Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe.

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

Plasma concentrations of the cardiovascular risk factor asymmetric dimethylarginine (ADMA) are increased in patients with HIV-1 infection and correlate with immune activation markers.

OBJECTIVE: Higher concentrations of inflammation and immune activation markers as well as the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are associated with an increased cardiovascular risk. In vitro, parallel formation of ADMA and macrophage marker neopterin was found in stimulated human peripheral blood mononuclear cells. METHODS: In 112 HIV-1 infected patients, concentrations of ADMA, SDMA and arginine were compared to C-reactive protein and neopterin concentrations before they were referred to antiretroviral therapy. Disease activity was determined by viral load (qPCR), CD4(+) cell counts (FACS) and neopterin concentrations in plasma and urine (HPLC and ELISA). Additionally, concentrations of lipids were determined. RESULTS: HIV-1 infected patients presented with increased neopterin, ADMA and SDMA concentrations, whereas CD4(+) counts and arginine and plasma lipid concentrations were low. ADMA and SDMA concentrations significantly correlated with markers of immune activation, but not with plasma lipids. CONCLUSIONS: Results of this study indicate that increased ADMA and SDMA production may be related to an increased activity of immune activation pathways.

Quality of life and immune activation in patients with HIV-infection.

Depression and impaired quality of life (QoL) are frequently observed in patients suffering from HIV-infection. As an enhanced degradation of the serotonin precursor tryptophan is well documented in HIV-infected patients, disturbances in tryptophan metabolism may be causally linked to HIV-related depression. In this study, the relationship between QoL, depression, various laboratory parameters and tryptophan metabolism was investigated. To estimate QoL and mood, 152 HIV-infected patients (classified according to CDC-criteria) were requested to complete the following psychological questionnaires: BDI and MQoL-HIV. Disease progression was monitored by determination of viral load (VL), CD4(+) cell counts, haemoglobin and urinary/plasma neopterin, tryptophan and kynurenine concentrations. Increasing VL, decreasing CD4(+) cell counts, and enhanced tryptophan degradation reflected disease progression. Forty-one patients presented with mild, 22 with moderate and 14 with severe depression. BDI and MQoL scores were associated strongly with each other (rs=-0.838; p<0.001). Patients without depression had significantly lower plasma neopterin concentrations, higher CD4(+) cell counts and haemoglobin concentrations and better QoL scores (all p<0.01) than depressive patients. Furthermore, they showed lower rates of tryptophan degradation (p<0.05). Significant associations were observed between tryptophan degradation and immune activation. Haemoglobin and viral load were predictive for impaired QoL, while high urinary neopterin concentrations and low haemoglobin were the best predictors for depression. In HIV-infected patients, depressive mood and impaired QoL appear to be related to clinical parameters like immune activation, haemoglobin values and viral load.

Loss of zidovudine related mutations in the reverse transscriptase gene of HIV after switching therapy.

The standard treatment for HIV infected patients is the highly active antiretroviral therapy. Due to resistance developments treatment failure can be found in some patients. In our study two different strategies are compared, which may reduce resistance mutations. Six patients (group A and B) have been monitored for about six years. Group A patients had a switch in their AZT-containing treatment to non AZT-containing regimens. In group B patients AZT-containing regimens' were interrupted by drug holidays. Early mono- and dual-therapies containing zidovudine (AZT) have been applied in all patients with poor long-term improvements. Due to the rapid development of escape mutants viral rebound was observed soon after treatment initiation. Genotypic assays were developed to asses AZT-resistance mutations. The longer AZT had been applied the more mutations had developed. These mutations disappeared when patients were taking "drug-holidays" and drug selection pressure was missing. Besides, it was demonstrated in two patients that these AZT-mutations could disappear, if in combination therapies AZT was replaced by other antiretroviral drugs. This study shows that not only by drug-holidays but also by switches in therapy mutations can disappear, which is especially important for patients with low CD 4 cell counts and high viral load levels.

Capillary electrophoretic separation of protease inhibitors used in human immunodeficiency virus therapy.

