Ende, M.E. van der

Deep sequencing does not reveal additional transmitted mutations in patients diagnosed with HIV-1 variants with single nucleoside reverse transcriptase inhibitor resistance mutations (Article)

2013-03-01T00:00:00Z

Objectives: The aim of the study was to gain more insight into the relationship between transmitted singletons found at HIV diagnosis by population sequencing and the possible presence of clinically relevant viral minorities containing additional resistance mutations. Methods: We studied the viral quasispecies and therapy response in 10 individuals with transmitted single nucleoside reverse transcriptase inhibitor (NRTI)-related resistance mutations as detected by population sequencing. Results: Ultra-deep pyrosequencing did not reveal additional drug-resistance mutations in nine of 10 patients. In these nine patients, no breakthrough with resistant viruses was observed despite the use of low genetic nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens in the majority of patients. Conclusions: These data suggest that viral minority variants containing additional resistance mutations may be rare in patients with transmitted NRTI singletons in the Netherlands. Larger studies are required to confirm these findings and to determine the therapeutic consequences.

Long-term response rates of successful hepatitis B vaccination in HIV-infected patients (Article)

2013-02-04T00:00:00Z

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 ≥10. IU/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 <10. IU/I were defined as transient responders (TR*) and with persistent anti-HBs titers ≥10. IU/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 >100-1000. IU/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 10-100. IU/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 10-100. IU/I, >100-1000. IU/I and >1000. IU/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.

Therapy failure resulting from superinfection by a drug-resistant HIV variant (Article)

2012-12-01T00:00:00Z

Background: HIV-1-infected patients can be superinfected with additional HIV-1 variants. Therapy failure can be the consequence of an infection with a resistant strain. Methods: A patient was diagnosed with a recent HIV-1 infection in April 2005 and subsequently clinically monitored. HIV-1 evolution was studied by population sequencing of the first 984 bases of the pol gene as well as 454 ultra-deep pyrosequencing (UDPS) of parts of the pol and env genes. Results: The patient was diagnosed with a wild-type HIV-1 strain, but experienced rapid virological failure after initiating a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimen 3 years later. Population sequencing and UDPS revealed the presence of a second HIV-1 strain with a Y188L NNRTI resistance mutation in a sample obtained shortly prior to initiation of therapy. Phylogenetic analyses showed that the two HIV-1 strains were genetically distinct, providing evidence for superinfection. Conclusions: The virological treatment failure in this patient was probably due to the superinfection with an NNRTI-resistant HIV-1 variant. Superinfection with drug-resistant strains can undermine HIV-1 treatment regimens selected on the basis of resistance testing at diagnosis. Patients, especially in high-risk groups, as well as their clinicians, should be aware of the risks and dangers of superinfections.

Photodynamic therapy with systemic meta-tetrahydroxyphenylchlorin in the treatment of anal intraepithelial neoplasia, grade 3 (Article)

2012-10-01T00:00:00Z

Background and Objective Anal cancer and preneoplastic anal lesions (anal intraepithelial neoplasia, AIN) rising especially in men having sex with men (MSM). There are no widely accepted treatment standards for AIN. Photodynamic therapy (PDT) using the systemic sensitizer meta-tetrahydroxyphenylchlorin (mTHPC) has the potential to treat the anal area even when the exact borders of the preneoplastic anal lesion cannot easily be visualized. Study Design/Materials and Methods In this prospective intervention study, 15 HIV-positive MSM with AIN 3 were treated in 25 PDT-sessions using mTHPC intravenously administered at drug doses of 0.075-0.15 mg ml-1and illumination at 48 hours. The illumination was performed using a custom made applicator using either red light (652 nm) to a measured intended fluence of 10 and 20 J cm-2and green light (532 nm) to a measured intended fluence of 105, 210, and 340 J cm-2. Red and green illuminations were performed at a (green) equivalent fluence rate of 105 mW cm-2. Results Initial complete response was seen in 7/25 (28%) of treatments and another 4/25 (16%) initial partial responses. After an average 8 months, recurrences were detected in 7/11 (64%) of sessions that initially showed response. A total 4/25 (16%) showed persistent complete response 6-15 months after green light illumination. Red light illuminations caused more significant side effects combined with no persistent complete response. Reported side effects were intense pain, bloody and purulent rectal discharge, and anal stricture formation, in one patient. Conclusion The results show that the use of systemic mTHPC is partially effective for the treatment of AIN 3. Lasers Surg.

