RESUMO
Eight in vitro selection experiments under brincidofovir pressure elicited the known cytomegalovirus DNA polymerase amino acid substitutions N408K and V812L and the novel exonuclease domain substitutions D413Y, E303D, and E303G, which conferred ganciclovir and cidofovir resistance with 6- to 11-fold resistance to brincidofovir or 17-fold when E303G was combined with V812L. The new exonuclease domain I resistance mutations selected under brincidofovir pressure add to the single instance previously reported and show the expected patterns of cross-resistance.
Assuntos
Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Citosina/análogos & derivados , DNA Polimerase Dirigida por DNA/genética , Mutação , Organofosfonatos/farmacologia , Proteínas Virais/genética , Cidofovir , Citomegalovirus/genética , Citomegalovirus/crescimento & desenvolvimento , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/virologia , Citosina/farmacologia , Farmacorresistência Viral/genética , Foscarnet/farmacologia , Ganciclovir/farmacologia , Expressão Gênica , Humanos , Testes de Sensibilidade Microbiana , Domínios ProteicosRESUMO
Brincidofovir is an oral antiviral in development for prevention of cytomegalovirus disease. Cytomegalovirus genotyping results from a phase 2 trial comparing brincidofovir to placebo for prophylaxis against cytomegalovirus infection in hematopoietic cell transplant recipients provided initial data on the clinical resistance profile for brincidofovir. In this study, no known resistance-associated mutations were detected in brincidofovir-treated subjects; identified genotypic substitutions did not confer resistance to cytomegalovirus antivirals in vitro, suggesting that these changes represent polymorphisms unrelated to brincidofovir resistance. Lack of evidence for genotypic resistance during prophylaxis suggests that first-line use of brincidofovir for prevention of cytomegalovirus infection may preserve downstream options for patients.
Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/genética , Citosina/uso terapêutico , Farmacorresistência Viral/genética , Mutação/efeitos dos fármacos , Transplantados , Citomegalovirus/genética , Infecções por Citomegalovirus/fisiopatologia , DNA Polimerase Dirigida por DNA/genética , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro Imunocomprometido , Masculino , Estados UnidosRESUMO
Brincidofovir (BCV) is the 3-hexadecyloxy-1-propanol (HDP) lipid conjugate of the acyclic nucleoside phosphonate cidofovir (CDV). BCV has established broad-spectrum activity against double-stranded DNA (dsDNA) viruses; however, its activity against RNA viruses has been less thoroughly evaluated. Here, we report that BCV inhibited infection of Ebola virus in multiple human cell lines. Unlike the mechanism of action for BCV against cytomegalovirus and other dsDNA viruses, phosphorylation of CDV to the diphosphate form appeared unnecessary. Instead, antiviral activity required the lipid moiety and in vitro activity against EBOV was observed for several HDP-nucleotide conjugates.
