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Only a decade ago, human immunodeficiency virus (HIV)-seropositivity was considered an absolute contraindication for organ transplantation. With the currently available experience, it is no longer justified to deny HIV-positive patients access to transplantation. To the best of our knowledge, we here present the longest surviving HIV-positive patient after renal transplantation. The follow-up period after renal transplantation in this HIV-positive female is now 13 yr and she is in good general condition with excellent renal function. Throughout her post-transplant follow-up, we encountered a number of problems that are illustrative of the HIV-positive patient. [ABSTRACT FROM AUTHOR]

Abstract: To establish whether efficient suppression of virus replication in HIV-2-infected individuals is associated with low replicative capacity of HIV-2, replication kinetics of HIV-2 variants from long-term aviremic individuals was analyzed and compared with that of the relatively slow-replicating HIV-1 variants from asymptomatics and long-term nonprogressors (AS/LTNP). On average, HIV-2 from aviremic individuals had lower replication rates than HIV-1 variants from AS/LTNP in cells of 8 donors (0.45 log10 [range 0.14–0.77] vs. 0.58 log10 [range 0.32–0.99] pg RT/ml/day, P = 0.036). The relatively low replication rate of HIV-2 compared to HIV-1 variants was not related to different sensitivities to inhibition by CD8+ T cells or different degrees of infectivity. HIV-2 replication rates increased with progressive infection and with switch from CCR5 to CXCR4 usage. The relatively low replicative capacity of HIV-2 variants from aviremic individuals likely contributes to the low viral load and benign course of infection in these individuals. [Copyright &y& Elsevier]

Examines the phenotypic and genotypic resistance of HIV-2 against nucleoside reverse transcriptase inhibitors (NRTI). Isolation of biologic virus clones; Antiviral drug susceptibility testing; Phenotypic and genotypic resistance to NRTI of biologic HIV-2.

In this observational cohort study, 10 patients with extensive or treatment-refractory AIDS-associated Kaposi sarcoma were treated with peginterferon alfa-2a. Tumor responses were observed in 9 patients with a median progression-free survival of 645 days. Peginterferon alfa-2a could be an effective therapy for extensive or treatment-resistant Kaposi sarcoma. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Effect of early versus deferred antiretroviral therapy for HIV on survival," by M. M. Kitahata and colleagues in the April 30, 2009 issue.

Examines the heterosexual transmission of HIV by hemophiliacs. Prevalence of HIV infection among female partners of hemophiliacs; Rate of HIV transmission by unprotected and protected sexual intercourse; Frequency of HIV transmission from men to women by vaginal intercourse.

Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2. [ABSTRACT FROM AUTHOR]

A letter to the editor on antiretroviral therapy in patients suffering from dual infection with human immunodeficiency virus (HIV) types 1 and 2 is presented.

Objectives: The incidence of anal cancer is increasing especially in HIV-positive men having sex with men. Screening for the cancer precursor, high-grade squamous intraepithelial lesions (HSIL), is challenging, as current treatment is suboptimal. The aim of this prospective study was to establish the efficacy of five consecutive days a week self-administered treatment with imiquimod 5% cream for both perianal and intra-anal HSIL and to assess the adverse effects and burden of this regimen.Methods: 44 patients with histologically proved perianal or intra-anal HSIL were treated with a five consecutive days a week imiquimod 5% cream regimen. When no response could be confirmed after the first 16 weeks of therapy, patients were encouraged to continue the use of the cream for a further 16 weeks. Side effects were routinely assessed.Results: Complete or partial response was observed in 20 (45%) of 44 patients with HSIL after 16 weeks of treatment; another nine patients showed complete or partial response after an additional 16 weeks of treatment, resulting in a response rate of 29 (66%) out of 44 patients.Conclusions: Topical imiquimod 5% cream is useful in HSIL. A five consecutive days treatment regimen with imiquimod 5% cream for HSIL does not seem to be more effective compared with the customary prescription for 3 days a week. A prolonged course of imiquimod 5% cream is warranted for intra-anal HSIL. Adverse effects are comparable between 3 and 5 days treatment regimen. [ABSTRACT FROM AUTHOR]