Risk factors and outcome of HIV-associated idiopathic noncirrhotic portal hypertension (Article)

2012-09-17T00:00:00Z

Background: Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection. Aim: To evaluate the number of nationwide diagnosed HIV-associated INCPH cases and to assess its clinical features, risk factors and outcome. Methods: All HIV centres in the Netherlands were contacted and requested to notify INCPH cases diagnosed in their population. A case-control study was performed to identify the risk factors of INCPH. The cases were group-matched for duration of follow-up after HIV diagnosis to controls. Controls were selected from a database of HIV patients with negative screening for signs of portal hypertension on abdominal ultrasound. Univariate and multivariate conditional logistic regression analyses were performed. Results: On 1st of July 2011, 18.085 individuals were infected with HIV in the Netherlands. Within this population, sixteen patients with clinically overt INCPH were identified. At the time of INCPH diagnosis, cases had a lower platelet count and a higher ALT level. In univariate and multivariate analyses, didanosine [OR: 1.9 (1.3-2.8)], concomitant didanosine and stavudine treatment [OR: 6.3 (2.1-19.1)] and concomitant didanosine and tenofovir treatment [OR: 5.1 (1.2-22.6)] were independently associated INCPH. During follow-up, 4 patients died [malignancy (n = 3), liver failure (n = 1)]. A significant decline in platelets was observed after didanosine discontinuation (P = 0.003). Conclusions: HIV-associated clinically relevant idiopathic noncirrhotic portal hypertension appears to be a rarely diagnosed disease. Long-term exposure to didanosine and short-term combination of didanosine and stavudine or tenofovir exposure are associated with idiopathic noncirrhotic portal hypertension. Mortality in HIV-associated idiopathic noncirrhotic portal hypertension is mainly related to HIV-associated disorders. Portal hypertension continues despite didanosine discontinuation.

Risk factors and outcome of HIV-associated idiopathic noncirrhotic portal hypertension (Article)

2012-09-17T00:00:00Z

Hepatitis B surface antigen declines and clearance during long-term tenofovir therapy in patients coinfected with HBV and HIV (Article)

2012-09-15T00:00:00Z

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. © 2012 The Author.

Efficient Nef-mediated downmodulation of TCR-CD3 and CD28 Is associated with high CD4+ T cell counts in viremic HIV-2 infection (Article)

2012-05-01T00:00:00Z

The role of the multifunctional accessory Nef protein in the immunopathogenesis of HIV-2 infection is currently poorly understood.Here, we performed comprehensive functional analyses of 50 nef genes from 21 viremic (plasma viral load,>500 copies/ml) and 16 nonviremic (<500) HIV-2-infected individuals. On average, nef alleles from both groups were equally active in modulatingCD4, TCR-CD3, CD28, MHC-I, and Ii cell surface expression and in enhancing virion infectivity. Thus, many HIV-2-infected individuals efficiently control the virus in spite of efficient Nef function. However, the potency of nef alleles indownmodulating TCR-CD3 and CD28 to suppress the activation and apoptosis of T cells correlated with high numbers of CD4+T cells in viremic patients. No such correlations were observed in HIV-2-infected individuals with undetectable viral load. Furtherfunctional analyses showed that the Nef-mediated downmodulation of TCR-CD3 suppressed the induction of Fas, Fas-L, PD-1, and CTLA-4 cell surface expression as well as the secretion of gamma interferon (IFN-γ) by primary CD4+T cells. Moreover, we identified a single naturally occurring amino acid variation (I132T) in the core domain of HIV-2 Nef that selectivelydisrupts its ability to downmodulate TCR-CD3 and results in functional properties highly reminiscent of HIV-1 Nef proteins. Taken together, our data suggest that the efficient Nef-mediated downmodulation of TCR-CD3 and CD28 help viremic HIV-2-infected individuals to maintain normal CD4+T cell homeostasis by preventing T cell activation and by suppressing the inductionof death receptors that may affect the functionality and survival of both virally infected and uninfected bystander cells.

A phase I/IIa immunotherapy trial of HIV-1-infected patients with Tat, Rev and Nef expressing dendritic cells followed by treatment interruption (Article)

2012-03-01T00:00:00Z

In a phase I/IIa clinical trial, 17 HIV-1 infected patients, stable on cART, received 4 vaccinations with autologous dendritic cells electroporated with mRNA encoding Tat, Rev and Nef, after which cART was interrupted. Vaccination was safe and feasible. During the analytical treatment interruption (ATI), no serious adverse events were observed. Ninety-six weeks following ATI, 6/17 patients remained off therapy. Although induced and/or enhanced CD4+and CD8+T-cell responses specific for the immunogens were observed in most of the patients, we found no correlation with the number of weeks off cART. Moreover, CD4+T-cell counts, plasma viral load and the time remaining off cART following ATI did not differ from historical control data. To conclude, the vaccine was safe, well tolerated and resulted in vaccine-specific immune responses. Since no correlation with clinical parameters could be found, these results warrant further research in order to optimize the efficacy of vaccine-induced T-cell responses.

