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PubMed2006

Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment.

BACKGROUND: The recording of outcomes from large-scale, simplified HAART (highly active antiretroviral therapy) programmes in sub-Saharan Africa is critical. We aimed to assess the effectiveness of such a programme held by Médecins Sans Frontières (MSF) in the Chiradzulu district, Malawi. METHODS: We scaled up and simplified HAART in this programme since August, 2002. We analysed survival indicators, CD4 count evolution, virological response, and adherence to treatment. We included adults who all started HAART 6 months or more before the analysis. HIV-1 RNA plasma viral load and self-reported adherence were assessed on a subsample of patients, and antiretroviral resistance mutations were analysed in plasma with viral loads greater than 1000 copies per mL. Analysis was by intention to treat. FINDINGS: Of the 1308 patients who were eligible, 827 (64%) were female, the median age was 34.9 years (IQR 29.9-41.0), and 1023 (78%) received d4T/3TC/NVP (stavudine, lamivudine, and nevirapine) as a fixed-dose combination. At baseline, 1266 individuals (97%) were HAART-naive, 357 (27%) were at WHO stage IV, 311 (33%) had a body-mass index of less than 18.5 kg/m2, and 208 (21%) had a CD4 count lower than 50 cells per muL. At follow-up (median 8.3 months, IQR 5.5-13.1), 967 (74%) were still on HAART, 243 (19%) had died, 91 (7%) were lost to follow-up, and seven (0.5%) discontinued treatment. Low body-mass index, WHO stage IV, male sex, and baseline CD4 count lower than 50 cells per muL were independent determinants of death in the first 6 months. At 12 months, the probability of individuals still in care was 0.76 (95% CI 0.73-0.78) and the median CD4 gain was 165 (IQR 67-259) cells per muL. In the cross-sectional survey (n=398), 334 (84%) had a viral load of less than 400 copies per mL. Of several indicators measuring adherence, self-reported poor adherence (<80%) in the past 4 days was the best predictor of detectable viral load (odds ratio 5.4, 95% CI 1.9-15.6). INTERPRETATION: These data show that large numbers of people can rapidly benefit from antiretroviral therapy in rural resource-poor settings and strongly supports the implementation of such large-scale simplified programmes in Africa.

Adult↗

PubMed1998

Efficient inhibition of both syncytium-inducing and non-syncytium-inducing wild-type HIV-1 by lamivudine in vivo.

OBJECTIVE: To determine the effect of lamivudine (3TC) on syncytium-inducing (SI) and non-SI (NSI) HIV-1 populations in vivo. DESIGN: Responses in virus load and 3TC resistance in 40 3TC-treated subjects were analysed in relation to the presence or absence of SI HIV-1 variants. METHODS: Peripheral blood samples were collected at regular intervals from 40 HIV-1-infected subjects during 3TC treatment. Virus isolates obtained at the start of treatment were typed for SI-capacity by coculture with MT-2 cells. Changes in levels of viral RNA in plasma were determined by quantitative reverse transcriptase PCR. The relative amount of wild-type and mutant virus at codon 184, associated with HIV resistance to 3TC, was determined using a primer-guided nucleotide incorporation assay after amplification of part of the reverse transcriptase gene. In five subjects the frequency of productively infected CD4+ cells with SI or NSI variants was determined in relation to codon 184 genotype. RESULTS: Twenty-six subjects harboured only NSI variants at baseline, whereas 14 subjects also harboured SI variants. Although baseline plasma viral RNA load and CD4 cell counts were different between the two groups, no differences in the response to 3TC therapy were observed for these parameters. In-depth analysis of five subjects showed that the kinetics of virus load changes and emergence of 3TC resistance mutations were similar in plasma and cells, and comparable for the SI and NSI populations present in one individual. CONCLUSIONS: These data show that, in contrast to didanosine and zidovudine, the pressure exerted by 3TC is similar for SI and NSI M184 populations.

