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PubMed2001

Correlation between mutations in the interferon sensitivity-determining region of NS5A protein and viral load of hepatitis C virus subtypes 1b, 1c, and 2a.

In the present study, we analyzed the possible relationship between interferon (IFN) sensitivity-determining region (ISDR) sequence variation of various hepatitis C virus (HCV) subtypes and serum HCV titers in Indonesian patients without IFN treatment. The viremia titers (mean +/- standard deviation) of HCV subtype 1b (HCV-1b) isolates with low (three or fewer) and high (four or more) numbers of ISDR mutations were 5.4 +/- 0.6 and 4.2 +/- 0.9 log(10) RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Similarly, the viremia titers of HCV-1c isolates with low and high numbers of ISDR mutations were 5.3 +/- 0.6 and <3.0 +/- 0.0 log(10) RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Also, the virus titers of HCV-2a isolates with low and high numbers of ISDR mutations were 4.3 +/- 0.7 and 3.5 +/- 0.4 log(10) RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Thus, our results demonstrated that virus load in Indonesian patients infected with HCV-1b, HCV-1c, or HCV-2a correlated inversely with the number of mutations in the ISDR sequence, implying the possibility that the ISDR sequence plays an important role in determining the levels of HCV viremia.

Amino Acid Sequence↗
PubMed2000

Increased efficiency of folding and peptide loading of mutant MHC class I molecules.

Class I molecules, encoded by diverse alleles at several loci of the major histocompatibility complex (MHC) are assembled in the endoplasmic reticulum (ER) from heavy chain, beta2 microglobulin and peptide in association with accessory proteins of the peptide loading complex. We show here, that mutations in the alpha2 domain (Q115A; D122A) of the human class I allele HLA-A2 cause a lack of apparent association with the loading complex and a faster assembly. Despite the drastically reduced association with the TAP loading complex, i. e. less than 20 % of HLA-A2 expressed in the cells can be co-precipitated with either TAP, calreticulin or tapasin, the mutant proteins are expressed on the cell surface in a stable conformation, and bind a complex set of peptides almost identical to that of wild-type HLA-A2. Furthermore, the mutant class I molecules are more rapidly exported from the ER than wild-type HLA-A2 and undergo faster maturation. The mutation Q115A does not destroy a binding site for the loading complex as this HLA-A2 mutant associates with the loading complex when peptide supply is limited. The association of class I molecules with the TAP-associated loading complex appears to be a reflection of how quickly the stable conformation is gained.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Beta-cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1alpha mutation carriers.

OBJECTIVE: Patients with diabetes due to hepatocyte nuclear factor (HNF)-1alpha mutations have beta-cell deficiency, insulin sensitivity, altered proinsulin levels, and a low renal threshold for glucose. It is uncertain how many of these features precede the development of diabetes. The aim of our study was to test for these characteristics in young nondiabetic HNF-1alpha mutation carriers. RESEARCH DESIGN AND METHODS: A total of 47 offspring from 19 extended families underwent genetic testing, a standard oral glucose tolerance test, and urine testing. RESULTS: HNF-1alpha mutations were found in 20 offspring, 7 with diabetes and 13 without diabetes. The 13 nondiabetic mutation carriers were compared with 27 family control subjects, who were matched for age, sex, and BMI. There was marked beta-cell deficiency with reduced insulinogenic index (53.5 [31.5-90.9] vs. 226.0 [126.0-407.1], SD [range], P < 0.001) and area under the curve for insulin (P < 0.001). Insulin sensitivity was increased in mutation carriers (homeostatic model assessment of insulin sensitivity 144.6 [82.7-252.7] vs. 100 [66.9-149.4], P = 0.025). A total of 38% of mutation carriers had glycosuria at 2 h compared with 0% of control subjects (P = 0.0034). Those with glycosuria had peak glucose values that were higher than the mutations carriers without glycosuria (range 8.1-11.8 vs. 6.2-8.4 mmol/l, P = 0.002). The seven subjects with diabetes all showed glycosuria. CONCLUSIONS: We conclude that marked beta-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1alpha mutation carriers. The presence of glycosuria post-glucose load could be used to screen children of mutation carriers as it occurs in all mutation carriers with a peak glucose in the oral glucose tolerance test >8.4 mmol/l.