The scope of this work was to investigate the migration behavior of the currently used protease inhibitors for antiretroviral therapy of people infected with the human immunodeficiency virus and to develop a method for their capillary electrophoretic separation and determination. All of the protease inhibitors (indinavir, saquinavir, nelfinavir, amprenavir, and ritonavir) contain at least one basic amino functional group. As a consequence, they can be separated by capillary zone electrophoresis using acidic buffer electrolytes. A fast electroosmotic flow is established in order to increase separation speed, by adding a cationic electroosmotic flow modifier to the electrolyte. After using conventional serum pretreatment procedures it is possible to separate all five protease inhibitors within less than 5 min. In addition, a non-aqueous CE method is also presented which enables the separation of three protease inhibitor compounds within less than 3 min.

Pyuria in patients treated with indinavir is associated with renal dysfunction.

BACKGROUND: Indinavir therapy is associated with a continuum of crystal-related syndromes, including nephrolithiasis, renal colic, flank pain without recognizable stone formation, dysuria and asymptomatic crystalluria. A frank nephropathy has been recognized recently as part of the spectrum. METHODS: A retrospective analysis of 72 HIV-infected individuals receiving indinavir was performed to identify the frequency and risk factors for indinavir-associated nephropathy and urinary complications. Individuals treated with nucleoside analogues alone served as controls. RESULTS: Mean serum creatinine levels rose from 1.03 +/- 0.16 mg/dl to 1.11 +/- 0.22 mg/dl at week 12 and 1.15 +/- 0.27 mg/dl at week 24 (both, p < 0.01). Thirteen individuals developed serum creatinine levels > or =1.4 mg/dl. Increased serum creatinine levels were found more frequently in women (p < 0.01) and were associated with pyuria and microhematuria (p < 0.01). Frank renal colic and/or nephrolithiasis (seven patients) and urinary pH were not associated with serum creatinine levels > or =1.4 mg/dl. The mean duration of indinavir treatment, until sterile pyuria occurred, were 22 weeks and 32 weeks until the first rise of serum creatinine levels to > or =1.4 mg/dl. Ten patients showed both findings, pyuria preceded the first rise in serum creatinine levels to > or = 1.4 mg/dl (18 vs. 27 weeks, p = 0.02). Renal biopsy, done in three patients, revealed tubulointerstitial disease with crystals in collecting ducts. In 21 patients, among them 11 with pyuria, indinavir was replaced for various reasons and pyuria disappeared in nine. In these patients mean serum creatinine levels decreased from 1.43 mg/dl at withdrawal of indinavir to 1.04 mg/dl three months later (p < 0.01). CONCLUSION: Indinavir therapy is associated with a decrease in renal function which is reversible after withdrawal. In addition, indinavir-associated tubulointerstitial disease does no in patients taking indinavir may help to identify patients being at risk for nephrotoxicity.

Specific serum IgG, IgM and IgA antibodies to human papillomavirus types 6, 11, 16, 18 and 31 virus-like particles in human immunodeficiency virus-seropositive women.

To evaluate the humoral immune response to human papillomavirus (HPV) in women infected with human immunodeficiency virus (HIV), serum samples of 83 HIV-positive individuals were analysed by ELISA for specific antibodies of the isotypes IgG, IgA and IgM recognizing HPV-6, -11, -16, -18 and -31 L1 virus-like particles (VLPs). Papillomavirus-related lesions were present in 30 of 83 HIV-positive women. Twenty-one women (25%) presented with high-/intermediate-grade anogenital squamous intraepithelial lesions. PCR analysis and sequencing for HPV typing was done from biopsy specimens of 18 women; PCR-positive results were obtained in 90% of cases. In addition, HPV DNA hybrid capture assays were performed from cervical swabs of 58 HIV-positive women, 53% of whom had a positive result for high-risk HPV. Overall, positive IgG reactivity to HPV-6/-11 and HPV-16/-18/-31 was seen in 19%/31% and 49%/30%/24% of HIV-positive women, respectively. HPV-seropositivity was even higher than in 48 HIV-negative cervical intraepithelial neoplasia/cancer patients with percentages as follows: 8%/2% and 31%/15%/15%. This difference was significant for HPV-16 (P=0.046). IgA responses were comparable to IgG. IgM responses were low. The extraordinarily high rate of antibodies to the capsid protein L1 of high-risk HPVs (HPV-16, -18 and/or -31) in 58% of HIV-positive women compared to 19% (P=0.00001) of 102 healthy HIV-negative control women suggests a high lifetime cumulative exposure to HPV and increased expression of capsid proteins due to cellular immunodeficiency in HIV-infected women.

