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PubMed1992

Atypical (mild) forms of dihydropteridine reductase deficiency: neurochemical evaluation and mutation detection.

We investigated two patients with an atypical (mild) form of dihydropteridine reductase (DHPR) deficiency. Both responded to the loading test with tetrahydrobiopterin; their plasma phenylalanine levels were lowered from 278 mumol/L to 85 and 48 mumol/L and from 460 mumol/L to 97 and 36 mumol/L after 4 and 8 h, respectively. In one of the patients, a combined loading test with phenylalanine followed by tetrahydrobiopterin was also carried out and showed a profile typical for DHPR deficiency. The phenylalanine hydroxylation rate was calculated to be 43 and 87%, 4 and 8 h after cofactor administration, respectively. Diagnosis was confirmed by the absence of DHPR activity in the patient's erythrocytes. In cultured fibroblasts, residual activity of 4 and 10%, respectively, was found. Excretion of urinary pterins was essentially normal, and the biopterin to neopterin ratio in cerebrospinal fluid was increased. Although in both patients cerebrospinal fluid homovanillic acid was found to be normal, and 5-hydroxyindoleacetic acid was substantially reduced, there was no sign of neurologic alterations until the age of 2 y. However, one of the patients recently developed deceleration of head growth, whereas psychomotor development continued to be normal for age. Using the chemical cleavage method on the amplified cDNA, mismatches of T to G at nucleotide 659 and of G to A at nucleotide 475, respectively, were identified. These results also demonstrate that screening for tetrahydrobiopterin deficiency by urinary pterin analysis alone can miss some newborns with mild DHPR deficiency and that all children with tetrahydrobiopterin defects need full neurochemical evaluation together with analysis of the enzyme activity.

Amino Acid Metabolism, Inborn Errors↗

PubMed2004

Impact of insertions in the HIV-1 p6 PTAPP region on the virological response to amprenavir.

We evaluated the impact of genetic changes within p6Gag gene on the virological response (VR, mean decrease in plasma viral load at week 12) to unboosted amprenavir (APV). Gag-protease fragments, including gag p2, p7, p1, p6 regions and whole protease (PR) were sequenced from baseline plasma specimens of 84 highly pre-treated but APV-naive patients included in the NARVAL (ANRS 088) trial. The correlation between baseline p6Gag polymorphism, PR mutations, baseline characteristics and VR to APV was analysed in univariate analysis. Insertions (P459Ins) within p6 protein, leading to partial or complete duplication of the PTAPP motif, were significantly associated with a decreased VR (P459Ins versus wild-type; -0.3 +/- 0.8 vs -1.1 +/- 1.2 log copies/ml, P=0.007) and were more frequent when the V82A/F/T/S PR mutation was present (P=0.020). In multivariate analysis, after adjustment on the predictive factors of the VR in the NARVAL trial and on the PR mutations linked with response, there was a strong trend to an association (P=0.058) between the presence of P459Ins and an altered VR. In conclusion, these results suggest that insertions in the p6 region of HIV-1 gag gene may affect the VR, in highly pre-treated patients receiving an unboosted APV-containing regimen.

Adult↗

PubMed2000

Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression.

OBJECTIVE: To investigate the virological and immunological impact of a structured treatment interruption (STI) in a cohort of HIV-1 chronically infected patients with a further long-lasting effective virus suppression. METHODS: Twelve HIV-1 chronically infected adults who had maintained viral suppression (< 20 copies/ml) for more than 2 years, as well as a CD4:CD8 ratio > 1 for a median time of 22 months, were included in the study. Participants interrupted their antiretroviral treatment during a maximum period of 30 days or until a viral load rebound > 3000 copies/ml was detected. The same prior antiretroviral regimen was resumed after STI. Kinetics of plasma viral rebound was evaluated every 2 days during the treatment interruption period. Flow cytometry and cell proliferation assays were performed before and after STI. Genotypic resistance was assessed at the time of treatment resumption. RESULTS: No adverse events occurred during the interruption period. In two patients no viral rebound was detected after 30 days of treatment interruption. In the remaining 10 patients, viral load became detectable (> 20 copies/ml) at a median time of 14 days after treatment interruption. Afterwards, viral load increased exponentially with a mean t1/2 of 1.6 days. Treatment was successfully resumed in all patients. No resistance-conferring mutations associated with the pre-interruption antiretroviral regimen were detected. The percentage of CD4 and CD8 lymphocytes did not vary during the STI period; however, the level of expression of T-cell activation antigen CD38 on CD8 T cells increased significantly in response to viral rebound. Four patients gained T-helper cell responses to recall antigens (tuberculin and tetanus toxoid), two of who developed an HIV-specific response to p24. CONCLUSIONS: STI in chronically HIV-1-infected patients is not associated with reductions in CD4 T lymphocytes or to clinical complications in this group of patients after 2 years of effective plasma viral suppression. Viral load rebounds in most but not all patients, without evidence of selection of resistance-conferring mutations. Thereafter, viraemia can be effectively controlled by antiretroviral agent reintroduction. HIV-specific T-helper cell responses may be achieved after one cycle of treatment interruption suggesting some degree of immune-stimulation. These data do not discard consecutive cycles of STI as a therapeutic strategy to boost HIV-specific immunity in order to maintain viral replication under effective control.