Adolescent↗
PubMed2004

Mechanotransduction in bone does not require a functional cyclooxygenase-2 (COX-2) gene.

UNLABELLED: COX-2 is a key enzyme involved in the response of bone to loading. However, using mice with a null mutation of the COX-2 gene, we found that a functional COX-2 gene is not required for mechanotransduction. This paradoxical finding may have resulted, in part, from mechanically induced COX-1 activity. INTRODUCTION: Cyclooxygenase-2 (COX-2) is an important mediator in the response of bone to mechanical loading, with pharmacological inhibition of COX-2 effectively eliminating or reducing mechanically induced bone formation. In this study, we further investigated the role of COX-2 in skeletal mechanotransduction using a genetic approach. The aim was to compare the skeletal responsiveness of COX-2 homozygous mutant (COX-2(-/-)) and wildtype control (COX-2(+/+)) mice to investigate whether a functional COX-2 gene is necessary for mechanotransduction. MATERIALS AND METHODS: Adult female COX-2(+/+) and COX-2(-/-) mice on a C57BL/6x129/ola background were studied using the ulna axial loading model. The response to 2 days of loading for 120 cycles/day at 2 Hz was measured histomorphometrically. Phenotypic characterization of the femurs in these mice was also performed. In a separate group of animals, the expression of the remaining COX isozyme, COX-1, was assessed using real-time RT-PCR 4 h after one bout of 120 loading cycles. RESULTS: Null mutation of the COX-2 gene resulted in a consistent femoral phenotype of reduced bone mass, altered architecture, and inferior mechanical properties. Many of these differences were nullified after adjustment for body weight. Nevertheless, body weight-corrected values showed a consistent trend of reduced mechanical properties in COX-2(-/-) mice. Genotype did not influence the response to mechanical loading, with no histomorphometric differences being found between COX-2(+/+) and COX-2(-/-) mice. Real-time RT-PCR showed COX-2(-/-) mice to express significantly greater COX-1 expression in loaded ulnas than in loaded ulnas in COX-2(+/+) mice. There were no differences in COX-1 expression in nonloaded ulnas. CONCLUSIONS: A functional COX-2 gene was not found to be required for skeletal mechanotransduction. This is in contrast to previous pharmacological studies showing that COX-2 is critical to the response of bone to loading. Investigating a potential reason for the absence of a genotype difference in this study, we found that mice with a null mutation in the COX-2 gene possess inductive skeletal COX-1 expression.

Animals↗
PubMed2004

Detection of HIV-1 antiretroviral resistance from patients with persistently low but detectable viraemia.

We modified the Abbott diagnostics HIV-1 Viroseq version 2 assay trade mark in order to detect the presence of HIV-1 drug resistance mutations in patients with viraemia below 1000 copies/ml of plasma. One hundred and forty-four patients with a detectable HIV-1 plasma viral load below 1000 copies/ml were selected and HIV-1 genetic analysis carried out using a modification of the Abbott Diagnostics Viroseq 2.0 assay trade mark. The procedure differs from the standard protocol in that a nested PCR amplification step was introduced. The oligonucleotide primers for the first round of PCR were those supplied in the RT-PCR module of the kit. The nested PCR primers were primers A and H taken from the sequencing module. One hundred and twenty-eight out of 144 (89%) plasma samples with an HIV-1 viral load of less than 1000 copies/ml (ranging from 54 to 992 copies) were successfully sequenced. HIV-1 genotypes were obtained from 68 out of 81 (84%) samples with a viral load of greater than 50 but less than 300 copies/ml and 60/63 (95%) of samples with a viral load of greater than 300 but less than 1000 copies/ml. Serial dilution of a sample with a high viral load did not affect the detection of resistance mutations. Multiple sequencing of samples with low viral load did not result in detection of additional mutations, although, in one sample the K103N mutation was detected in 3/6 replicates while wild-type was detected in 2/6 and a mixture of wild-type/mutant in 1/6. Samples from patients infected with both clade B and non-B clades of HIV-1 could be genotyped at low copy number. Modification of the Abbott Viroseq assay allows reproducible sequencing of the HIV-1 genome from patients with low, but detectable, plasma virus burden.

