Low incidence of genotypic and phenotypic resistance in paediatric HIV-infected patients on long-term first-line antiretroviral triple therapy.
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Adolescent↗
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Results for “mutation load”
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Drug resistance in patients experiencing early virological failure under a triple combination including indinavir.
OBJECTIVE: To assess the pattern of drug resistance mutations selected in HIV-1-infected patients failing a first line triple combination therapy including indinavir. PATIENTS AND METHODS: Plasma samples from 87 patients collected at the time of the first virological rebound (> 50 HIV-RNA copies/ml) were examined for the presence of drug-resistant genotypes. RESULTS: The mean level of plasma viraemia at rebound was 7824 HIV-1 RNA copies/ml in 73 subjects with good compliance, whereas it was 359,460 HIV-1 RNA copies/ml in 14 patients who admitted to poor adherence. Genetic sequence analysis yielded results for 51 (70%) of the patients having good adherence. More than half of them (26/51, 51%) carried primary mutations associated with resistance to nucleoside analogues. In contrast, primary protease inhibitor resistance mutations were recognized less frequently (14/51, 27%; P < 0.05). Moreover, in 23 (45%) patients there was no evidence of drug-resistant viruses at all. The most frequent drug-resistant genotypes in the reverse transcriptase gene were at codons 184 (n = 19), 215 (n = 14) and 41 (n = 8), whereas for the protease they were at codons 46 (n = 10), 82 (n = 9) and 90 (n = 7). No resistance genotypes were found among non-compliant patients. CONCLUSION: The overall rate of drug-resistant HIV genotypes was 38% (28/73) in patients with good adherence and who were experiencing a first virological failure under a triple combination regimen including indinavir; resistance to nucleoside analogues was more frequent than resistance to indinavir. Therefore, treatment intensification in those patients without resistance, or a selective substitution of nucleosides in those with resistance limited to these compounds, might be justified.
Adult↗
Virological evaluation of the 'Ottawa case' indicates no evidence for HIV-1 superinfection.
An HIV-1 infected man who experienced rapid disease progression and poor response to therapy after starting a new sexual relationship with an infected partner is known as the 'Ottawa superinfection case'. Subsequent analysis of viral sequences of protease, reverse transcriptase, Gag p17, and Env V3 provided no evidence for the acquisition of genetically divergent viruses before disease progression or drug resistance during virological failure of combination therapy. Whether HIV-1 superinfection contributes to disease progression or the spread of drug-resistant HIV-1 remains unknown.
Antiretroviral Therapy, Highly Active↗
Foscarnet used in salvage therapy of HIV-1 patients harbouring multiple nucleotide excision mutations.
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Anti-HIV Agents↗
Early multitherapy including a protease inhibitor for human immunodeficiency virus type 1-infected infants.
BACKGROUND: To assess tolerance and efficacy of early multitherapy including a protease inhibitor for infants perinatally infected with HIV. METHODS: Observational study of tolerance and clinical and immunovirologic evolution in HIV-infected infants treated before the age of 1 year in the French Perinatal Study. RESULTS: Thirty-one infants were included. The median age was 3.7 months at initiation of multitherapy. Clinical stage was C (n = 8), B (n = 5) or A/N (n = 18). The median HIV RNA viral load was 5.8 log copies/ml, and the median CD4 cell percentage was 29%. Median follow-up of treatment was 27 months. Of 31 infants 15 experienced mild to moderate adverse events. No infant had clinical or immunologic progression. The median change in viral load was -2.7 log copies/ml after 3 months, -2.0 log after 12 months and -1.7 log after 24 months of treatment. The proportion of infants with a viral load below 500 copies/ml decreased from 53% at 6 months to 18% at 24 months of treatment. The virologic response was not correlated with viral load at baseline. However, the slope of the viral load decrease during the first month of treatment was predictive of the virologic response at 3 and 6 months. Fourteen infants with a viral load of >500 copies/ml after 6 months of treatment displayed viruses with antiretroviral resistance mutations in reverse transcriptase and/or protease genes. CONCLUSIONS: Despite the absence of clinical or immunologic progression, the high frequency of virologic failure associated with genotypic resistance reveals the difficulties associated with implementing antiretroviral multitherapy in infants. Suboptimal doses of protease inhibitor could be a factor contributing to treatment failure.
Drug Therapy, Combination↗
HIV-1 reverse transcriptase codon 215 mutation in plasma RNA: immunologic and virologic responses to zidovudine. The AIDS Clinical Trials Group Study 175 Virology Team.