Objectives The incidence of anal cancer is increasing especially in HIV-positive men having sex with men. Screening for the cancer precursor, high-grade squamous intraepithelial lesions (HSIL), is challenging, as current treatment is suboptimal. The aim of this prospective study was to establish the efficacy of five consecutive days a week self-administered treatment with imiquimod 5% cream for both perianal and intra-anal HSIL and to assess the adverse effects and burden of this regimen. Methods 44 patients with histologically proved perianal or intra-anal HSIL were treated with a five consecutive days a week imiquimod 5% cream regimen. When no response could be confirmed after the first 16 weeks of therapy, patients were encouraged to continue the use of the cream for a further 16 weeks. Side effects were routinely assessed. Results Complete or partial response was observed in 20 (45%) of 44 patients with HSIL after 16 weeks of treatment; another nine patients showed complete or partial response after an additional 16 weeks of treatment, resulting in a response rate of 29 (66%) out of 44 patients. Conclusions Topical imiquimod 5% cream is useful in HSIL. A five consecutive days treatment regimen with imiquimod 5% cream for HSIL does not seem to be more effective compared with the customary prescription for 3 days a week. A prolonged course of imiquimod 5% cream is warranted for intra-anal HSIL. Adverse effects are comparable between 3 and 5 days treatment regimen. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the adherence and virological treatment response of highly active antiretroviral therapy.

Background: We aimed to investigate whether very low-level HIV-1 viraemia (VLLV) <20 copies/mL in HIV-1-infected patients on antiretroviral therapy (ART) whose VL was <20 copies/mL, was associated with a subsequent VL > 20 copies/mL. Methods: VLLV was defined as VL <20 copies/mL and positive HIV-1-PCR. We compared patients with positive and negative HIV-1-PCRs <20 copies/mL at two time points, T0 and T1, after 21st of January 2016. Factors associated with a VLLV and subsequent VL >20 copies/mL were identified by logistic regression models. Results: Of 1341 participants at T0, 958 (71.4%) had a negative and 383 patients (28.6%) had positive HIV-RNA PCR signal during VL < 20 copies/mL. The negative relative to the positive signal at T0 was independently associated with dolutegravir (DTG) mono and/or DTG-lamivudine dual therapy (compared to nevirapine), a pre-ART-VL of 1000–9999 copies/mL (compared to ≥100,000 copies/mL), and each additional year of virologic suppression. Having a virolologic outcome at T1 of 20 copies/mL was independently associated with prior positive signal at T0. (OR = 2.291, 95% CI = 1.457–3.601, p value <.001), a past ART interruption, and a change in ART regimen during follow-up. Each additional year of virologic suppression was independently associated with a lower risk for a subsequent VL ≥ 20 copies/mL. Conclusions: A positive HIV-1 RNA PCR <20 copies/mL at T0, was associated with a subsequent VL ≥ 20 copies/mL at T1. This was not a rare phenomenon among patients with VL <20 copies/mL. In most patients with a positive PCR signal, this was not followed by a clinically relevant HIV-1 viraemia, defined as ≥ 200 copies/mL. [ABSTRACT FROM AUTHOR]

Background: Dolutegravir (DTG) is an integrase strand-transfer inhibitor (INSTI) used for treatment of human immunodeficiency virus (HIV)-infected individuals. Owing to its high genetic barrier to resistance, DTG has been clinically investigated as maintenance monotherapy to maintain viral suppression and to reduce complication and healthcare costs. Our study aims to explain the underlying mechanism related to the emergence of a S230R substitution in patients who experienced virologic failure while using DTG monotherapy.Methods: We evaluated the effect of the S230R substitution in regard to integrase enzyme activity, viral infectivity, replicative capacity, and susceptibility to different INSTIs by biochemical and cell-based assays.Results: The S230R substitution conferred a 63% reduction in enzyme efficiency. S230R virus was 1.29-fold less infectious than wild-type virus but could replicate in PM1 cells without significant delay. Resistance levels against DTG, cabotegravir, raltegravir, and elvitegravir in tissue culture were 3.85-, 3.72-, 1.52-, and 1.21-fold, respectively, in virus with the S230R substitution.Conclusions: Our data indicate that the S230R substitution is comparable to the previously reported R263K substitution in some respects. Virologic failure during DTG monotherapy can occur through the development of the S230R or R263K mutation, without the need for high-level DTG resistance. [ABSTRACT FROM AUTHOR]