Anti-HIV Agents↗
PubMed1998

The RAD52 recombinational repair pathway is essential in pol30 (PCNA) mutants that accumulate small single-stranded DNA fragments during DNA synthesis.

To identify in vivo pathways that compensate for impaired proliferating cell nuclear antigen (PCNA or Pol30p in yeast) activity, we performed a synthetic lethal screen with the yeast pol30-104 mutation. We identified nine mutations that display synthetic lethality with pol30-104; three mutations affected the structural gene for the large subunit of replication factor C (rfc1), which loads PCNA onto DNA, and six mutations affected three members of the RAD52 epistasis group for DNA recombinational repair (rad50, rad52 and rad57). We also found that pol30-104 displayed synthetic lethality with mutations in other members of the RAD52 epistasis group (rad51 and rad54), but not with mutations in members of the RAD3 nor the RAD6 epistasis group. Analysis of nine different pol30 mutations shows that the requirement for the RAD52 pathway is correlated with a DNA replication defect but not with the relative DNA repair defect caused by pol30 mutations. In addition, mutants that require RAD52 for viability (pol30-100, pol30-104, rfc1-1 and rth1delta) accumulate small single-stranded DNA fragments during DNA replication in vivo. Taken together, these data suggest that the RAD52 pathway is required when there are defects in the maturation of Okazaki fragments.

Cell Division↗
PubMed1998

Mutation and selection within the individual.

Selection within the individual may have played a critical and creative role in evolution, boosting the survival chances of mutations beneficial to the cell and the individual, hindering the spread of deleterious mutations, and reducing the genetic load imposed on the population. We review the literature and present new results to describe the effects of cell-lineage selection on the rate and fixation probability of new mutations. Cell-lineage selection can alter these quantities by several orders of magnitude. Cell-lineage selection is especially important in the case of rare recessive mutations, which are hidden from selection at the individual level but may be exposed to selection at cellular level. Because selection within the individual acts as a sieve eliminating deleterious mutations and increasing the frequency of beneficial ones, mutations observed among progeny will have been pre-selected and are more likely to increase cell proliferation than would randomly generated mutations. Although many authors have focused on the potential conflict between selection at the cellular and individual levels, it must be much more common that the two levels act concordantly. When selection at the cell and individual levels act in a cooperative manner, increased rather than decreased opportunity for germline selection will be favored by evolution.

Animals↗
PubMed2007

Nephrogenic syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large pedigree.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently described genetic cause of hyponatremia in male infants. Whether this X-linked condition could be detected in the adult or also could affect women is unknown. A large five-generation family was identified in which the recently described arginine-vasopressin receptor type 2 (AVPR2) mutation that is responsible for NSIAD was segregated. The proband was a 74-yr-old patient who had a syndrome of inappropriate antidiuresis and whose hyponatremia resisted administration of two AVPR2 antagonists. The phenotype of family members who carry the mutation was investigated. Patients with normal serum sodium were subjected to a water-load test. The previously reported activating missense R137C mutation in the AVPR2 gene in three hemizygous male and four heterozygous female individuals was identified. Except in one woman, spontaneous episodes of hyponatremia or abnormal water-load test were identified in all patients with the mutation, whether male or female. Skewed X inactivation was evidenced in the blood of the asymptomatic woman, which is compatible with preferential inactivation of her mutated allele. NSIAD is not limited to male infants. The diagnosis also should be considered in both male and female adults.

Adult↗
PubMed2004

Plasma RNA viral load is not associated with intrapatient quasispecies heterogeneity in HIV-1 infection.

