[Grounds for the inclusion of vaccination against cervical cancer within the National Immunisation Programme]. / Gronden voor opname van vaccinatie tegen baarmoederhalskanker in het Rijksvaccinatieprogramma.

The recent advice on vaccination against cervical cancer from the Health Council of the Netherlands and the decision by the Minister of Health, Welfare and Sport to implement the vaccination within the National Immunisation Programme by September 2009, has been criticized by a group of authors because five of seven criteria for vaccination in public programmes are considered not to have been met; notably with respect to efficacy and safety. It appears that the available scientific data have been weighted differently by the Health Council committee and the criticising group of authors. In the original advisory report, the committee of the Health Council lists all uncertainties, and argues that a linked monitoring programme will provide public vaccination with sufficient warranties for efficacy and safety. Thus, new opportunities for primary prevention can be taken, and a significant health benefit is likely to be gained. On the other hand, postponing a decision until all uncertainties have been resolved will postpone a significant potential health benefit for many years.

[Vaccines against human papillomavirus (HPV); between registration and implementation]. / Vaccins tegen Humaan papillomavirus (HPV); tussen registratie en implementatie.

--Each year, 600-700 women in the Netherlands are diagnosed with cervical cancer. Over the last 10 years, an average of 250 women have died annually due to cervical cancer. --Gardasil, the first vaccine for Human papillomavirus (HPV), was recently approved in Europe for the prevention of cervical cancer. --The availability of a vaccine for HPV prompts the question whether it should be included in the Dutch National Immunisation Programme. --At the end of 2006, the Medicines Evaluation Board, the Health Council of the Netherlands and the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment organised a workshop for experts in the field to answer that question. --The HPV vaccine provides protection against HPV-16 and HPV-18, which cause approximately 70% of cervical cancers. --Because the efficacy of vaccination is only evident after many years, preserving good participation in the screening programme is essential. --The current screening could be improved by introducing an HPV test combined with self-sampling for women who do not participate in screening. --Vaccination is unarguably an important development. However, there are still several unanswered questions regarding vaccination and its actual protection, duration of protection, long-term safety and cost-effectiveness. --April 1st, 2008, the Health Council of the Netherlands had recommended including HPV vaccination in the National Immunisation Programme.

Use of antiviral agents and other measures in an influenza pandemic.

The Dutch Ministry of Health asked the Health Council for advice on how to prepare for a possible influenza pandemic. In two advisory reports the Committee responsible indicated the measures that it believes would need to be taken if such a pandemic were to reach the Netherlands. During a pandemic, the Committee recommends that every resident of the Netherlands with influenza-like illness should be treated with neuraminidase inhibitors such as antiviral agents. This approach serves to mitigate the course of the disease, to reduce infectivity and to allow patients to build up immunity to the virus. Since up to 30% of the population could become ill, the Committee anticipates that a stock of five million courses of the neuraminidase inhibitor oseltamivir is sufficient. If a pandemic were to occur at a time that the stock does not exceed the present 225,000 courses, the committee advises restricting treatment to three specified groups of patients. If the first few patients are traced shortly after they fall ill, the Committee recommends treatment of the patient and postexposure prophylaxis for his/her close contacts. The Committee does not advocate prophylaxis in general, but it can envisage prophylaxis for particular groups of patients or under particular circumstances. The Committee believes that in order to reduce rapid spread of the virus, schools should be closed and events where large numbers of people gather in a confined space should be cancelled. Because this recommendation would have major social and economic consequences, the Committee understands that its implication will depend on the anticipated severity and extent of the pandemic. The Committee regards vaccination against influenza as the best means of protecting the population. The development of a vaccine should be the absolute priority.

Antibody response to a synthetic peptide covering a LAV-1/HTLV-IIIB neutralization epitope and disease progression.

