Management of persons infected with human immunodeficiency virus requiring admission to the intensive care unit.

Rates of admission to the intensive care unit (ICU) for persons infected with human immunodeficiency virus (HIV) remain relatively unchanged in the modern era despite advances in antiretroviral therapy (ART) and improvements in ICU survival. Critical care may be required for patients with HIV because of severe opportunistic infections or malignancy, antiretroviral drug toxicity, or critical illness seemingly unrelated to HIV, and each of these scenarios may present different management challenges. In this article, the epidemiology of HIV-related ICU admission is reviewed and key management issues are discussed.

HLA-B*5701 genetic screening prior to abacavir prescription in Georgia.

A hypersensitivity reaction to abacavir develops in approximately 2-8% of HIV patients receiving this drug and is strongly associated with presence of the human leukocyte antigen (HLA)-B*5701. Screening for HLA-B*5701 reduces the risk of developing an abacavir hypersensitivity reaction. The carriage rate of HLA-B*5701 has not been studied in Georgia before 2009. Objective of the study was to determine HLA-B*5701 prevalence in HIV-infected patients in Georgia. One hundred and sixty HIV positive patients attending Georgian Infectious Diseases, AIDS and Clinical Immunology Research Center in 2009 were recruited for the study. None of the patients had previously been treated with abacavir. Blood samples were collected and screened for HLA-B*5701 prior to abacavir prescription. Of 160 patients recruited 9 tested HLA B*5701 positive - 5.6% (95% CI: 2.6-10.4%). Of these nine patients 7 were males (male prevalence: 6.5%, 95% CI: 2.6-12.9 %) and 2 females (female prevalence: 4.8%, 95% CI: 0.6-16.2%). The first prospective study of HLA-B*5701 prevalence in Georgia show similar results to the results of other studies. Abacavir still remains one of the key drugs of antiretroviral regimens in Georgia and other countries. Therefore, prospective HLA-B*5701 screening should be implemented in all settings where abacavir is widely used to guide selection of ART regimens and to reduce the risk of potentially life threatening hypersensitivity reaction.

[HLA-B*5701 and abacavir hypersensitivity reaction]. / Génotype HLA-B*5701 et hypersensibilité à l'abacavir.

A potentially life-threatening hypersensitive reaction occurs in association with initiation of HIV nucleoside analogue abacavir therapy in 4 to 8% of patients. Preliminary studies appear to confirm the role of the immune system in abacavir hypersensitivity. The reaction is possibly the result of presentation of drug peptides onto HLA, that may induce a pathogenic T-cell response. Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele and prospective HLA-B*5701 genetic screening has now been instituted in clinical practice to reduce the risk of hypersensitivity reaction.

Women exposed to single-dose nevirapine in successive pregnancies: effectiveness and nonnucleoside reverse transcriptase inhibitor resistance.

OBJECTIVE: To assess the impact of prior exposure to single-dose nevirapine (sdNVP) on mother-to-child transmission and genotypic resistance in HIV-infected women. DESIGN: Prospective study of 120 women exposed to the HIVNET 012 sdNVP regimen in two successive pregnancies and 240 antiretroviral (ARV)-naïve, multiparous women who received sdNVP for the first time. RESULTS: One hundred and eight of 120 and 193 of 240 women returned for a postpartum visit by 6 weeks. HIV-1 was detected in 11.1% (95% confidence interval = 5.9-18.6) of the infants of women previously exposed to sdNVP and 4.2% (95% confidence interval = 1.3-7.0) of those exposed for the first time (P = 0.028). Rates of maternal HIV-1 genotypic resistance at 6 weeks postdelivery were 37.5% and 46.4%, respectively (P = 0.119). Sensitive mutation-specific real-time PCR testing found three of 12 previously exposed women who transmitted HIV-1 to their infants had either K103N or Y181C at baseline compared with one of eight ARV-naïve, transmitting women who had Y181C. None of 40 randomly selected nontransmitting women from either group had detectable NVP resistance mutations prior to sdNVP exposure. CONCLUSION: This study shows that effectiveness of sdNVP may be compromised by prior exposure to sdNVP, although the increase in transmission rate after prior exposure could not be explained by the detection of NVP resistance mutations prior to re-exposure as measured both by standard genotyping and highly sensitive allele-specific PCR assays. Furthermore, transmission rates of women with prior exposure were not higher than those reported elsewhere.

Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen.

BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use. METHODS: Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment interruption in a subset (N = 141). RESULTS: Overall, 601/688 (87.4%) patients who restarted an NNRTI achieved viral resuppression. The adjusted odds ratio (95% confidence interval) for achieving resuppression was 1.94 (1.02-3.69) for patients with a staggered interruption and 3.64 (1.37-9.64) for those with a switched interruption compared with patients with a simultaneous interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous interruption, 12.5% patients with staggered interruption and 4.2% patients with switched interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). CONCLUSION: In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs.

Distinct mechanisms for mitochondrial DNA loss in T and B lymphocytes from HIV-infected patients exposed to nucleoside reverse-transcriptase inhibitors and those naive to antiretroviral treatment.

OBJECTIVE: Mitochondrial DNA (mtDNA) loss in peripheral blood mononuclear cells (PBMCs) has been found in both nucleoside reverse-transcriptase inhibitor (NRTI)-exposed and antiretroviral therapy (ART)-naive patients with human immunodeficiency virus (HIV) infection. Persistent immune activation might play a role in this phenomenon in HIV-infected, ART-naive patients. PBMC subsets with differential growth kinetics were therefore purified to study this similarity. METHODS: CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes were purified from PBMCs. mtDNA levels were quantified using real-time polymerase chain reaction and compared among the 2 groups of HIV-infected patients and a group of HIV-negative control subjects. mtDNA levels in a separate group of ART-naive patients stratified by the rate of disease progression were also evaluated with respect to their relationship to immune-activation markers (i.e., CD38 and programmed cell death-1 [PD-1]) on CD8(+) T cells and the rate of CD4(+) T cell loss. RESULTS: mtDNA levels in CD8(+) T cells and B cells from 15 ART-naive patients were approximately 50% less than those observed for 14 control subjects (P < or = .01). mtDNA levels in all lymphocyte subsets correlated negatively with CD38(+)PD-1(+) expression (r= -0.66 P < -0.9; P < or = .03), and mtDNA levels in B cells correlated with the rate of CD4(+) T cell loss (r =0.66; P< .3). In 17 HIV-infected, NRTI-exposed patients, mtDNA loss was observed in both T cell subsets (P < or = .02) and was most pronounced in patients who received didanosine (P < or = .002). CONCLUSIONS: In HIV-infected, ART-naive patients, mtDNA loss was found in CD8(+) T cells and B cells. These losses correlated with immune activation and, in B cells, with the rate of CD4(+) T cell loss. In patients receiving ART, only T lymphocytes had reduced mtDNA levels. This finding was probably associated with NRTI use, because it was most pronounced in patients with a history of didanosine exposure.

Improved synthesis and pharmacological evaluation of racemic 11 -demethylcalanolide A.

An improved and practical synthesis of racemic 11-demethylcalanolide A [(+/-)-1] was developed. This improved process involved Pechmann reaction on phloroglucinol with ethyl butyrylacetate to give 5,7,-dihydroxy4-n-propylcoumarin (3). Poly phosphoric acid (PPA) catalyzed acylation of compound (3) with crotonic acid, then intramolecular cyclization was achieved simultaneously in one step to afford the key intermediate chromanone (4). A microwave assisted synthetic method preparing chromene (6) using chromenynation of chromanone (4) with 1, 1-diethoxy-methyl-2-butene was conducted. Luche reduction of chromene (6) using NaBH4 with CeCl3 x 7H2O preferably gave (+/-)-1. The overall yield of this four step synthesis of (+/-)-1 was around 32% increasing one fold more than that of the previous method. An in vitro investigation showed that (+/-)-1 exhibited inhibitory activities against both wild-type and drug-resistant HIV-1 in HIV-1 RT and cell culture assay, and significant synergistic effects in combination with AZT, T-20, and indinavir. Its LD50 of acute toxicity in mice by intragastric administration and by intraperitoneal injection were 735.65 mg kg(-1) and 525.10 mg x kg(-1), respectively. The Cmax and AUC(0-infinity) were 0.54 microg x mL(-1) and 1.08 (microg x mL(-1) x h, respectively. The dynamics study of the inhibition of mice sera on HIV-1 RT showed that mice treated with 100 mg x kg(-1 (+/-)-1 once intraperitoneally were similar to that of 5 mg x kg(-1) of known clinical effective anti-HIV-1 drug neverapine. The results suggested that further investigation of the anti-HIV candidate (+/-)-1 was warranted.

Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity.

The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet's disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B*1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B*5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B*5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders.

Current topics in prevention of human T-cell leukemia virus type i infection: NF-kappa B inhibitors and APOBEC3.

Human T-cell leukemia virus type I (HTLV-I) is the first human retrovirus and causes adult T-cell leukemia/lymphoma (ATL). Constitutive activation of nuclear factor-kappa B (NF-kappa B) in the leukemic cells is essential for their growth and survival. Thus, NF-kappa B inhibitors have been attracting attention as a potential strategy to treat ATL. Recently, the field of retrovirus research has been stimulated by the discovery of an innate host defense factor, APOBEC3, against the retroviruses. HTLV-I is relatively resistant to the antiviral effects of APOBEC3. To clarify the resistance of HTLV-I against APOBEC3 might contribute to the design of effective therapeutic approaches.

Is it safe to switch between efavirenz and nevirapine in the event of toxicity?

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are chemically distinct, but both may cause cutaneous hypersensitivity and hepatotoxicity. We reviewed the literature to assess the evidence for cross-reactivity between nevirapine and efavirenz. All papers, abstracts, or presentations, regardless of study design, that made reference to the response of patients who were switched from one NNRTI to another as a result of an adverse drug reaction were included. Most of the studies were retrospective. Recurrent reactions occurred in 30 (12.6%) of 239 reported patients with rash who were switched from nevirapine to efavirenz, compared with eight (50%) of 16 patients switched from efavirenz to nevirapine. Hepatitis did not recur in either the 11 reported patients switched from nevirapine to efavirenz, or in the single reported patient who was switched from efavirenz to nevirapine. Substituting efavirenz for nevirapine following hepatotoxicity or cutaneous hypersensitivity appears to be reasonable, providing that the adverse reaction to nevirapine was not life-threatening. There is insufficient evidence to recommend substituting nevirapine for efavirenz following either hepatotoxicity or cutaneous hypersensitivity.

Ferritin levels during structured treatment interruption of highly active antiretroviral therapy.

OBJECTIVE: The aim of the study was to investigate the influence of highly active antiretroviral therapy (HAART) on iron status and, conversely, the influence of iron status on the response to HAART. METHODS: Ferritin levels were retrospectively determined in stored plasma from 138 HAART-naïve, moderately immunosuppressed HIV-infected Thai patients participating in a structured treatment interruption trial. Ferritin levels were determined at three predefined time-points: (1) HAART initiation; (2) HAART discontinuation; and (3) HAART resumption. RESULTS: At baseline, 31% and 16% of the HIV-infected patients included in the study had high (>200 ng/mL) and low (<30 ng/mL) ferritin levels, respectively. Ninety-five per cent of patients with low ferritin levels were female. Ferritin decreased significantly during the interruption phase of HAART (-8.8 ng/mL; P=0.0005) but remained elevated in 62% of the patients with high baseline levels. A low baseline ferritin level was associated with a shorter time (P=0.041) to reach the CD4 cell target for HAART interruption (350 cells/microL), compared with a normal or high baseline ferritin level. Moreover, in a multivariate model, the relative risk (RR) of arriving at this CD4 cell target was significantly higher [RR 1.81; 95% confidence interval (CI) 1.05-3.14] in patients with low baseline ferritin. It is unlikely that inflammation affected ferritin in our patients, as mean levels of C-reactive protein were not elevated in patients with either high or low ferritin levels. CONCLUSIONS: Both high and low ferritin levels were highly prevalent in moderately immunosuppressed HIV-positive Thai patients. Structured treatment interruption of HAART resulted in a significant decrease in overall ferritin levels. Furthermore, subjects with low baseline ferritin levels had a faster and greater CD4 response to HAART, suggesting a potential beneficial effect of iron deficiency on immunological recovery after initiation of HAART.

Immune responses to abacavir in antigen-presenting cells from hypersensitive patients.

