The ASSURE study: HIV-1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir.

OBJECTIVES: HIV treatment guidelines endorse switching or simplification of antiretroviral therapy in therapy-experienced patients with suppressed viraemia; ritonavir discontinuation may also enhance tolerability and reduce long-term adverse events (AEs). This open-label, multicentre, noninferiority study enrolled HIV-1-infected, treatment-experienced adults with confirmed HIV-1 RNA ≤ 75 HIV-1 RNA copies/mL currently receiving tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC + ATV/r) for ≥ 6 months with no reported history of virological failure. METHODS: Participants were randomized 1:2 to continue current treatment or switch to abacavir/lamivudine + atazanavir (ABC/3TC + ATV). Endpoints included the proportion of participants with HIV-1 RNA < 50 copies/mL by time to loss of virological response (TLOVR), AEs, fasting lipids, and inflammatory, coagulation, bone and renal biomarkers. RESULTS: After 48 weeks, 76% (152 of 199) of ABC/3TC + ATV-treated and 79% (77 of 97) of TDF/FTC + ATV/r-treated participants had HIV-1 RNA < 50 copies/mL (TLOVR; P = 0.564). Other efficacy analyses yielded similar results. Rates of new grade 2-4 AEs were 45% in both groups, but an excess of hyperbilirubinaemia made the rate of treatment-emergent grade 3-4 laboratory abnormalities higher with TDF/FTC + ATV/r (36%) compared with ABC/3TC + ATV (19%). Most fasting lipid levels remained stable over time; high-density lipoprotein (HDL) cholesterol increased modestly in ABC/3TC + ATV-treated participants. Bone and renal biomarkers improved significantly between baseline and week 48 in participants taking ABC/3TC + ATV and were stable in participants taking TDF/FTC + ATV/r. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. CONCLUSIONS: The ABC/3TC + ATV treatment-switch group had similar viral suppression rates up to 48 weeks to the TDF/FTC + ATV/r comparator group, with lower rates of moderate- to high-grade hyperbilirubinaemia and improvements in bone and renal biomarkers.

A randomised comparison of safety and efficacy of nevirapine vs. atazanavir/ritonavir combined with tenofovir/emtricitabine in treatment-naïve patients.

BACKGROUND: We report data from NEWART, a randomised phase 4 clinical trial comparing virologic efficacy and safety of nevirapine (NVP) vs. ritonavir-boosted atazanavir (ATV/r) on a background of tenofovir/emtricitabine (TDF/FTC) in HIV-1-infected treatment-naïve patients. This study enrolled patients according to CD4-based initiation criteria for NVP (<250 cells/mm(3) for women and <400 cells/mm(3) for men), to reduce the likelihood of symptomatic hepatic events. NEWART was designed to support and confirm results from ARTEN, an international trial with similar design and study endpoints. METHODS: A total of 152 patients were randomised 1 : 1 to open-label NVP 200 mg twice daily or ATV/r (300/100 mg) once daily, plus once daily TDF/FTC (300/200 mg). All participants met CD4(+) guidelines at entry. The primary endpoint for non-inferiority was virologic response prior to and at week 48 (confirmed HIV plasma viral load <50 copies/ml, without rebound or change in ARVs). Safety data, including plasma lipids, were recorded throughout the study. RESULTS: The primary endpoint was achieved in 46/75 (61.3%) and 50/77 (64.9%) of patients taking NVP and ATV/r, respectively. Frequency of adverse events (AEs) was similar between arms, with 88.0% of NVP-treated patients and 94.8% of ATV/r-treated patients experiencing at least one AE. Nine patients (12%) in each arm experienced an AE that led to discontinuation. At week 48, a significantly greater increase was seen in mean plasma HDL cholesterol (HDL-C) in the NVP arm (9.6 mg/dl) vs. the ATV/r arm (3.5 mg/dl); p = 0.016. Also, total cholesterol (TC):HDL-C ratio on-treatment was -0.38 and -0.02 for the NVP and ATV/r arms, respectively (p = 0.038). CONCLUSIONS: Efficacy results were consistent with the ARTEN study demonstrating that NVP was non-inferior to ATV/r when taken in combination with TDF/FTC. Rates of AEs were similar between the two arms, whereas HDL-C increased and TC:HDL-C decreased significantly more in patients taking NVP than ATV/r.

An updated report on the incidence and epidemiological trends of keratinocyte cancers in the United Kingdom 2013-2018.