Adult↗

PubMed2005

Contribution of Irf-1 promoter polymorphisms to the Th1-type cell response and interferon-beta monotherapy for chronic hepatitis C.

We recently reported promoter polymorphisms in the IRF-1 gene, an interferon-inducible gene that plays an important role in host antiviral function. The promoter activity was shown to be different between different polymorphisms. In this study, we investigated the relationship between IRF-1 promoter polymorphisms and the response to interferon monotherapy for chronic hepatitis C. Eighteen patients with a low initial viral load or hepatitis C virus (HCV) genotype non-1b received 6-months course of interferon-beta monotherapy. IRF-1 gene mutations and the treatment response were investigated. The IRF-1 promoter type possessing a higher promoter activity (-415C/-410A/-300A) was found in only three patients, all of which had a lower viral load than those with other promoter types and were able to obtain a sustained viral response. Flow cytometric analysis of peripheral blood mononuclear cells showed that the patients with a higher promoter activity of the IRF-1 had a significantly higher proportion of T helper 1-type CD4(+) cells after interferon administration than those of other promoter types. These results suggest that IRF-1 promoter polymorphisms may contribute, at least partially, to host antiviral activity for chronic hepatitis C.

Journal Article↗

PubMedDate not supplied

Differences between semen and plasma of nucleoside reverse transcriptase resistance mutations in HIV-infected patients, using a rapid assay.

The emergence of HIV-resistant strains generally occurs during treatment failure. A high rate of viral replication, low patient adherence to therapy, poor drug absorption or increased drug metabolism may be related to treatment failure and favour the onset of resistance. Recently, despite the absence of detectable HIV viral load in plasma, the importance of the persistence of HIV replication in other reservoirs has been underlined. Paired semen and plasma specimens stored from HIV male patients were tested using the LiPA assay, detecting genotype mutations related to Nucleoside Reverse Transciptase Inhibitors (NRTI) resistance. Overall, 32 paired semen and plasma samples were analyzed. The presence of HIVsequences was determined in 13 paired specimens (40.6%). Sixteen semen and 10 plasma specimens failed to amplify. At least one mutation was identified in the plasma of 77.8% of treated and 50.0% of naive patients. Similarly, mutations were identified in the semen of 66.7% of treated and 50.0% of untreated patients. Different mutation patterns between the two compartments were found in 46.2% of patients. The use of rapid assessment of HIV resistance in plasma and semen may be useful in some situations, such as HIV infection transmitted by sexual contact. Our data reinforce the evidence that, regarding HIV replication, the male genital tract must be considered as a separate compartment from the plasma.

Anti-HIV Agents↗

PubMed1999

Iron overload in urban Africans in the 1990s.

BACKGROUND: In a previously described model, heterozygotes for an African iron loading locus develop iron overload only when dietary iron is high, but homozygotes may do so with normal dietary iron. If an iron loading gene is common, then homozygotes with iron overload will be found even in an urban population where traditional beer, the source of iron, is uncommon. AIMS: To determine whether iron overload and the C282Y mutation characteristic of hereditary haemochromatosis are readily identifiable in an urban African population. METHODS: Histological assessment, hepatocellular iron grading, and dry weight non-haem iron concentration were determined in post mortem tissue from liver, spleen, heart, lungs, and skin. DNA of subjects with elevated hepatic iron indexes was analysed for the C282Y mutation. Iron concentrations in other tissues were compared. RESULTS: A moderate increase (>30 micromol/g) in hepatic iron concentrations was found in 31 subjects (23%; 95% confidence interval 15.9 to 30.1%), and they were considerably elevated (>180 micromol/g) in seven subjects (5.2%; 95% confidence interval 1.5 to 8.9%). Appreciably elevated hepatic iron concentrations were associated with heavy iron deposition in both hepatocytes and macrophages, and either portal fibrosis or cirrhosis. All were negative for the C282Y mutation. Very high concentrations were uncommon in subjects dying in hospital. Concentrations of iron in spleen, heart, lung, and skin were significantly higher in subjects with elevated hepatic iron. CONCLUSIONS: Iron overload is readily identified among urban Africans and is associated with hepatic damage and iron loading of several tissues. The condition is unrelated to the genetic mutation found in hereditary haemochromatosis.

