[Is there more to hypodontia then missing teeth?] / Ernstige hypodontie: meer dan alleen ontbrekende gebitselementen?

Dental care professionals regularly see patients with hypodontia. Hypodontia can be acquired, for example through chemotherapy or radiation at a young age, but is hereditary in most patients. Due to an error (pathogenic variant) in one of the many genes that control odontogenesis, the formation of the tooth germ is disrupted at an early stage. The genes involved are not only crucial for tooth development, but they also play an important role in other physical processes. This article provides background information on hypodontia. Based on an inventory of gastrointestinal complaints in patients with hypodontia and a case description of the simultaneous occurrence of a coagulation disorder and hypodontia, the importance of a broad view of this patient group is illustrated. It is concluded that, in addition to a dental assessment, examination of these patients should include a limited physical examination and the medical history of the patient and his close relatives.

Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection.

Vertical transmission of hepatitis B virus (HBV) can occur occasionally despite vaccination of the child. This vaccination breakthrough has been associated with high maternal viraemia. We treated eight highly viraemic (HBV-DNA >/= 1.2 x 10(9) geq/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. HBV-DNA, hepatitis B surface antigen (HBsAg), anti-HBs and anti-HBc of their offspring were measured at birth and at 3, 6 and 12 months, respectively. Twenty-four children, born to untreated HBsAg-positive mothers with HBV-DNA levels >/=1.2 x 10(9) geq/mL served as historical controls. All children received passive-active immunization at birth and were followed-up for 12 months. In the lamivudine group one of the eight children (12.5%) was still HBsAg and HBV-DNA positive at the age of 12 months. All other children seroconverted to anti-HBs and maintained seroprotection. In three children, HBV-DNA was temporarily detected by polymerase chain reaction. In the untreated historical control group, perinatal transmission occurred in seven of 25 children (28%). In highly viraemic HBsAg-positive mothers, reduction of viraemia by lamivudine therapy in the last month of pregnancy may be an effective and safe measure to reduce the risk of child vaccination breakthrough. This approach should be evaluated in a large controlled trial.

Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase.

BACKGROUND AND AIMS: Interferon (IFN) induced hepatitis B e antigen (HBeAg) seroconversion is durable in 80-90% of chronic hepatitis B patients. Preliminary reports on the durability of HBeAg seroconversion following lamivudine are contradictory. We investigated the durability of response following IFN, lamivudine, or IFN-lamivudine combination therapy in a meta-analysis of individual patient data. PATIENTS AND METHODS: Twenty four centres included 130 patients in total with an HBeAg seroconversion (HBeAg negative, antibodies to hepatitis B e antigen positive) at the end of antiviral therapy: 59 with lamivudine, 49 with interferon, and 22 with combination therapy. Relapse was defined as confirmed reappearance of HBeAg. RESULTS: The three year cumulative HBeAg relapse rate by the Kaplan-Meier method was 54% for lamivudine, 32% for IFN, and 23% for combination therapy (p=0.01). Cox regression analysis identified pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and therapy as independent predictive factors of post-treatment relapse; Asian race, previous therapy, centre, and type of study were not predictive of relapse. The relative HBeAg relapse risk of lamivudine compared with IFN therapy was 4.6 and that of combination therapy to IFN therapy 0.7 (p(overall)=0.01). CONCLUSIONS: The durability of HBeAg seroconversion following lamivudine treatment was significantly lower than that following IFN or IFN-lamivudine combination therapy. The risk of relapse after HBeAg seroconversion was also related to pretreatment levels of serum ALT and HBV DNA, but independent of Asian race.

Passive immunization of chronic hepatitis B patients on lamivudine therapy: a feasible issue?