Background: A high genetic barrier to resistance to the integrase strand transfer inhibitor (INSTI) dolutegravir has been reported in vitro and in vivo. We describe the dynamics of INSTI resistance-associated mutations (INSTI-RAMs) and mutations in the 3'-polypurine tract (3'-PPT) in relation to virologic failure (VF) observed in the randomized Dolutegravir as Maintenance Monotherapy for HIV-1 study (DOMONO, NCT02401828).Methods: From 10 patients with VF, plasma samples were collected before the start of cART and during VF, and were used to generate Sanger sequences of integrase, the 5' terminal bases of the 3' long terminal repeat (LTR), and the 3'-PPT.Results: Median human immunodeficiency virus RNA load at VF was 3490 copies/mL (interquartile range 1440-4990 copies/mL). INSTI-RAMs (S230R, R263K, N155H, and E92Q+N155H) were detected in 4 patients, no INSTI-RAMs were detected in 4 patients, and sequencing of the integrase gene was unsuccessful in 2 patients. The time to VF ranged from 4 weeks to 72 weeks. In 1 patient, mutations developed in the highly conserved 3'-PPT. No changes in the terminal bases of the 3'-LTR were observed.Conclusions: The genetic barrier to resistance is too low to justify dolutegravir maintenance monotherapy because single INSTI-RAMs are sufficient to cause VF. The large variation in time to VF suggests that stochastic reactivation of a preexisting provirus containing a single INSTI-RAM is the mechanism for failure. Changes in the 3'-PPT point to a new dolutegravir resistance mechanism in vivo.Clinical Trials Registration: NCT02401828. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aims: Infection with Hepatitis E virus (HEV) can cause chronic liver disease in immunocompromised hosts. In transplant recipients, the use of certain immunosuppressants and food habits has been proposed as risk factors for HEV. In individuals infected with the human immunodeficiency virus (HIV), risk factors for HEV infection are less clear. We aimed to study the association between a mutation in the progesterone receptor (PR) named PROGINS and HEV‐infected in HIV‐positive individuals. Methods: We evaluated the presence of the SNP PROGINS via KASP in serum samples of 64 HIV‐positive individuals and 187 healthy controls. We performed ELISA tests to address the serum levels of IL‐10 and IL‐12, as well as T‐cell stimulation assays in peripheral blood to address immune response in individuals with PROGINS. Results: We found a significant association between the presence of PROGINS mutation and HEV seroprevalence in individuals infected with HIV (30% in HIV+/HEV+ versus 2% in HIV+/HEV, respectively, P = .009). Moreover, we found that HIV+/HEV+ individuals expressing the PROGINS mutation had lower serum levels of IL‐10 and higher levels of IL‐12. The presence of the mutation led to a reduced response upon stimulation of CD4+ and CD8+ T cells compared to those without the mutation, suggesting an immune modulation associated with PROGINS. Conclusions: Our study identified a mutation in the PR that provides significant insights into mechanisms of HEV infection in immunosuppressed individuals. [ABSTRACT FROM AUTHOR]