Treatment of HIV infection with zidovudine (ZDV) may select for changes in the genetic sequence of the viral reverse transcriptase (RT) that imparts drug resistance. The presence of a 2-bp mutation at codon 215 of RT (from threonine to phenylalanine or tyrosine) was assessed in plasma viral RNA in 85 subjects treated with ZDV in the AIDS Clinical Trials Group (ACTG) 175 virology substudy. Median CD4 cell numbers, HIV plasma RNA levels, and infectious titers of virus were significantly different over 56 weeks of treatment among 58 subjects with the wild-type threonine at codon 215 virus at study entry compared with the 27 subjects with mutations to phenylalanine or tyrosine (MUT) virus. Thirty percent (13 of 44 subjects) with wild-type virus at study entry developed a new codon 215 mutation. Genotypic resistance at codon 215 in plasma HIV RNA is associated with the subsequent immunologic and virologic failure of ZDV monotherapy in subjects with 200 to 500 CD4 cells/mm3.
Anti-HIV Agents↗
Phenotypic resistance pattern of HIV-1 isolates with zidovudine and/or multidrug resistance mutations after didanosine-stavudine combination therapy.
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Anti-HIV Agents↗
Patterns of resistance mutations to antiretroviral drugs in extensively treated HIV-1-infected patients with failure of highly active antiretroviral therapy.
Resistance-mutation patterns in the reverse transcriptase (RT) and protease genes of HIV-1 were analyzed in 22 patients who had been extensively pretreated and who failed to respond to highly active antiretroviral therapy (HAART). The number of mutations ranged from 8 to 19 (median, 13): 4 to 12 (median, 6) mutations in the RT gene, and 4 to 8 (median, 7) mutations in the protease gene. In the RT gene, the most frequent resistance mutations were found at codons 215 (100%), 41 (95%), 67 (91%), and 210 (77%). Multidrug-resistant mutation patterns including Q151M and insertion mutations at codon 69, which confer cross-resistance to the different nucleoside analogue RT inhibitors were detected in 1 and 3 patients, respectively; 1 patient with insertion mutation displayed a NGQGV [corrected] sequence at codons 67 to 70. In the protease gene, the most frequent mutations were found at codons 63 (95%), 10 (86%), 90(86%), 71(77%), 46 (50%), 36 (45%), and 84 (45%). Genotypic resistance to zidovudine, saquinavir, and indinavir was found in 100% of the patients. All patients showed also resistance or possible resistance to stavudine, abacavir, ritonavir, and nelfinavir. Mutations conferring genotypic resistance to nonnucleoside analogue RT inhibitors (NNRTIs) were found in 12 (80%) of the NNRTI-experienced patients and 1 of 7 NNRTI-naive patients. Our results indicate that failure of HAART in the patients extensively pretreated results from the multiplicity of RT and protease mutations that confer genotypic resistance to almost all available antiretroviral drugs. In these patients, genotypic resistance tests confirm the lack of alternative salvage therapy strategies based on the currently available antiretroviral drugs.
Algorithms↗
Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine or stavudine, each in combination with lamivudine and indinavir.
The authors studied the effect of zidovudine (ZDV) resistance mutation on virologic response to treatment with ZDV or stavudine (d4T) each in combination with lamivudine and indinavir. Viral genotyping was performed on plasma HIV-1 RNA at study entry and concerned 155 patients previously treated with ZDV, didanosine, or zalcitabine and enrolled in the NOVAVIR (Agence National de Recherche sur le SIDA [ANRS] 073) trial. Three virologic responses were investigated: early response (<50 copies/mL at week 24), late response (<500 copies/mL at week 80), and virologic failure (two HIV-1 RNA >5000 copies/mL). Patients were classified as resistant or susceptible to ZDV according to the ANRS algorithm. Plasma viral RNA from 123 of 155 patients had two or more ZDV resistance mutations. The number of ZDV resistance mutations was positively correlated with the duration of prior antiviral therapy (p <.001). At week 24, 74% and 77% of patients with virus classified as resistant were responders in the d4T and ZDV arm, respectively. Similar results were found at week 80. Virologic failure was reached in 7 of 24 patients with virus classified as susceptible and in 26 of 131 patients with resistant virus (p =.29). In the ZDV arm, patients classified as resistant had longer times to virologic failure than those classified as susceptible (p =.003). In conclusion, sustained virologic response despite presence of ZDV resistance mutations implies that these mutations do not preclude an early and durable response to treatment with a potent three-drug regimen in these patients. Patients susceptible to ZDV had lower median mean corpuscular volumes and lower random indinavir levels, suggesting that adherence was the main reason for failure.
Anti-HIV Agents↗
Activity of adefovir dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses in patients.