The human immunodeficiency virus type 1 (HIV-1) viral set point has been associated with the rate of, disease progression and with the level of HIV-specific immune response. The analysis of the possible association between viral set point and quasispecies heterogeneity has important consequences in the understanding of HIV-1 in vivo evolution. In this study, we analyzed the association between intrapatient viral diversity and RNA viral load in 16 antiretroviral therapy-naive HIV-1-infected patients at a single time point, during the disease free period. Patients were separated into low and high viral load groups according to plasma RNA values. HIV-1 quasispecies complexity was assessed in the C2-V5 env region. The average intrapatient quasispecies heterogeneity in both groups was not significantly different (t-test, P > 0.05). However, while within the low viral load group both synonymous and non-synonymous mutations contribute to the variation observed, in the heterogeneity observed in the high viral load group there was an increase in the contribution of the non-synonymous mutations. Thus, this study show that although intrapatient quasispecies heterogeneity is not associated with viral set point in HIV-1 infection, some differences exist between the two groups in the pattern of mutation accumulation.

Amino Acid Substitution↗
PubMed2005

A Quasi species of the pre-S/S gene and mutations of enhancer II/core promoter/pre-C in mothers and their children infected with hepatitis B virus via mother-to-infant transmission.

BACKGROUND: Hepatitis B virus (HBV) infection has a tendency to be chronic. The quasi species of HBV in the pre-S/S gene and mutations in enhancer II (EnhII)/core promoter (CP)/pre-C of HBV were studied in asymptomatic carrier (AsC) mothers and their children with different virus loads, to gain a better understanding of the pathogenic mechanisms of HBV. METHODS: Quasi species were analyzed using an established phylogenetic tree based on the sequences of the pre-S/S gene from 3 mother-child pairs. The mutations of EnhII/CP/pre-C were studied in 15 mother-child pairs. RESULTS: Substitution was the main mutation model. The phylogenetic tree indicated that the pre-S/S gene in every mother-child pair had the same root. The sequences of the pre-S/S gene of each patient were somewhat different from one another, but there was limited evolutionary distance between them. The evolutionary distances between the pre-S/S gene and the base of the tree in patients with low virus loads were greater than those in patients with high virus loads. The mutations in patients with low virus loads were much more frequent than those in patients with high virus loads and were not related to age, irrespective of whether the pre-S/S gene or EnhII/CP/pre-C was considered. CONCLUSIONS: There are HBV quasi species in the sera of AsCs, and the mutations are related to virus load and hepatitis B e antigen seroconversion, irrespective of age.

Adult↗
PubMed2005

A loss-of-function mutation in AtYSL1 reveals its role in iron and nicotianamine seed loading.

The Arabidopsis Yellow Stripe 1-Like (YSL) proteins have been identified by homology with the maize (Zea mays) Yellow Stripe 1 (YS1) transporter which is responsible for iron-phytosiderophore (PS) uptake by roots in response to iron shortage. Although dicotyledonous plants do not synthesize PS, they do synthesize the PS precursor nicotianamine, a strong metal chelator essential for maintenance of iron homeostasis and copper translocation. Furthermore, ZmYS1 and the rice (Oryza sativa) protein OsYSL2 have metal-nicotianamine transport activities in heterologous expression systems. In this work, we have characterized the function of AtYSL1 in planta. Two insertional loss-of-function ysl1 mutants of Arabidopsis were found to exhibit increased nicotianamine accumulation in shoots. More importantly, seeds of both ysl1 knockouts contained less iron and nicotianamine than wild-type seeds, even when produced by plants grown in the presence of an excess of iron. This phenotype could be reverted by expressing the wild-type AtYSL1 gene in ysl1 plants. ysl1 seeds germinated slowly, but this defect was rescued by an iron supply. AtYSL1 was expressed in the xylem parenchyma of leaves, where it was upregulated in response to iron excess, as well as in pollen and in young silique parts. This pattern is consistent with long-distance circulation of iron and nicotianamine and their delivery to the seed. Taken together, our work provides strong physiological evidence that iron and nicotianamine levels in seeds rely in part on AtYSL1 function.