Background: The benefits of combination anti-retroviral therapy (cART) in HIV-positive pregnant women (improved maternal health and prevention of mother to child transmission [pMTCT]) currently outweigh the adverse effects due to cART. As the variety of cART increases, however, the question arises as to which type of cART is safest for pregnant women and women of childbearing age. We studied the effect of timing and exposure to different classes of cART on adverse birth outcomes in a large HIV cohort in the Netherlands. Materials and methods: We included singleton HEU infants registered in the ATHENA cohort from 1997 to 2015. Multivariate logistic regression analysis for single and multiple pregnancies was used to evaluate predictors of small for gestational age (SGA, birth weight <10th percentile for gestational age), low birth weight and preterm delivery. Results: A total of 1392 children born to 1022 mothers were included. Of these, 331 (23.8%) children were SGA. Women starting cART before conception had an increased risk of having a SGA infant compared to women starting cART after conception (OR 1.35, 95% CI 1.03−1.77, p = 0.03). The risk for SGA was highest in women who started a protease inhibitor-(PI) based regimen prior to pregnancy, compared with women who initiated PI-based cART during pregnancy. While the association of preterm delivery and preconception cART was significant in univariate analysis, on multivariate analysis only a non-significant trend was observed (OR 1.39, 95% CI 0.94−1.92, p = 0.06) in women who had started cART before compared to after conception. In multivariate analysis, the risk of low birth weight (OR 1.34, 95% CI 0.94−1.92, p = 0.11) was not significantly increased in women who had started cART prior to conception compared to after conception. Conclusion: In our cohort of pregnant HIV-positive women, the use of cART prior to conception, most notably a PI-based regimen, was associated with intrauterine growth restriction resulting in SGA. Data showed a non-significant trend in the risk of PTD associated with preconception use of cART compared to its use after conception. More studies are needed with regard to the mechanisms taking place in the placenta during fetal growth in pregnant HIV-positive women using cART. It will only be with this knowledge that we can begin to understand the potential impact of HIV and cART on the fetus, in order to be able to determine the optimal individualised drug regimen for HIV-infected women of childbearing age. [ABSTRACT FROM AUTHOR]

Background. The use of antiretroviral therapy during pregnancy is important for control of maternal human immunodeficiency virus (HIV) disease and the prevention of perinatal HIV transmission. Physiological changes during pregnancy can reduce antiretroviral exposure. We studied the pharmacokinetics of rilpivirine 25 mg once daily in HIV-1-infected women during late pregnancy. Methods. We conducted a nonrandomized, open-label, multicenter, phase 4 study. HIV-infected pregnant women receiving rilpivirine 25 mg once daily were included. Intensive 24-hour pharmacokinetic sampling was performed in the third trimester and at least 2 weeks postpartum. Pharmacokinetic parameters were calculated by noncompartmental analysis. Results. Sixteen subjects were included. Geometric mean ratios of third trimester vs postpartum were 0.55 (90% confidence interval [CI], .46-.66) for the 24-hour area under the concentration-time curve (AUC0-24h); 0.65 (90% CI, .55-.76) for the maximum concentration; and 0.51 (90% CI, .41-.63) for the minimum observed concentration (Cmin). Four of 16 (25%) subjects had Cmin below the target concentration (0.04 mg/L) in the third trimester of pregnancy. No subtherapeutic levels were observed postpartum. No detectable viral loads were observed in this study. All newborns tested negative for HIV. No birth defects were reported. The median (range, n = 5) rilpivirine cord-to-maternal plasma concentration ratio was 0.50 (range, .35--.81). Conclusions. Rilpivirine exposure is substantially lowered during late pregnancy. Despite lower exposure, virologic suppression was maintained and no perinatal transmission was observed. Overall, these results suggest that rilpivirine 25 mg once daily may be an alternative treatment option for HIV-1-infected pregnant women who are virologically suppressed, in settings where therapeutic drug monitoring and/or close viral load monitoring are feasible to detect suboptimal antiretroviral therapy. Clinical Trials Registration. NCT00825929. [ABSTRACT FROM AUTHOR]

Background. The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. Methods. An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. Results. Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). Conclusions. Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. [ABSTRACT FROM AUTHOR]

In HIV-negative patients, radiotherapy (RT) decreases CD4+ T-cell counts. We studied the effects of RT in HIV-1 positive patients.HIV-1 positive patients with a subsequent diagnosis of a solid tumor were selected from the Dutch national observational HIV cohort, Aids Therapy Evaluation in the Netherlands (ATHENA). The patients were grouped according to whether they had received RT or not. Primary endpoint of the study was the time from baseline to reaching CD4 cell counts higher than those at baseline. Kaplan-Meier estimates of the percentage of patients reaching the endpoint were calculated.Ninety patients were included of whom 36 received RT and 54 did not. Median duration of RT was 46 [interquartile range (IQR) 30-63] days. Median first CD4 cell count after stopping RT was 150 (IQR 30-270) × 106/L lower compared with baseline. In 13 of the 36 patients receiving RT, CD4 cell counts recovered to baseline, after a median of 469 (IQR 345-595) days. In 35 of the 54 patients without RT, the CD4 cell count recovered to baseline or higher, after a median of 112 (IQR 42-182) days. After 3 years, in 39% of patients who had RT compared with 71% of patients without RT, CD4 cell counts recovered to baseline or higher (P < 0.0001). In a Cox regression adjusted for potential confounders, RT was associated with a longer (hazard ratio 0.29; 95% confidence interval 0.13 to 0.63) and combination antiretroviral therapy use with a shorter time to return to baseline [hazard ratio 2.46 (95% confidence interval 1.11 to 5.48)].RT resulted in a significant and prolonged decrease in CD4 cell counts. [ABSTRACT FROM AUTHOR]