Anti-HIV Agents↗

PubMed2001

Influence of the genetic heterogeneity of the ISDR and PePHD regions of hepatitis C virus on the response to interferon therapy in chronic hepatitis C.

Two genomic regions of hepatitis C virus (HCV), the interferon sensitivity-determining region (ISDR) of the non-structural 5A gene (NS5A) and the protein kinase-RNA activated (PKR)-eukariotic transcription factor (eIF2-alpha) phosphorylation homology domain (PePHD) of the structural E2 gene, interact in vitro with the interferon-inducible cellular PKR protein kinase. Mutations within these regions might, therefore, influence the response to interferon therapy. Viral load at baseline and sequence heterogeneity of HCV in NS5A and E2 regions was studied in 74 HCV-1b and in 12 HCV-3a infected patients with chronic hepatitis C who were treated with interferon. As previously reported by us, in a smaller series of patients in which the ISDR region was analyzed [Saiz et al. (1998) Journal Infectious Diseases 177:839-847], in the present study a low viral load and a high number of amino acid mutations within the ISDR, but not within the PePHD region, were significantly associated with long-term response to interferon among HCV-1b infected patients. No relationship between these viral features and response to therapy was disclosed in patients infected with HCV-3a.

Adult↗

PubMed1998

Detection of clonal T cells in cutaneous T cell lymphoma by polymerase chain reaction: comparison of mutation detection enhancement-polyacrylamide gel electrophoresis, temperature gradient gel electrophoresis and fragment analysis of sequencing gels.

Cutaneous T cell lymphomas (CTCL) can be differentiated from benign inflammatory dermatoses by the demonstration of clonal T cells in skin biopsy. As a marker of the T cell clonality, the rearrangement of the T cell receptor (TCR) genes is amplified by polymerase chain reaction (PCR) and subsequently analyzed by several electrophoresis techniques. Since the validity of this approach depends substantially on the separating capacity of the applied electrophoresis technique, we investigated in the present study the lower detection limit and the sensitivity of heteroduplex-loaded polyacrylamide gel electrophoresis on MDE (mutation detection enhancement) gels (HD-MDE PAGE), of heteroduplex-loaded temperature gradient gel electrophoresis (HD-TGGE) and fragment analysis (FA) on sequencing gels. Genomic DNA from formalin-fixed, paraffin-embedded skin biopsies of 53 CTCL specimens and 27 samples of benign dermatoses was analyzed by TCRy PCR followed by electrophoretic separation. Clonality was detected by HD-MDE PAGE in 22, by HD-TGGE in 34, and by FA in 33 of the 53 CTCL cases. Additionally, FA revealed an oligoclonal fragment profile in seven CTCL specimens. In the 27 samples from benign dermatoses, HD-MDE PAGE and HD-TGGE showed the expected polyclonal pattern in 26, and FA in 25 specimens. HD-TGGE and FA detected a clonal pattern down to a dilution of 10(3) monoclonal cells in 10(6) peripheral blood mononuclear cells (PBMC), while HD-MDE PAGE revealed a detection limit of 10(4) monoclonal cells in 10(6) PBMC. In conclusion, HD-TGGE and FA possess a higher sensitivity and lower detection limit than HD-MDE PAGE. Therefore, both former techniques are useful tools for the routine diagnostic procedure. With regard to time and cost, we recommend HD-TGGE.

Cell Separation↗

PubMed2003

Alternation of antiretroviral drug regimens for HIV infection. A randomized, controlled trial.