Sequential sera of homosexual men participating in a prospective study on the incidence of HIV-1 infection and risk factors for AIDS were tested for the presence of antibodies to a synthetic 17-mer (Neu21; KSIRIQRGPGRAFVTIG) representing a neutralization epitope as present on the LAV-1/HTLV-IIIB strain of HIV-1. Of 191 at entry, 143 (75%) HIV-1-seropositive men remained anti-Neu21-negative during the follow-up period of 36 months. Thirty-seven (19%) HIV-1-seropositive men were persistently anti-Neu21-positive. Eleven (6%) HIV-1 seropositive men seroconverted for anti-Neu21 during follow-up. Of 75 men developing antibodies to HIV-1, 17 (23%) developed antibodies to Neu21. The incidence of anti-Neu21 seroconversion (calculated as attack rate) after 36 months was significantly lower (P less than 0.00001) among HIV-1-seropositive individuals (8%) than among the 75 HIV-1 seroconverters tested (25%), indicating that seroconversion to this neutralization domain occurs early during infection. AIDS and AIDS-related complex were diagnosed in 17% of the anti-Neu21 negatives and in 11% of the anti-Neu21 positives; this difference was not significant. The presence of HIV-1 antigen (29 versus 28%), the absence of antibodies to core proteins (45 versus 46%) and low CD4+ cell numbers (34 versus 40%) were not seen more frequently among anti-Neu21 negatives than among anti-Neu21 positives. These results argue against a role for antibodies to this LAV-1/HTLV-IIIB neutralization domain in protection against disease progression.

Appearance of predictors of disease progression in relation to the development of AIDS.

To study the natural history of HIV-1 infection in relation to serological and immunological profiles, 199 asymptomatic HIV-1-antibody (HIV-1-core-antibody)-seropositive and 76 seroconverted homosexual men were followed prospectively for 39 months. AIDS was diagnosed in 38 men. The AIDS attack rate was 20.8% after 39 months. The AIDS attack rate in the HIV-I-core-antibody positives was 12.1, versus 30.1% in the HIV-1-core-antibody negatives (P less than 0.001), and it was 13.3% in the HIV-1-antigen (HIV-1-Ag) negatives versus 53.9% in the HIV-1-Ag positives (P less than 0.001). The AIDS attack rate after 39 months was 10.9% in men with counts greater than or equal to 0.5 x 10(9)/l and 49.9% in those with CD4+ lymphocyte counts less than 0.5 x 10(9)/l. AIDS attack rates after 30 months in the same cohort have been previously reported [1], and were as follows: 6.8% in the core-antibody positives versus 35.7% in the core-antibody negatives. 6.9% in the HIV-1-Ag negatives versus 43.9% in the HIV-1-Ag positives, and 6.1% in those with CD4+ lymphocyte counts greater than or equal to 0.5 versus 51.9% in those with CD4+ lymphocyte counts less than 0.5 x 10(9)/l. The disappearance of core antibody, the appearance of antigen and the occurrence of low CD4+ lymphocyte counts preceded AIDS by a mean (s.d.) of 21.3 (8.9), 17.7 (8.8) and 15.7 (8.9) months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistent human immunodeficiency virus type 1 antigenemia in children correlates with disease progression.

In a longitudinal study, human immunodeficiency virus type 1 (HIV-1) antigen (HIV-Ag) was measured in serum specimens from 54 children with HIV-1 infection followed for a median duration of 17 months. The persistent detection of free HIV-Ag in a group of 25 children was associated with clinical deterioration in 22 (88%) and a mortality of 52%, whereas the persistent nondetection of free HIV-Ag in a group of 18 children was associated with clinical deterioration in five (28%) and a mortality of 11% during the period of observation. Nine children had transient HIV-1 antigenemia and two children converted from HIV-Ag negative to positive during the study. Free HIV-Ag levels varied inversely with antibody reactivity to viral core proteins p24 and p17 determined by Western immunoblot, suggesting either the formation of immune complexes or a balance between viral expression and the host immune response. Five mother-infant pairs were studied for HIV-Ag expression in the perinatal period. In three of these pairs, both mother and infant were HIV-Ag negative, in one pair the mother had high levels of HIV-Ag and the infant was HIV-Ag negative. In the remaining mother-infant pair, the neonate became HIV-Ag positive but the mother was HIV-Ag negative prepartum and postpartum. These data suggest that HIV-Ag probably does not cross the placenta and that the detection of free HIV-Ag in the offspring of a HIV-1 infected mother most likely indicates viral infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Decline in CD4+ cell numbers reflects increase in HIV-1 replication.