Arabidopsis↗
PubMed1996

Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine.

The association between human immunodeficiency virus type I (HIV-1) RNA load changes and the emergence of resistant virus variants was investigated in 24 HIV-1-infected asymptomatic persons during 2 years of treatment with zidovudine by sequentially measuring serum HIV-1 RNA load and the relative amounts of HIV-1 RNA containing mutations at reverse transcriptase (RT) codons 70 (K-->R), 41 (M-->L), and 215 (T-->Y/F). A mean maximum decline in RNA load occurred during the first month, followed by a resurgence between 1 and 3 months, which appeared independent of drug-resistance. Mathematical modeling suggests that this resurgence is caused by host-parasite dynamics, and thus reflects infection of the transiently increased numbers of CD4+ lymphocytes. Between 3 and 6 months of treatment, the RNA load returned to baseline values, which was associated with the emergence of virus containing a single lysine to arginine amino acid change at RT codon 70, only conferring an 8-fold reduction in susceptibility. Despite the relative loss of RNA load suppression, selection toward mutations at RT codons 215 and 41 continued. Identical patterns were observed in the mathematical model. While host-parasite dynamics and outgrowth of low-level resistant virus thus appear responsible for the loss of HIV-1 RNA load suppression, zidovudine continues to select for alternative mutations, conferring increasing levels of resistance.

Base Sequence↗
PubMed2006

Evolution of transmitted HIV-1 with drug-resistance mutations in the absence of therapy: effects on CD4+ T-cell count and HIV-1 RNA load.

Sequence analysis of HIV-1 from 440 therapy-naive individuals included within the CASCADE study, who seroconverted within 18 months of the last negative test, identified 65 persons infected with a strain carrying resistance-associated mutations. Population-based sequencing was performed for 20 of these individuals during the therapy-free follow-up period. The median time of follow-up was 15 months (interquartile range from 10 to 23 months). Of these individuals, 12 showed subsequent evolution at the resistance positions, whereas the virus of 8 people was stable during this period. In the reverse transcriptase (RT) gene, the drug-resistant 215Y or 215F codons evolved to alternative codons in all six cases, 70R reverted to the wild-type 70K in 3 of the 4 individuals, 67N evolved only in 1 of 4 patients to a wild-type 67D, 215S evolved to wild-type 215T in 1 of 3 patients, 219N evolved to 219K in 1 of 2 patients, and one patient with 184V reversed to the wild-type 184M. The 181C variant evolved to the wild-type 181Y in 1 of 2 individuals. These codon changes were caused by single nucleotide mutations. No evolution was observed for other RT mutations: 41L, 69D, 69N, 190S, 210W, 215L, 215C, 215E and 219Q. In the protease gene, resistance mutations 84V and 90M were stable in 2 individuals. Comparing the CD4+ T-cell count of the 12 evolving versus the 8 stable cases revealed no statistically significant difference at the date of the first sequence following seroconversion. Interestingly, a lower CD4+ T-cell count was observed in the group without evolution at the second sequence time point (P = 0.043). No difference in HIV-1 RNA load was observed. These results, together with the apparent pressure to mutate at the resistance-associated positions exemplify the decreased fitness of viruses carrying 21 5Y/F, 70R or 184V.

Anti-HIV Agents↗
PubMed2003

Mutation patterns of the reverse transcriptase genes in HIV-1 infected patients receiving combinations of nucleoside and non nucleoside inhibitors.