Current and future applications of dried blood spots in viral disease management (Article)

2012-03-01T00:00:00Z

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.

A randomized controlled study of accelerated versus standard hepatitis B vaccination in HIV-positive patients (Article)

2011-04-01T00:00:00Z

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 [-13.4,19.7]). 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.

Determination of the antiretroviral drug tenofovir in plasma from HIV-infected adults by ultrafast isotope dilution MALDI-triple quadrupole tandem mass spectrometry (Article)

2011-03-01T00:00:00Z

A new and reliable mass spectrometric method using an isotope dilution method in combination with matrix-assisted laser desorption/ionization-triple quadrupole tandem mass spectrometry (ID-MALDI-QqQ-MS/MS) has been developed and validated for the determination of concentrations of the antiretroviral drug tenofovir (TNV) in plasma from HIV-infected adults. The advantage of this new method is that (1) the method is ultrafast and(2) can be applied for high-throughput measurement of TNV in plasma. The method is based on a simple plasma deproteinization step in combination with the use of [adenine-13C5]-TNV as the internal standard. TNV and [adenine-13C5]-TNV were monitored by multiple reaction monitoring using the transition m/z 288.0 → 176.2 and m/z 293.2 → 181.2 for TNV and [adenine-13C5]-TNV, respectively. The method was validated according to the most recent FDA guidelines for the development and validation of (new) bio-analytical assays. Validated method parameters were: linearity, accuracy, precision and stability of the method. The lowest limit of quantification was 0.10 μmol/l, whereas the limit of detection determined at a signal-to-noise ratio (S/N = 3 : 1) in pooled drug free human control plasma was 0.04 μmol/l. The validated method was successfully applied and tested for its clinical feasibility by the analysis of plasma samples from selected HIV-infected adults receiving the prodrug tenofovir disoproxil fumarate. Observed plasma TNV concentrations ranged between 0.11 and 0.76 μmol/l and measured plasma TNV concentrations were within the therapeutically relevant concentration range. Copyright

HIV transmission patterns among the Netherlands, Suriname, and the Netherlands Antilles: A molecular epidemiological study (Article)

2011-02-01T00:00:00Z

We aimed to study patterns of HIV transmission among Suriname, The Netherlands Antilles, and The Netherlands. Fragments of env, gag, and pol genes of 55 HIV-infected Surinamese, Antillean, and Dutch heterosexuals living in The Netherlands and 72 HIV-infected heterosexuals living in Suriname and the Antilles were amplified and sequenced. We included 145 pol sequences of HIV-infected Surinamese, Antillean, and Dutch heterosexuals living in The Netherlands from an observational cohort. All sequences were phylogenetically analyzed by neighbor-joining. Additionally, HIV-1 mobility among ethnic groups was estimated. A phylogenetic tree of all pol sequences showed two Surinamese and three Antillean clusters of related strains, but no clustering between ethnic groups. Clusters included sequences of individuals living in Suriname and the Antilles as well as those who have migrated to The Netherlands. Similar clustering patterns were observed in env and gag. Analysis of HIV mobility among ethnic groups showed significantly lower migration between groups than expected under the hypothesis of panmixis, apart from higher HIV migration between Antilleans in The Netherlands and all other groups. Our study shows that HIV transmission mainly occurs within the ethnic group. This suggests that cultural factors could have a larger impact on HIV mobility than geographic distance.

Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis b virus (Article)

2010-12-01T00:00:00Z

Background & Aims We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy. Methods We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF. Results At baseline, 80% of patients had a detectable viral load (HBV DNA >20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA <20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (interquartile range, 4163 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m2, which was most pronounced shortly after TDF therapy was initiated. Conclusions TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed.

Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir (Article)

2010-05-01T00:00:00Z

HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. We compared atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)0→t for atovaquone relative to the healthy volunteers was 0.25 (0.16-0.38), 0.26 (0.17-0.41) and 0.54 (0.35-0.83) for patients on efavirenz, lopinavir/ritonavir and atazanavir/ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38-43%). Physicians should be alert for atovaquone/proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.