Adult↗

PubMed2002

Analysis of Cdc6 function in the assembly of mammalian prereplication complexes.

Eukaryotic DNA replication requires the previous formation of a prereplication complex containing the ATPase Cdc6 and the minichromosome maintenance (Mcm) complex. Although considerable insight has been gained from in vitro studies and yeast genetics, the functional analysis of replication proteins in intact mammalian cells has been lacking. We have made use of adenoviral vectors to express normal and mutant forms of Cdc6 in quiescent mammalian cells to assess function. We demonstrate that Cdc6 expression alone is sufficient to induce a stable association of endogenous Mcm proteins with chromatin in serum-deprived cells where cyclin-dependent kinase (cdk) activity is low. Moreover, endogenous Cdc6 is sufficient to load Mcm proteins onto chromatin in the absence of cdk activity in p21-arrested cells. Cdc6 synergizes with physiological levels of cyclin E/Cdk2 to induce semiconservative DNA replication in quiescent cells whereas cyclin A/Cdk2 is unable to collaborate with Cdc6. Cdc6 that cannot be phosphorylated by cdks is fully capable of inducing Mcm chromatin association and replication. Mutation of the Cdc6 ATP-binding site severely impairs the ability of Cdc6 to induce Mcm chromatin loading and reduces its ability to induce replication. Nevertheless, the ATPase domain of Cdc6 in the absence of the noncatalytic amino terminus is not sufficient for either Mcm chromatin loading or DNA replication, indicating a requirement for this domain of Cdc6.

Adenoviridae↗

PubMed2006

Protein phosphatase 2A antagonizes ATM and ATR in a Cdk2- and Cdc7-independent DNA damage checkpoint.

We previously used a soluble cell-free system derived from Xenopus eggs to investigate the role of protein phosphatase 2A (PP2A) in chromosomal DNA replication. We found that immunodepletion of PP2A or inhibition of PP2A by okadaic acid (OA) inhibits initiation of DNA replication by preventing loading of the initiation factor Cdc45 onto prereplication complexes. Evidence was provided that PP2A counteracts an inhibitory protein kinase that phosphorylates and inactivates a crucial Cdc45 loading factor. Here, we report that the inhibitory effect of OA is abolished by caffeine, an inhibitor of the checkpoint kinases ataxia-telangiectasia mutated protein (ATM) and ataxia-telangiectasia related protein (ATR) but not by depletion of ATM or ATR from the extract. Furthermore, we demonstrate that double-strand DNA breaks (DSBs) cause inhibition of Cdc45 loading and initiation of DNA replication and that caffeine, as well as immunodepletion of either ATM or ATR, abolishes this inhibition. Importantly, the DSB-induced inhibition of Cdc45 loading is prevented by addition of the catalytic subunit of PP2A to the extract. These data suggest that DSBs and OA prevent Cdc45 loading through different pathways, both of which involve PP2A, but only the DSB-induced checkpoint implicates ATM and ATR. The inhibitory effect of DSBs on Cdc45 loading does not result from downregulation of cyclin-dependent kinase 2 (Cdk2) or Cdc7 activity and is independent of Chk2. However, it is partially dependent on Chk1, which becomes phosphorylated in response to DSBs. These data suggest that PP2A counteracts ATM and ATR in a DNA damage checkpoint in Xenopus egg extracts.

Animals↗

PubMed1998

Quantitative differences in the distribution of zidovudine resistance mutations in multiple post-mortem tissues from AIDS patients.