A genotyping assay was used to define human immunodeficiency virus type 1 (HIV-1) reverse transcriptase codons in plasma samples from 80 HIV-1 patients extensively treated with two nucleoside reverse transcriptase (zidovudine and lamivudine) and one non nucleoside reverse transcriptase (nevirapine) inhibitor. The frequencies of T215S/Y/F, M41L, D67N, L210W K70R, K219Q mutations, detectable in plasma samples, conferring resistance to zidovudine were 61.2, 56.2, 36.2, 31.5, 27.5 and 17.5%, respectively. Mutations (M184V or M184I) conferring resistance to lamivudine were detected in an extremely high percentage of patients (61%). Among mutations correlated to high (K103N, V106A, Y181C/I, Y188C/H/L, G190A/C/E/Q/S/T) or moderate (V108I, V118I) levels of nevirapine resistance, the predominant amino acid change was a substitution at 103 codon, present in 24 of 80 samples tested. Finally Q151M, the marker mutation able to confer resistance to all nucleoside analogues, was detected in seven patients with a viral load of between 1 x 10(4) and 9 x 10(4) HIV-1 RNA copies/ml. The relationship between the genotype and the viral load showed that the incidence of some specific mutations [M41L, T215Y (correlated to zidovudine resistance) and K103N (correlated to all NNRTIs drugs)] significantly (P=0.001) increased with higher viral load. Our results, albeit limited to a small cohort, showed a high frequency of mutations correlated to drugs in use, suggesting a need for therapeutic change in the near future and demonstrating that the development of genotyping tests helps to guide the therapeutic management of HIV-1 infected people. Our data highlight the dangers of selecting antiretroviral therapy without previous antiretroviral drug testing. Although the cost of these assays is a concern, prescribing inefficacious drugs could create serious problems for HIV-1 patients.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells.

BACKGROUND: The atypical cells of nodular lymphocyte-predominant Hodgkin's disease, designated lymphocytic and histiocytic (L&H) cells, have a B-cell phenotype. To clarify the clonality of these cells, we studied rearranged immunoglobulin genes for the variable region of the heavy chain (V[H] genes) in individual L&H cells from 11 patients with nodular lymphocyte-predominant Hodgkin's disease. We also studied the expression of immunoglobulin light chains by those cells in six of the same patients. METHODS: Single CD20+ L&H cells were isolated from frozen sections by a technique of micromanipulation. The rearranged V(H) genes of these cells were amplified by the polymerase chain reaction (PCR), sequenced, and compared with germ-line V(H) genes. Immunoglobulin light-chain messenger RNA (mRNA) was detected by in situ hybridization. RESULTS: Of 615 L&H cells isolated from all the frozen sections, 160 yielded PCR products. In each of the 11 patients, the L&H cells that could be evaluated had identically rearranged V(H) genes, whether they were isolated from the same nodule, different nodules, or different blocks of tissue. All the V(H) sequences derived from the L&H cells were highly mutated (7.5 to 27.2 percent). In two cases the coding capacity of the V(H) genes was completely or partially disrupted by mutations. Intraclonal diversity was found in six cases, and monotypic immunoglobulin light-chain mRNA was found in six. CONCLUSIONS: The L&H cells of nodular lymphocyte-predominant Hodgkin's disease represent a monoclonal expansion of B cells. The high load of V(H) gene mutations and signs of intraclonal diversity suggest a relation between L&H cells and germinal-center B cells at the centroblastic stage of differentiation.

B-Lymphocytes↗
PubMed2005

Optimality of codon usage in Escherichia coli due to load minimization.

The canonical genetic code is known to be highly efficient in minimizing the effects of mistranslational errors and point mutations, an ability which in term is designated "load minimization". One parameter involved in calculating the load minimizing property of the genetic code is codon usage. In most bacteria, synonymous codons are not used with equal frequencies. Different factors have been proposed to contribute to codon usage preference. It has been shown that the codon preference is correlated with the composition of the tRNA pool. Selection for translational efficiency and translational accuracy both result in such a correlation. In this work, it is shown that codon usage bias in Escherichia coli works so as to minimize the consequences of translational errors, i.e. optimized for load minimization.

Codon↗
PubMed2001

Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377).

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy-experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance mutations were assessed before study treatment (baseline) and at virologic failure. Zdv, ddI, and ddC mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp and 3TC mutations were detected frequently at virologic failure, and Nvp mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp and 3TC mutations plus Rtv and Nfv mutations. However, Rtv and Nfv mutations were detected at unexpectedly low rates.

Adolescent↗