Atazanavir sulfate + cobicistat for the treatment of HIV infection.

INTRODUCTION: During last two decades several drugs were developed to offer long-term benefits in terms of virologic efficacy, favourable tolerability and toxicity profiles in treatment of HIV infection. Pharmacokinetics boosting of protease inhibitor allows a higher genetic barrier, as few or no drug-resistant mutations are detected in patients with virologic failure. Areas covered: Atazanavir sulfate + cobicistat (ATV/c) was recently approved for the treatment of HIV-1 infection. Bioequivalence between cobicistat (COBI) and ritonavir (RTV) as a pharmacoenhancer of ATV was established. Additionally, randomized clinical trials demonstrated that ATV/c and ATV/ritonavir had comparable efficacy and safety profiles. Low rates of virologic failure and no ATV resistance mutations were observed in these clinical trials. Therefore, COBI shows increased advantages over RTV, such as no activity against HIV, fewer drug-drug interactions and better solubility, which promotes coformulation strategies with less pill burden, better tolerability, and, potentially, higher life-long treatment adherence. Expert commentary: ATV/c regimen supports its useas an effective treatment option for HIV-1 infected patients with increased cardiovascular disease and chronic kidney disease risk associated with aging. In addition, ATV/c is a new opportunity to expand the strategy of switch to a dual therapy to lower the risk of long-term toxicities as well as the advantage of its cost-benefit.

Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients.

The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were higher in SP than in BP (median AUC0-24, 7.01 versus 2.97 mg · liter-1 · h, respectively). The median (range) SP-to-BP AUC0-24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC0-24 or TFV SP-to-BP AUC0-24 ratio on spVL was not significant (P = 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.

[CLINICAL AND PHARMACOECONOMIC RESULTS OF THE USAGE OF VARIOUS HIV REVERSE TRANSCRIPTASE INHIBITORS IN THE SCHEMES OF ANTIRETROVIRAL THERAPY OF PATIENT RECEIVING THERAPY FOR THE CHRONIC HEPATITIS C VIRUS].

Efficacy, safety, and economical aspects of treatment with abacavir, zidovudine, stavudine, and phosphazide in the schemes of antiretroviral therapy of the HIV-infected patients receiving therapy for hepatitis C virus were tested. Clinical, immunological, and virologic efficacy of treatment and dynamics of hemoglobin, thrombocytes, and alanine aminotransferase as markers of common adverse events recorded at the start of the antiviral therapy of chronic hepatitis C and after 4, 8, 12, 24, 48 weeks of the treatment were evaluated. The usage of these drugs in the schemes of antiretroviral therapy exhibited efficacy, high tolerability and safety for all HIV reverse transcriptase inhibitors.

Value of perfusion-weighted MR imaging in the assessment of early cerebral alterations in neurologically asymptomatic HIV-1-positive and HCV-positive patients.