Plasma HCV-RNA decline in the first 48 h identifies hepatitis C virus mono-infected but not HCVHIV-coinfected patients with an undetectable HCV viral load at week 4 of peginterferon-alfa-2aribavirin therapy (Article)

2009-12-01T00:00:00Z

During peginterferon-alfa-2aribavirin therapy, plasma hepatitis C virus (HCV)-RNA decreases with a rapid first phase and a slower second phase. We compared the viral load decrease and slope in the first 48 h in patients with a rapid viral response (RVR, i.e. HCV-RNA < 50 IUmL at week 4) with patients not achieving an RVR. From 23 HCV-infected (14 mono-infected and nine HCVHIV-coinfected) genotype 1 or 4 positive peginterferon-alfa-2aribavirin- treated patients, plasma HCV-RNA was determined at baseline, 48 h, weeks 1, 2, 4, 8, 12, 48 and 72. The HCV viral load decrease (0-48), the slope (λ1) and the efficiency factor (ε) were determined in the first 48 h after the start of therapy. Five (36%) HCV mono-infected patients and three (33%) HIVHCV-coinfected patients achieved an RVR whereas six (43%) HCV mono-infected patients and five (56%) HIVHCV-coinfected patients reached a sustained viral response (SVR). In contrast to HIVHCV-coinfected patients, five HCV mono-infected patients with an RVR showed both a larger 0-48 and steeper1(-1.77log10IUmL ± 0.66 and -2.04day ± 0.76) compared to nine non-RVR patients (-0.66log10IUmL ± 0.39; P = 0.019 and -0.76day ± 0.41; P = 0.019). When divided by SVR, a greater 0-48 and steeper λ1were also seen in both HCV mono-infected and HIVHCV-coinfected patients. Thus, in the first 48 h after the start of therapy, HCV mono-infected patients with an RVR have a larger viral load decrease, steeper viral slope and a higher efficiency factor as compared with non-RVR patients.

P18-03. Dendritic cell-based immune therapy against HIV-1 (Article)

2009-10-22T00:00:00Z

Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations (Article)

2009-10-01T00:00:00Z

OBJECTIVE: To establish whether efavirenz dose reduction in patients with high plasma concentrations prevents toxicity-induced efavirenz discontinuations. METHODS: HIV-infected patients with a high efavirenz plasma concentration (≥4.0 mg/L) while using efavirenz 600 mg once daily as part of their highly active antiretroviral therapy regimen were selected from the AIDS Therapy Evaluation in The Netherlands cohort study. These patients were classified into 2 groups. The reduced-dose group contained all patients who underwent dose reduction after the high plasma concentration measurement; the standard-dose group consisted of patients who had no dose reduction. Kaplan-Meier and Cox proportional hazards analysis were used to assess the impact of dose reduction on toxicity-induced efavirenz discontinuations. RESULTS: One hundred eighty patients with high plasma efavirenz levels were included, 47 of them subsequently had their efavirenz dose reduced from 600 mg to 400 mg once-daily, which resulted in a 41% decrease in the median efavirenz plasma concentration. At week 48, the Kaplan-Meier estimated cumulative incidence of toxicity-induced efavirenz discontinuations was 11.5% in patients who continued the standard dose versus 2.3% in patients who had a dose reduction; P = 0.066 (log-rank test). Dose reduction was not associated with loss of virological suppression. CONCLUSIONS: Dose reduction may prevent toxicity-induced discontinuations in patients with high efavirenz plasma concentrations, whereas not compromising virological efficacy. Copyright

Photodynamic therapy with topical metatetrahydroxychlorin (Fosgel) is ineffective for the treatment of anal intraepithelial neoplasia, grade III (Article)

2009-09-01T00:00:00Z

Long-term survival after kidney transplantation in an HIV-positive patient (Article)

2009-04-17T00:00:00Z

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.