OBJECTIVES: A potentially life-threatening hypersensitive reaction accompanies the use of HIV nucleoside analogue abacavir (ABC) in 4-8% of Caucasian individuals. HLA-B*5701 and Hsp70 493T alleles have been shown to predict susceptibility to this hypersensitivity. DESIGN AND METHODS: This study was undertaken to provide a mechanistic understanding of the highly significant genetic association of HLA Class I and Hsp70 alleles with ABC hypersensitivity. RESULTS: In this study an ABC-induced localization of intracellular HSP70 to endosomal vesicles of antigen-presenting cells was demonstrated. This ABC-stimulated redistribution of endogenous HSP70 was substantially higher in the genetically homogenous HLA-B*5701, Hsp70 493T ABC-hypersensitive individuals and ABC-naive individuals in comparison with the heterogeneous tolerant patients (P = 0.023). Increased expression of HSP70 was also detected in the hypersensitive group as measured by flow cytometry (P = 0.032). Blocking of HSP70 and HSP70 cell surface receptors CD14 and TLR2 abrogated ABC-stimulated HSP70 redistribution in sensitized individuals to basal levels (P < 0.004). In addition, the use of TcRalphabeta and HLA-B57/58 antibodies also ablated the expression of HSP70. Cells expressing the activation markers CD40 were increased after ABC stimulation in the hypersensitive patients (P = 0.006). ABC-stimulated interferon-gamma levels were higher in hypersensitive patients in comparison with ABC-tolerant individuals with a mean of 123.54 versus 0 pg/ml (P = 0.001). CONCLUSION: The present data indicates that ABC stimulates an innate immune response and activates antigen-presenting cells via the endogenous HSP70-mediated Toll-like receptor pathway in genetically susceptible individuals potentially initiating the immuno-pathological hypersensitive response.

CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy.

Nucleoside reverse transcriptase inhibitors (NRTIs) are known to produce painful neuropathies and to enhance states of pain hypersensitivity produced by HIV-1 infection. It has also been observed that in some neuropathic pain models, chemokines and their receptors are upregulated, perhaps contributing to the pain state. In order to understand if chemokines are involved in NRTI-mediated sensory neuropathies, we treated rats with the anti-retroviral drug, 2',3'-dideoxycytidine (ddC), which is known to produce an extended period of hyperalgesia and allodynia. Using in situ hybridization, we observed that under normal conditions, CXCR4 chemokine receptors were widely expressed by satellite glia in the dorsal root ganglia (DRG) and Schwann cells in the sciatic nerve. A limited number of DRG neurons also expressed CXCR4 receptors. The chemokine SDF-1/CXCL12 was similarly expressed in glial cells in the DRG and peripheral nerve. Following a single administration of ddC, expression levels of CXCR4 mRNA in glia and neurons and SDF-1 mRNA in glia increased considerably. The functional nature of increased CXCR4 mRNA expression was confirmed by measuring SDF-1 induced [Ca2+]i increases in acutely isolated DRG neurons and glia. In contrast, the expression of the chemokine receptors CCR2 and CCR5 did not change following ddC treatment. Pain hypersensitivity produced by ddC could be inhibited by treatment with the CXCR4 antagonist, AMD3100. Hence, we postulate that NRTIs produce pain hypersensitivity through the upregulation of CXCR4 signaling in the DRG. Increased numbers of CXCR4 receptors would also explain the synergism observed between NRTI treatment and the proalgesic effects of HIV-1 infection.

[Hypersensitivity reactions to antiretroviral agents in HIV-infected patients]. / Reacciones de hipersensibilidad a antirretrovirales en pacientes con infección por el virus de la inmunodeficiencia humana.

Drug hypersensitivity reactions in the HIV-positive patient are a major problem in management of these patients and, nowadays the antiretroviral agents are the main cause of those reactions, exceeding cotrimoxazole. The present review focuses on immunologic reactions that have been reported associated with antiretroviral agents. We have reviewed case reports on Medline(R) to September 2005. Evidence that these reactions are immune mediated is largely based on the typical symptomatology and few studies have been done to determine the pathogenesis mechanisms. The clinical management of this type of reactions is complex because of differential diagnosis and of potential severity. It is essential that research is now carried out into the pathogenic mechanisms and so, we shall be able to offer an efficacious protocol to manage these situations.

Tenofovir plus didanosine as Nrti backbone in HIV-infected subjects.