Changes in CD4+ cell numbers were studied in relation to the presence of HIV-1 antigen (HIV-1-Ag) in serum from homosexual men followed prospectively. During 30 months of follow-up the mean CD4+ cell number (x 10(9) per liter) was stable in 134 at entry HIV-1 antibody (HIV-1-Ab) seropositives, who remained HIV-1-Ag negative (from 0.59 to 0.62) and declined in 38 at entry HIV-1-Ab seropositives who were persistently HIV-1-Ag positive (from 0.43 to 0.34). In sera of 9 of 65 HIV-1-Ab seroconverters HIV-1-Ag was detected only once, 3 months before or concomitantly with antibody seroconversion. Another 11 men became persistently HIV-1-Ag positive with antibody seroconversion or 2-6 weeks thereafter. A decline in CD4+ cell numbers was seen between 6 months before and the moment of HIV-1-Ab seroconversion, independently of duration and level of antigen expression. This indicates initial HIV-1 replication in both HIV-1-Ag negatives and positives. Following antibody seroconversion, HIV-1-Ag negatives had higher CD4+ cell numbers than HIV-1-Ag positives. Similarly to those who were HIV antigenemic from entry of the study, the HIV-1-Ab seroconverters who concomitantly with seroconversion or shortly thereafter became HIV-1 antigenemic showed a steady and significant (p = 0.01) decline in CD4+ cell numbers. In those who remained HIV-1-Ag negative after antibody seroconversion, CD4+ cell numbers were stable during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term zidovudine treatment of asymptomatic HIV-1-infected subjects.

Eighteen asymptomatic men with persistent human immunodeficiency virus type 1 (HIV-1) p24 antigenemia were treated with zidovudine 250-500 mg (+/- acyclovir 800 mg) 6-hourly for 4-12 weeks, and thereafter with zidovudine 500 mg (+/- acyclovir 1600 mg) 12-hourly for 92 weeks. Six additional HIV-1 p24 antigenemic subjects were treated with zidovudine 500 mg 12-hourly for 76 weeks. Disease progression occurred in 4 subjects, despite sustained reduction of serum HIV-1 p24 antigen levels: Pneumocystis carinii pneumonia was diagnosed after 60, 80, 90 and 93 weeks, respectively. The median CD4+ cell count of these 4 men at study entry was 0.2 x 10(9)/l, and it declined to 0.07 x 10(9)/l at the moment AIDS was diagnosed. In 20 subjects no disease progression occurred. The median CD4+ cell count of these 20 men at study entry was 0.4 x 10(9)/l and it was 0.45 x 10(9)/l at the end of the study period. Median serum HIV-1 p24 antigen levels at the end of the study period were 42% lower than at study entry in these 20 subjects. In 5/20 men, an initial decline was followed by a rise in antigen levels to above pretreatment value. Treatment with zidovudine was well tolerated. Anemia caused symptoms in 3/24 men, but prolonged leucopenia or neutropenia did not occur. None developed clinical or convincing biochemical evidence of zidovudine-associated myopathy.

Interactions between simultaneously activated behavioral systems in the rat.

Interactions between electrically induced attack and teeth-chattering from 1 electrode and grooming from another were examined in male albino rats. The interaction between electrically induced attack and deprivation-induced feeding, as well as the effect of food deprivation on attack, was also studied. Results indicate that attack appears to be a dominant response, for it suppressed grooming and feeding at a low level of activation. On the other hand, it was not affected by simultaneously induced grooming or feeding. However, food deprivation decreased the threshold for attack, leaving attack latency, attack form, or bite targets unaffected. Teeth-chattering, suggested to be related to attack and flight, was also a dominant response. Results suggest that interactions between behavioral systems are in favor of the systems that must act acutely on activation in order to survive. Apparently, the regulations governing these interactions are represented in the functional organization of the brain.

Markers for progression to acquired immune deficiency syndrome and zidovudine treatment of asymptomatic patients.