Assuntos
Antivirais/química , Antivirais/farmacologia , Citosina/análogos & derivados , Ebolavirus/efeitos dos fármacos , Doença pelo Vírus Ebola/tratamento farmacológico , Organofosfonatos/química , Organofosfonatos/farmacologia , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Cidofovir , Citosina/química , Citosina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Células HeLa , Doença pelo Vírus Ebola/prevenção & controle , Doença pelo Vírus Ebola/virologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipídeos/química , Lipídeos/farmacologia , Masculino , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
Natural orthopoxvirus outbreaks such as vaccinia, cowpox, cattlepox and buffalopox continue to cause morbidity in the human population. Monkeypox virus remains a significant agent of morbidity and mortality in Africa. Furthermore, monkeypox virus's broad host-range and expanding environs make it of particular concern as an emerging human pathogen. Monkeypox virus and variola virus (the etiological agent of smallpox) are both potential agents of bioterrorism. The first line response to orthopoxvirus disease is through vaccination with first-generation and second-generation vaccines, such as Dryvax and ACAM2000. Although these vaccines provide excellent protection, their widespread use is impeded by the high level of adverse events associated with vaccination using live, attenuated virus. It is possible that vaccines could be used in combination with antiviral drugs to reduce the incidence and severity of vaccine-associated adverse events, or as a preventive in individuals with uncertain exposure status or contraindication to vaccination. We have used the intranasal mousepox (ectromelia) model to evaluate the efficacy of vaccination with Dryvax or ACAM2000 in conjunction with treatment using the broad spectrum antiviral, brincidofovir (BCV, CMX001). We found that co-treatment with BCV reduced the severity of vaccination-associated lesion development. Although the immune response to vaccination was quantifiably attenuated, vaccination combined with BCV treatment did not alter the development of full protective immunity, even when administered two days following ectromelia challenge. Studies with a non-replicating vaccine, ACAM3000 (MVA), confirmed that BCV's mechanism of attenuating the immune response following vaccination with live virus was, as expected, by limiting viral replication and not through inhibition of the immune system. These studies suggest that, in the setting of post-exposure prophylaxis, co-administration of BCV with vaccination should be considered a first response to a smallpox emergency in subjects of uncertain exposure status or as a means of reduction of the incidence and severity of vaccine-associated adverse events.
Assuntos
Antivirais/administração & dosagem , Citosina/análogos & derivados , Vírus da Ectromelia/fisiologia , Ectromelia Infecciosa/prevenção & controle , Organofosfonatos/administração & dosagem , Vacina Antivariólica/administração & dosagem , Animais , Citosina/administração & dosagem , Vírus da Ectromelia/imunologia , Ectromelia Infecciosa/imunologia , Ectromelia Infecciosa/virologia , Feminino , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Vacina Antivariólica/imunologia , Vacinação , Replicação ViralRESUMO
Brincidofovir (CMX001), a lipid conjugate of the acyclic nucleotide phosphonate cidofovir, is under development for smallpox treatment using "the Animal Rule," established by the FDA in 2002. Brincidofovir reduces mortality caused by orthopoxvirus infection in animal models. Compared to cidofovir, brincidofovir has increased potency, is administered orally, and shows no evidence of nephrotoxicity. Here we report that the brincidofovir half-maximal effective concentration (EC50) against five variola virus strains in vitro averaged 0.11 µM and that brincidofovir was therefore nearly 100-fold more potent than cidofovir.
Assuntos
Antivirais/farmacologia , Citosina/análogos & derivados , Organofosfonatos/farmacologia , Varíola/tratamento farmacológico , Vírus da Varíola/efeitos dos fármacos , Animais , Linhagem Celular , Chlorocebus aethiops , Cidofovir , Citosina/farmacologia , DNA Viral/análise , DNA Viral/genética , Modelos Animais de Doenças , Humanos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Vírus da Varíola/crescimento & desenvolvimentoRESUMO
CMX001 is an orally available lipid acyclic nucleotide phosphonate that delivers high intracellular levels of cidofovir (CDV)-diphosphate and exhibits enhanced in vitro antiviral activity against a wide range of double-stranded DNA viruses, including cytomegalovirus (CMV). Mutations in the DNA polymerase of CMV that impart resistance to CDV also render the virus resistant to CMX001. Here, we report a novel resistance mutation that arose under the selective pressure of CMX001. The wild-type CMV strain AD169 was propagated in human foreskin fibroblasts under increasing concentrations of CMX001 over 10 months, and the resulting strain (named CMX001(R)) was less susceptible to CDV and CMX001 in a plaque reduction assay. Genotypic analysis of virus strain CMX001(R) via conventional sequencing of the genes encoding the CMV DNA polymerase (UL54) and UL97 kinase (UL97) demonstrated one mutation that changed the wild-type aspartate to glutamate at position 542 in UL54. A recombinant virus with this novel D542E mutation was generated via bacterial artificial chromosome-mediated marker transfer experiments. Subsequent phenotypic resistance analysis of the D542E mutant demonstrated reductions in susceptibility of greater than 10-fold to CMX001 and CDV, but no resistance to foscarnet (FOS) or ganciclovir (GCV). Analysis of replicative fitness showed that both strain CMX001(R) and the D542E mutant viruses demonstrated a smaller plaque phenotype and slower replication kinetics than their respective parent viruses. These data describe the first resistance mutation generated under the selective pressure of CMX001 and suggest that CMX001 may have a unique resistance profile associated with reduced viral replication and maintenance of sensitivity to FOS and GCV.