Introduction: The most common cancers in the UK are keratinocyte cancers (KCs): the combined term for basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (cSCCs). Registration of KC is challenging due to high numbers and multiplicity of tumours per person. Methods: We provide an updated report on the descriptive epidemiology of trends in KC incidence for the resident populations of UK countries (England, Northern Ireland, Scotland and Wales) using population-based cancer registry and pathology report data, 2013-18. Results: Substantial increases in cSCC incidence in England, Scotland and Northern Ireland can be detected for the period of 2013-18, and the incidence of cSCC also increased in Wales from 2016 to 2018. In contrast, however, the pattern of annual change in the incidence of BCC across the nations differs. In England, the incidence of BCC declined slightly from 2016 to 2018, however, the overall trend across 2013-18 is not statistically significant. In Scotland, the incidence of BCC shows some variability, declining in 2017 before increasing in 2018, and the overall trend across 2013-18 was also not statistically significant. In Northern Ireland, the incidence of BCC increased significantly over the study period, and in Wales, the incidence of BCC increased from 2016 to 2018. One in five people will develop non-melanoma skin cancers (NMSC) in their lifetime in England. This estimate is much higher than the lifetime risk of melanoma (1 in 36 males and 1 in 47 females born after 1960 in the UK), which further highlights the burden of the disease and importance of early prevention strategies. Conclusions: We highlight how common these tumours are by publishing the first ever lifetime incidence of NMSC. Additionally, the first time reporting of the age standardised incidence of KC in Wales further confirms the scale of the disease burden posed by these cancers in the UK. With approximately one in five people developing NMSC in their lifetime, optimisation of skin cancer prevention, management and research are essential.

Hepatitis C patients' self-reported adherence to treatment with pegylated interferon and ribavirin.

BACKGROUND: Prior research on adherence to hepatitis C treatment has documented rates of dose reductions and early treatment discontinuation, but little is known about patients' dose-taking adherence. AIMS: To assess the prevalence of missed doses of pegylated interferon and ribavirin and examine the correlates of dose-taking adherence in clinic settings. METHODS: One hundred and eighty patients on treatment for hepatitis C (23% coinfected with HIV) completed a cross-sectional survey at the site of their hepatitis C care. RESULTS: Seven per cent of patients reported missing at least one injection of pegylated interferon in the last 4 weeks and 21% reported missing at least one dose of ribavirin in the last 7 days. Dose-taking adherence was not associated with HCV viral load. CONCLUSIONS: Self-reported dose non-adherence to hepatitis C treatment occurs frequently. Further studies of dose non-adherence (assessed by method other than self-report) and its relationship to HCV virological outcome are warranted.

The quest of infertile women in squatter settlements of Karachi, Pakistan: a qualitative study.

OBJECTIVES: There is a dearth of knowledge regarding Pakistani women's perceptions and treatment seeking behavior for infertility. We conducted this study to explore the contextual factors that influence the health-seeking behavior of infertile women in the lower socio-economic group. METHODS: In-depth interviews were conducted with 17 women, identified from clinics and community using pre-tested interview guidelines covering issues as the chronological sequence of the number and types of the health care providers consulted for infertility, household dynamics regarding decision making, perceived causes and social and psychological effects of infertility on the woman and her family. RESULTS: 14 of the 17 women interviewed presented with primary infertility and three with secondary infertility. Reasons reported for seeking treatment for primary infertility were: someone to carry on the family name, feeling alone and akhrat par maan bap bun kar uthna (getting up as a parent on judgment day). Two of the three women suffering from secondary infertility were seeking treatment because they did not have any male offspring. Of the 14 women, 11 initially sought treatment within the first two years of marriage; one woman reported that she was "coerced" by her mother-in-law to seek treatment following the first week of marriage. On average, a woman went to three health care providers (general practitioners, gynecologists and Traditional Birth Attendants) in her quest for assistance. The effects that infertility had on these women ranged from social pressure, coercion by in-laws and/or social isolation. Only one woman reported being put off by sex because it was not giving her what she 'desired'. CONCLUSION: Women in Pakistan seek care for infertility early and go to various types of health care providers. Infertility is usually treated as a clinical disease by the health care providers without considering its social ramifications.

Domestic violence and health of Pakistani women.

OBJECTIVE: Assessment of the prevalence and health consequences of domestic violence among women in Karachi, Pakistan. METHODS: Confidential interviews were conducted among 150 women randomly selected from health facilities. RESULTS: 34% reported ever being physically abused, 15% ever being physically abused whilst pregnant and 72% of physically abused women were anxious/depressed. Physical abuse was a major predictor of anxiety/depression. CONCLUSIONS: The magnitude, physical and mental health consequences of domestic violence represents a serious reproductive health concern for Pakistan.

