individuals with protective HLA class I alleles, viremic control was associated with broad CD8(+) T cells that targeted the Gag protein, and CD8(+) T cells from these individuals exhibited superior virus inhibition capacity. In individuals without protective HLA class I alleles, HIV-1-specific CD8(+) T cell responses were narrow and poorly inhibited virus replication. These results suggest that broad, highly functional cytotoxic T cells (cytotoxic T lymphocytes [CTLs]) against the HIV-1 Gag protein are associated with control among those with protective HLA class I alleles and that loss of these responses eventually leads to viremia. A subset of individuals appears to have alternative, non-CTL mechanisms of viral control. These controllers may hold the key to an effective HIV vaccine.

IL-1R1 is required for dendritic cell–mediated T cell reactivation within the CNS during West Nile virus encephalitis

Infections of the central nervous system (CNS) with cytopathic viruses require efficient T cell responses to promote viral clearance, limit immunopathology, and enhance survival. We found that IL-1R1 is critical for effector T cell reactivation and limits inflammation within the CNS during murine West Nile virus (WNV) encephalitis. WNV-infected IL-1R1(-/-) mice display intact adaptive immunity in the periphery but succumb to WNV infection caused by loss of virologic control in the CNS with depressed local Th1 cytokine responses, despite parenchymal entry of virus-specific CD8(+) T cells. Ex vivo analysis of CD4(+) T cells from WNV-infected CNS of IL-1R1(-/-) mice revealed impaired effector responses, whereas CD8(+) T cells revealed no cell intrinsic defects in response to WNV antigen. WNV-infected, IL-1R1(-/-) mice also exhibited decreased activation of CNS CD11c(+)CD11b(-)CD103(+) and CD11c(+)CD11b(-)CD8α(+)Dec-205(+) cells with reduced up-regulation of the co-stimulatory molecules CD80, CD86, and CD68. Adoptive transfer of wild-type CD11c-EYFP(+) cells from WNV-infected CNS into WNV-infected IL-1R1(-/-) mice trafficked into the CNS restored T cell functions and improved survival from otherwise lethal infection. These data indicate that IL-1R1 signaling promotes virologic control during WNV infection specifically within the CNS via modulation of CD11c(+) cell-mediated T cell reactivation at this site.

Free and Total Plasma Levels of Lopinavir during Pregnancy, at Delivery and Postpartum: Implications for Dosage Adjustments in Pregnant Women

Physiological changes associated with pregnancy may alter antiretroviral plasma concentrations and might jeopardize prevention of mother-to-child HIV transmission. Lopinavir is one of the protease inhibitors more frequently prescribed during pregnancy in Europe. We described the free and total pharmacokinetics of lopinavir in HIV-infected pregnant and non-pregnant women, and evaluated whether significant alterations in its disposition and protein binding warrant systematic dosage adjustment. Plasma samples were collected at first, second and third trimester of pregnancy, at delivery, in umbilical cord and postpartum. Lopinavir free and total plasma concentrations were measured by HPLC-MS/MS. Bayesian calculations were used to extrapolate total concentrations to trough (Cmin). A total of 42 HIV-positive pregnant women and 37 non-pregnant women on lopinavir/ritonavir were included in the study. Compared to postpartum and control values, total lopinavir Cmin was decreased moderately (31-39%) during pregnancy, and free Cmin minimally, showing significant alteration only at delivery (-35%). However, total and free Cmin remained in all patients above the target concentrations for wild-type virus of 1,000 ng/ml, and above the unbound IC50(WT) of 0.64-0.77 ng/ml of lopinavir, respectively. Lopinavir free fractions remained higher during pregnancy compared to postpartum and controls, and were influenced by α-1-acid-glycoprotein and albumin decrease. Free cord-to-mother ratio (0.43) was 2.7-fold higher than total cord-to-mother ratio (0.16), suggesting higher fetal exposure. The moderate decrease of total lopinavir concentrations during pregnancy is not associated with proportional decrease in free concentrations. Both reach a nadir at delivery, albeit not to an extent that would put treatment-naive women at risk of insufficient exposure to the free, pharmacologically active concentrations of lopinavir. No dosage adjustment is therefore needed during pregnancy as it is unlikely to further enhance treatment efficacy but could potentially increase the risk of maternal and fetal toxicity. Nonetheless, in case of viral resistance in treatment-experienced pregnant women, loss of virological control or questionable adherence, it is justified to consider lopinavir dosage adjustment based on total plasma concentration measurement.