Background: The presence of a vpx gene distinguishes HIV-2 from HIV-1, the main causative agent of AIDS. Vpx degrades the restriction factor SAMHD1 to boost HIV-2 infection of macrophages and dendritic cells and it has been suggested that the activation of antiviral innate immune responses after Vpx-dependent infection of myeloid cells may explain why most HIV-2-infected individuals efficiently control viral replication and become long-term survivors. However, the role of Vpx-mediated SAMHD1 antagonism in the virological and clinical outcome of HIV-2 infection remained to be investigated. Results: Here, we analyzed the anti-SAMHD1 activity of vpx alleles derived from seven viremic and four long-term aviremic HIV-2-infected individuals. We found that effective Vpx-mediated SAMHD1 degradation and enhancement of myeloid cell infection was preserved in most HIV-2-infected individuals including all seven that failed to control the virus and developed AIDS. The only exception were vpx alleles from an aviremic individual that predicted a M68K change in a highly conserved nuclear localization signal which disrupted the ability of Vpx to counteract SAMHD1. We also found that HIV-2 is less effective than HIV-1 in inducing innate immune activation in dendritic cells. Conclusions: Effective immune control of viral replication in HIV-2-infected individuals is not associated with increased Vpx-mediated degradation of SAMHD1. [ABSTRACT FROM AUTHOR]

Abstract: Background: Data on long-term response rates after successful primary hepatitis B (HBV) vaccination in HIV-infected patients are scarce. Objective: To evaluate the durability of an effective anti-HBs titer up to 5 years after primary vaccination in a cohort of 155 HIV-infected adults. Methods: From a previous multicenter HBV vaccination trial we selected patients with an anti-HBs titer of ≥10IU/l 28 weeks after the first vaccination. The anti-HBs titer was measured in annually stored plasma samples up to 5 years after vaccination. Patients with decreasing anti-HBs titers <10IU/I were defined as transient responders (TR*) and with persistent anti-HBs titers ≥10IU/I as long-term responders (LTR^). Results: We included 155 patients, 87 were TR and 68 LTR. Mean age, percentage of female participants and duration of HAART use at primary vaccination were similar in LTR and TR. Anti-HBs level after primary vaccination was the strongest predictor for the durability of anti-HBs. Anti-HBs >100–1000IU/I and >1000 resulted in an OR 8.3, 95% CI 3.38–20.16; p <0.0001 and OR 75.6, 95% CI 13.41–426.45; p <0.0001 versus anti-HBs titer of 10–100IU/I after primary vaccination respectively. The mean time to loss of an effective anti-HBs titer was 2.0, 3.7 and 4.4 years respectively, for patients with an anti-HBs titer of 10–100IU/I, >100–1000IU/I and >1000IU/I at primary vaccination. An undetectable HIV-RNA load and use of HAART during vaccination and at follow-up were, though not significantly, associated a higher long-term persistence of an effective antibody titer. Conclusion: The durability of an effective anti-HBs level appears to be significantly related to the height of the antibody titers after the primary immunization procedure. Schedules to improve the vaccination response in HIV-infected patients therefore seem to be justified. Whether a HBV booster is indicated remains to be elucidated. [Copyright &y& Elsevier]