Baseline lipid levels rather than the presence of reported body shape changes determine the degree of improvement in lipid levels after switching to atazanavir (Article)

2009-01-01T00:00:00Z

Purpose: To study factors influencing lipid changes after switching to atazanavir (ATV) and the effectiveness of ATV in maintaining virus suppression. Methods: Retrospective cohort study in patients with viral suppression, comparing patients switching to ATV with those continuing combination antiretroviral therapy (cART). Outcome measures were 48-week total (TC), high-density (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) changes, stratified for dyslipidemia and lipodystrophy and virological failure (time to first of two consecutive detectable HIV RNA). Results: 225 patients switched to ATV (193 [85.8%] RTV boosted), and 3120 continued cART. In patients with baseline TC >6.2 mmol/L, those switching had greater mean (95% CI) TC decreases compared to those continuing cART (-1.26 [-1.63 to -0.89] and -0.54 [-0.64 to -0.44] mmol/L, p = .002). Likewise greater TG changes were observed in patients with high (>2.3 mmol/L) baseline TG (-1.44 [-2.05 to -0.83] and -0.54 [-0.70 to -0.38] mmol/L, p = .002). Effects were seen irrespective of presence of lipodystrophy. Patients switching to ATV had virological failure more often (17/224 [7.8%]) than those continuing cART (73/3100 [2.4%], p < .0001). Conclusions: Patients with virological suppression, including those with lipodystrophy, may benefit from switching to ATV with lipid profile improvement, especially if baseline lipid levels are high. This should be balanced against a possible higher virological failure risk.

Lower perceived necessity of HAART predicts lower treatment adherence and worse virological response in the ATHENA cohort (Article)

2008-12-01T00:00:00Z

Immunologic, virologic, and clinical consequences of episodes of transient viremia during suppressive combination antiretroviral therapy (Article)

2008-05-01T00:00:00Z

OBJECTIVE: To investigate immunologic, virologic, and clinical consequences of episodes of transient viremia in patients with sustained virologic suppression. METHODS: From the AIDS Therapy Evaluation Project, Netherlands cohort, 4447 previously therapy-naive patients were selected who were on continuous combination antiretroviral therapy and had initial success (2 consecutive HIV RNA measurements <50 copies/mL). During episodes of viral suppression (RNA <50 copies/mL), low-level viremia (RNA 50 to 1000 copies/mL), or high-level viremia (RNA >1000 copies/mL) after initial success, the occurrence of therapy changes, drug resistance, and clinical events was assessed. RESULTS: During 11,187 person-years of follow-up, 1281 (28.8%) patients had at least 1 RNA measurement >50 copies/mL. Among 8069 episodes, there were 5989 (74.2%) episodes of suppression, 1711 (21.2%) episodes of low-level viremia, and 369 (4.6%) episodes of high-level viremia. Most episodes of low-level viremia consisted of ≤2 RNA measurements (93.7%), were without clinical events or therapy changes (79.6%), and were without changes in CD4 cell counts. Therapy changes (52.3% of episodes) and resistance (23.3%) were frequently observed during high-level viremia. CONCLUSIONS: Episodes of low-level viremia are frequent and short lasting, and the low proportion of episodes with clinical events suggests that leaving therapy unchanged is a clinically acceptable strategy. In contrast, high-level viremia is associated with resistance and is often followed by therapy changes.

Steady-state nevirapine plasma concentrations are influenced by pregnancy (Article)

2008-04-01T00:00:00Z

Objectives: Optimal plasma concentrations of antiretroviral drugs are required during pregnancy to treat maternal HIV infection and prevent mother-to-child transmission. We investigated the effect of pregnancy on nevirapine (NVP) plasma concentrations. Methods: We included all HIV-1-infected women for whom NVP plasma concentrations were available as part of routine patient care at two university hospitals. Plasma NVP concentrations were compared for pregnant (n = 45) and non-pregnant (n = 152) women. Univariate and multivariate linear regression analyses were used to identify and adjust for other confounding factors associated with NVP plasma concentrations. For pregnant women who had a plasma NVP concentration available both during and outside pregnancy, a paired analysis was performed. Results: Steady-state NVP plasma concentrations were lower in pregnant women: 5.2mg/L (interquartile range 3.9-6.8) vs. 5.8mg/L (4.3-7.7) (P = 0.08). After adjusting for confounders, both pregnancy (regression coefficient = -0.90mg/L, P = 0.046) and African descent (regression coefficient = +1.13mg/L, P = 0.005) influenced NVP concentrations significantly. The paired analysis showed mean concentrations of 4.8mg/L during pregnancy and 5.8mg/L outside pregnancy (paired t-test, P = 0.073). Conclusions: Pregnancy has a moderate but significant lowering effect on NVP plasma concentrations. Being of African descent compensates for the lowering effect of pregnancy on NVP concentrations.

Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: The ATHENA cohort study (Article)

2008-03-15T00:00:00Z

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.