Epidemiology and clinical characteristics of elite controllers

Recent studies have been published characterizing the epidemiology of elite controllers. The demographic features, clinical characteristics, and HIV disease outcomes of elite controllers are summarized. Elite controllers are defined by the ability to spontaneously suppress plasma viremia. Despite differing definitions in the literature, studies have shown that elite control of HIV infection is established soon after seroconversion and occurs in less than 1% of HIV-infected individuals. Elite controllers are demographically heterogeneous with diverse racial backgrounds and modes of HIV transmission, though genetic studies demonstrate an overrepresentation of protective HLA alleles. Elite controllers typically have elevated CD4 cell counts, stable CD4 trajectories, and more favorable clinical outcomes compared with viremic patients. A proportion of elite controllers, however, may experience HIV disease progression with loss of virologic control, CD4 cell declines, and rarely AIDS-defining events. Elite controllers are a subgroup of HIV-infected individuals characterized by the ability to spontaneously maintain virologic control. The mechanisms underlying elite control are aggressively being sought to guide vaccine development and novel therapeutic strategies. As elite control may be a temporary state, the ability to distinguish and further characterize elite controllers with long-term clinical success from those with HIV disease progression is of major importance.

Clinical Implications of the Nelfinavir‐Proton Pump Inhibitor Drug Interaction in Patients with Human Immunodeficiency Virus

To determine if the concomitant use of nelfinavir and proton pump inhibitors (PPIs) in patients with human immunodeficiency virus (HIV) infection results in the loss of virologic control. Retrospective cohort study. Pharmacy, laboratory, and administrative databases of a large integrated health care system in northern California. A total of 1147 HIV-positive adults who started nelfinavir therapy between November 1, 1998, and June 20, 2003; within this cohort, 141 patients (12.3%) were also prescribed PPIs. The effects on two virologic outcomes--achievement of undetectable HIV viral load and subsequent virologic rebound--were compared between patients receiving nelfinavir alone and those receiving nelfinavir with PPIs. Cox proportional hazards models were used, with adjustments for age, sex, race, HIV risk factors, hepatitis B or C coinfection, and other concurrent drugs known to affect the metabolism of nelfinavir. The use of PPIs had little effect on the ability to achieve an undetectable HIV viral load (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.58-1.19, p=0.29), but there was an approximate 50% increased risk of virologic rebound with the concurrent use of PPIs (adjusted HR 1.53, 95% CI 1.06-2.19, p=0.02). Short-term use of PPIs (defined as within 30 days of initial PPI dispensation) was not associated with increased risk of virologic rebound (HR 1.07, 95% CI 0.26-4.41, p=0.93) compared with no use of PPIs. Use of PPIs should be minimized or avoided in patients who have attained an undetectable HIV viral load while taking a nelfinavir-based antiretroviral regimen. However, concomitant use of these drugs may be acceptable for indications where PPIs are required for fewer than 30 days.

Lopinavir potenciado con ritonavir en monoterapia para el tratamiento de la infección por el virus de la inmunodeficiencia humana Tipo 1: emergencia de resistencias

Treatment with lopinavir/ritonavir (LPV/r) monotherapy has been shown to be an effective alternative, especially in the maintenance of patients previously treated with combination therapy and prolonged virological suppression. LPV/r monotherapy is associated with a greater number of low-level viremia episodes than combination therapy, without resistance mutations being detected in the majority of patients. The incidence of the development of major resistance mutations in the OK pilot and OK04 studies was very low: 0.51 per 100 patients-year, and was mainly related to mutations in positions 46, 54 and 82, which have not compromised other therapeutic options. The contribution of low-level resistance mutations to loss of virological control seems small, and no different from that observed in combination therapy. However, this phenomenon should be studied in larger, long-term trials.