Eighteen asymptomatic men with persistent human immunodeficiency virus type I (HIV-I) p24 antigenaemia were treated with zidovudine 250-500 mg (+/- acyclovir 800 mg) 6-hourly for 4-12 weeks, and subsequently with zidovudine 500 mg (+/- acyclovir 1600 mg) 12-hourly for 36 weeks. After 24 weeks six additional HIV antigenaemic subjects were entered and treated directly with zidovudine 500 mg 12-hourly. Over the treatment period serum HIV-I p24 (HIV-Ag) levels declined in all 24 subjects; significantly so in 17, and to below cut-off values in five. Mean serum HIV-Ag levels in different treatment groups declined in 68-78%. Initial increases in CD4+ cell counts were not sustained. Over 48 weeks serum HIV-Ag levels rose in three out of five non-treated men with persistent HIV antigenaemia, and they slightly declined in two; the mean serum HIV-Ag level in this group rose 67%. Regression of enlarged lymph nodes was seen in 19 out of 19 of the zidovudine-treated subjects. In the 24 zidovudine-treated subjects no disease progression occurred during follow-up, whereas two out of five non-treated men went on to develop CDC group IV A, and IV C-2 disease, respectively. Adverse reactions to the study drugs were infrequent and mild. Anaemia caused symptoms in two, but serious leucopenia or neutropenia was not observed. An initial positive effect on thrombocyte numbers was not sustained. These data demonstrate that in asymptomatic HIV-infected subjects zidovudine 500 mg 12-hourly is well tolerated and has a persistent inhibitory effect on viral replication.

Blood products and parvovirus B19.

A Committee of the Health Council of The Netherlands has expressed its opinion on introducing testing of blood products for parvovirus B19 (B19). Although infections with B19 generally run their course without any serious health problems, for some groups, such as pregnant women, patients with underlying haematological problems and patients with immunodeficiency, infections with B19 can result in serious complications. For cellular blood products, which are derived either from a single donor or a limited number of donors and are administered either to a single patient or to a limited number of patients, the Committee recommends that a risk-group approach be adopted and that 'Big-virus safe' blood products be administered to the risk groups mentioned above. The Committee defines as 'Big-virus safe' cellular blood products from a donor in which IgG antibodies against B19 have been detected in two separate blood samples, one taken at least six months after the other. Patients other than those in the risk groups should continue to receive cellular blood products that have been produced in accordance with current safety criteria. For plasma products, which are prepared from plasma pools and are administered to large numbers of patients, the measures must be aimed at cutting down the levels of B19 infectivity in such pools. For plasma pools, the Committee proposes a maximum permissible limit of 104 genome copies of Bl9 per ml.

[Acyclovir-resistant herpes simplex virus infections in immunocompromised patients]. / Aciclovir-resistente herpes simplex-virusinfecties bij immuungecompromitteerde patiënten.

In order to determine the sensitivity of herpes simplex virus (HSV) isolates from immunocompromised patients treated with antiviral compounds, a retrospective study was carried out in the Clinical Virology Department of the University Medical Centre, Amsterdam. Virus isolates from four AIDS patients and one bone marrow transplant recipient were examined for their sensitivity for the antiviral compounds used by means of plaque reduction assay. In some of the virus isolates, from patients in whom resistance was assumed on clinical grounds, in vitro resistance of the HSV to acyclovir (ACV) could be demonstrated, both after oral and after parenteral administration. There was a clear correlation between the clinical course of the HSV infection and in vitro resistance. ACV resistant virus isolates were sensitive to foscarnet, both clinically and in vitro. In immunocompromised patients treated for some time with ACV for HSV infection, resistance should be considered at lack of results or progression of the lesion and when necessary be demonstrated in vitro. Alternative therapy then consists of intravenous foscarnet treatment.

Cytomegalo and herpes simplex virus infections in renal transplant recipients.

In a prospective study data were obtained from renal transplant recipients with respect to the incidence and source of infections by CMV and HSV. The incidence of infections with CMV and HSV appeared to be related to the immune suppression regimen used. Especially the high incidence of reinfection with CMV (88.0%) and HSV (81.0) at high prednisolone dosage compared to the lower incidence (CMV 54.5%, HSV 44.1%) at low prednisolone dosage was apparent. Even in very moderate immune suppressed patients infections occurred in at least 40% of them. These infections are known to be potentially harmful to the recipient or to the graft. CMV can be transmitted by the graft in both seronegative and seropositive recipients as demonstrated by restriction enzyme analysis. Therefore CMV related disease has to be considered in all recipients with grafts from seropositive donors. For CMV infection the diagnostic value of serology (CF test) appeared high, while for the diagnosis of HSV infection virus-isolation was of more value.