BACKGROUND: Mathematical modeling has suggested that alternating antiretroviral regimens while patients' viral load remains suppressed would minimize HIV resistance mutations. OBJECTIVE: To compare alternation of antiretroviral regimens with the current standard of switching regimens after viral load rebound. DESIGN: Randomized, multicenter, open-label, pilot trial. SETTING: 15 outpatient HIV clinics in Spain and Argentina. PATIENTS: 161 HIV-1-infected, antiretroviral-naive persons. INTERVENTION: Patients were assigned to continuously receive stavudine, didanosine, and efavirenz (standard of care, regimen A) or zidovudine, lamivudine, and nelfinavir (standard of care, regimen B) until virologic failure, or to alternate between those two regimens every 3 months while viral load was suppressed (regimen C). MEASUREMENTS: Time to virologic failure, percentage of patients with undetectable plasma viremia over 48 weeks, CD4 and CD8 cell counts, adverse events, emergence of drug resistance, drug adherence, and quality of life. RESULTS: Patients receiving standard-of-care regimens A and B did not differ. Virologic failure over 48 weeks was delayed in the alternating therapy group compared with the pooled standard-of-care group (incidence rate, 1.2 events/1000 person-weeks [95% CI, 0.3 to 3.6 events/1000 person-weeks] vs. 4.8 events/1000 person-weeks [CI, 2.9 to 7.4 events/1000 person-weeks]; P = 0.01). Genotypic drug resistance emerged in 79% of patients in the standard-of-care group who experienced on-therapy treatment failure. Patients in the standard-of-care and alternating therapy groups had similar CD4 cell counts, frequency of adverse events, reported drug adherence, and quality of life. CONCLUSIONS: Virologic outcome was better with alternating therapy than with the current standard of care, while adverse events and adherence were similar. The strategy of alternating therapy merits further investigation.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Kinetics of disappearance of resistance mutations and reappearance of wild-type during structured treatment interruptions.

OBJECTIVE: To monitor the disappearance of resistance-associated mutations and reappearance of wild-type (WT) virus during structured treatment interruptions (STI) using DNA sequencing and line probe assay. METHODS: Eleven HIV-1-infected patients participating in the MUTAVIR study undergoing a 3-month STI after multi-HAART failure were monitored biweekly. Genotypes were assessed by sequencing and VERSANT HIV-1 Resistance Assays (LiPA). RESULTS: At treatment interruption, 54 mutations in total were identified with both methods among the patients. LiPA provided a result for 93.3% of the codons at baseline. For 37 mutations, a complete reversion of mutant to WT was observed with one of the two methods. Among these, LiPA detected mutations in 23 codons for 7 to 52 days longer, in 10 codons for the same period, and in four codons for a shorter time than sequencing. Similarly, LiPA detected 35 WT codons 8 to 86 days earlier, and 15 at the same time point as sequencing. A sharp reduction in the number of mutations was observed at the time of viral load increase in five of the 11 patients. Taking only the codons detected by LiPA into consideration, two patients showed a complete reversion to WT according to both genotyping assays at the end of the STI period. CONCLUSIONS: The determination of the timepoint at which a virus population of an HIV-1 patient undergoing STI reverts to WT is dependent on the assay used. The viral load increase in most patients is compatible with the outgrowth of virus with fewer or no mutations.

Antiretroviral Therapy, Highly Active↗

PubMed2005

Skeletal muscle gene expression profiling in mitochondrial disorders.