BACKGROUND AND PURPOSE: Asymptomatic central nervous system (CNS) involvement occurs in the early stage of the human immunodeficiency virus (HIV) infection. It has been documented that the hepatitis C virus (HCV) can replicate in the CNS. The aim of the study was to evaluate early disturbances in cerebral microcirculation using magnetic resonance (MR) perfusion-weighted imaging (PWI) in asymptomatic HIV-1-positive and HCV-positive patients, as well as to assess the correlation between PWI measurements and the clinical data. MATERIALS AND METHODS: Fifty-six patients: 17 HIV-1-positive non-treated, 18 HIV-1-positive treated with combination antiretroviral therapy (cART), 7 HIV-1/HCV-positive non-treated, 14 HCV-positive before antiviral therapy and 18 control subjects were enrolled in the study. PWI was performed with a 1.5T MR unit using dynamic susceptibility contrast (DSC) method. Cerebral blood volume (CBV) measurements relative to cerebellum (rCBV) were evaluated in the posterior cingulated region (PCG), basal ganglia (BG), temporoparietal (TPC) and frontal cortices (FC), as well as in white matter of frontoparietal areas. Correlations of rCBV values with immunologic data and liver histology activity index (HAI) were analyzed. RESULTS: Significantly lower rCBV values were found in the right TPC and left FC as well as in PCG in HIV-1-positive naïve (p = 0.009; p = 0.020; p = 0.012), HIV-1 cART treated (p = 0.007; p = 0.009; p = 0.033), HIV-1/HCV-positive (p = 0.007; p = 0.027; p = 0.045) and HCV-positive patients (p = 0.010; p = 0.005; p = 0.045) compared to controls. HIV-1-positive cART treated and HIV-1/HCV-positive patients demonstrated lower rCBV values in the right FC (p = 0.009; p = 0.032, respectively) and the left TPC (p = 0.036; p = 0.005, respectively), while HCV-positive subjects revealed lower rCBV values in the left TPC region (p = 0.003). We found significantly elevated rCBV values in BG in HCV-positive patients (p = 0.0002; p<0.0001) compared to controls as well as to all HIV-1-positive subjects. There were no significant correlations of rCBV values and CD4 T cell count or HAI score. CONCLUSIONS: PWI examination enables the assessment of HIV-related as well as HCV-related early cerebral dysfunction in asymptomatic subjects. HCV-infected patients seem to reveal the most pronounced perfusion changes.

The high cost of fidelity.

The notoriously low fidelity of HIV-1 replication is largely responsible for the virus's rapid mutation rate, facilitating escape from immune or drug control. The error-prone activity of the viral reverse transcriptase (RT) is predicted to be the most influential mechanism for generating mutations. The low fidelity of RT has been successfully exploited by nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs) that halt viral replication upon incorporation. Consequently, drug-resistant strains have arisen in which the viral RT has an increased fidelity of replication, thus reducing analogue incorporation. Higher fidelity, however, impacts on viral fitness. The appearance of compensatory mutations in combination with higher fidelity NRTI resistance mutations and the subsequent reversion of NRTI-resistant mutations upon cessation of antiretroviral treatment lend support to the notion that higher fidelity exacts a fitness cost. Potential mechanisms for reduced viral fitness are a smaller pool of mutant strains available to respond to immune or drug pressure, slower rates of replication, and a limitation to the dNTP tropism of the virus. Unraveling the relationship between replication fidelity and fitness should lead to a greater understanding of the evolution and control of HIV.

Validation of a clinical prediction score to target viral load testing in adults with suspected first-line treatment failure in resource-constrained settings.

BACKGROUND: Although routine viral load (VL) monitoring currently is too costly for poor countries, clinical failure criteria perform poorly. We previously developed an algorithm combining a clinical predictor score (CPS) with targeted VL testing in a Cambodian patient population (derivation population). We now prospectively validate the algorithm in the same clinical setting (validation population), assess its operational performance, and explore its cost-saving potential. METHODS: We performed a cross-sectional study in a tertiary hospital in Phnom Penh, Cambodia, applying the CPS in adults on first-line antiretroviral treatment for at least 1 year. Treatment failure was defined as a VL >1000 copies per milliliter. The area under the receiver-operating characteristic (AUROC) curve of the CPS to detect treatment failure in the current study population (validation population) was compared with the AUROC of the CPS obtained in the patient population where the CPS was derived from in 2008 in the same study setting (derivation population). Costs related to VL testing and second-line regimens with the different testing strategies were compared. RESULTS: One thousand four hundred ninety individuals {56.6% female, median age 38 years [interquartile range (IQR): 33-44]} were included, with a median baseline CD4 cell count of 94 cells per microliter (IQR: 28-205). Median time on antiretroviral treatment was 3.6 years (IQR: 2.1-5.1), 45 (3.0%) individuals had treatment failure. The AUROC of the CPS in validation was 0.75 (95% confidence interval: 0.67 to 0.83), relative to an AUROC of 0.70 in the derivation population. At the CPS cutoff ≥ 2, VL was indicated for 164 (11%) individuals, preventing inappropriate switching to second line in 143 cases. Twenty-four cases of treatment failure would be missed. When applied in routine care, the AUROC was 0.69 (95% confidence interval: 0.60 to 0.77). Overall 1-year program costs with targeted VL testing were 4-fold reduced. CONCLUSIONS: The algorithm performed well in validation and has cost-saving potential. Further studies to assess its performance, feasibility, and impact in different settings are warranted.