Assuntos
Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Citosina/análogos & derivados , Farmacorresistência Viral/genética , Mutação , Organofosfonatos/farmacologia , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Cromossomos Artificiais Bacterianos , Cidofovir , Citomegalovirus/genética , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Citosina/farmacologia , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/genética , Foscarnet/farmacologia , Ganciclovir/farmacologia , Humanos , Fenótipo , Análise de Sequência de DNARESUMO
Although acyclovir (ACV) has proven to be of value in the therapy of certain herpes simplex virus (HSV) infections, there is a need for more effective therapies, particularly for serious infections in neonates and immunocompromised individuals, where resistance to this drug can be problematic. CMX001 is an orally bioavailable lipid conjugate of cidofovir that is substantially less nephrotoxic than the parent drug and has excellent antiviral activity against all the human herpesviruses. This compound retains full antiviral activity against ACV-resistant laboratory and clinical isolates. The combined efficacy of CMX001 and ACV was evaluated in a new real-time PCR combination assay, which demonstrated that the combination synergistically inhibited the replication of HSV in cell culture. This was also confirmed in murine models of HSV infection, where the combined therapy with these two drugs synergistically reduced mortality. These results suggest that CMX001 may be effective in the treatment of ACV-resistant HSV infections and as an adjunct therapy in individuals with suboptimal responses to ACV.
Assuntos
Aciclovir/farmacologia , Antivirais/farmacologia , Citosina/análogos & derivados , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Organofosfonatos/farmacologia , Aciclovir/uso terapêutico , Aciclovir/toxicidade , Animais , Antivirais/uso terapêutico , Antivirais/toxicidade , Células Cultivadas , Citosina/farmacologia , Citosina/uso terapêutico , Citosina/toxicidade , Farmacorresistência Viral , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Herpes Simples/virologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Organofosfonatos/uso terapêutico , Organofosfonatos/toxicidadeRESUMO
Adenovirus infection is a serious and often fatal complication in hematopoietic stem cell transplant patients. There are currently no FDA-approved therapies for adenovirus infection, with only anecdotal, off-label uses described for a variety of anti-viral agents or immune therapies. We report the first case of successful eradication of disseminated adenovirus infection by the novel antiviral agent CMX001 in a severely immunocompromised pediatric stem cell transplant recipient following failure to respond to intravenous cidofovir. Complete clinical and virologic response was documented; virologic and pharmacokinetic data are reported. CMX001 is a promising new oral antiviral agent under development for the prophylaxis and treatment of severe infections caused by double-stranded DNA viruses including adenovirus in immunocompromised patients.