Replication of HIV introduces errors into the genome which are responsible for conferring a growth advantage over wildtype virus when drugs such as zidovudine (ZDV) exert a selective pressure. The molecular basis for HIV-1 resistance to ZDV has been mapped to codons 41, 67, 70, 215 and 219 of the reverse transcriptase gene both in vitro and in clinical samples of blood. This study has investigated the relationship between the quantitative prevalence of ZDV resistance in multiple organs of the same individual. Proviral HIV-1 load was measured by quantitative-competitive PCR in 90 samples from organs of 11 patients dying with AIDS. Nine of these patients had been prescribed zidovudine. The distribution of wildtype and mutant sequences at the positions 41, 67, 70, 215 and 219 of the reverse transcriptase was assessed using a point mutation assay. The results showed that the highest proviral loads were predominately found in lymph node, spleen and lung and there was a significant association between viral load and resistance to ZDV (P=0.008). Inter-organ distribution of wildtype and mutant sequences at codons 41, 67, 70, 215 and 219 was frequently not uniform and in some patients differed markedly between the lymphoreticular system and other organs. These results demonstrate that treatment of HIV-1 infection with zidovudine does not exert uniform selective pressures in multiple organs. These findings have implications for the interpretation of resistance data and design of treatment strategies for HIV, arguing in particular that alterations in therapeutic regimens should consider the likelihood of different resistance patterns being present in multiple sites within the same individual.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Multiple drug resistance genotype causing failure of antiretroviral treatment in an HIV-infected patient heavily exposed to nucleoside analogues.

A 37-year-old homosexual man began antiretroviral combination therapy with didanosine (ddI), lamivudine (3TC) and indinavir (IDV) after being exposed previously to zidovudine (ZDV), ddI and 3TC in different sequential regimens. The patient's viral load did not fall below a detectable level despite his adherence to drug therapy, which was considered optimal. Stavudine (d4T) was prescribed in the third month of treatment instead of ddI without any evident improvement in the treatment response. A point mutation nested PCR assay showed that the patient carried a virus with a codon Q151M mutation, which confers multiple drug resistance to nucleoside analogues. Genetic sequence analysis showed that, despite none of the classically associated mutations to Q151M being present at the beginning of treatment, continuous genetic evolution under selective drug pressure allowed the virus to accumulate mutations at codons 62, 74 and 116 over time. As expected, the CD4+ cell count declined during the study period, and the viral load remained detectable.

Adult↗

PubMed2006

Dendritic cell immunotherapy for breast cancer.

Novel adjuvant therapies are urgently needed to complement the existing treatment options for breast cancer. The advent of the use of dendritic cells (DCs) for cancer immunotherapy provides a unique opportunity to overcome the relative non-immunogenic property of breast tumours and address the underlying immunodeficiency. To date, the success of this approach has been limited, possibly due to the targeting of specific tumour antigens that rapidly mutate and, thus, become undetectable to the immune system. A more efficient approach would include preparations encompassing multiple antigens, such as those provided by loading of whole tumour cells or tumour RNA. It is proposed that targeting mammary stem cells responsible for resistance to chemo/immunotherapy, through the expression of a broad array of wild-type and mutated tumour antigens in the context of DCs, will become a mainstay for immunotherapy of breast cancer.

Animals↗

PubMed2004

Lack of association between the brain-derived neurotrophin factor (C-270T) polymorphism and late-onset Alzheimer's disease (LOAD) in Brazilian patients.

After the identification of the apolipoprotein E gene isoform (APOE-epsilon4) as a risk factor for late-onset Alzheimer's disease (LOAD), the search for other polymorphisms associated with AD has been undertaken by many groups of investigators around the world. These studies have shown controversial results in many populations. More recently, a single nucleotide polymorphism in the promoter region of the brain-derived neurotrophin factor (BDNF) was found to be a risk factor for AD in two independent population studies. Here we report the analysis of this polymorphism in a group of 188 LOAD Brazilian patients compared to matched normal controls. A strong association between the APOE-epsilon4 polymorphism and LOAD was observed, but there was no significant association between this BNDF polymorphism and affected patients. The possibility that other polymorphisms or mutations in this gene play a role in the development of AD cannot be ruled out. However, the results of the present study suggest that in opposition to the two reported studies, this polymorphism does not seem to be implicated in LOAD Brazilian patients. It also shows the importance of replication studies in different populations, as susceptibility loci might differ in different ethnic groups; this will have important implications in future treatments with pharmacological agents.

Aged↗

PubMed2001

A synthetic theory of molecular evolution.