Paronychia with pyogenic granuloma in a child treated with indinavir: the retinoid-mediated side effect theory revisited.

BACKGROUND: The introduction of HIV-1 protease inhibitors into the treatment of patients infected with HIV-1 has had a major influence on clinical practice. However, the use of protease inhibitors is frequently associated with the development of resistance and several side effects and interactions with other drugs have been reported. OBSERVATIONS: We present the first pediatric patient with paronychia with pyogenic granuloma associated with the administration of the protease inhibitor indinavir. Clinical findings are discussed in view of a possible interference of indinavir with endogenous retinoid metabolism. CONCLUSION: Considerable evidence advocates the mediation of indinavir side effects by impaired oxidative metabolism of retinoic acid through the inhibition of cytochromes P450 3A by indinavir rather than by impaired formation of 9-cis-retinoic acid.

Persistent flank pain, low-grade fever, and malaise in a woman treated with indinavir.

This case report describes a 32-year-old woman treated with indinavir who developed mild to moderate flank pain, malaise, and low-grade fever. Sterile pyuria preceded increased serum creatinine levels. Workup revealed persistent pyuria, normal-sized kidneys, a normal intravenous pyelography, and negative urinary cultures. Renal biopsy showed interstitial nephritis and chronic inflammation. Collecting ducts contained crystals. Two months after treatment with indinavir was discontinued, serum creatinine levels returned to normal and pyuria disappeared. Sterile pyuria in patients taking indinavir may help to identify patients at risk for renal dysfunction and interstitial nephritis. Markedly increasing the fluid intake above the recommended dosage may ameliorate or even reverse the process of tubulointerstitial disease.

Serum HIV-1 RNA levels compared to soluble markers of immune activation to predict disease progression in HIV-1-infected individuals.

We assessed the value of HIV-1 RNA level compared to soluble immune activation markers, namely neopterin, beta2-microglobulin and soluble TNF receptor 75 (sTNFR-75), to predict the change in the number of CD4+ T cells over a 1-year period, the development of AIDS, and survival (median follow-up 54 months). The study population comprised a cohort of 47 individuals for the analysis of the change in CD4+ T cells and survival (20 died), and a subgroup of 31 individuals with a baseline CD4+ T cells above 200 x 10(6)/l for the development of AIDS (11 developed AIDS). HIV-1 RNA was measured from stored sera by quantitative PCR. The CD4+ T cell count obtained at study entry strongly correlated with baseline serum HIV-1 RNA levels (r=-0.47), and to a lesser extent with neopterin (r=-0.41) and beta2-microglobulin (r=-0.29). The percentage change in CD4+ T cells over a 1-year period correlated with HIV-1 RNA levels (r=-0.32, p=0.03), however, stronger correlations were found for neopterin, beta2-microglobulin and sTNFR-75 (r=-0.51, r=-0.41, r=-0.42; p< 0.01). No progression to AIDS or death was observed in individuals with baseline HIV-1 RNA levels below 20,000 copies/ml (10 of 31 and 15 of 47 individuals, respectively). A Cox's proportional hazard model to predict AIDS revealed that HIV-1 RNA, the change in CD4+ cells over a 1-year period and sTNFR-75 levels independently predict AIDS; the change in CD4+ cells, the absolute CD4+ T cell count and neopterin were jointly significant to predict death. All results were adjusted for nucleoside monotherapy. In conclusion, to improve the predictive power, quantitation of HIV-1 RNA as a 'natural history marker' may be supplemented by measurement of sTNFR-75 for 'early'-stage disease progression and neopterin for 'late'-stage disease progression.

[Guidelines for implementing antiretroviral therapy]. / Richtlinien für die Durchführung einer antiretroviralen Therapie.