Fitness costs and diversity of the cytotoxic T lymphocyte (CTL) response determine the rate of CTL escape during acute and chronic phases of HIV infection.

HIV-1 often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs. We used single-genome amplification and sequencing of complete HIV genomes to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set point at 1 year after the infection. We found that the rate of viral escape from CTL responses in a given patient decreases dramatically from acute infection to the viral set point. Using a novel mathematical model that tracks the dynamics of viral escape at multiple epitopes, we show that a number of factors could potentially contribute to a slower escape in the chronic phase of infection, such as a decreased magnitude of epitope-specific CTL responses, an increased fitness cost of escape mutations, or an increased diversity of the CTL response. In the model, an increase in the number of epitope-specific CTL responses can reduce the rate of viral escape from a given epitope-specific CTL response, particularly if CD8+ T cells compete for killing of infected cells or control virus replication nonlytically. Our mathematical framework of viral escape from multiple CTL responses can be used to predict the breadth and magnitude of HIV-specific CTL responses that need to be induced by vaccination to reduce (or even prevent) viral escape following HIV infection.

Cost-effectiveness of raltegravir in antiretroviral treatment-experienced HIV-1-infected patients in Switzerland.

OBJECTIVES: Raltegravir, a novel integrase inhibitor, has shown great efficacy in reducing HIV viral load among treatment-experienced patients. A cohort state-transition model was used to assess the long-term effect of raltegravir treatment on costs and quality-adjusted life expectancy from a Swiss perspective. METHODS: Patients were stratified into health states according to opportunistic infection status, HIV RNA level, and CD4 count, with each group assigned a treatment cost and utility (quality of life) score. Model inputs came from published studies, clinical trials, and database analyses. Results were used to calculate incremental cost-effectiveness ratio (ICER) of raltegravir use, expressed in Swiss francs (CHF) as incremental cost/quality-adjusted life-year (QALY) gained. Future costs and QALYs were discounted at 3% per year. RESULTS: Five years of raltegravir treatment increased discounted quality-adjusted life expectancy by 3.73 years over placebo, with additional discounted cost of CHF 170,347, resulting in an ICER of CHF 45,687/QALY. ICERs ranged from CHF 42,751 to 53,478/QALY for treatment duration of 3 and 10 years, respectively. Results were most sensitive to changes in raltegravir treatment duration, source of estimated quality of life weights, and raltegravir price. CONCLUSIONS: Adding raltegravir to optimized background therapy was a cost-effective strategy for treatment-experienced patients in Switzerland.

In vivo fitness cost of the M184V mutation in multidrug-resistant human immunodeficiency virus type 1 in the absence of lamivudine.

Lamivudine therapy selects for the M184V mutation. Although this mutation reduces the replicative capacity of human immunodeficiency virus in vitro, its impact on viral fitness in vivo has not been well defined. We used quantitative allele-specific PCR to precisely calculate the fitness differences between the mutated M184V virus and one that had reverted to the wild type in a cohort of patients by selectively interrupting reverse transcriptase inhibitor therapy, and we found that the M184V variants were consistently 4 to 8% less fit than the wild type in the absence of drug. After a lag phase of variable duration, wild-type variants emerged due to continued evolution of pol and back mutation rather than through emergence of an archived wild-type variant.

Modeling and estimation of kinetic parameters and replicative fitness of HIV-1 from flow-cytometry-based growth competition experiments.