Extremely variable clinic and genetic features characterize mitochondrial encephalomyopathy (MEM). Pathogenic mitochondrial DNA (mtDNA) defects can be divided into large-scale rearrangements and single point mutations. Clinical manifestations become evident when a threshold percentage of the total mtDNA is mutated. In some MEM, the "mutant load" in an affected tissue is directly related to the severity of the phenotype. However, the clinical phenotype is not simply a direct consequence of the relative abundance of mutated mtDNA. Other factors, such as nuclear background, can contribute to the disease process, resulting in a wide range of phenotypes caused by the same mutation. Using Affymetrix oligonucleotide cDNA microarrays (HG-U133A), we studied the gene expression profile of muscle tissue biopsies obtained from 12 MEM patients [4 common 4977 bp deleted mtDNA and 8 A3243G: 4 progressive external ophthalmoplegia (PEO) and 4 mitochondrial myopathy, encephalopathy, lactic cidosis, and stroke-like episodes syndrome (MELAS) phenotypes] compared with age-matched healthy individuals. We found several differentially expressed genes: 35 were markedly up-regulated in the mtDNA macro-deletion group (vs. the control group) and 4 decreased; 56 genes were dysregulated in A3243G-related disorders (53 down-regulated in PEO and 3 up-regulated in MELAS). Finally, 12 genes were similarly regulated in the majority of the MEM patients under study. Amongst these, we identified an increased expression of genes related to the metabolism of the amino groups, as well as of several genes involved in genetic information processing. Moreover, few genes were similarly decreased in MEM patients vs. the control group. Real-time PCR demonstrated excellent reproducibility of the microarray-based findings. The observed expression changes are likely to represent a molecular signature for mitochondrial disorders. Furthermore, the differential expression profile of MELAS(A3243G) vs. PEO(A3243G) may support a role of nuclear background in contributing to these different clinical phenotypes. MEM microarray data are available from GEO database (http://www.ncbi.nlm.nih.gov/geo/) with the accession number: GSE1462.

Adolescent↗

PubMed2006

Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment.

ATP7A is a P-type ATPase that transports copper from cytosol into the secretory pathway for loading onto cuproproteins or efflux. Mutations in Atp7a cause Menkes disease, a copper-deficiency disorder fatal in the postnatal period due to severe neurodegeneration. Early postnatal copper injections are known to diminish degenerative changes in some human patients and mice bearing mutations in Atp7a. In situ hybridization studies previously demonstrated that ATP7A transcripts are expressed widely in the brain. ATP7A-specific antibody was used to study the neurodevelopmental expression and localization of ATP7A protein in the mouse brain. Based on immunoblot analyses, ATP7A expression is most abundant in the early postnatal period, reaching peak levels at P4 in neocortex and cerebellum. In the developing and adult brain, ATP7A levels are greatest in the choroid plexus/ependymal cells of the lateral and third ventricles. ATP7A expression decreases in most neuronal subpopulations from birth to adulthood. In contrast, ATP7A expression increases in CA2 hippocampal pyramidal and cerebellar Purkinje neurons. ATP7A is expressed in a subset of astrocytes, microglia, oligodendrocytes, tanycytes and endothelial cells. ATP7A is largely localized to the trans-Golgi network, adopting the cell-specific and developmentally-regulated morphology of this organelle. The presence of ATP7A in the axons of postnatal, but not adult, optic nerve suggests stage-specific roles for this enzyme. In sum, the precisely-regulated neurodevelopmental expression of ATP7A correlates well with the limited therapeutic window for effective treatment of Menkes disease.

Adenosine Triphosphatases↗

PubMed2003

Treatment of antiretroviral-drug-resistant HIV-1 infection.

Drug-resistant HIV-1 is a cause of growing clinical and public-health concern. In many patients, combination antiretroviral therapy fails to achieve complete viral suppression (virological failure). Continuing viral replication during therapy leads to the accumulation of drug-resistance mutations, resulting in increased viral load and a greater risk of disease progression. Patients with drug-resistant HIV-1 infection have three therapeutic options: a change to a salvage regimen with the aim of fully suppressing viral replication; interruption of therapy; or continuation of a partially effective regimen. The first strategy is preferred for most patients failing their first or perhaps their second regimen. However, the best approach remains unclear for patients who have failed multiple treatment regimens and who have limited options for complete viral suppression. The management of such patients requires a careful understanding of the pathogenesis of drug-resistant HIV-1, the clinical consequences of virological failure, the potential benefits and limitations of diagnostic assays, and the likelihood that agents in development will be effective.

Anti-HIV Agents↗

PubMed2000

Determination of the HLA-DM interaction site on HLA-DR molecules.

