Fabiola Martin

Increased Rates of Preterm Delivery Are Associated with the Initiation of Highly Active Antiretrovial Therapy during Pregnancy: A Single-Center Cohort Study

It remains controversial whether in human immunodeficiency virus (HIV)-positive pregnant women an increased rate of preterm delivery is associated with highly active antiretroviral therapy (HAART). Since 1995 the management and outcome of all HIV-infected pregnant women delivering at St. Marys Hospital London have been prospectively documented. The prevalence of preterm delivery and the correlation between gestational age and type of antiretroviral therapy were sought: preterm delivery occurred in 14.2% of the 211 deliveries. Initiation of HAART during pregnancy was associated with an increased risk of preterm delivery. This was independent of maternal health and class of antiretroviral therapy.

Anal intraepithelial neoplasia in HIV positive people

Objective: To review the current literature on HIV associated anal intraepithelial neoplasia (AIN). Methods: A comprehensive Medline/Pubmed search was performed for the years 1980–2001 (January) for articles pertaining to HIV associated anal intraepithelial neoplasia. From the MeSH terms “anal intraepithelial neoplasia” and “anal cancer” the following subheadings were used: HIV, homosexual men, HPV, Epidemiology, Etiology, Mortality, Diagnosis, Screening, Drug Therapy, Surgical Therapy, Radio Therapy, Risk factors, ASIL. The search was limited to “human” for all searches. In the absence of enough “randomised controlled trials” the search was extended to clinical trials, reviews, and case reports. One analysis on cost effectiveness and two abstracts presented at 12th World AIDS Conference and 6th Conference on Retrovirus and Opportunistic Infections were included. The 44 publications referred to originate from the United Kingdom (9), the United States (26), and Denmark (5), with one each from Switzerland, Germany, Australia, and France. The Cochrane Database of systematic reviews yielded 11 complete reviews for “anal cancer” and none for “anal intraepithelial neoplasia.” The textbook of AIDS-related cancers and their treatment was consulted. We also included our personal experience from the treatment of patients at the Chelsea and Westminster Hospital, one of the largest centres for the management of HIV disease in Europe. Conclusion: Routine anal cytological screening followed by appropriate management of AIN is an important issue for HIV infected patients. The natural history of AIN has not been fully established and this prevents clinicians from defining clear management protocols. There is early evidence that the benefits of highly active antiretroviral therapy (HAART) in terms of restoring immune function and reducing opportunistic infections and some neoplasms may not extend to regression of AIN. Under these circumstances it might be predicted that AIN and subsequent progression to invasive anal cancer would rise as HAART prolongs the lives of seropositive people. However, routine anal cytological screening will surely have to await an effective proved intervention for AIN and this would seem to be a pressing clinical goal. Sex Transm Inf (Sex Transm Inf 2001;77:327–331)

Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness: a systematic review and meta-analysis

Summary Background Although people with serious mental illnesses have a high risk of contracting blood-borne viral infections, sexual health has largely been neglected by researchers and policy makers involved in mental health. Failure to address this shortcoming could increase morbidity and mortality as a result of undetected and untreated infection. We did a systematic review and meta-analysis to estimate the prevalence of blood-borne viral infection in people with serious mental illness. Method We searched the Cochrane Library, Medline, Embase, PsycInfo, CINAHL, and DARE for studies of the prevalence of HIV, hepatitis B virus, and hepatitis C virus in people with serious mental illness, published between Jan 1, 1980, and Jan 1, 2015. We group prevalence data by region and by virus and estimated pooled prevalence. We did a sensitivity analysis of the effect of study quality on prevalence. Findings After removal of duplicates, we found 373 abstracts, 91 of which met our eligibility criteria. The prevalences of blood-borne viral infections in people with serious mental illness were higher than in the general population in places with low prevalence of blood-borne viruses, such as the USA and Europe, and on par with the general population in regions with high prevalence of blood-borne viruses (Africa for HIV and southeast Asia for hepatitis B virus and hepatitis C virus). Pooled prevalence of HIV in people with serious mental illness in the USA was 6·0% (95% CI 4·3–8·3). Sensitivity analysis showed that quality scores did not significantly affect prevalence. Interpretation People with serious mental illness are at risk of blood-borne viral infections. However, because of methodological limitations of the studies the prevalence might be overestimated. Serious mental illness is unlikely to be a sole risk factor and risk of blood-borne viral infection is probably multifactorial and associated with low socioeconomic status, drug and alcohol misuse, ethnic origin, and sex. Health providers should routinely discuss sexual health and risks for blood-borne viruses (including risks related to drug misuse) with people who have serious mental illness, as well as offering testing and treatment for those at risk. Funding Wellcome Trust.