Significant Decrease in Nelfinavir Systemic Exposure After Omeprazole Coadministration in Healthy Subjects

To assess the effect of omeprazole on the multiple-dose (steady-state) pharmacokinetics and safety of nelfinavir, and to evaluate the safety and tolerability of nelfinavir when administered alone and with omeprazole. Open-label, two-period, single-fixed-sequence study. Clinical research unit of a large, teaching hospital. Twenty healthy volunteers (mean age 26 +/- 9 yrs, range 18-48 yrs). Intervention. Subjects received nelfinavir 1250 mg every 12 hours for 4 days (period 1). After a 7-day washout period, subjects were coadministered nelfinavir 1250 mg every 12 hours and omeprazole 40 mg every 24 hours for 4 days (period 2). The pharmacokinetics of nelfinavir and its active metabolite M8 were determined on day 4 of both periods. Plasma samples were assayed by a high-performance liquid chromatography-ultraviolet method for nelfinavir and M8 concentrations, and noncompartmental pharmacokinetic analysis was performed by using analytical software. In the presence of omeprazole, nelfinavir area under the concentration-time curve over the dosing interval (AUC(tau)), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) were reduced by an average of 36%, 37%, and 39%, respectively, relative to administration of nelfinavir alone. The AUC(tau), C(max), and C(min) of M8 were reduced by an average of 92%, 89%, and 75%, respectively. The slopes of the terminal elimination phase of nelfinavir and M8 plasma concentration-time curves were similar between treatments. Nelfinavir was well tolerated when administered alone and when coadministered with omeprazole. The observed reduction in the systemic exposure to both nelfinavir and its active metabolite M8 after coadministration with omeprazole could result in loss of virologic control and potential emergence of drug resistance. Hence, omeprazole should not be coadministered to patients taking nelfinavir.

The Virologic, Immunologic, and Clinical Effects of Interleukin 2 With Potent Antiretroviral Therapy in Patients With Moderately Advanced Human Immunodeficiency Virus Infection

Interleukin 2 (IL-2) administration increases CD4 counts in persons with higher counts. This study investigated persons with moderately advanced human immunodeficiency virus infection receiving highly active antiretroviral therapy (HAART). Two hundred four patients with CD4 T-cell counts from 50/microL to 350/microL who were treatment naive or had been treated only with reverse transcriptase inhibitors began a specified protease inhibitor HAART regimen. Virologic responders (< or =5000 copies/mL) at 12 weeks were randomized to open-label continuous-infusion IL-2 (IV IL-2), subcutaneous IL-2 (SC IL-2), or HAART alone. Thirty were not randomized and 15 enrolled in a substudy, leaving 159 for analysis. Subjects continued HAART alone for 72 weeks (n = 52) or with IV IL-2 (n = 53) or SC IL-2 (n = 54) for 5 days every 8 weeks. The IV IL-2 subjects could switch to SC IL-2 if their CD4 T-cell count increased by 100/microL or by 25%. Patients receiving IV or SC IL-2 had greater increases in CD4 cell counts. At week 84, median increases were 459/microL, 312/microL, and 102/microL. Increases of greater than 50% at week 60 (primary end point) were achieved in 39 patients (81%) and 32 (67%) in the IV and SC IL-2 arms, respectively, compared with 13 (29%) in the HAART arm (P<.001 for both). Treatment with IL-2 did not increase plasma human immunodeficiency virus RNA levels. There were fewer new AIDS-defining events in the IV (P = .006) and SC (P = .03) IL-2 groups than in the HAART group (0, 1, and 7, respectively). Drug-related adverse events were more frequent with IL-2 treatment. Addition of IL-2 to HAART can significantly expand CD4 T-cell counts in moderately advanced human immunodeficiency virus infection, without loss of virologic control.