Recent trends in incidence of nonmelanoma skin cancers in the East of Scotland, 1992-2003.

BACKGROUND: Historically, ascertainment of nonmelanoma skin cancer (NMSC) by cancer registries in the U.K. has been shown to be incomplete in several studies. However, recent evidence suggesting that almost all clinically diagnosed NMSCs are verified histologically, coupled with the increasing availability of electronic histopathology data to cancer registries, raises the possibility that this situation may have improved. OBJECTIVES: To assess recent trends in incidence of the main types of NMSC and carcinoma in situ (CIS) of the skin in Scotland. METHODS: The study was restricted to selected health board areas in the East of Scotland for which pathology data have been used routinely to support cancer registration since the early 1990s. Incident cases of squamous cell carcinoma (SCC) of the skin, CIS of the skin, and first ever basal cell carcinoma (BCC) were extracted from the Scottish Cancer Registry covering the period of diagnosis 1992-2003. Sex-specific, age-standardized and age-specific incidence rates were calculated for four consecutive 3-year periods of diagnosis. Estimated annual percentage changes (EAPCs) in incidence were calculated by Poisson regression modelling, with adjustment for age. The percentage distribution of SCC, BCC and CIS of the skin by anatomical site and sex was calculated for the period of diagnosis 1997-2003. RESULTS: The crude incidence of SCC for the period 1995-97 was 34.7 per 100,000, comparable with the best existing Scottish estimate of 32.2 derived from a prospective survey in Glasgow during March 1995. Age-adjusted rates of SCC, first ever BCC, and CIS of the skin have all increased significantly in both sexes between 1992 and 2003 (all P < 0.001), with EAPCs ranging in magnitude from +1.4% (first ever BCC in males) to +5.1% (CIS in males). The majority of lesions arose on the head and neck area, with the exception of CIS, which in females was more commonly located on the limbs. CONCLUSIONS: Ascertainment of NMSC has probably improved since the advent and use of electronic pathology data. Ongoing increases in age-adjusted incidence, combined with ageing of the population, will have major implications for the clinical workload associated with NMSC for the foreseeable future.

Increasing incidence of squamous cell carcinoma of the anus in Scotland, 1975-2002.

In Scotland, since 1975-1979 (world) age-standardised incidence of squamous cell carcinoma of the anus has more than doubled, reaching 0.37 per 100,000 in males and 0.55 in females during 1998-2002, being somewhat higher in socioeconomically deprived areas.

Transcriptional regulation by retinoic acid of interleukin-2 alpha receptors in human B cells.

In this study, we demonstrated that retinoic acid (RA) up-regulated interleukin-2 receptor-alpha (IL-2R alpha) expression on two human B-cell lines, IE8.6 and SKW6.4. Deleted forms of the human IL-2R alpha promoter linked to the bacterial chloramphenicol acetyltransferase reporter gene were transfected into IE8.6 cells in order to define RA-responsive regulatory domains. Experiments using the -1.6 kb construct, which contains all known regulatory regions in the IL-2R alpha promoter, indicated that RA could induce IL-2R alpha promoter activity. The basal activity of the -471 construct was initially low, but was markedly enhanced by the addition of RA. Deletion of promoter sequences between -471 and -317 resulted in a significant augmentation of basal promoter activity and abolished promoter induction by RA. This finding revealed a requirement for sequences 5' of base -317 for RA-induced promoter activation, raising the possibility of the presence of both a RA response element and a negative regulatory element (NRE) upstream of base -317. Transfection studies with internal deletion mutants with the putative NRE removed resulted in increases in basal promoter activity and unresponsiveness to RA similar to the -317 construct. In contrast, an internal deletion mutant with the NRE intact had low basal activity and was inducible by RA similar to the -471 construct. Taken together, our results suggested that RA-induced activation of the IL-2R alpha promoter was through changes in the function of a NRE present between bases -400 and -368. This 31-base pair element may interact with an adjacent RA-responsive regulatory site as well as being responsible for down-regulation of basal IL-2R alpha expression under certain conditions.

Upregulation by retinoic acid of interleukin-2-receptor mRNA in human T lymphocytes.