Assuntos
Infecções por Adenovirus Humanos/tratamento farmacológico , Antivirais/uso terapêutico , Citosina/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Hospedeiro Imunocomprometido , Organofosfonatos/uso terapêutico , Infecções por Adenovirus Humanos/complicações , Criança , Citosina/uso terapêutico , Feminino , Humanos , Reação em Cadeia da PolimeraseRESUMO
CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Nucleosídeos/uso terapêutico , Nucleotídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Adenina/efeitos adversos , Adenina/farmacologia , Adenina/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Farmacorresistência Viral/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Macrófagos/virologia , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacologia , TenofovirRESUMO
Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy.Consistent with this notion were (1) the presence of low level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus in subjects receiving failing first-line regimens consisting of tenofovir (TDF), abacavir (ABC), and lamivudine (3TC); (2) lower fold resistance associated with mixtures versus mutants in a clinical-isolate database; and (3) dose dependent changes in susceptibility to ABC, 3TC, TDF, and didanosine on titration of K65R and/or M184V with wild-type virus. These findings underscore the limitations of stand-alone phenotypic susceptibility measures and emphasize the importance of complementary and/or more sensitive techniques.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Adenina/análogos & derivados , Adenina/uso terapêutico , Didanosina/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Quimioterapia Combinada , Predisposição Genética para Doença , Genótipo , Humanos , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Fenótipo , Plasmídeos , Tenofovir , Carga ViralRESUMO
BACKGROUND: Transmitted HIV-1 drug resistance can compromise initial antiretroviral therapy (ART); therefore, its detection is important for patient management. The absence of drug-associated selection pressure in treatment-naïve persons can cause drug-resistant viruses to decline to levels undetectable by conventional bulk sequencing (minority drug-resistant variants). We used sensitive and simple tests to investigate evidence of transmitted drug resistance in antiretroviral drug-naïve persons and assess the clinical implications of minority drug-resistant variants. METHODS AND FINDINGS: We performed a cross-sectional analysis of transmitted HIV-1 drug resistance and a case-control study of the impact of minority drug resistance on treatment response. For the cross-sectional analysis, we examined viral RNA from newly diagnosed ART-naïve persons in the US and Canada who had no detectable (wild type, n = 205) or one or more resistance-related mutations (n = 303) by conventional sequencing. Eight validated real-time PCR-based assays were used to test for minority drug resistance mutations (protease L90M and reverse transcriptase M41L, K70R, K103N, Y181C, M184V, and T215F/Y) above naturally occurring frequencies. The sensitive real-time PCR testing identified one to three minority drug resistance mutation(s) in 34/205 (17%) newly diagnosed persons who had wild-type virus by conventional genotyping; four (2%) individuals had mutations associated with resistance to two drug classes. Among 30/303 (10%) samples with bulk genotype resistance mutations we found at least one minority variant with a different drug resistance mutation. For the case-control study, we assessed the impact of three treatment-relevant drug resistance mutations at baseline from a separate group of 316 previously ART-naïve persons with no evidence of drug resistance on bulk genotype testing who were placed on efavirenz-based regimens. We found that 7/95 (7%) persons who experienced virologic failure had minority drug resistance mutations at baseline; however, minority resistance was found in only 2/221 (0.9%) treatment successes (Fisher exact test, p = 0.0038). CONCLUSIONS: These data suggest that a considerable proportion of transmitted HIV-1 drug resistance is undetected by conventional genotyping and that minority mutations can have clinical consequences. With no treatment history to help guide therapies for drug-naïve persons, the findings suggest an important role for sensitive baseline drug resistance testing.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Estudos de Casos e Controles , Estudos Transversais , Farmacorresistência Viral/genética , Ligação Genética , Genótipo , Infecções por HIV/virologia , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: HIV-associated encephalopathy (HIV-AE) is a severe neurologic condition that affects HIV-infected children. The potential benefit of antiretroviral (ARV) agents with good cerebrospinal fluid (CSF) penetration remains to be defined. Abacavir (ABC) achieves good CSF concentrations and studies of high-dose ABC showed benefit in adults with HIV dementia. The present study evaluated the safety and virologic, immunologic and neuropsychological responses of an ARV regimen including high-dose ABC in children with HIV-AE. METHODS: Children between 3 months and 18 years old and abacavir-naive with HIV-AE and virologic failure were eligible. RESULTS: : Seventeen children (16 ARV-experienced) were enrolled and 14 children completed 48 weeks of therapy. The overall tolerability was good; 2 children had a possible hypersensitivity reaction. At week 48, 53% and 59% of the children achieved HIV RNA levels below the limit of quantitation in plasma and CSF, respectively. The median (25%-75% range) change of HIV RNA from baseline to week 48 was -2.29 (-0.81 to -2.47) log10 copies/mL in plasma and -0.94 (0 to -1.13) log10 copies/mL in CSF. The mean increases in CD4 (+/-standard error of mean) cell count and CD4% were 427 (+/-169) cells/mm and 8% (+/-2), respectively. Concentrations of soluble tumor necrosis factor receptor II were reduced in plasma and CSF. Children less than 6 years of age demonstrated significant neuropsychological improvement at week 48. CONCLUSIONS: In the present study with a limited number of children, highly active ARV therapy including high-dose ABC showed a safety profile similar to standard dose ABC and provided clinical, immunologic and virologic response in children with HIV-AE at week 48. Children less than 6 years of age also demonstrated significant neuropsychological improvement.