Background. The kinetics of hepatitis B surface antigen (HBsAg) are predictive in HBV-infected patients treated with pegylated interferon. Knowledge about the value of HBsAg levels in patients coinfected with HBV and human immunodeficiency virus (HIV) is lacking.Methods. We quantified serum HBsAg in a Dutch multicenter cohort of 104 patients coinfected with HIV and HBV who were treated with tenofovir disoproxil fumarate (TDF) as part of highly active antiretroviral therapy. The median duration of therapy was 57 months (interquartile range, 34–72 months).Results. Hepatitis B e antigen (HBeAg)–positive patients achieved a decline of 2.2 log IU/mL in HBsAg, whereas HBeAg-negative patients only achieved a decline of 0.6 log IU/mL during 6 years of TDF therapy. Declines in HBsAg at months 6 and 12 correlated with CD4 cell count for HBeAg-positive patients. Five HBeAg-positive patients (8%) and 3 HBeAg-negative patients (8%) cleared HBsAg. HBeAg-negative patients who cleared HBsAg had lower baseline HBsAg as compared to patients who remained HBsAg positive. The majority of patients who cleared HBsAg achieved this end point within the first year. In HBeAg-positive patients, decline in HBsAg at month 6 was predictive of achieving HBsAg seroclearance.Conclusions. Receipt of TDF therapy by HIV/HBV-coinfected patients for up to 6 years led to a significant decrease in HBsAg in the HBeAg-positive population. HBsAg kinetics early during treatment were predictive of HBsAg seroclearance and correlated with an increased CD4 cell count, underlining the importance of immune restoration in HBV clearance. [ABSTRACT FROM PUBLISHER]

Background: The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). Methods and Findings: Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1:1:1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1:1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count <350 cells/mm³ or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log10 copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log10 copies/ml in the 24- and 60-wk treatment arms (between groups: p<0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0-1.8) y compared to 3.0 (1.9-4.2) and 1.8 (0.5-3.0) y in the 24- and 60-wk treatment arms (log rank test, p<0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25-0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32-0.95]) were associated with time to (re)start of cART. Conclusions: In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection. [ABSTRACT FROM AUTHOR]

Abstract: Almost five decades after their first application in diagnostics, dried blood spot (DBS) cards remain to be of key interest in many research areas and clinical applications. The advantages of sample stability during transport and storage, can now be combined with the high sensitivity of novel diagnostic techniques for the measurement and analysis of nucleic acids, proteins and small molecules which may overcome the limitations of the small samples sizes in DBS cards. Here we present a survey of the literature on the use of DBS cards for diagnosis, monitoring and epidemiological studies of virus infections other than HIV, including CMV, HBV, HCV, HAV, HEV, HTLV, EBV, HSV, measles-, rubella- and dengue-virus. The minimal invasiveness of sampling and the relative ease of handling and storing DBS cards is expected to offer additional opportunities to measure and analyze biomarkers of viral disease in resource poor settings or when limited amount of blood can be obtained. Large retrospective studies of virus infections in newborns using stored DBS cards have already been undertaken for screening of congenital infections. In addition, DBS cards have been used prospectively for prevalence studies, outbreak surveillance, mass screening for viral infections, follow-up of chronic infection and its treatment in resource-limited areas. We do not expect that current wet sampling techniques of plasma or serum will be replaced by DBS sampling but it allows extension of sampling in persons and settings that are currently difficult to access or that lack suitable storage facilities. In conclusion, DBS card sampling and storage will aid adequate outbreak management of existing and emerging viral diseases. [Copyright &y& Elsevier]