It was previously demonstrated that retinoic acid (RA) can enhance the functional responses of human T lymphocytes by increasing surface IL-2R alpha chain protein expression on proliferating T blasts, resulting in augmented IL-2-dependent growth. In the present study, we used IL-2-maintained lymphoblasts generated from human thymocytes to show that RA enhancement of IL-2R alpha is accompanied by an increase in steady-state levels of IL-2R alpha mRNA. This increase occurred within 1 hr after the addition of RA to the culture and was inhibited by the presence of the protein synthesis inhibitor cycloheximide. RA did not alter the stability of either IL-2R alpha on the cell surface or IL-2R alpha mRNA, suggesting regulation by RA at the level of transcription. This contention was supported by the demonstrated ability of RA to activate the IL-2R alpha promoter in a chloramphenicol acetyltransferase plasmid construct that was transfected into the blast cells. In addition to inducing IL-2R alpha expression, RA also increased the surface expression and mRNA levels of IL-2R beta, the 75-kDa component of the IL-2 receptor that mediates IL-2 signal transduction. These new findings showing regulation by RA of both IL-2R alpha and IL-2R beta suggest multiple pathways by which this retinoid can modulate functional IL-2 receptors.

T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses.

This study documents the differential requirements of T4+ T helper cells in the induction of virus-specific cytotoxic T-lymphocyte (CTL) and antibody responses during acute lymphocytic choriomeningitis virus infection. Two monoclonal antibodies (GK1.5 and RL172.4) directed against the L3T4 (T4) molecule were used for depleting T helper cells from mice. Depletion of T4+ cells caused a pronounced suppression of antiviral antibody response (20-fold decrease) but had minimal effect on virus-specific CTL response (less than 2-fold reduction). Despite the elimination of greater than 90% of T helper cells, anti-L3T4-treated mice were able to generate a CTL response of sufficient magnitude to control the viral infection. In contrast, depletion of Lyt2+ T cells abrogated the CTL response and the ability to eliminate virus. Thus, our results underscore the importance of the Lyt2+ T-cell subset in controlling infection with this virus and show that a deficiency of T4+ T cells is likely to have a more severe effect on antibody production than on CTL responses.

Inhibition of B cell proliferation by antisense DNA to both alpha and beta forms of Fc epsilon R II.

Epstein-Barr Virus (EBV) infection activates B lymphocyte proliferation through partially understood mechanisms, resulting in phenotypic changes, including the appearance of new antigens. One such antigen is Fc epsilon R II/CD-23 which may be relevant for B cell proliferation. We have used anti-sense oligonucleotides to study the importance of the two forms of this molecule for proliferation in the EBV-transformed, Fc epsilon R II +ve lymphoblastoid B cell line, RPMI 8866. Anti-sense oligodeoxynucleotides were generated to the two forms of Fc epsilon R II; Fc epsilon R IIa (alpha) and IIb (beta) which differ only in their intracytoplasmic domains. Addition of increasing concentrations of anti-sense oligonucleotides, ranging from 1 to 30 microM, significantly decreased cellular proliferation as measured by the incorporation of [3H]thymidine (inhibition range 8-88%). Optimum inhibition of cellular proliferation was apparent at 15 microM concentration of both anti-sense Fc epsilon R IIa and IIb (Fc epsilon R IIa, mean +/- SE = 75 +/- 7% inhibition, p less than 0.001; Fc epsilon R IIb, mean +/- SE = 71 +/- 7% inhibition, p less than 0.001). Anti-sense oligonucleotides complementary to the common part of Fc epsilon R II resulted in a similar inhibition of proliferation. Sense oligonucleotides did not induce significant inhibition. Preincubation of sense and anti-sense oligonucleotides resulted in an abrogation of proliferation inhibition. Moreover, none of these oligonucleotides had any effect on a Fc epsilon R II -ve cell line. Incubation with both anti-sense IIa and IIb resulted in additive, but not synergistic inhibition of proliferation. Addition of soluble Fc epsilon R II did not reverse inhibition of proliferation, suggesting that membrane-bound or intracellular rather than soluble Fc epsilon R II was important for the induced proliferation. Analysis of cell surface expression for Fc epsilon II indicated that while there was a pronounced effect on cell number following incubation with anti-sense oligonucleotides, surface expression of Fc epsilon R II was consistent as measured over different time points. PCR analysis revealed that while most cells expressed either the alpha or the beta form of Fc epsilon R II, EBV-transformed cell lines, particularly RPMI 8866, were found to express both alpha and beta forms simultaneously. This may constitute a mechanism whereby EBV infection confers an immortal state to the cell, resulting in its uncontrolled proliferation. Cell lines expressing only one receptor form, either alpha or beta, were unaffected after incubation with anti-sense oligonucleotides.(ABSTRACT TRUNCATED AT 400 WORDS)