Assuntos
Complexo AIDS Demência/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/uso terapêutico , Terapia de Salvação , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/psicologia , Complexo AIDS Demência/virologia , Adolescente , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Relação CD4-CD8 , Criança , Pré-Escolar , Didesoxinucleosídeos/administração & dosagem , Hipersensibilidade a Drogas , Feminino , HIV/genética , Humanos , Lactente , Masculino , Projetos Piloto , RNA Viral/sangue , RNA Viral/líquido cefalorraquidiano , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/líquido cefalorraquidiano , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
BACKGROUND: We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome. METHODS: We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured. RESULTS: M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 +/- 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P < 0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns. CONCLUSIONS: Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.
Assuntos
Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/classificação , Mutação , Seleção Genética , Timidina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Criança , Pré-Escolar , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Lactente , Concentração Inibidora 50 , Lamivudina/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Fenótipo , Inibidores da Transcriptase Reversa/uso terapêutico , Replicação Viral , Zidovudina/farmacologia , Zidovudina/uso terapêuticoRESUMO
OBJECTIVE: To identify optimal first-line therapies based on the rate of virologic success (VS) and the preservation of future treatment options in antiretroviral therapy (ART)-naive subjects. DESIGN: Systematic overview of genotypic resistance mutations from clinical trials of combination ART. METHODS: Various sources were searched for studies in ART-naive subjects providing virologic response rates and genotypes from subjects with virologic failure. The International AIDS Society-USA genotypic resistance guidelines were used to calculate regimen resistance cost (RCreg) and number of active drug (AD) scores for each regimen and to rank the regimens. RESULTS: Intra- and interstudy comparisons showed higher VS rates for nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens (range: 51%-76%) and boosted protease inhibitor (boosted PI) regimens (range: 55%-79%). Boosted PI failures had the lowest RCreg (range: 0.12-0.21) and the highest AD (range: 19.80-20.18) scores. NNRTI failures had higher RCreg (range: 0.00-1.22) and lower AD (range: 16.83-21) scores. CONCLUSIONS: NNRTI and boosted PI regimens provide the highest rates of VS in treatment-naive HIV-infected persons. Treatment option scores were higher in subjects who failed boosted PI- containing regimens versus NNRTI-containing regimens, however.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV/efeitos dos fármacos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Genótipo , HIV/genética , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , Humanos , Metanálise como Assunto , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