In view of the limited efficacy of lamivudine monotherapy for chronic hepatitis B (HBV) infection, combination with other drugs seems logical. Intravenous neutralization of circulating HBsAg by specific hepatitis B immunoglobulin (HBIg) has been shown to protect hepatocytes against (re-)infection with HBV in the setting of liver transplantation and postexposure prophylaxis. Large controlled vaccination trials have revealed that HBV can be prevented by HBIg therapy in the majority of newborns after perinatal infection. A benefit of anti-HBs in HBV patients has so far only been investigated in three small studies. In this pilot study we investigated the effects of polyclonal i.v. HBIg (HepatectR, Biotest) administration in HBV-infected patients. Six liver biopsy-proven HBV-infected patients, all on lamivudine treatment and HBV DNA negative by PCR, were investigated. Pre-treatment HBsAg levels varied between 120 and 9760 ng/mL. On day 1, 10.000 IU HBIg was given, followed by 10.000 IU once, twice or three times on day 29. Long-term follow-up lasted at least 4 months. HBsAg and anti-HBs were measured quantitatively by standard MEIA and also by an experimental EIA. In vitro neutralization of HBsAg by Hepatect was mimicked in an 'inhibition in solution assay'. Complete neutralization of HBsAg by HBIg in vitro was possible, 50% inhibition concentrations varied between 100 and 250 IU/L HBIg with HBsAg levels of 68 and 120 ng/mL. No HBIg-related side-effects were observed. In two patients with low pretreatment HBsAg levels HBsAg reached levels below the detection limit of the assay, which persisted a maximum of 31 and 7.5 h, respectively. Peak anti-HBs concentrations were 5100 and 4648 IU/L. In the other four patients, with higher pretreatment HBsAg levels, HBsAg concentrations in serum hardly changed. For the whole population, the drop in HBsAg did not reach statistical significance. However, in four of the six patients a further decrease in HBsAg [18%-66%] was observed. In conclusion, HBIg was well tolerated; however, efficacy was limited due to high HBsAg levels in spite of maximum inhibition of virion production. 'Neutralization' was achieved only in two patients with low HBsAg levels. Passive immunization in HBV-DNA negative patients is not a feasible option. This strategy seems only feasible if agents inhibiting both the production of viral proteins and Dane particles more selectively, become available.

Is combination therapy with lamivudine and interferon-alpha superior to monotherapy with either drug?

For the treatment of chronic hepatitis B (CHB) two drugs have been licensed world-wide: interferon-alpha (IFN) and lamivudine. Both drugs significantly increase the hepatitis B e-antigen (HBeAg) seroconversion rate, but a sustained treatment response occurs in less than 40% of patients. To explore whether there is an additional benefit of combining these two drugs, we reviewed the literature on lamivudine-IFN combination therapy in comparison to the two monotherapies in compensated, HBeAg-positive, CHB patients. We focussed on two clinically relevant outcome measures: HBeAg seroconversion, and change in liver histology. Candidates for lamivudine-IFN combination therapy were, previously untreated, patients with moderately elevated alanine aminotransferase (ALT). Such regimen should still be considered experimental. Viral kinetics may provide insight into how long therapy should be continued; prolongation of therapy to 52 weeks currently appears a reasonable approach. According to principles of anti-viral therapy today, simultaneously dosing of both drugs is to be preferred, since rapid maximal virus suppression is thought to be essential to prevent drug resistance and enhance seroconversion. From an immunological point of view, pre-treatment with lamivudine or IFN may alter the virus-host balance and set the stage for the other drug to enhance the effect of treatment. Further clinical research on lamivudine-IFN combination therapy appears warranted.

Administration of a human monoclonal antibody (TUVIRUMAB) to chronic hepatitis B patients pre-treated with lamivudine: monitoring of serum TUVIRUMAB in immune complexes.

A human monoclonal anti-hepatitis B antibody preparation (TUVIRUMAB) was administered 6 times over a 2-week period in a dose-escalating scheme to chronic hepatitis B patients pre-treated with lamivudine. The capacity of the TUVIRUMAB antibody to "neutralize" hepatitis B surface antigen in the circulation was investigated by means of experimental enzyme-immunoassays. Monoclonal antibody conjugates enabled the detection of HBsAg, TUVIRUMAB, and HBsAg/TUVIRUMAB complexes. The results showed that (1) TUVIRUMAB was able partially to "neutralize" in vitro and in vivo, (2) HBsAg/TUVIRUMAB complexes can be traced by assays that capture the complex at either its HBsAg or its TUVIRUMAB component, (3) the final concentration of TUVIRUMAB at the end of therapy varied greatly but seemed to be related to HBsAg production at the start of therapy, (4) for at least 14 days after discontinuation of therapy, a minimal HBsAg level could be maintained in the presence of a declining TUVIRUMAB titer in patients with less than 3 microg/ml HBsAg before the start of therapy, (5) three months after therapy, all HBsAg levels had returned to pre-treatment levels and TUVIRUMAB had disappeared.