Nucleoside reverse transcriptase inhibitors (NRTI) are essential components of highly active antiretroviral treatment (HAART). Although several combinations can be used as NRTI backbones, not all are associated with good virological and/or immunological results. In particular, some NRTI combinations should be avoided due to antagonism (zidovudine plus stavudine) or to high rate of toxicity (didanosine plus stavudine). Tenofovir (TDF) and didanosine (ddI) are among the more often prescribed NRTI for their convenient posology (one pill each per day), relatively high genetic barrier for resistance, quite acceptable safety profile and remarkable antiviral potency when such drugs have been used as single drug or in combinations with other NRTIs. However, antiretroviral regimens containing TDF and ddI have been associated with a high rate of virological failure in HIV-infected naïve patients due to possible drug-interactions. The virological efficacy of this backbone in HIV-infected, HAART pre-treated subjects, is still controversial. Aim of this review is to assess the possible role that antiretroviral regimens containing TDF and ddI can have in the treatment of HIV-positive subjects, focusing on their plasmatic and/or intracellular interactions to optimize the antiretroviral efficacy and minimize the toxicities of this combination.

Switching from protease inhibitor-based-HAART to a protease inhibitor-sparing regimen is associated with improved specific HIV-immune responses in HIV-infected children.

To evaluate the effects of switching from successful long-term protease inhibitor (PI)-based HAART to a three nucleoside reverse transcriptase inhibitor PI-sparing regimen, viral load quantification, HIV-specific lymphoproliferative assay and T-cell receptor (TCR) spectratyping were performed during 96 weeks of simplification follow-up in 19 HIV-infected children. Our data showed that simplification of therapeutic strategies acts positively on immune competence in HIV paediatric patients. Our children maintained viral suppression, increased lymphoproliferative responses and normalized TCRBV repertoire on the CD8 subset.

HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients.

BACKGROUND: Hypersensitivity reaction to nevirapine, which in some cases can be fatal, shows a higher prevalence in Sardinia in comparison with other Italian regions. OBJECTIVE: This study demonstrates that hypersensitive reaction to nevirapine in Sardinian HIV-infected patients is associated with the HLA Cw8-B14 haplotype. These two HLA class I antigens are in strong linkage disequilibrium in the Sardinian population. METHODS: Forty-nine Sardinian HIV-positive patients treated with nevirapine were studied. Thirteen (26%), developed a hypersensitive reaction thus requiring the drug to be discontinued. HLA class I and II molecular typing was performed in both nevirapine-hypersensitive and nevirapine-tolerant patients. To avoid biased representation of the allele frequencies in the two groups of treated patients, molecular typing was also performed in 82 HIV-positive patients who had not been treated with nevirapine. RESULTS: Considerable overlap was observed for the clinical, immunological and demographic characteristics of the 13 hypersensitive patients and 36 tolerant patients. Clinical parameters included viral load, status of HIV infection, CD4 and CD8 cell counts, hepatitis C virus/hepatitis B virus co-infections. Forty-six percent (6/13) of the nevirapine-hypersensitive subjects had the HLA-Cw8 and HLA-B14(65) antigens compared with 5% (2/36) of the nevirapine-tolerant group (P = 0.004; Pc = 0.05). CONCLUSION: In agreement with other recent reports, the utility of HLA typing in HIV patients to identify genetic factors that may confer susceptibility to drug-induced hypersensitive reaction was confirmed. A careful choice of antiretroviral therapy in susceptible individuals should significantly reduce the risk of severe hypersensitive reaction.

Drug-specific T cells in an HIV-positive patient with nevirapine-induced hepatitis.

BACKGROUND: Nevirapine is associated with idiosyncratic reactions such as skin rash, hepatitis and hypersensitivity syndrome, which have the hallmarks of being immune mediated. However, there is little laboratory evidence to support an immune pathogenesis. METHODS: A HIV-positive individual who developed hepatitis within 6 weeks of starting nevirapine, in the absence of any cutaneous manifestations, is described. Other causes of hepatitis were excluded, and the patients liver function normalized on withdrawal of nevirapine. Lymphocytes from the patient, and six individuals with HIV who were on nevirapine without adverse effects, were exposed to nevirapine and its metabolites, and lymphocyte proliferation assessed by 3H-thymidine incorporation on day 5. RESULTS: The T cells taken from the nevirapine-hypersensitive patient proliferated in the presence of nevirapine with a stimulation index of greater than 2. There was no proliferation with nevirapine metabolites. T cells taken from HIV-positive control individuals showed no proliferation with either nevirapine or its metabolites. CONCLUSION: The results from our patient suggest that T cells may be involved in the pathogenesis of nevirapine-induced hepatitis. Larger numbers of patients need to be studied to fully evaluate the role of T cells in nevirapine-induced hepatitis and nevirapine hypersensitivity syndrome.