Background. In human immunodeficiency virus (HIV)−infected patients, the immunogenicity of hepatitis B vaccines is impaired. The primary and secondary aims of our study were to investigate the effectiveness and compliance of 2 different vaccination regimen in an HIV-infected population.Methods. A noninferiority trial with a 10% response margin was designed. Included were patients ≥18 years old, with negative HBsAg/anti-HBc serology, and not previously vaccinated against hepatitis B. Patients were stratified according to CD4+ cell count: <200, 200–500, >500. Participants received 10 μg HBvaxPRO intramuscularly according to a 0–1–3 week schedule or the standard 0–4–24 week schedule. Anti-HBs levels were measured at week 28, considered protective ≥10 IU/L.Results. Modified intention to treat analysis in 761 patients was performed. Overall response difference was 50%(standard arm) versus 38.7% (accelerated arm) =11.3% (95% confidence interval [CI], [4.3, 18.3]), close to the 10% response margin. In CD4+ cell count group 200–500 cells/mm3, the response difference was 20.8% (95% CI [10.9, 30.7]). However, the response difference in CD4+cell count group >500 cells/mm3 was -1.8% (95% CI [-13.4,+9.7]). Compliance was significantly superior with the accelerated schedule, 91.8% versus 82.7% (P ≤ .001).Conclusion. In HIV-infected patients, compliance with an accelerated hepatitis B vaccination schedule is significantly better. The efficacy of an accelerated schedule proved to be non-inferior in CD4+ cell count group >500 cells/mm3.Clinical Trials Registration. CT00230061. [ABSTRACT FROM PUBLISHER]

The article presents a study on the safety of dose reduction in patients with high plasma efavirenz and its ability to prevent toxicity-induced efavirenz discontinuations. It explores the results of the study using the human immunodefficiency virus (HIV)-positive patients with high plasma efavirenz level as subjects. It concludes that toxicity-induced continuation in patients with high efavirenz plasma concentrations can be prevented by dose reduction without compromising virological efficacy.

The article presents a study on the immunologic, virulogic and clinical consequences of episodes of transient viremia in HIV-1-infected patients with sustained virologic suppression. Results showed that episodes of low-level viremia are frequent and short lasting in such patient, and the low proportion of episodes with clinical events suggests that leaving combination antiretroviral therapy (cART) unchanged is a clinically accepted method.

Background. Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell counts >250 cells/μL and in male individuals with CD4 cell counts >400 cells/μL are based on findings in treatment-naive patients. It is unclear whether these guidelines also apply to treatment-experienced patients switching to NVP-based combination therapy. Methods. Patients in the ATHENA cohort study who had used NVP-based combination therapy were included. We identified patients who discontinued NVP-based combination therapy because of hypersensitivity reactions (HSRs; rash and/or hepatotoxicity) within 18 weeks after starting such therapy. We grouped patients according to their CD4 cell count at the start of NVP-based combination therapy (current CD4 cell count) as having a high CD4 cell count (for female patients, >250 cells/μL; for male patients, >400 cells/μL) or a low CD4 cell count. Treatment-experienced patients were further subdivided according to the last available CD4 cell count before first receipt of antiretroviral therapy (ART; pre-ART CD4 cell count) using the same criteria. Risk factors for HSR were assessed using multivariate logistic regression. Results. Of 3752 patients receiving NVP-based combination therapy, 231 patients (6.2%) discontinued NVP therapy because of HSRs. Independent risk factors included female sex and Asian ethnicity. Having an undetectable viral load (VL) at the start of NVP therapy was associated with reduced risk of developing an HSR (adjusted odds ratio [OR], 0.52; 95% confidence interval [CI], 0.38-0.71). Pretreated patients with low pre-ART and high current CD4 cell counts and a detectable VL when switching to NVP-based combination therapy had a significantly higher risk of developing an HSR, compared with treatment-naive patients who started NVP therapy with low CD4 cell counts (adjusted OR, 1.87; 95% CI, 1.11-3.12); pretreated patients with low pre-ART CD4 cell counts who switched to NVP therapy with a high current CD4 cell count and an undetectable VL did not have an increased risk of developing an HSR (adjusted OR, 1.03; 95% CI, 0.66-1.61). Conclusions. Treatment-experienced patients who start NVP-based combination therapy with low pre-ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of HSRs, compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds. [ABSTRACT FROM AUTHOR]