HLA-DM removes CLIP and other loosely bound peptides from MHC class II molecules. The crystal structures of class II molecules and of HLA-DM have not permitted identification of their interaction sites. Here, we describe mutations in class II that impair interactions with DM. Libraries of randomly mutagenized DR3 alpha and beta chains were screened for their ability to cause cell surface accumulation of CLIP/DR3 complexes in EBV-B cells. Seven mutations were associated with impaired peptide loading in vivo, as detected by SDS stability assays. In vitro, these mutant DR3 molecules were resistant to DM-catalyzed CLIP release and showed reduced binding to DM. All mutations localize to a single lateral face of HLA-DR, which we propose interacts with DM during peptide exchange.

Amino Acid Sequence↗

PubMed2004

Effects of chemical chaperones on partially retarded NaCl cotransporter mutants associated with Gitelman's syndrome in a mouse cortical collecting duct cell line.

BACKGROUND: Epithelial cells lining the distal convoluted tubule express the thiazide-sensitive Na-Cl cotransporter (NCC) that is responsible for the reabsorption of 5-10% of the filtered load of Na(+) and Cl(-). Mutations in NCC cause the autosomal recessive renal disorder Gitelman's syndrome (GS). GS mutations give rise to mutant transporters that are either fully (class I) or partially (class II) retarded. Recent evidence indicates that class II mutations do not alter the intrinsic transport activity of NCC. These findings suggest that in GS caused by class II NCC mutations, pharmacological chaperones may be useful in treatment. METHODS: Initial attempts using 4-phenylbutyrate and glycerol to increase Na(+) uptake in Xenopus laevis oocytes expressing the class II mutant L215P were unsuccessful. To study the effect of the chaperones in a more physiological setting, we next expressed hNCC in the polarized epithelial cell line of distal tubular origin, mpkCCD. RESULTS: mpkCCD cells readily expressed the class II mutant R955Q, but not the class I mutant G741R. Wild-type hNCC was predominantly present in the approximately 120-1403 kD complex glycosylated form. In contrast, the R955Q mutant was predominantly present in a lower molecular weight form of approximately 100 kD. Pretreatment of R955Q expressing cells with 4-phenylbutyrate (5 mM, 16 h), but not thapsigargin (1 microM, 90 min), dimethyl sulfoxide (1%, 16 h) or glycerol (4%, 16 h), increased the expression of the complex glycosylated form and in parallel the number of hNCC positive cells. CONCLUSIONS: Taken together, the data indicate that 4-phenylbutyrate is a promising candidate for rescuing partially retarded but otherwise functional class II GS mutants.

Animals↗

PubMed2005

Proteomic determination of widespread detergent-insolubility including Abeta but not tau early in the pathogenesis of Alzheimer's disease.

Biochemical characterization of the major detergent-insoluble proteins that comprise hallmark histopathologic lesions initiated the molecular era of Alzheimer's disease (AD) research. Here, we reinvestigated detergent-insoluble proteins in AD using modern proteomic techniques. Using liquid chromatography (LC)-mass spectrometry (MS)-MS-based proteomics, we robustly identified 125 proteins in the detergent-insoluble fraction of late-onset AD (LOAD) temporal cortex that included several proteins critical to Abeta production, components of synaptic scaffolding, and products of genes linked to an increased risk of LOAD; we verified 15 of 15 of these proteins by Western blot. Following multiple analyses, we estimated that these represent ~80% of detergent-insoluble proteins in LOAD detectable by our method. Abeta, tau, and 7 of 8 other newly identified detergent-insoluble proteins were disproportionately increased in temporal cortex from patients with LOAD and AD derived from mutations in PSEN1 and PSEN2; all of these except tau were elevated in individuals with prodromal dementia, while none except Abeta were elevated in aged APPswe mice. These results are consistent with the amyloid hypothesis of AD and extend it to include widespread protein insolubility, not exclusively Abeta insolubility, early in AD pathogenesis even before the onset of clinical dementia.

Alzheimer Disease↗

PubMed1998

Risk factors for mortality in young children living under various socio-economic conditions in Lahore, Pakistan: with particular reference to inbreeding.