According to the neo-Darwinian view of evolution evolution rate nu depends solely on the environment variation rate gamma, whereas in the non-Darwinian view evolution rate is determined mainly by the mutation rate mu. We have studied two kinds of population genetics models which exhibit both types of evolution in different parametric regions: one is a dynamical model representing infinite population, and the other is a Markov process model representing a nearly monomorphic finite population. In the infinite population model, after proving general time-derivative and mu-derivative formulas for the population average of quantitative traits, we show that if the mutation rate is adaptively determined, mu must be larger than nu in the stationary state. Loads of evolution are obtained in both regions. A high evolution rate such as nu = 1 per genome per generation is consistent with Haldane's value of tolerable load if and only if the functional constraint is not large and selection is weak, independent of whether the evolution is neo-Darwinian or non-Darwinian. As the selection intensity increases, nu is shown to change discontinuously from nearly mu to gamma at the transition point. In the finite population model, the transition of v is not discontinuous, but is very steep. On the other hand, no steep change of polymorphism takes place at the transition point. The steepness of the transition in our model suggests that real molecular evolution can be divided into either neo-Darwinian or non-Darwinian,and that the intermediate type of evolution is rather rare.

Epistasis, Genetic↗

PubMed2006

Patterns of hepatitis B virus infection in Brazilian human immunodeficiency virus infected patients: high prevalence of occult infection and low frequency of lamivudine resistant mutations.

Hepatitis B virus (HBV) molecular profiles were determined for 44 patients who were infected with human immunodeficiency virus (HIV) type 1 and had antibodies to the hepatitis B core antigen (anti-HBc), with and without other HBV serological markers. In this population, 70% of the patients were under lamivudine treatment as a component of antiretroviral therapy. HBV DNA was detected in 14 (32%) patients. Eight out of 12 (67%) HBsAg positive samples, 3/10 (30%) anti-HBc only samples, and 3/22 (14%) anti-HBs positive samples were HBV DNA positive. HBV DNA loads, measured by real time polymerase chain reaction, were much higher in the HBsAg positive patients (mean, 2.5 x 10(9) copies/ml) than in the negative ones (HBV occult infection; mean, 2.7 x 10(5) copies/ml). Nine out of the 14 HBV DNA positive patients were under lamivudine treatment. Lamivudine resistant mutations in the polymerase gene were detected in only three patients, all of them belonging to the subgroup of five HBsAg positive, HBV DNA positive patients. A low mean HBV load (2.7 x 10(5) copies/ml) and an absence of lamivudine resistant mutations were observed among the cases of HBV occult infection.

Adult↗

PubMed2006

Importance of the N-distal AP-2 binding element in Nef for simian immunodeficiency virus replication and pathogenicity in rhesus macaques.

Point mutations in SIVmac239 Nef disrupting CD4 downmodulation and enhancement of virion infectivity attenuate viral replication in acutely infected rhesus macaques, but changes selected later in infection fully restore Nef function (A. J. Iafrate et al., J. Virol. 74:9836-9844, 2000). To further evaluate the relevance of these Nef functions for viral persistence and disease progression, we analyzed an SIVmac239 Nef mutant containing a deletion of amino acids Q64 to N67 (delta64-67Nef). This mutation inactivates the N-distal AP-2 clathrin adaptor binding element and disrupts the abilities of Nef to downregulate CD4, CD28 and CXCR4 and to stimulate viral replication in vitro. However, it does not impair the downmodulation of CD3 and class I major histocompatibility complex (MHC-I) or MHC-II and the upregulation of the MHC-II-associated invariant chain, and it has only a moderate effect on the enhancement of virion infectivity. Replication of the delta64-67Nef variant in acutely infected macaques was intermediate between grossly nef-deleted and wild-type SIVmac239. Subsequently, three of six macaques developed moderate to high viral loads and developed disease, whereas the remaining animals efficiently controlled SIV replication and showed a more attenuated clinical course of infection. Sequence analysis revealed that the deletion in nef was not repaired in any of these animals. However, some changes that slightly enhanced the ability of Nef to downmodulate CD4 and moderately increased Nef-mediated enhancement of viral replication and infectivity in vitro were observed in macaques developing high viral loads. Our results imply that both the Nef functions that were disrupted by the delta64-67 mutation and the activities that remained intact contribute to viral pathogenicity.

Acute Disease↗

PubMed2004

The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants.