Aims To characterize the demographic and pharmacogenetic factors that influence interpatient variability in the plasma concentrations of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz. Methods Data from all samples analyzed for efavirenz in our TDM service in 2002 and 2003 were reviewed. Information on gender, age, body weight, height, race, hormonal contraceptive use (in a subset of patients), and time between sampling and last intake was recorded. PCR-restriction fragment length polymorphism analysis was performed to detect the cytochrome P450 2B6 ( CYP2B6) C1459T variant (present in CYP2B6*6 and CYP2B6*7) which is associated with low CYP2B6 activity. Results A total of 255 patients were included in this analysis. The median plasma efavirenz concentration was 2.50 (interquartile range: 1.85–3.55) mg l−1. Eight patients (3.1%) were considered to have a subtherapeutic plasma concentration (<1.0 mg l−1) and 48 (18.9%) a toxic efavirenz concentration (>4.0 mg l−1). Gender, time after last intake, and race were the only factors that were significantly related to plasma efavirenz concentration in a multivariate analysis. No influence was observed for body weight, hormonal contraceptive use, and the presence of the CYP2B6 C1459T polymorphism. Conclusions Gender and race are important factors in determining interpatient variability in plasma efavirenz concentrations which were unaffected by the presence of the CYP2B6 C1459T polymorphism. Physicians should be particularly alert for signs of efavirenz-induced toxicity in females and non-Caucasian patients. [ABSTRACT FROM AUTHOR]

Objective: To assess the relationship between plasma nevirapine concentrations and plasma HIV-1 RNA response in HIV-1-infected patients.Design: An observational cohort analysis.Methods: Plasma samples were obtained on a routine basis from 189 patients receiving nevirapine 200mg twice daily, and plasma nevirapine concentrations were measured with reversed phase high performance liquid chromatography. Patients were divided into two groups based on plasma nevirapine concentrations below (and equal to) or above 3 mg/L. The association between steady-state nevirapine concentrations and plasma HIV-1 RNA was determined by multivariate analysis.Results: Out of 189 patients, 13 (7%) had low nevirapine plasma concentrations and 176 patients had concentrations above 3 mg/L. In total, 22 (12%) patients showed virological failure and 8 patients (4%) discontinued nevirapine because of adverse effects. The risk of failure in patients with nevirapine plasma concentrations Conclusions: Low nevirapine drug concentrations are predictive of virological failure. [ABSTRACT FROM AUTHOR]

There is little information about the risk of treatment failure after a switch from human immunodeficiency virus (HIV) protease inhibitors (PIs) to nevirapine (Nvp) for patients with successful virus suppression. This study compared the 1-year risk of treatment failure for patients switching from a first PI-containing antiretroviral regimen to Nvp (Nvp group) with the risk for patients switching to second-line PIs (PI group) in the ATHENA (AIDS Therapy Evaluation, The Netherlands) study cohort (n = 2470) whose HIV-1 RNA loads were ≤ 500 copies/mL. Treatment failure was defined as measurement of HIV-1 RNA loads > 500 twice or > 10,000 copies/mL once or discontinuation of treatment for any reason. There were 446 eligible patients, 125 in the Nvp group and 321 in the PI group. The risk of treatment failure in the Nvp group, after data were adjusted for other risk factors, was 5-fold (95 % confidence interval, 0.1-0.4) lower than the risk in the PI group, primarily because the discontinuation rate was lower. In patients with virus suppression, a switch to Nvp is more likely than a switch to second-line PIs to result in sustained virus suppression and maintenance of the new regimen. [ABSTRACT FROM AUTHOR]

Investigates adherence to highly active antiretroviral therapy for HIV type 1 infection among clinical patients. Effect of therapy failure on the association between adherence and virologic outcome; Importance of the patient's ability to adhere when choosing among different treatment options; Factors that influence the risk of treatment failure using an antiretroviral regimen.

Double-dose hepatitis B virus revaccination of human immunodefIciency virus (HIV)-infected patients proved to be effective in 50.7% of 144 patients who had previously failed to respond to standard doses. In the multivariate analysis, female patients were found to have a significantly better response (P = .03). The effect of age on the response depended on the viral load at the time of revaccination. For patients with a detectable HIV RNA load, the effect of age was stronger (odds ratio [OR], 0.34 per 10 years older [95% confidence interval {CI}, 0.16-0.72]; P = .005) than for patients with an undetectable HIV RNA load (OR, 0.74 per 10 years older [95% CI, 0.50-1.09];P = .12). [ABSTRACT FROM AUTHOR]

Presents a letter to the editor regarding the effect of routine therapeutic drug monitoring of nevirapine in treatment-naive HIV-1 infected patients on pharmacokinetic variability.