Inflammatory manifestations of HTLV-1 and their therapeutic options

Human T lymphotropic virus type 1 (HTLV-1) is one of the most intriguing retroviruses infecting humans. Most commonly, infection remains undetected, since it does not cause obvious harm, yet in 4–9% of patients, this infection can be devastating, causing adult T-cell leukemia/lymphoma and/or HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). This review concentrates on all inflammatory aspects of HTLV-1 infection: HAM/TSP, HTLV-1 associated uveitis, HTLV-1 associated conjunctivitis, sicca syndrome and interstitial keratitis, HTLV-1 associated Sjögren’s syndrome, Hashimoto’s thyroiditis and Graves’ disease, HTLV-1 associated pulmonary disease, infective dermatitis associated with HTLV-1, HTLV-1 associated inflammatory myositis and HTLV-1 associated arthritis. With the exception of HAM/TSP treatment, studies of these conditions are sparse and even for HAM/TSP, the level of evidence is limited. While control or elimination of infection remains a goal, most therapy beyond symptomatic management is directed at the immune response to HTLV-1.

Pregnant women with HIV infection can expect healthy survival: three-year follow-up.

Objectives:To document postpartum disease-free survival of HIV-infected women taking antiretroviral therapy (ART) during pregnancy. Methods:Laboratory and clinical data were collected on all HIV-infected pregnant women delivering from 1998 to 2002 and followed up until September 2004 at 6 hospitals in London. Mothers were grouped according to receipt of zidovudine monotherapy (ZDVm), highly active antiretroviral therapy (HAART) given during and continued after pregnancy (cHAART), and short-term HAART given during pregnancy and discontinued on delivery (START). Results:Eight-five women took ZDVm, 155 took cHAART, and 71 took START. The mean follow-up for all mothers was 33 months, with a total of 847 person-years. At the first antenatal clinic (ANC) visit, 72% of women were in Centers for Disease Control and Prevention (CDC) stage A, 85% were treatment naive, and the ZDVm group had a median HIV viral load (VL) 10-fold less than those mothers who started HAART during pregnancy. At last follow-up, 1 patient had died and 6 (1.9%) had progressed to CDC stage C; 62% of all women, including a quarter of the ZDVm group, were receiving HAART for their own health; and 83% of all mothers had a VL <50 HIV RNA copies/mL of plasma regardless of whether they were on treatment or not. Conclusions:The median-term postpartum prognosis of HIV-infected pregnant women with access to HAART is good. Exposure to short-course ZDVm or START during pregnancy did not jeopardize their response to subsequent therapy.

Susceptibility of Primary HTLV-1 Isolates from Patients with HTLV-1-Associated Myelopathy to Reverse Transcriptase Inhibitors

Since human T-lymphotropic virus type 1 (HTLV-1)-associated diseases are associated with a high HTLV-1 load, reducing this load may treat or prevent disease. However, despite in vitro evidence that certain nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) are active against HTLV-1, in vivo results have been disappointing. We therefore assayed the sensitivity of HTLV-1 primary isolates to a panel of RT inhibitors. HTLV-1 primary isolates were obtained, pre- and post- NRTI treatment, from patients with HTLV-1-associated myelopathy. Sensitivity to azidothymidine (AZT), lamivudine (3TC), tenofovir (TDF) and three phosphonated carbocyclic 2’-oxa-3’aza nucleosides (PCOANs) was assessed in a RT inhibitor assay. With the exception of 3TC, HTLV RT from primary isolates was less sensitive to all tested inhibitors than HTLV-1 RT from MT-2 cells. HTLV-1 RT from primary isolates and from chronically infected, transformed MT-2 cells was insensitive to 3TC. Sensitivity of primary isolates to RT inhibitors was not reduced following up to 12 months of patient treatment with AZT plus 3TC. The sensitivity of HTLV-1 primary isolates to NRTIs differs from that of cell lines and may vary among patients. Failure of NRTIs to reduce HTLV-1 viral load in vivo was not due to the development of phenotypic NRTI resistance. AZT and the three PCOANs assayed all consistently inhibited primary isolate HTLV-1 RT.