Efficacy and safety of an intravenous monoclonal anti-HBs in chronic hepatitis B patients.

BACKGROUND/AIMS: In this study the safety and efficacy of a monoclonal anti-HBs, Tuvirumab (Mab), were investigated. Tuvirumab is a human monoclonal antibody recognizing the stable 'a'-determinant of the HBsAg. METHODS: We included ten chronic hepatitis B patients: four received monotherapy, and six combination therapy with interferon alpha 2b. RESULTS: Because the development of insoluble [HBsAg-HBsAb] complexes led to adverse events, the Mab dose had to be reduced in seven patients. In nine patients treatment was stopped prematurely because of lack of efficacy, i.e. neutralization of HBsAg in serum. However, temporary HBsAg levels were reduced by at least 50% in all patients; in three patients receiving combination therapy, background levels of HBsAg in serum were reached. A loss of serum HBV-DNA was seen in three patients in the combination group, followed by HBeAg seroconversion in two patients. CONCLUSIONS: We conclude that Mab was not effective in achieving primary efficacy as assessed by neutralization of circulating HBsAg. Whether a combination of Mab with an antiviral agent that reduces the HBsAg load--and therefore minimizes the risk of adverse events--may result in clinical efficacy should be investigated.

Suppression of hepatitis B virus replication mediated by hepatitis A-induced cytokine production.

BACKGROUND: Acute hepatitis A virus (HAV) infection can cause severe hepatitis especially in patients with underlying chronic liver disease. In patients with pre-existing chronic hepatitis B (HBV) acute HAV infection can suppress HBV replication. The exact mechanism of HBV suppression during acute HAV infection is still a subject of debate. One mechanism may be the production of HAV infection-induced cytokines leading to suppression of HBV replication and viral clearance. AIM: To evaluate cytokine production and HBV-specific lympho-proliferative responses (LPR) during acute HAV infection in a patient with chronic HBV infection-clearing markers of active HBV replication. DESIGN: Early detection of a case of acute HAV infection in an HBeAg-positive, HBV DNA-positive chronic HBV patient treated with lamivudine. RESULTS: At the time of HAV infection a sharp peak in the gamma-interferon (IFN-gamma) level occurred just before the rise in serum transaminase activity. This was subsequently followed by a decrease in HBV DNA and HBeAg below the limit of detection of the assay. However the HBV-specific T-cell response was not modified. After resolution of the acute HAV infection and withdrawal of antiviral therapy HBV replication relapsed. CONCLUSION: The sharp rise in IFN-gamma production mediated by the acute HAV infection may be pivotal in the suppression of HBV replication in chronic hepatitis B.

Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus.

Currently, the best option for patients with hepatitis delta is interferon alpha therapy for at least one year. To evaluate the effect of the combination lamivudine-high-dose interferon alpha therapy, we first treated eight patients with chronic hepatitis delta infection with lamivudine for at least 24 weeks; then lamivudine was combined with a high dose of interferon alpha followed by a regular dose (9 MU tiw). Follow-up was 12 weeks. Virological, biochemical and histological features were evaluated for response to therapy. At baseline, all patients were HBsAg positive in serum and HDV RNA-(PCR)positive in plasma; HBV DNA was undetectable with the Digene Hybrid Capture assay (limit of detection 1.5 x 10(6) geq ml-(1)) in all cases. Transaminases were elevated in all patients; median ALT 68 (range 48-143) IU l(1). Seven of eight patients completed the course; one patient with a pre-existing sickle cell trait was withdrawn from the trial due to the development of a nephrotic syndrome. The HBsAg-concentration in serum decreased in two out of seven patients (29%). However, there was no significant decrease in the HBsAg-concentration in serum during treatment (median 3654 PEU l(-1) (range 548-7,684) to 5300 PEU l(-1) (range 168-19,639)). The drop of HDV RNA in plasma from baseline during treatment was not significant. Decrease of HDV RNA was observed in three out of seven patients (43%) (median 10(5) geq ml(-1); range 10(3)-10(6) to median 10(3) geq ml(-1); range 10(2)-10(7)). Serum ALT did not change as reflected by a median of 68 IU l(-1) (range 48-143) at start of therapy to 63 IU l(-1) (range 20-171) at the end of therapy. At the end of treatment transaminases had normalised in one patient and decreased in three other patients (improvement in 57%). However, three of these four patients showed a rebound after withdrawal of therapy. The Histology Activity Index (HAI) indicated a drop from a median score of 7 (range 5-9) at baseline to 5 (range 3-8) at the end of treatment, but an increase in fibrosis from a median grade of 2 (range 1-3) at baseline to 3 (range 1-4) at the end of treatment was observed. In conclusion, this study does not yield support for the combination of an HBV suppressor and 16 weeks of high-dose interferon for therapy aimed at eradicating the hepatitis delta virus.