The rapid evolution of new information has introduced extraordinary complexity into the treatment of HIV-infected persons. Therefore it is recommended that care should be supervised by an expert. With regard to specific recommendations, treatment should be offered to all patients with the acute HIV syndrome and all patients with symptoms ascribed to HIV infection. The strength of the recommendation to treat asymptomatic patients should be based on the patient's willingness to accept therapy, the probability of adherence with the prescribed regimen, and the prognosis in term of time to an AIDS-defining disease as predicted by plasma HIV RNA levels and CD4+ T-cell counts. Once the decision has been made to initiate antiretroviral therapy, the goal is maximum viral suppression for as long as possible. Results of therapy are evaluated primarily with plasma HIV RNA levels: these are expected to show a one-log (10-fold) decrease at 8 weeks and no detectable virus at 4 to 6 months after initiation of treatment. Failure of therapy may be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, resistance, and other factors that are poorly understood. Patient education and involvement in therapeutic decisions is important for all medical conditions but is considered especially critical for HIV-infection and its treatment.

Decreased plasma concentrations of HDL cholesterol in HIV-infected individuals are associated with immune activation.

We investigated 63 individuals with HIV infection, 34 of whom were asymptomatic (nine had oral candidiasis, four had constitutional signs and symptoms, and 16 had AIDS), for plasma lipids, soluble tumor necrosis factor receptor 75 (sTNF-R75) and other immune activation markers, namely urinary neopterin, beta 2-microglobulin, and the CD4+ T cell count. The median CD4+ T cell count was 318 x 10(6)/L. All individuals were allowed to have light breakfast in the morning; the venipuncture for the plasma lipids was done between 11 a.m. and 3 p.m.. Decreased plasma concentrations were found for total cholesterol, and HDL and LDL cholesterol in 3.2%, 46%, and 56% of the subjects, respectively. Plasma triglyceride levels were increased in 31.7% of the study population. The frequency and the extent of the decrease of HDL and LDL cholesterol and the increase in triglyceride levels were greater in those with a CD4+ T cell count below the median (p = 0.003, p = 0.05, and p = 0.01); when comparing individuals with CD4+ T cell counts above and below 500 x 10(6)/L (19 individuals), a difference was only found for HDL cholesterol (p = 0.01). Plasma levels of triglycerides correlated significantly however weakly with serum concentrations of sTNF-R75 (rs = 0.32, p = 0.01) but not at all with urinary neopterin or serum beta 2-microglobulin. HDL cholesterol correlated inversely with sTNF-R75 (rs = -0.53, p < 0.0001) and to a lesser extent with urinary neopterin (rs = -0.46, p = 0.0003) and beta 2-microglobulin (rs = -0.34, p = 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased concentrations of soluble tumor necrosis factor receptor 75 but not of soluble intercellular adhesion molecule-1 are associated with the decline of CD4+ lymphocytes in HIV infection.

Immune activation seems to be involved in the pathogenesis of human immunodeficiency virus (HIV) infection. The immune activation markers neopterin and beta 2-microglobulin can predict the future rate of the decrease in CD4+ T cells. In a longitudinal study, we assessed whether the decline in the CD4+ T-cell count is associated with increased concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble tumor necrosis factor receptor 75 (sTNFR 75), compared to increased concentrations of beta 2-microglobulin and urinary neopterin. Forty-seven individuals representing all stages of HIV infection were followed-up for a mean of 12.7 months (range, 8 to 16 months). The percentage of the change of the CD4+ T-cell count from study entry to study end ranged from -97 to +98%; the median was -33%. Concentrations of urinary neopterin, sTNFR 75, and beta 2-microglobulin correlated with the percentage of the change of the CD4+ T-cell count from study entry to study end (r = -0.45, confidence interval (CI) -0.65 to -0.19; r = -0.42, 95% CI -0.63 to -0.15; and r = -0.416, 95% CI -0.62 to -0.15), but those of sICAM-1 did not. This difference was found despite significant correlations between sICAM-1 and sTNFR 75 and beta 2-microglobulin. Levels of sICAM-1 obtained at study entry correlated with levels of sICAM-1 obtained at study end (r = 0.46, 95% CI 0.17 to 0.68). In a multivariate linear regression analysis, urinary neopterin and sTNFR 75 were jointly significant for the percentage of the change of the CD4+ T-cell count. These results suggest that sTNFR 75 is a useful marker to estimate disease progression in HIV infection, whereas sICAM-1 does not seem to provide any information related to the decline of the CD4+ T-cell count.

Tumor necrosis factor alpha and soluble tumor necrosis factor receptors in individuals with human immunodeficiency virus infection.