CCR5-restricted HIV type 2 variants from long-term aviremic individuals are less sensitive to inhibition by β-chemokines than low pathogenic HIV type 1 variants (Article)

2008-03-01T00:00:00Z

Many HIV-2-infected individuals maintain low, often undetectable, viral loads for prolonged periods. Virus and/or host factors that contribute to this high level of virus control are largely unknown. Previously we demonstrated that HIV-2 variants from long-term aviremic individuals have relatively low replication kinetics in vitro in comparison to HIV-1 variants. We hypothesized that the relatively low replication rates of HIV-2 in vitro as well as the high level of virus control in vivo might be explained by HIV-2 replication being more sensitive to inhibitory host factors like β-chemokines or other CD8+T cell-derived factors than HIV-1 replication. To test this we determined the effect of exogenously added β-chemokines and healthy donor CD8+T cells on the in vitro virus production of HIV-2 and HIV-1 variants from long-term nonprogressors (LTNPs). Contrary to expectations, HIV-2 replication was inhibited less efficiently by RANTES and MIP-1α than HIV-1 replication. CD8+T cells from 8 of 12 healthy donors reduced HIV replication minimally 2-fold. Interestingly, cells from five of these donors inhibited HIV-1 but hardly affected HIV-2 replication, while the reverse was observed for cells from one donor. For HIV-1, but not HIV-2, the magnitude of the antiviral effect of CD8+T cells correlated with their effect on RANTES levels in culture supernatants. Our findings indicate that RANTES is a more important factor of CD8+T cell-associated anti-HIV-1 activity than it is of HIV-2 activity and that the benign clinical course of HIV-2 infection is not due to enhanced β-chemokine sensitivity of HIV-2 variants.

A prospective open study of the efficacy of high-dose recombinant hepatitis B rechallenge vaccination in HIV-infected patients (Article)

2008-01-15T00:00:00Z

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).

Therapeutic drug monitoring of the HIV protease inhibitor atazanavir in clinical practice (Article)

2007-10-01T00:00:00Z

Background: Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little is known about the use of TDM for atazanavir. Methods: This is a retrospective cohort analysis on theuse of TDM of atazanavir at three clinical sites in The Netherlands. Patients were divided into three groups: (i) all patients with evaluable data of plasma atazanavir concentrations and its relationship with hyperbilirubinaemia; (ii) patients who started atazanavir without documented evidence of protease inhibitor (PI) mutations; (iii) patients who started atazanavir with documented evidence of PI mutations. The genotypic inhibitory quotient (GIQ) was calculated by dividing the mean atazanavir plasma trough concentration by the number of PI mutations. Results: A total of 108 patients were included; 70 (65.8%) were using atazanavir/ritonavir (300/100 mg once daily). No significant relationship was observed between atazanavir plasma trough concentration and antiviral response in patients starting atazanavir without PI mutations (group 2; n = 82). In contrast, a significant relationship was observed between atazanavir GIQ and treatment response in patients starting atazanavir while having PI mutations (group 3; n = 26). The cut-off value for GIQ most predictive of virological failure was 0.23 mg/L/mutation: patients (n = 8) with a GIQ equal to or below this value had 50% virological failure whereas patients (n = 18) with a GIQ above 0.23 mg/L/mutation had only 11% virological failure (χ2: P = 0.030). Atazanavir plasma trough concentrations were significantly related with the occurrence of increased total bilirubin concentrations. Conclusions: TDM of atazanavir might be beneficial for patients with documented PI resistance or patients with hyperbilirubinaemia. The

CCR5, GPR15, and CXCR6 are major coreceptors of human immunodeficiency virus type 2 variants isolated from individuals with and without plasma viremia. (Article)

2005-02-01T00:00:00Z

Human immunodeficiency virus type 2 (HIV-2) is generally considered capable of using a broad range of coreceptors. Since HIV-2 variants from individuals with nonprogressive infection were not studied previously, the possibility that broad coreceptor usage is a property of variants associated with progressive infection could not be excluded. To test this, we determined the coreceptor usage of 43 HIV-2 variants isolated from six long-term-infected individuals with undetectable plasma viremia. Using GHOST indicator cells, we showed for the first time that the only coreceptors efficiently used by low-pathogenic HIV-2 variants are CCR5, GPR15 (BOB), and CXCR6 (BONZO). Surprisingly, control HIV-2 variants (n = 45) isolated from seven viremic individuals also mainly used these three coreceptors, whereas use of CCR1, CCR2b, or CCR3 was rare. Nearly a quarter of all HIV-2 variants tested could infect the parental GHOST cells, which could be partially explained by CXCR4 usage. Use of CXCR4 was observed only for HIV-2 variants from viremic individuals. Thirty-eight variants from aviremic and viremic HIV-2-infected individuals were additionally tested in U87 cells. All except one were capable of infecting the parental U87 cells, often with high efficiency. When virus production in parental cells was regarded as background in the coreceptor-transduced cell lines, the results in U87 cells were largely in agreement with the findings in GHOST cells. HIV-2 isolates from aviremic individuals commonly use as coreceptors CCR5, GPR15, and CXCR6, as well as an unidentified receptor expressed by U87 cells. Broad coreceptor usage, therefore, does not appear to be associated with pathogenicity of HIV-2.