A T8993G point mutation in the mtDNA results in a Leu156Arg substitution in the MTATP6 subunit of the mitochondrial F1F0-ATPase. The T8993G mutation causes impaired oxidative phosphorylation (OXPHOS) in two mitochondrial disorders, NARP (neuropathy, ataxia and retinitis pigmentosa) and MILS (maternally inherited Leigh's syndrome). It has been reported, in some studies, that the T8993G mutation results in loss of assembled F1F0-ATPase. Others reported that the mutation causes impairment of proton flow through F0. In addition, it was shown that fibroblasts from NARP subjects have a tendency to undergo apoptotic cell death, perhaps as a result of increased free radical production. Here, we show that the T8993G mutation inhibits oxidative phosphorylation and results in enhanced free radical production. We suggest that free radical-mediated inhibition of OXPHOS contributes to the loss of ATP synthesis. Importantly, we show that antioxidants restore respiration and partially rescue ATP synthesis in cells harboring the T8993G mutation. Our results indicate that free radicals might play an important role in the pathogenesis of NARP/MILS and that this can be prevented by antioxidants. The effectiveness of antioxidant agents in cultured NARP/MILS cells suggests that they might have a potential beneficial role in the treatment of patients with NARP.

Adenosine Triphosphate↗

PubMed2004

Sequential combination therapy of HBe antigen-negative/virus-DNA-positive chronic hepatitis B with famciclovir or lamivudine and interferon-alpha-2a.

BACKGROUND/AIMS: Hepatitis B e antigen-negative/hepatitis B virus (HBV) DNA-positive chronic hepatitis B (CHBe-) exhibits a high relapse rate on monotherapy with lamivudine or interferon-alpha (IFN-alpha). We investigated, whether sequential therapy with famciclovir or lamivudine followed by combination with IFN-alpha-2a improves durable virologic response in CHBe- characterized by mutation analysis of the HBV precore genome region. METHODS: Fourteen patients were treated with famciclovir (n=3) or lamivudine for 4 weeks to reduce the viral load, and subsequently with the combination of the nucleoside analogue and IFN-alpha-2a until 16 weeks beyond the loss of serum HBV-DNA. RESULTS: Median duration of therapy was 29.0 weeks (range 20.6-48.3 weeks). Serum HBV-DNA was undetectable and alanine aminotransferase had normalized in all patients at the end of treatment. Seven (50%) patients maintained a sustained response 12 months after end of treatment. Only two of them had been infected by HBV with the G1896A mutation. Most patients (5/7) with the G1896A mutation relapsed within 4 months after therapy. CONCLUSION: Sequential combination therapy can induce sustained virologic response in a subgroup of CHBe-, but most with the G1896A precore mutant HBV relapse. Trials of CHBe- should be based on characterization of HBV mutants.

2-Aminopurine↗

PubMed2004

Evolution of precore/core promoter mutations in hepatitis B carriers with hepatitis B e antigen seroreversion.

The evolution of precore stop codon mutation (A1896) and dinucleotide mutation (T1762/A1764) in the basic core promoter (BCP) of hepatitis B virus (HBV) genome during transient seroconversion and seroreversion of hepatitis B e antigen (HBeAg) remains unclarified. Five HBeAg-positive HBV carriers who experienced transient seroconversion followed by seroreversion of HBeAg (Group I, 3.3%) and 3 HBeAg-negative HBV carriers with documented reversion of HBeAg (Group II, 2.5%) in a prospective cohort of 272 patients with chronic hepatitis B were thus identified. The sequential changes at the precore nucleotide 1896 and BCP dinucleotide 1762/1764 were determined by polymerase chain reaction and direct sequencing. At enrollement, precore A1896 and BCP T1762/A1764 were noted in 4 (50%) and 1 (13%) of the eight patients. During a median follow-up period of 58 months (range: 31-76 months), 12 episodes of transient HBeAg seroconversion followed by seroreversion were encountered in Group I patients and 3 episodes of HBeAg seroreversion in Group II patients. Accompanying acute exacerbations were found in two-thirds of patients with either HBeAg seroconversion or seroreversion. Overall, precore nucleotide A1896 remained identical in 73% and 83% of the seroconversion and seroreversion events, respectively. BCP dinucleotide T1762/A1764 remained unchanged in 94% and 92% of the seroconversion and seroreversion events, respectively. At the end of follow-up, only one had both precore and BCP mutations. In conclusion, these data suggested that HBeAg seroreversion might be due to the lack of sustained precore and BCP mutations after HBeAg seroconversion. Although uncommon, HBeAg seroreversion can be associated with hepatitis exacerbation.

Adolescent↗