Ciclosporin A Proof of Concept Study in Patients with Active, Progressive HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis

Introduction Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-α, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP. Materials and Methods Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with ‘early’ (50% deterioration in timed walk during the preceding three months) HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure. Results All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas) disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse. Conclusions These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agents safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression.

Exposure to sodium channel-inhibiting drugs and cancer survival: protocol for a cohort study using the QResearch primary care database

Introduction Metastasis from solid tumours is associated with significant morbidity and mortality, and is the leading cause of cancer-related deaths. Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. VGSCs are also present in cancer cells, where they regulate metastatic cell behaviours, including cellular movement and invasion. Treating cancer cells with the VGSC-inhibiting anticonvulsant phenytoin reduces cellular invasion and migration. Together, these suggest that VGSCs may be useful targets for inhibiting metastasis. The purpose of this study is to test the hypothesis that use of VGSC-inhibiting drugs will reduce metastasis, and therefore increase survival time in patients with cancer. Methods and analysis A cohort study based on primary care data from the QResearch database will include patients with one of the three common tumours: breast, bowel and prostate. The primary outcome will be overall survival from the date of cancer diagnosis. Cox proportional hazards regression will be used to compare the survival of patients with cancer taking VGSC-inhibiting drugs (including anticonvulsants and class I antiarrhythmic agents) with patients with cancer not exposed to these drugs, adjusting for age and sex. Exposure to VGSC-inhibiting drugs will be defined as having at least one prescription for these drugs prior to cancer diagnosis. High and low exposure groups will be identified based on the length of use. A number of sensitivity and secondary analyses will be conducted. Ethics and dissemination The protocol has been independently peer-reviewed and approved by the QResearch Scientific Board. The project has also been approved by the University of York Ethical Review Process. The results will be presented at international conferences and published in an open access peer-reviewed journal, in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria.

Conference highlights of the 15th international conference on human retrovirology: HTLV and related retroviruses, 4-8 june 2011, Leuven, Gembloux, Belgium

The June 2011 15th International Conference on Human Retrovirology: HTLV and Related Viruses marks approximately 30 years since the discovery of HTLV-1. As anticipated, a large number of abstracts were submitted and presented by scientists, new and old to the field of retrovirology, from all five continents. The aim of this review is to distribute the scientific highlights of the presentations as analysed and represented by experts in specific fields of epidemiology, clinical research, immunology, animal models, molecular and cellular biology, and virology.

Sodium channel-inhibiting drugs and survival of breast, colon and prostate cancer: a population-based study

Metastasis is the leading cause of cancer-related deaths. Voltage-gated sodium channels (VGSCs) regulate invasion and metastasis. Several VGSC-inhibiting drugs reduce metastasis in murine cancer models. We aimed to test the hypothesis that patients taking VGSC-inhibiting drugs who developed cancer live longer than those not taking these drugs. A cohort study was performed on primary care data from the QResearch database, including patients with breast, bowel or prostate cancer. Cox proportional hazards regression was used to compare the survival from cancer diagnosis of patients taking VGSC-inhibiting drugs with those not exposed to these drugs. Median time to death was 9.7 years in the exposed group and 18.4 years in the unexposed group, and exposure to these medications significantly increased mortality. Thus, exposure to VGSC-inhibiting drugs associates with reduced survival in breast, bowel and prostate cancer patients. This finding is not consistent with the preclinical data. Despite the strengths of this study including the large sample size, the study is limited by missing information on potentially important confounders such as cancer stage, co-morbidities and cause of death. Further research, which is able to account for these confounding issues, is needed to investigate the relationship between VGSC-inhibiting drugs and cancer survival.