Growth competition assays have been developed to quantify the relative fitness of HIV-1 mutants. In this article, we develop mathematical models to describe viral/cellular dynamic interactions in the assay system from which the competitive fitness indices or parameters are defined. In our previous HIV-viral fitness experiments, the concentration of uninfected target cells was assumed to be constant (Wu et al. 2006). But this may not be true in some experiments. In addition, dual infection may frequently occur in viral fitness experiments and may not be ignorable. Here, we relax these two assumptions and extend our earlier viral fitness model (Wu et al. 2006). The resulting models then become nonlinear ODE systems for which closed-form solutions are not achievable. In the new model, the viral relative fitness is a function of time since it depends on the target cell concentration. First, we studied the structure identifiability of the nonlinear ODE models. The identifiability analysis showed that all parameters in the proposed models are identifiable from the flow-cytometry-based experimental data that we collected. We then employed a global optimization approach (the differential evolution algorithm) to directly estimate the kinetic parameters as well as the relative fitness index in the nonlinear ODE models using nonlinear least square regression based on the experimental data. Practical identifiability was investigated via Monte Carlo simulations.

Quantitation of HLA proteins incorporated by human immunodeficiency virus type 1 and assessment of neutralizing activity of anti-HLA antibodies.

Human anti-human leukocyte antigen (HLA) antibodies were assessed for neutralizing activity against human immunodeficiency virus type 1 (HIV-1) carrying HLA alleles with matching specificity. Multiparous women carrying anti-HLA antibodies were identified. Plasma samples from those women were confirmed as having antibodies that specifically bound to HLA proteins expressed on the peripheral blood mononuclear cells (PBMCs) of their husbands. A primary HIV-1 isolate was cultured in the husband's PBMCs so that the virus carried matching HLA alleles. To determine the HIV-1-neutralizing activity of anti-HLA antibodies, the infectivity of the virus for GHOST cells (which express green fluorescent protein after HIV infection) was investigated in the presence of a plasma sample positive for the respective anti-HLA antibody. A neutralization assay was also performed using purified immunoglobulin G (IgG) from two plasma samples, and two plasma samples were investigated in the presence of complement. The prerequisite for anti-HLA antibody-mediated neutralization is incorporation of HLA proteins by HIV-1. Therefore, the extent of incorporation of HLA proteins by the primary HIV-1 isolate was estimated. The ratios of HLA class I protein to HIV-1 capsid (p24) protein cultured in the PBMCs of two healthy individuals were 0.017 and 0.054. These ratios suggested that the HIV-1 strain used in the assay incorporated more HLA proteins than gp160 trimers. Anti-HLA antibody-positive plasma was found to contain antibodies that specifically reacted to HIV-1 carrying cognate HLA alleles. However, incubation of HIV-1 with anti-HLA antibody- positive plasma or purified IgG did not show a reduction in viral infectivity. HIV-1-neutralizing activity was also not detected in the presence of complement. This study shows that HIV-1 primary isolates cultured in PBMCs contain significant amounts of HLA proteins. However, the binding of antibodies to those HLA proteins does not mediate a reduction in viral infectivity.

Effective evaluation of novel low-cost CD4 monitoring assays.

Indian generic pharmaceutical manufacturers have dramatically reduced the price of antiretroviral therapy thus improving access, but monitoring costs of the patients on therapy remain high. Few low-cost monitoring assays are available and validation against gold standard is exceedingly important before implementation. Validity is defined as the degree to which the results of the new technique correspond to the true state of the phenomena being measured by the gold standard. Majority of publications report validation of low-cost CD4 assay using correlation coefficient, which is the best measure of association, and a few publications report intra-class correlation coefficient, which is a measure of reliability. However, Bland-Altman analysis that directly quantifies the difference seen between the novel low-cost CD4 assay and the gold standard is the most ideal approach. Absolute CD4 counts estimated for samples collected from 110 HIV+ and 118 HIV- individuals using novel EasyCD4 assay and the gold standard FACSCount assay were validated using correlation coefficient, intra-class correlation coefficient and Bland Altman analysis. The results from these different analyses have been compared and the significance of each has been explained. Hence, to validate a low-cost assay Bland-Altman analysis and plot is recommended.