Clinical, immunological and virological response to different antiretroviral regimens in a cohort of HIV-2-infected patients (Article)

2003-01-01T00:00:00Z

OBJECTIVE: To assess the clinical, immunological and virological response and the emergence of resistance towards antiretroviral therapy (ART) in a cohort of HIV-2-infected patients. DESIGN: Observational study. PATIENTS: HIV-2-infected patients residing in the Netherlands. RESULTS: From 1995 to 2001 seven patients failed various ART regimens. The resistance mutations were analysed retrospectively. Development of mutations proved to be similar to that observed in HIV-1-infected patients, with the exception of a higher occurrence of the Q151M mutation within the reverse transcriptase gene. In a prospective study, comprising 13 consecutive naive HIV-2-infected patients, all patients achieved plasma HIV-2-RNA suppression below the detection limit (500 copies/ml). The antiretroviral regimen consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) and indinavir, with a boosting dose of ritonavir; the median follow-up was 91 weeks. Two patients experienced a temporary virological rebound, while at the same time therapeutic drug monitoring showed sub-therapeutic plasma levels of indinavir. CONCLUSION: Sustained viral suppression in HIV-2-infected patients can be achieved using an antiretroviral regimen of two NRTIs and boosted indinavir or lopinavir.

Antiretroviral therapy in patients with dual infection with human immunodeficiency virus types 1 and 2. (Letter To Editor)

2000-06-08T00:00:00Z

Human immunodeficiency virus type 2: pathogenesis and antiretroviral therapy (Doctoral Thesis)

2000-04-26T00:00:00Z

Human immunodeficiency virus type1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), and simian immunodeficiency virus (SIV) have been identified as hither unknown primate members of the Lentivirinae subfamily of the family Retroviridae in 1983, 1986 and 1985 respectively, HIV-1 and HIV-2 were identified as the causative agents of the newly emerging acquired immunodeficiency syndrome (AIDS) of humans (1-3) and SIV was shown to cause AIDS in certain primate species, HIV-1 is clearly an emerging virus, which is expected to have infected between 30 and 40 million people by the year 2000, Although lentiviruses of different animal species share many biological features, the natural course of the disease they cause in their respective host species varies considerably, Table 1 summarises the currently known lentiviruses and their pathogenic characteristics in different host species, Elucidation of the differences in the pathogenesis of infection with different lentiviruses as well as the underlying mechanisms, may be expected to lead to a better understanding of the course of the natural infection with any of these viruses and will provide new tools for the development of intervention strategies, Most notably, the understanding of the marked differences between the natural diseases caused by the respective primate lentiviruses HIV-1, HIV-2 and SIV, may lead to the identification of new therapeutic and preventive measures for AIDS in humans, which in the light of the current pandemic spreading of this disease are more needed than ever.

Broadening of coreceptor usage by human immunodeficiency virus type 2 does not correlate with increased pathogenicity in an in vivo model. (Article)

2000-01-01T00:00:00Z

The pathogenic properties of four primary human immunodeficiency virus type 2 (HIV-2) isolates and two primary HIV-2 biological clones were studied in an in vivo human-to-mouse chimeric model. The cell-associated viral load and the ability to reduce the severity of the induced graft-versus-host disease symptoms, the CD4/CD8 ratio and the level of repopulation of the mouse tissues by the graft, were determined. All HIV-2 strains, irrespective of their in vitro biological phenotype, replicated to high titres and significantly reduced graft-versus-host disease symptoms as well as the CD4/CD8 ratios. Reduction of graft repopulation caused by infection with the respective HIV-2 strains showed that the in vitro replication rate, syncytium-inducing capacity and ability to infect human macrophages did influence the in vivo pathogenic potential whereas broadening of coreceptor usage did not.