Osteopenia and osteoporosis in Crohn's disease: prevalence in a Dutch population-based cohort.

Reduced bone mineral density (BMD) has been reported in 3-77% of patients with inflammatory bowel disease (IBD). The majority of these studies are cross-sectional and from tertiary referral centres. The aim of our study was to estimate the prevalence of metabolic bone disease and of symptomatic fractures in a population of patients with Crohn's disease (CD) living in a well-defined geographic area. Patients with CD living in three adjacent municipalities within the IBD South-Limburg study area were investigated. BMD was measured by dual X-ray absorptiometry (DXA) of the femoral neck, lumbar spine and total body. The population comprised of 181 CD patients, 23 of whom were excluded. One-hundred-and-nineteen (75%) of the 158 eligible patients (37 males, 82 females with a mean age of 42 years (17-78)) were investigated. Osteopenia of lumbar spine and/or femoral neck was found in 45% of patients. Osteoporosis was found in another 13% of patients. Mean BMD (T-score) of femoral neck was significantly lower than of lumbar spine (P < 0.001). Male CD patients and patients aged under 18 at diagnosis are more at risk of having a low bone mass at the lumbar spine (P < 0.001) and total body (P = 0.018). The prevalence of osteoporosis in postmenopausal CD patients (29%) was significantly higher than in premenopausal patients (3%) (odds ratio: 12). Twenty-nine of 119 (24%) patients had a history of symptomatic fractures. Osteopenia and osteoporosis are frequent in CD and should have the full attention of the treating physician.

Contrasting patterns of response to lamivudine monotherapy in chronic hepatitis B patients.

In this paper we describe a cohort of patients treated with lamivudine, a reverse transcriptase inhibitor with a strong virus-suppressive effect on the hepatitis B virus. Eighty-nine patients were included in the intention-to-treat analysis. Evaluation with the Kaplan-Meier method was based on response to therapy of HBV DNA levels as well as normalization of transaminases. Subgroup evaluation based on the per protocol data was performed on two groups within this cohort based on the HBV DNA level at the end of therapy. During a 52-week treatment period, the chance of being HBV DNA negative at one point in time, as measured by the Digene Hybrid Capture assay (HCS) (limit of detection 1.5 x 10(6) geq/ml), the quantitative PCR assay (Q PCR) (limit of detection 1000 geq/ml), or the chance of normalization of transaminases at one point in time is 78%, 57% and 66%, respectively. Nineteen out of 73 patients who had continuing active viral replication after at least 24 weeks of lamivudine therapy were evaluated for the emergence of mutations resistant to lamivudine. In 3 out of 19 patients a mutation in the highly conservative YMDD region of the polymerase gene was detected. Baseline viral load in this group was significantly higher compared to the other 54 patients who were treated for 24 weeks or longer. Thirty-one out of 73 patients (46%) became negative by Q PCR. HBV DNA level at start of treatment was significantly lower compared to the 42 patients who remained HBV DNA positive. Eleven consecutive patients within this group who became negative by qualitative PCR (limit of detection 400 geq/ml) were evaluated to obtain characteristics for lamivudine withdrawal. Ten out of 11 patients became HBeAg negative with anti-HBe in 6. HBeAg in the liver biopsy was negative in 10 out of 11 patients; 9 out of 10 obtained biopsies were positive for HBV DNA, indicating low-level viral replication. In two patients in whom lamivudine was withdrawn, rebound of virus occurred. Further research is needed to obtain better insight into the variability in response. This might lead to a tailor-made individualized treatment regimen.