Risk factors such as maternal age, parity, previous siblings' death, inbreeding of parents, birth weight, birth length were examined in a population-based prospective study in four population groups at different levels of urbanization in and round Lahore, Pakistan. From September 1984 to March 1995, 2967 full-term, single born infants were followed from the 5th month of gestation to 12 months of age. Logistic regression analysis showed a significant relative risk (RR) of infant death associated with parents' consanguinity (RR = 1.8), birth weight (RR = 1.8) and elder siblings' death (RR = 1.7). The risk attributed to these factors was 28, 17 and 25%, respectively. The number of lethal equivalents per gamete is about one. The B/A ratio 10.36 suggests that the genetic load is likely to be mutational. In countries like Pakistan, where consanguinity is favourably practiced, a substantial proportion of infant deaths may be prevented by cessation of such marriages. The implications of this finding for the Pakistani community are discussed.

Adolescent↗

PubMed2003

Screening for iron overload in the Turkish population.

BACKGROUND/AIMS: Hereditary hemochromatosis (HH), the most common autosomal recessive disease in the white population, is characterized by excessive gastrointestinal absorption of iron and loading of parenchymal organs. HFE mutations of C282Y and H63D are largely responsible for HH in populations of Celtic ancestry. Although many screening studies related to HH have been done in Northern Europe, the USA and Australia, as yet, no such study has been published on Turkey. In this study we aimed to screen the Turkish population for iron overload. METHODS: Random samples were obtained from 4,633 healthy adults (3,827 male, 806 female, mean age +/- SD 35 +/- 8 years, range 14-76) for the measurement of transferrin saturation (TS). Measurements were repeated after an overnight fast in the subjects whose initial TS was > or =50%. Serum ferritin levels and C282Y and H63D gene mutations were studied in cases when fasting TS was > or =50%. In cases where the serum ferritin level was >200 ng/ml with or without HFE mutations, liver biopsy was performed for histological evaluation and determination of iron content. RESULTS: In 158 subjects, TS was > or =50% in the non-fasting state. A second determination of TS after an overnight fast was performed in 135 subjects. In 26 subjects, the TS was > or =50% in the fasting state. HFE mutation and serum ferritin levels were measured in these 26 subjects. Eleven subject (10 male, 1 female) were heterozygote and 1 male subject was homozygote in reference to H63D. C282Y mutation was not found. Four of these 26 subjects (all males, aged 23, 24, 40, 49) had increased serum ferritin levels and liver biopsy was performed. In 1 male (aged 49) who was heterozygote for H63D genotype with a serum ferritin level of 645 ng/ml, iron overload in liver tissue was shown by histology as well as atomic absorption spectrophotometry. CONCLUSION: The prevalence of hemochromatosis in the Turkish population is much lower in comparison to populations of Celtic ancestry and C282Y mutation is non-existent.

Adolescent↗

PubMed2004

The paradox of simian immunodeficiency virus infection in sooty mangabeys: active viral replication without disease progression.

Simian immunodeficiency virus SIVsm causes an asymptomatic infection in its natural host, the sooty mangabey, but induces an immunodeficiency syndrome very similar to human AIDS when transferred to a new host species such as the rhesus macaque. Unexpectedly, SIVsm replication dynamics is comparable in the two species, with rapid accumulation of viral mutations and a high viral load detected in both mangabeys and macaques. In contrast, clear differences are observed in immune parameters. Pathogenic SIV infection in macaques is associated with decreased CD4+ T cell numbers and signs of generalized immune activation, such as increased numbers of cycling and apoptotic T cells, hyperplasic lymphoid tissues, and exacerbated immune responses. Mangabeys with asymptomatic SIV infection show normal T cell regeneration parameters and signs of a moderate immune response, appropriate in the setting of chronic viral infection. The comparative analysis of simian models thus suggests that viral load alone cannot account for progression to disease, and that the capacity of primate lentiviruses to induce abnormal immune activation underlies AIDS pathogenesis.