There is some ongoing debate as to whether tumor necrosis factor (TNF) alpha levels are elevated in human immunodeficiency virus infection (HIV), however TNF alpha is rapidly cleared from the circulation and long-term markers have to be analyzed. Two distinct TNF alpha receptors have been identified, which also exist in soluble forms. The aim of this study was to investigate whether an association in HIV infection exists between the serum levels of TNF alpha, the two soluble TNF receptors (sTNFRs) and other soluble immune activation markers, namely neopterin and beta 2-microglobulin, and the number of CD4+ T-cells. We investigated 63 individuals with HIV infection for serum levels of TNF alpha, sTNFR 55, sTNFR 75, beta 2-microglobulin and urinary neopterin. The study population comprised all stages of HIV infection: 35 were asymptomatic, 8 had oral candidiasis, 4 had constitutional signs and 16 had AIDS. Circulating levels of TNF alpha were detectable in 22 of 63 (34.9%) individuals. For those with detectable TNF alpha levels the median concentration was 40 pg/ml. The frequency and extent of TNF alpha levels found in those with advanced HIV infection as defined by a CD4+ T-cell count below 320 x 10(6)/l did not differ significantly compared to those with a higher CD4+ T-cell count. Increased concentrations were found in 69.8% of the patients for sTNFR 55 and in 87.3% for sTNFR 75. Serum concentrations of sTNFR 55 and sTNFR 75 were higher in the group with the lower CD4 T-cell count (P = 0.006 and P = 0.0003). TNF alpha correlated with sTNFR 75 and weakly with sTNFR 55 and beta 2-microglobulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of body mass index with urinary neopterin in individuals infected with human immunodeficiency virus.

We assessed correlations between body mass index and plasma lipids, immune activation markers and the CD4+ T-cell count. The subjects of this cross-sectional study were randomly selected and comprised all those who attended the AIDS Out-Patient Clinic at the University Hospital in Innsbruck in March and April 1992. Patients with signs and symptoms of acute bacterial and secondary opportunistic infections were excluded. We investigated 63 individuals with HIV infection of whom 35 were asymptomatic, 8 had oral candidiasis, 4 had constitutional signs and symptoms and 16 had AIDS, for an association among body mass index, urinary neopterin, soluble tumor necrosis factor receptors (sTNFRs), plasma lipids, and the numbers of CD4+ T cells. The body mass index correlated inversely with urinary neopterin (rs = -0.42, p = 0.0009) and weakly with the numbers of CD4+ T cells (rs = 0.29, p = 0.02) but not with plasma lipids, sTNFRs and beta 2-microglobulin. The results show that body mass index correlates with immune activation. The data suggest that endogenous formation of interferon-gamma may be an important mediator of wasting in HIV infection, since this cytokine is responsible for the observed elevation of neopterin concentrations in body fluids.

Increased serum concentrations of soluble tumor necrosis factor receptors in HIV-infected individuals are associated with immune activation.

Serum concentrations of soluble tumor necrosis factor receptors (sTNF-Rs) were measured in 61 human immunodeficiency virus (HIV)-infected individuals. Thirty-five percent of these had increased serum concentrations of sTNF-R type I (p55) (sTNF-R55) and 82% had increased concentrations of sTNF-R type II (p75) (sTNF-R75). The extent of the increase of sTNF-R75 was greater in more advanced HIV infection (p = 0.046) as it was measured by dividing the 61 individuals into two groups according to the median of the CD4+ T-cell count. However, the increase in concentrations of sTNF-R55 in the group with a CD4+ T-cell count below the median was only moderate and did not reach statistical significance. A strong correlation was found between sTNF-R75 and the soluble immune activation markers beta 2-microglobulin (rs = 0.74, p < 0.0001) and urinary neopterin (rs = 0.67, p < 0.0001), and a less strong correlation was found with interferon-gamma (rs = 0.51, p = 0.0001). The correlations observed for sTNF-R55 were also significant but were always weaker than that of sTNF-R75. A weak inverse correlation was found between the number of CD4+ T cells and sTNF-R75 (rs = -0.33, p = 0.012), but no such correlation was observed with sTNF-R55. Our findings suggest that increased concentrations of serum sTNF-Rs in HIV infection are linked to immune activation, in which synergistic actions of interferon-gamma and the TNF-alpha system are likely to play an important role.