One hundred and thirty-one post-liver transplantation patients with chronic hepatitis B and failing lamivudine therapy with detectable serum hepatitis B virus (HBV) deoxyribonucleic acid by hybridization assays or > or =1 x 10(6) copies/mL by polymerase chain reaction, and elevated alanine transaminase levels despite continuous lamivudine, were enrolled in an open-label study of adefovir dipivoxil. The B and C domains of HBV polymerase were sequenced for baseline samples to determine the presence of lamivudine resistance mutations. The results showed that 98% of the samples had tyrosine-methionine-aspartate-aspartate (YMDD) mutations, indicating a strong correlation between the above clinical definition of lamivudine treatment failure and the presence of YMDD mutations. In addition to the rtM204V/I and the rtL180M mutations, the mutation rtV173L was identified in 19% of patients. Four major patterns of lamivudine-resistant HBV were identified: rtL180M + rtM204V (60%), rtV173L + rtL180M + rtM204V (19%), rtM204I (9%) and rtL180M + rtM204I (9%). Treatment with adefovir dipivoxil showed similar antiviral efficacy in patients with lamivudine-resistant virus from all four patterns.
Adenine↗
The daunting challenge of keeping HIV suppressed.
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Acquired Immunodeficiency Syndrome↗
Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.
The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
Anti-HIV Agents↗
Purification and biochemical characterization of the lambda holin.
Holins are small phage-encoded cytoplasmic membrane proteins, remarkable for their ability to make membranes permeable in a temporally regulated manner. The purification of S105, the lambda holin, and one of the two products of gene S is described. Because the wild-type S105 holin could be only partially purified from membrane extracts by ion-exchange chromatography, an oligohistidine tag was added internally to the S105 sequence for use in immobilized metal affinity chromatography. An acceptable site for the tag was found between residues 94 and 95 in the highly charged C-terminal domain of S. This allele, designated S105H94, had normal lysis timing under physiological expression conditions. The S105H94 protein was overproduced, purified, and characterized by circular dichroism spectroscopy, which revealed approximately 40% alpha-helix conformation, consistent with the presence of two transmembrane helices. The purified protein was then used to achieve release of fluorescent dye loaded in liposomes in vitro, whereas protein from an isogenic construct carrying an S mutation known to abolish hole formation was inactive in this assay. These results suggest that S is a bitopic membrane protein capable of forming aqueous holes in bilayers.
Amino Acid Sequence↗
Different viral rebound following discontinuation of antiretroviral therapy in cases of infection with viruses carrying L74V or thymidine-associated mutations.
A total of 76 patients discontinued treatment with didanosine plus hydroxyurea after 1 year of maintenance therapy. The greatest human immunodeficiency virus (HIV)-RNA rebounds were seen in 10 patients harboring an L74V mutation, and the presence of viruses with this mutation rapidly waned. In contrast, viral rebounds were significantly less pronounced (P < 0.01) in 12 subjects harboring thymidine-associated mutations; these mutations persisted in all instances. Thus, selection of an L74V mutation during didanosine therapy may compromise HIV replication in vivo.
Acquired Immunodeficiency Syndrome↗
Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus.
Episodes of low-level viremia (LLV), with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels ranging from 50 to 400 copies (c)/ml, occur commonly during highly active antiretroviral therapy (HAART). LLV has been associated with virologic failure of HAART in some studies, while in others LLV did not appear to affect the clinical outcome. To understand the processes leading to LLV, genetic analyses were used to determine whether plasma virions emanated from archived or from newly evolved viral genomes. Episodes of LLV (plasma HIV-1 RNA, 50 to 379 [median, 77] c/ml) were detected in 21/37 (57%) HIV-1-infected children with median plasma HIV-1 RNA levels of <50 c/ml during 79 patient years of HAART. Viral sequences were derived by direct sequencing of PCR products from 21 plasma specimens diluted to end point. In phylogenetic analysis, LLV viral sequences grouped with virus from early in the course of infection in 8/11 subjects. Six specimens had multiple identical viral sequences, suggesting origin from clonally expanded infected cells. LLV plasma virus evolved over time, indicating viral replication, in 3/11 subjects. Two of these had frequent LLV, including the selection of drug-resistant mutants. In summary, plasma virus from episodes of LLV during effective HAART appeared to originate from two distinct processes, (i) clonal outgrowth from long-lived HIV-1-infected cells, presumably following activation and proliferation of these cells, and (ii) ongoing viral replication that included the selection of new drug-resistant mutants. These observations provide a plausible explanation for the divergent clinical outcomes previously associated with LLV.
Amino Acid Sequence↗
Antiretroviral resistance and genetic diversity of human immunodeficiency virus type 1 isolates from the Federal District, Central Brazil.
