Caroline Sabin

Frequency of inherited bleeding disorders in women with menorrhagia

BACKGROUNDnAlthough menorrhagia is a common gynaecological symptom, a specific cause is identified in less than 50% of affected women. We investigated the frequency of inherited bleeding disorders in women with menorrhagia.nnnMETHODSnWomen referred for investigation of menorrhagia whose pelvis was normal on clinical examination and who had an estimated menstrual blood loss of more than 80 mL were studied. A detailed menstrual history and history about other bleeding symptoms was taken. The activated partial thromboplastin time, factor VIII activity, von-Willebrand-factor antigen and activity, and factor XI (FXI) were measured in all patients; further tests were done when results were at or outside the limits of the assays.nnnFINDINGSn150 women were screened. An inherited bleeding disorder was diagnosed in 26 (17%) patients: the disorders were von Willebrands disease of mild (15) or moderate severity (three), mild FXI deficiency (four), mild von Willebrands disease and FXI deficiency (one), combined von Willebrands disease, FXI deficiency, and factor X deficiency (one), carriage of haemophilia-A gene (one), and platelet dysfunction (one). The frequency of von Willebrands disease and FXI deficiency were 13% (95% CI 7.9-18.8%) and 4% (1.5-8.5%), respectively. Menorrhagia since menarche was noted in 11 (8.9%) of 123 women without a bleeding disorder compared with 13 (65%) of 20 women with von Willebrands disease (p=0.001) and four (66.7%) of six women with FXI deficiency (p<0.001).nnnINTERPRETATIONnInherited bleeding disorders are found in a substantial proportion of women with menorrhagia and a normal pelvis examination. We suggest that such patients should be investigated for these disorders-especially von Willebrands disease-before invasive procedures are done.

The progression of HCV-associated liver disease in a cohort of haemophilic patients

We have studied morbidity and mortality related to hepatitis C virus infection in haemophilic patients treated at our centre. 11/255 HCV seropositive patients have developed hepatic decompensation. 20 years after first exposure to lyophilized clotting factor concentrate the risk of hepatic decompensation is estimated to be 10.8% (95% CI 3.8‐17.8%). There is a significantly increased risk associated with HIV infection, and also with increased age. For HIV seropositive patients the rates of decline in CD4 lymphocyte count and the development of p24 antigenaemia are significant risk factors for hepatic decompensation. Cirrhosis was seen in 9/19 HIV seropositive patients at post mortem. There was an association of cirrhosis with increased age but not with CD4 count, p24 antigenaemia or AIDS. In conclusion, HCV infection is associated with serious liver disease in haemophilic patients, but so far this has been restricted to a minority of those at risk. HIV coinfection accelerates progression to hepatic decompensation, and we speculate that this is probably due to enhanced HCV replication in the presence of immune deficiency.

Pregnancy in women with von Willebrand's disease or factor XI deficiency

Objective To assess the obstetric outcome in women with von Willebrands disease or factor XI deficiency.

Effective therapy has altered the spectrum of cause-specific mortality following HIV seroconversion.

Introduction:Although HAART has led to a reduction in overall mortality among HIV-infected individuals, its impact on death from specific causes is unknown. Methods:Twenty-two cohorts of HIV-infected individuals with known dates of seroconversion are pooled in the CASCADE collaboration. Causes of death (COD) were categorized into three AIDS-related and seven non-AIDS-related causes. The unknown causes were assigned a separate category. The cumulative incidence for each COD was calculated in the presence of the other competing COD, for the pre-HAART and HAART eras. A multivariate regression analyses for the cumulative rate of progression to the different COD was performed. Results:A total of 1938 of 7680 HIV-seroconverters died. Pre-HAART, AIDS opportunistic infections (OI) was the most common COD, followed by unknown and HIV/AIDS-unspecified. In the HAART era, the cumulative incidence for all AIDS-related COD decreased, OI remaining the most important. Large reductions in death due to other infections and organ failure were seen. Cumulative death risk decreased in the HAART era for most causes. The effect of HAART was not the same for all risk groups. The cumulative risk of death from AIDS-related malignancies, OI and non-AIDS-related malignancies decreased significantly among homosexual men (MSM), whereas the risk of dying from (un)-intentional death increased significantly among injecting drug users (IDU). A non-significant increase in hepatitis/liver-related death was seen in MSM, IDU and haemophiliacs. Conclusion:Overall and cause specific mortality decreased following the introduction of HAART. OI remain the most common COD in the HAART era, suggesting that AIDS-related events will continue to be important in the future. Future trends in COD should be monitored using standardized guidelines.

Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure.

ObjectiveTo analyse the immunological and virological effects of treatment interruptions in HIV-1-infected patients with treatment failure and multidrug-resistant virus. MethodsDrug susceptibility was assessed using Antivirogram and genotypic analysis was based on population and clonal sequencing for 48 patients who had interrupted treatment (⩾ 2 months). ResultsTreatment interruption resulted in viral load increases (mean 0.7 log10 copies/ml;P = 0.0001) and CD4 cell count decreases (mean 89 × 106 cells/l;P = 0.0001). A complete shift to wild-type virus at the phenotypic, genotypic and clonal level was observed in 28/45 patients. These patients differed from those that did not show a shift to wild type in baseline CD4 cell counts (192 versus 59 × 106 cells/l;P = 0.007) and in the relationship between baseline viral load and CD4 cell count (no correlation versus a significant negative correlation;P = 0.008). Response to re-initiation of treatment fell with increasing viral load [relative hazard (RH) 0.33;P = 0.001] and with increasing total number of drugs with reduced susceptibility (RH 0.51;P = 0.0003); it improved with the number of new drugs received (RH 2.12;P = 0.0002) and a shift to wild type (RH 5.22, P = 0.006). ConclusionsChanges in surrogate markers suggest that treatment provided benefit in spite of virological failure and resistant virus. Although patients with a shift to wild-type virus responded better in the short term to treatment re-initiation, the long-term effects are not known and the risk of immune deterioration needs to be carefully considered.

HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis.

BACKGROUNDnHighly active antiretroviral therapy (HAART) for the treatment of HIV infection was introduced a decade ago. We aimed to examine trends in the characteristics of patients starting HAART in Europe and North America, and their treatment response and short-term prognosis.nnnMETHODSnWe analysed data from 22,217 treatment-naive HIV-1-infected adults who had started HAART and were followed up in one of 12 cohort studies. The probability of reaching 500 or less HIV-1 RNA copies per mL by 6 months, and the change in CD4 cell counts, were analysed for patients starting HAART in 1995-96, 1997, 1998, 1999, 2000, 2001, and 2002-03. The primary endpoints were the hazard ratios for AIDS and for death from all causes in the first year of HAART, which were estimated using Cox regression.nnnRESULTSnThe proportion of heterosexually infected patients increased from 20% in 1995-96 to 47% in 2002-03, and the proportion of women from 16% to 32%. The median CD4 cell count when starting HAART increased from 170 cells per muL in 1995-96 to 269 cells per muL in 1998 but then decreased to around 200 cells per muL. In 1995-96, 58% achieved HIV-1 RNA of 500 copies per mL or less by 6 months compared with 83% in 2002-03. Compared with 1998, adjusted hazard ratios for AIDS were 1.07 (95% CI 0.84-1.36) in 1995-96 and 1.35 (1.06-1.71) in 2002-03. Corresponding figures for death were 0.87 (0.56-1.36) and 0.96 (0.61-1.51).nnnINTERPRETATIONnVirological response after starting HAART improved over calendar years, but such improvement has not translated into a decrease in mortality.

Incidence of tuberculosis among HIV-Infected patients receiving highly active antiretroviral therapy in Europe and North America

BACKGROUNDnWe obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence.nnnMETHODSnWe analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS-free persons starting HAART who were enrolled in 12 cohorts from Europe and North America. We used univariable and multivariable Poisson regression models to identify factors associated with the incidence.nnnRESULTSnDuring the first 3 years (36,906 person-years), 173 patients developed TB (incidence, 4.69 cases per 1000 person-years). In multivariable analysis, the incidence rate was lower for men who have sex with men, compared with injection drug users (relative rate, 2.46; 95% confidence interval [CI], 1.51-4.01), heterosexuals (relative rate, 2.42; 95% CI, 1.64-3.59), those with other suspected modes of transmission (relative rate, 1.66; 95% CI, 0.91-3.06), and those with a higher CD4+ count at the time of HAART initiation (relative rate per log2 cells/microL, 0.87; 95% CI, 0.84-0.91). During 28,846 person-years of follow-up after the first 6 months of HAART, 88 patients developed TB (incidence, 3.1 cases per 1000 person-years of follow-up). In multivariable analyses, a low baseline CD4+ count (relative rate per log2 cells/microL, 0.89; 95% CI, 0.83-0.96), 6-month CD4+ count (relative rate per log2 cells/microL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level >400 copies/mL (relative rate, 2.21; 95% CI, 1.33-3.67) were significantly associated with the risk of acquiring TB after 6 months of HAART.nnnCONCLUSIONnThe level of immunodeficiency at which HAART is initiated and the response to HAART are important determinants of the risk of TB. However, this risk remains appreciable even among those with a good response to HAART, suggesting that other interventions may be needed to control the TB epidemic in the HIV-infected population.

Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy.

OBJECTIVEnHIV-induced CD4 lymphocyte depletion is partially reversed by antiretroviral therapy but it is unclear if the degree to which the CD4 count rises depends on viral suppression (if so, the extent of viral suppression required to achieve a maximal CD4 count rise), whether the rise is sustainable and whether it occurs in patients with CD4 count <10 x 10(6) cells/l. We aimed to address these issues.nnnMETHODSnWe studied CD4 count and plasma HIV RNA values every 4 weeks for 72 weeks in 154 patients starting indinavir-containing regimens.nnnRESULTSnMean baseline HIV RNA and CD4 count were 4.8 log10 copies/ml and 180 x 10(6) cells/l, respectively. Overall, there was a mean increase in CD4 count of 143 x 10(6) cells/l by 72 weeks. The adjusted mean increase (adjusted for initial viral load, CD4 count and age) was strongly related to the mean viral suppression over the follow-up period (P < 0.0001). Importantly, there was a highly significant difference (P = 0.0004) in the rise in CD4 count between those with 2-3 log suppression (161 x 10(6) cells/l) and those with > 3 log suppression (314 x 10(6) cells/l; mean 3.6 log suppression in this group), suggesting that with even greater suppression the rise in CD4 lymphocytes may be still larger. We also studied whether CD4 counts were still rising after 72 weeks in patients with sustained suppression of at least 3 log in viral load. There was a significant (P = 0.004; paired t-test) rise in count of 43 x 10(6) cells/l between weeks 64 and 72 in these patients, suggesting that regeneration continues at least up to 72 weeks after therapy, provided virus replication continues to be suppressed. Patients with initial CD4 counts < 10 x 10(6) cells/l experienced no smaller rises than those at higher levels, even after adjustment for other factors.nnnCONCLUSIONnThese results strongly support a direct causal relationship between HIV replication and CD4 lymphocyte count depletion. The rise in those with > 3 log suppression provides the best available indicator of the potential for natural CD4 regeneration in HIV-infected patients. However, since still greater CD4 count rises may be seen with more suppressive regimens, it may not be possible to study the intrinsic CD4 regenerative capacity until such regimens are available.

Immune response to a new hepatitis B vaccine in healthcare workers who had not responded to standard vaccine: randomised double blind dose-response study

Abstract Objective: To evaluate the immunogenicity and reactogenicity of a new triple S recombinant hepatitis B vaccine in a cohort of healthy people in whom currently licensed hepatitis B vaccines had persistently not induced an immune response. Design: Single centre, randomised, double blind, dose-response study. Setting: Research vaccine evaluation centre at a teaching hospital. Subjects: 100 healthcare workers aged 18-70 years with a history of failure to seroconvert after at least four doses of a licensed hepatitis B vaccine containing the S component. Intervention: Each subject was randomly allocated two doses of 5, 10, 20, or 40 µg of a new hepatitis B vaccine two months apart. Main outcome measures: Immunogenicity of the four doses. Seroconversion and seroprotection were defined as an antibody titre >10 IU/l and >100 IU/l respectively against an international antibody standard. Results: 69 subjects seroconverted after a single dose of the vaccine. After the booster vaccination one other subject seroconverted, bringing the overall seroconversion rate to 70%. Fifteen subjects given 5 µg of vaccine, 19 given 10 µg, 16 given 20 µg, and 20 given 40 µg seroconverted. Seroconversion rates in the four antigen dose groups were 60% (15/25), 76% (19/25), 64% (16/25), and 80% (20/25). After the booster dose there was no significant dose-response effect on the overall seroconversion rate, although the small sample size meant that a clinically important dose-response could not be ruled out. Conclusion: A single dose of 20 µg of the vaccine was as effective as two doses of either 40 µg or 20 µg of this vaccine formulation in terms of seroconversion, seroprotection, and geometric mean titres. Key messages Up to 15% of healthy people do not respond to currently licensed hepatitis B vaccines Incorporation of the pre-S1 and pre-S2 components with the S antigen overcame this non-response in 69% of healthcare workers with a history of persistent non-response to conventional hepatitis B vaccines Significantly higher geometric mean titre levels were obtained with increased dosage of vaccine A single dose of 20 µg of the new vaccine seems to be effective in terms of seroconversion, seroprotection, and geometric mean titres

British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 2010

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