Increasing survival with HIV: impact on nursing care.

The introduction of highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV) infection from a rapidly progressive catastrophic illness to a chronic condition. Individuals with HIV are living longer and developing conditions usually associated with aging, as well as complications from pre-existing or subsequently acquired conditions. In addition, toxicities associated with HAART may precipitate or exacerbate comorbid conditions. As opportunistic infections account for fewer admission and lower mortality rates, new patterns of illness are emerging. Complex interactions among multiple, sometimes overlapping conditions require focused yet comprehensive attention in care and management. Nurses will encounter HIV-infected patients in an increasing range of care settings, and an understanding of the range and interaction of potential comorbidities and their treatments with HIV and its treatment will be required to provide safe and effective care.

Predicting the impact of antiretrovirals in resource-poor settings: preventing HIV infections whilst controlling drug resistance.

There is currently an opportunity to carefully plan the implementation of antiretroviral (ARV) therapy in the developing world. Here, we use mathematical models to predict the potential impact that low to moderate usage rates of ARVs might have in developing countries. We use our models to predict the relationship between the specific usage rate of ARVs (in terms of the percentage of those infected with HIV who receive such treatment) and: (i) the prevalence of drug-resistant HIV that will arise, (ii) the future transmission rate of drug-resistant strains of HIV, and (iii) the cumulative number of HIV infections that will be prevented through more widespread use of ARVs. We also review the current state of HIV/AIDS treatment programs in resource-poor settings and identify the essential elements of a successful treatment project, noting that one key element is integration with a strong prevention program. We apply both program experience from Haiti and Brazil and the insights gleaned from our modeling to address the emerging debate regarding the increased availability of ARVs in developing countries. Finally, we show how mathematical models can be used as tools for designing robust health policies for implementing ARVs in developing countries. Our results demonstrate that designing optimal ARV-based strategies to control HIV epidemics is extremely complex, as increasing ARV usage has both beneficial and detrimental epidemic-level effects. Control strategies should be based upon the overall impact on the epidemic and not simply upon the impact ARVs will have on the transmission and/or prevalence of ARV-resistant strains.

A Bayesian approach to parameter estimation in HIV dynamical models.

In the context of a mathematical model describing HIV infection, we discuss a Bayesian modelling approach to a non-linear random effects estimation problem. The model and the data exhibit a number of features that make the use of an ordinary non-linear mixed effects model intractable: (i) the data are from two compartments fitted simultaneously against the implicit numerical solution of a system of ordinary differential equations; (ii) data from one compartment are subject to censoring; (iii) random effects for one variable are assumed to be from a beta distribution. We show how the Bayesian framework can be exploited by incorporating prior knowledge on some of the parameters, and by combining the posterior distributions of the parameters to obtain estimates of quantities of interest that follow from the postulated model.

Longitudinal assessment of the effects of drug and alcohol abuse on HIV-1 treatment outcomes in an urban clinic.