Potential contributors to the high rate of virologic failure observed for tenofovir, abacavir, and lamivudine include a low genetic barrier to resistance for this regimen and antagonistic drug-drug interactions. To examine the second possibility, we tested combinations of abacavir, tenofovir, and lamivudine against wild-type and drug-resistant HIV-1 in vitro using peripheral blood mononuclear cells and MT-4 cells. Antagonistic interactions were not detected for any combination. If the systems examined accurately reflect the in vivo situation, antagonism does not substantially contribute to the poor efficacy of this triple combination.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Didesoxinucleosídeos/farmacologia , HIV-1/efeitos dos fármacos , Lamivudina/farmacologia , Organofosfonatos/farmacologia , Adenina/antagonistas & inibidores , Adenina/farmacologia , Fármacos Anti-HIV/antagonistas & inibidores , Linhagem Celular Transformada , Didesoxinucleosídeos/antagonistas & inibidores , Farmacorresistência Viral Múltipla/genética , Quimioterapia Combinada , HIV-1/genética , Humanos , Lamivudina/antagonistas & inibidores , Mutação , Organofosfonatos/antagonistas & inibidores , TenofovirRESUMO
BACKGROUND: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen. METHODS: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV+EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase. RESULTS: The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56%>or=100,000 copies/mL) and 210 cells/mm (48% <200 cells/mm), respectively. No significant differences were noted between ABC/3TC/ZDV+EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing=failure]; P=0.697) or time to treatment failure (P=0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV+EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV+EFV group; P=0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV+EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P=0.057). CONCLUSIONS: After induction with ABC/3TC/ZDV+EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Adolescente , Adulto , Idoso , Alcinos , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade , Benzoxazinas , Contagem de Linfócito CD4 , Ciclopropanos , Didesoxinucleosídeos/administração & dosagem , Farmacorresistência Viral , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxazinas/administração & dosagem , Cooperação do Paciente , RNA Viral/sangue , Zidovudina/administração & dosagemRESUMO
BACKGROUND: Maximum suppression of virus replication is often not achievable for persons infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). Available data suggest that lamivudine contributes to partial viral suppression, despite the presence of M184V mutations and high-level phenotypic lamivudine resistance. METHODS: Selective lamivudine withdrawal was studied in 6 subjects who had incomplete viral suppression during antiretroviral treatment for multidrug-resistant HIV-1 infection. RESULTS: Plasma levels of HIV-1 RNA increased to 0.5 log(10) copies/mL above baseline 6 weeks after the withdrawal of lamivudine treatment (P=.04), even though reversion of lamivudine resistance was not yet detected. Early increases in plasma levels of HIV-1 RNA after lamivudine withdrawal were associated with the presence of the T215Y/F mutation and broad phenotypic resistance to nucleoside reverse-transcriptase inhibitors at baseline. Genotypic and phenotypic reversion of lamivudine resistance was detected in 4 subjects 8-14 weeks after withdrawal of lamivudine therapy. The duration of lamivudine withdrawal ranged from 8 to 22 weeks; all subjects resumed lamivudine treatment. Plasma levels of HIV-1 RNA were 0.6 log(10) copies/mL above baseline (P=.03) when lamivudine therapy was resumed. After the resumption of lamivudine treatment, plasma HIV RNA levels decreased to baseline levels in 3 subjects but remained elevated in 3 subjects who had evolution of increased antiretroviral drug resistance during the period of lamivudine withdrawal. Safety concerns raised by this latter finding led to permanent closure of the study. CONCLUSIONS: In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.