Animals↗

PubMedDate not supplied

Heterozygosity for the H63D mutation in the hereditary hemochromatosis (HFE) gene may lead into severe iron overload in beta-thalassemia minor: observations in a thalassemic kindred.

Heterozygosity for beta-thalassemia (minor) by itself does not lead into iron overload; however, when it is inherited together with a homozygous state for either the H63D or the C282Y mutations of the hereditary hemochromatosis gene (HFE gene), iron overload may ensue. We describe here a kindred in which the propositus, being heterozygote for beta-thalassemia and the H63D mutation of the HFE gene, developed severe iron overload and in turn, chronic liver failure with portal hypertension. Other members of the family with either beta-thalassemia or heterozygous for the H63D gene mutation did not develop iron overload. The interaction between beta-thalassemia and hereditary hemochromatosis is briefly discussed and speculations about other possible genetic mutations leading into familial iron loading are done.

Adult↗

PubMed2002

Lamivudine therapy of chronic hepatitis B in three groups of patients: non transplanted patients, liver recipients, and kidney recipients.

OBJECTIVE: As conflicting results have been observed by some authors in liver recipients, the aim of the study was to evaluate lamivudine therapy in 3 groups of patients with chronic hepatitis B: non-transplanted patients, liver and kidney recipients. METHODS: All patients were studied for clinical symptoms, hepatic enzymes, hepatitis B virus (HBV) serology, serum HBV DNA load, and HBV polymerase genotype (mutations associated with lamivudine resistance). RESULTS: During the 48-144 week-long follow-up (mean: 75 weeks), 23 non-transplanted patients, 5 liver and 6 kidney recipients were studied. A sustained biochemical and virological response was obtained in 19 out of the 23 non-transplanted patients and in 4 of 6 kidney recipients, while the 5 liver recipients did not respond. After the development of lamivudine resistance, mutations rtM204V and rtL180M were detected in all studied patients, mutation rtM207I in one, with similar results from traditional nucleotide sequencing and a commercial line probe assay. CONCLUSION: The poor response to lamivudine in liver recipients requires further studies.

Alanine Transaminase↗

PubMed1999

Mutation patterns of the reverse transcriptase and protease genes in human immunodeficiency virus type 1-infected patients undergoing combination therapy: survey of 787 sequences.

The aim of the present study was to evaluate the resistance-associated mutations in 302 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving combination therapy and monitored in Marseille, France, hospitals from January 1997 to June 1998. In the reverse transcriptase (RT) gene, the most frequent mutations were found at codons 215 (53%), 41 (34%), and 67, 70, 184, and 210 (>20%). One deletion and two insertions in the beta3-beta4 hairpin loop of the finger subdomain (codon 69) were detected. Interesting associations and/or exclusions of specific mutations were observed. In 96% of RT genes, a mutation at codon 70 (most frequently, K70R) was associated with a wild-type genotype at position 210 (P < 10(-5)). Similarly, a mutation at codon 210 (most frequently, L210W) was generally associated with mutations at codons 41 (92%) and 215 (96%) but not at codon 219 (16%) or codon 70 (4%) (P < 10(-5)). In the protease gene, the most prevalent mutations were at codons 63 (84%), followed by codons 10, 36, 71, 77, and 93 (ca. 20%). As for RT, pairwise associations of mutations were observed. Analysis of the mutation patterns for patients with undetectable HIV-1 loads revealed a high proportion (65%) of wild-type RT genotypes but only 18% wild-type protease genotypes. For patients with high viral loads (>100,000 copies/ml), more than 50% of the RT and protease genes displayed three or more mutations. The significant correlation between the level of viremia in plasma and the number of resistance mutations in the protease (P = 0.007) and RT (P = 0.00078) genes strengthens the importance of defining the genotype of the predominant HIV-1 quasispecies before initiating antiretroviral therapy.

Amino Acid Substitution↗