OBJECTIVE: To assess the temporal association of changes in substance abuse with antiretroviral therapy use and adherence, HIV-1 RNA suppression, and CD4 cell count changes in patients attending an urban clinic. DESIGN: Prospective cohort study. METHODS: Six-hundred and ninety-five HIV-1-infected individuals, who completed two or more semi-annual standardized surveys and in whom antiretroviral therapy was indicated, were included in the analysis. Surveys addressed antiretroviral therapy use and adherence, and use of illicit drugs and alcohol. Substance abuse was defined as active heroin, cocaine, or heavy alcohol use in the 6 months preceding survey. The units of analysis were consecutive pairs of surveys (couplets) in individual participants. Couplets in which participants denied substance abuse in both surveys were compared to couplets in which participants switched from non-use to substance abuse, and couplets in which participants reported substance abuse in both surveys were compared to couplets where participants switched from substance abuse to non-use. RESULTS: Switching from non-use to substance abuse was strongly associated with worsening antiretroviral therapy use and adherence, less frequent HIV-1 RNA suppression, and blunted CD4 cell increases, compared to remaining free of substance abuse. Alternatively, switching from substance abuse to non-use was strongly associated with improvements in antiretroviral therapy use and adherence, and HIV-1 treatment outcomes, compared to persisting with substance abuse. CONCLUSIONS: This longitudinal study highlights the dynamic nature of substance abuse and its temporal association with the effectiveness of HIV-1 treatment in patients attending an inner-city clinic.

A stochastic modeling of early HIV-1 population dynamics.

In a recent paper, Tuckwell and Le Corfec [J. Theor. Biol. 195 (1998) 450-463] applied the multi-dimensional diffusion process to model early human immunodeficiency virus type-1 (HIV-1) population dynamics. The purpose of this paper is to assess certain features and consequences of their model in the context of Tan and Wu's stochastic approach [Math. Biosci. 147 (1998) 173-205].

Comparison of smoothing techniques for CD4 data in a Markov model with states defined by CD4: an example on the estimation of the HIV incubation time distribution.

Multi-state models defined in terms of CD4 counts are useful for modelling HIV disease progression. A Markov model with six progressive CD4-based states and an absorbing state (AIDS) was used to estimate the cumulative probability of progressing to AIDS in 158 HIV-1 infected haemophiliacs with known seroconversion (SC) dates. A problem arising in such analysis is how to define CD4-based states, since this marker is subject to measurement error and short timescale variability. Four approaches were used: no smoothing, ad hoc smoothing (to move to a later/previous state two consecutive measurements to later/previous states are needed), kernel smoothing and random effects (RE) models. The estimates were compared with the Kaplan-Meier estimate based solely on data concerning time to AIDS. There was an apparent lack of agreement between the Kaplan-Meier and the "no smoothing" estimate. With the exception of the "no smoothing" method, "ad hoc", kernel and RE estimates fell within the range of the 95 per cent CIs of the Kaplan-Meier curve. Simulations demonstrated that the use of raw CD4 counts provides overestimated transition intensities. Compared to the kernel method, ad hoc is easier to implement and overcomes the problem of the choice of bandwidth. The RE approach leads to simple models, since it usually results in very few transitions to previous states, and can handle individuals with sparse data by smoothing their predictions towards the population mean. Ad hoc was the method that performed better, in terms of bias, than the other smoothing approaches.

A comparison of immunocomplex-dissociated serum HIV-1 p24 antigenemia and plasma HIV-1 viral load: assessment of 3,129 paired assays.

In order to compare HIV-1 p24 antigenemia and plasma HIV-1 RNA levels as markers of viral replication, 3,129 paired determinations of alkaline immunocomplex-dissociated serum HIV-1 p24 antigenemia (performed with an immunoenzymatic assay), and plasma HIV-1 RNA levels (carried out with a branched DNA method, a reverse transcriptase-coupled polymerase chain reaction, and a nucleic acid sequence-based assay) were assessed over a two-year-period. When excluding samples with undetectable plasma HIV-1 RNA levels (which tested negative or borderline positive at serum p24 antigen assay in 97.9% of cases), immunocomplex-dissociated p24 antigenemia proved significantly less sensitive than viral load at all considered HIV-1 RNA reference levels, although the profile of positive serum p24 antigen assays (values above 10 pg/ml) paralleled the trend of plasma HIV-1 viral load, especially at higher levels. However, serum HIV-1 p24 antigenemia (even after immunocomplex dissociation) can be longer suggested as a the sole virological tool in the laboratory management of HIV-1 infection, due to its significantly lower sensitivity levels compared with viral load assessment.