In the context of universal access to antiretroviral therapy, the surveillance of human immunodeficiency virus type 1 (HIV-1) genetic diversity and resistance becomes pivotal. In this work our purpose was to describe the genetic variability; prevalence of drug-resistance mutations; and genotypic resistance profiles in HIV-1 infected individuals under antiretroviral treatment, from the Federal District, Brasilia, Central Brazil. The entire viral protease and codons 19 to 234 of the reverse transcriptase gene from 45 HIV-1 isolates were amplified and sequenced for subtyping and genotyping. By phylogenetic analysis, 96% of the samples clustered with subtype B and the remaining 4% with HIV-1 subtype F sequences. One major protease inhibitor resistance-associated mutation, I50V, was detected in 38% of the samples. Minor mutations were also found at the protease gene: L10I/V (7%), K20M (2%), M36I (11%), L63P (20%), A71T (2%), and V77I (7%). Many mutations associated with reduced susceptibility to nucleoside or non-nucleoside reverse transcriptase inhibitors were detected: M41L (11%), E44D (4%), D67N (11%), T69D (2%), K70R (11%), L74V (2%), L100I (4%), K103N (18%), V118I (9%), Y181C (11%), M184V (18%), G190A (4%), T215Y (4%), and K219E (4%). This study has shown that 84% of the studied population from the Federal District, showing evidences of therapy failure, presented viral genomic mutations associated with drug resistance. The main antiretrovirals to which this population showed resistance were the PI amprenavir (38%), the NNRTIs delavirdine, nevirapine (31%), and efavirenz (24%), and the NRTIs lamivudine (18%), abacavir, and zidovudine (13%).
Anti-HIV Agents↗
Pendrin regulation in mouse kidney primarily is chloride-dependent.
Recent studies indicate that pendrin, an apical Cl-/HCO3- exchanger, mediates chloride reabsorption in the connecting tubule and the cortical collecting duct and therefore is involved in extracellular fluid volume regulation. The purpose of this study was to test whether pendrin is regulated in vivo primarily by factors that are associated with changes in renal chloride transport, by aldosterone, or by the combination of both determinants. For achievement of this goal, pendrin protein abundance was studied by semiquantitative immunoblotting in different mouse models with altered aldosterone secretion or tubular chloride transport, including NaCl loading, hydrochlorothiazide administration, NaCl co-transporter knockout mice, and mice with Liddle's mutation. The parallel regulation of the aldosterone-regulated epithelial sodium channel (ENaC) was examined as a control for biologic effects of aldosterone. Major changes in pendrin protein expression were found in experimental models that are associated with altered renal chloride transport, whereas no significant changes were detected in pendrin protein abundance in models with altered aldosterone secretion. Moreover, in response to hydrochlorothiazide administration, pendrin was downregulated despite a marked secondary hyperaldosteronism. In contrast, alpha-ENaC was markedly upregulated, and the molecular weight of a large fraction of gamma-ENaC subunits was shifted from 85 to 70 kD, consistent with previous results from rat models with elevated plasma aldosterone levels. These results suggest that factors that are associated with changes in distal chloride delivery govern pendrin expression in the connecting tubule and cortical collecting duct.
Aldosterone↗
The challenge of antiretroviral-drug-resistant HIV: is there any possible clinical advantage?
Resistance to antiretroviral drugs is associated with reduced treatment options and, therefore, increased risk of disease progression or death. Despite the main goal of antiretroviral therapy should be achievement of complete suppression of HIV replication, the accumulation of resistance mutations in patients with multiple treatment failure makes this objective often difficult, or even impossible to obtain. Thus, clinicians should be aware about the complex relationship between drug pressure and viral replication capacity and about some potential advantages related to antiretroviral drug resistance. The two main biological mechanisms that can be at the origin of these clinical benefits are: reduction of viral fitness and viral hypersusceptibility. The term "fitness" indicates the ability of HIV to maintain high rate of replication capacity in presence of antiretroviral drugs. Consequently, replication capacity, high in presence of wild type virus, tends to decrease when HIV must adapt its enzymes to work in presence of drugs. A reduction of viral fitness is observed in patients harbouring mutations conferring resistance to all the three classes of antiretroviral drugs currently in use. Particularly, the effects on reduction of replication capacity related to M184V mutation in reverse transcriptase are analyzed. Viral isolates with reduced susceptibility or resistance to some antiretroviral drugs may exhibit significant increased susceptibility to other drugs acting on the same enzyme. This phenomenon is known as hypersusceptibility and can be demonstrated in vitro by phenotypic assays. Phenotypic hypersusceptibility has been demonstrated for all three drug classes. Particularly, NNRTI hypersusceptibility, associated with NRTI mutations, is analyzed and discussed.
Biomarkers↗