Assuntos
Farmacorresistência Viral Múltipla , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Lamivudina/farmacologia , Terapia de Salvação , Adulto , Fármacos Anti-HIV/farmacologia , Contagem de Linfócito CD4 , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , RNA Viral/sangue , Carga ViralRESUMO
BACKGROUND: Zidovudine, lamivudine, and efavirenz comprise a highly effective and well-tolerated triple regimen for antiretroviral-naive patients. Evaluating other unique nucleoside reverse-transcriptase inhibitor (NRTI) combinations for long-term viral suppression is desirable. METHODS: This multicenter, randomized, double-blind noninferiority clinical trial compared the efficacy and safety of abacavir with that of zidovudine plus lamivudine and efavirenz in 649 antiretroviral-naive HIV-infected patients. The primary objective was a comparison of proportions of patients achieving plasma HIV-1 RNA levels Assuntos
Didesoxinucleosídeos/uso terapêutico
, Infecções por HIV/tratamento farmacológico
, Lamivudina/uso terapêutico
, Oxazinas/uso terapêutico
, Zidovudina/uso terapêutico
, Adolescente
, Adulto
, Idoso
, Alcinos
, Fármacos Anti-HIV/efeitos adversos
, Fármacos Anti-HIV/uso terapêutico
, Benzoxazinas
, Contagem de Linfócito CD4
, Ciclopropanos
, Didesoxinucleosídeos/efeitos adversos
, Método Duplo-Cego
, Quimioterapia Combinada
, Feminino
, Humanos
, Lamivudina/efeitos adversos
, Masculino
, Pessoa de Meia-Idade
, Oxazinas/efeitos adversos
, RNA Viral/sangue
, Zidovudina/efeitos adversos
RESUMO
OBJECTIVE: To evaluate HIV-1 reverse transcriptase genotypic and phenotypic indicators of resistance to abacavir (ABC) as predictors of ABC antiviral efficacy. DESIGN: The study was a retrospective, combined analysis of five multicentre trials in which ABC was added as a single agent to background antiretroviral therapy in experienced adults. METHODS: Baseline HIV-1 genotype and phenotypic susceptibility to ABC were determined and the association of genotype and phenotype with virological response after addition of ABC was analysed. RESULTS: Overall, 68% of these therapy-experienced subjects had a virological response (>0.5 log10 or <400 copies/ml; 42% <400 copies/ml) 4 weeks after addition of ABC. Multivariable analyses revealed no significant difference in the response rate between subjects with wild-type virus and those carrying virus with 1-2 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations. At the 4-week time-point subjects harbouring virus with > or = 3 mutations associated with NRTI resistance were significantly less likely to respond to ABC than were subjects harbouring wild-type virus (P=0.015). However, at the last viral RNA measurement after addition of ABC (12-28 weeks), > or = 4 mutations were required to diminish virological response significantly (P=0.012). Phenotypic resistance was also predictive of antiviral response. Significant breakpoints were identified for virological responses for the PhenoSense HIV assay and the Antivirogram assay. CD4 responses generally paralleled the antiviral responses with a median increase of 55 cells/microl by weeks 12-28. CONCLUSIONS: Virological response to ABC may be diminished significantly by multiple NRTI-associated mutations and/or by reductions in phenotypic susceptibility to ABC. However, many subjects with baseline samples showing evidence of resistance to NRTIs respond to ABC.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , HIV-1/genética , Humanos , Mutação , Fenótipo , RNA Viral/sangue , RNA Viral/isolamento & purificação , Análise de Regressão , Estudos Retrospectivos , Falha de Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: The pathogenesis of HIV encephalopathy is poorly understood especially in children. Studies suggest that HIV replication and the release of proinflammatory mediators in the central nervous system contribute to the pathogenesis of HIV dementia in adults. METHODS: Cerebrospinal fluid (CSF) and plasma samples from 23 HIV-infected children were longitudinally analyzed at Weeks 0, 8, 16 and 48 for HIV RNA and concentrations of the following proinflammatory mediators: monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha, regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage-inflammatory protein (MIP)-1-alpha, MIP-1-beta and matrix metalloproteinase-9 (MMP-9). RESULTS: All 23 children had detectable concentrations of MCP-1 in the CSF at all time points evaluated. However, of the remaining of proinflammatory mediators measured in CSF at baseline, only a few children had detectable concentrations: tumor necrosis factor-alpha, n = 1; RANTES, n = 5; MMP-9, n = 9; MIP-1-alpha and MIP-1-beta, n = 0. A reduction from baseline to Week 48 was observed in CSF concentrations of MCP-1 and, among children with detectable values, MMP-9, which paralleled declines in CSF HIV RNA. CONCLUSION: These results suggest that MCP-1 and MMP-9 may be involved in the pathogenesis of central nervous system disease in HIV-infected children.