CD4 T cells remain the major source of HIV-1 during end stage disease. (Article)

1999-01-01T00:00:00Z

OBJECTIVE: To assess the source of HIV-1 production in lymphoid tissue biopsies from HIV-infected patients, with no prior anti-retroviral protease inhibitor treatment, with a CD4 cell count > 150 x 10(6)/l (group I) or < 50 x 10(6)/l (group II), co-infected with Mycobacterium tuberculosis or Mycobacterium avium complex. DESIGN AND METHODS: Lymphoid tissue biopsies from 11 HIV-1-infected patients, taken for diagnostic purposes, were studied by HIV-1 RNA in situ hybridization and immunohistochemistry. RESULTS: Patients of group I showed well organized granulomas, in contrast with patients of group II, in which granuloma formation was absent. HIV-1 RNA-positive cells in group I patients were found mainly around the granulomas, whereas in group II HIV-1-producing cells were confined to areas with remaining intact lymphoid tissue. Despite the abundant presence of macrophages, the productively infected HIV-1-positive cells in both groups were almost exclusively CD4 T cells. CONCLUSION: In contrast with previously published data, CD4 T cells appear to remain the major source of HIV-1 production in end-stage disease.

Coreceptor usage of human immunodeficiency virus type 2 primary isolates and biological clones is broad and does not correlate with their syncytium-inducing capacities (Article)

1998-01-01T00:00:00Z

Entry of human immunodeficiency virus type 1 (HIV-1) into target cells is mediated by binding of the surface envelope glycoprotein to the CD4 molecule. Interaction of the resulting CD4-glycoprotein complex with alpha- or beta-chemokine receptors, depending on the biological phenotype of the virus, then initiates the fusion process. Here, we show that primary HIV-2 isolates and biological clones, in contrast to those of HIV-1, may use a broad range of coreceptors, including CCR-1, CCR-3, CCR-5, and CXCR-4. The syncytium-inducing capacity of these viruses did not correlate with the ability to infect via CXCR-4 or any other coreceptor. One cell-free passage of the intermediate isolates in mitogen-stimulated, CD8+ cell-depleted peripheral blood mononuclear cells resulted in the outgrowth of variants with CCR-5 only, whereas the coreceptor usage of late and early isolates did not change. Since HIV-2 is less pathogenic in vivo than HIV-1, these data suggest that HIV pathogenicity in vivo is not directly related to the spectrum of coreceptors used in in vitro systems.

Coreceptor usage of human immunodeficiency virus type 2 primary isolates and biological clones is broad and does not correlate with their syncytium-inducing capacities. (Article)

1998-01-01T00:00:00Z

HIV-2 infection in 12 European residents: virus characteristics and disease progression. (Article)

1996-01-01T00:00:00Z

OBJECTIVE: To assess the disease progression rate among 12 HIV-2-infected West European residents (nine of West African descent), compared with the disease progression rate among HIV-1-infected individuals of the same population, and the characteristics of the HIV-2 strains involved. METHODS: HIV-2-infected individuals were identified by commercially available serological assays, their clinical status and CD4+ cell counts were monitored, and HIV-2 was isolated from their peripheral blood mononuclear cells. T-cell-line tropism and syncytium-inducing capacities of the isolated viruses were determined and their phylogenetic relationships were analysed by comparing polymerase chain reaction-amplified nucleotide sequences of reverse transcriptase (RT) gene segments. RESULTS: Eight of the 12 HIV-2-infected individuals presented with progressive disease and one of them progressed from Centers for Disease Control and Prevention group A1 to A3 within 36 months after seroconversion. The ratios of asymptomatic versus symptomatic individuals among residents of the Rotterdam region of West African descent were 2:7 for HIV-2 and 8:9 for HIV-1-infected individuals. HIV-2 was isolated from six of the nine individuals with progressive disease. The time required for virus isolation correlated inversely with the individuals' CD4+ cell counts. Five of the HIV-2 isolates replicated in immortalized T-cell lines, and two isolates from patients with AIDS were syncytium-inducing. Five HIV-2 isolates from patients born in the Cape Verdian Isles grouped together within subtype A. The HIV-2 isolate from a patient of Ghanese origin belonged to subtype B. Mutations were identified in the RT genes from HIV-2 isolates of two zidovudine-treated patients, one of which has also been shown to be involved in zidovudine resistance in HIV-1. CONCLUSION: Disease progression in HIV-2 infection may be as rapid as in HIV-1. HIV-2 isolation and viral phenotype were related to disease status, and mutations identical to those observed in HIV-1 zidovudine resistance were observed in patients treated with zidovudine.