Training, guideline access and knowledge of antiretroviral interactions: Is the South African private sector being left behind?

BACKGROUND: South Africa (SA) has the largest antiretroviral therapy programme in the world. While the majority of the country accesses healthcare in the public sector, 15.2% access private healthcare. In 2019, dolutegravir was introduced as first-line treatment for HIV. Dolutegravir has clinically significant interactions with numerous commonly used medicines, e.g. rifampicin and cation-containing medicines such as calcium and iron. They require dosage adjustments, detailed in public and private HIV guidelines. OBJECTIVES: To describe SA healthcare workers' guideline access, training and knowledge of dolutegravir's interactions, focusing on differences between the public and private sectors. METHODS: A cross-sectional, descriptive study was done using an online survey of healthcare workers in the field of HIV in SA, conducted by the National HIV and TB Healthcare Worker Hotline. Convenience sampling was used, with electronic dissemination to users of the hotline and by relevant HIV-focused organisations. Simple descriptive statistics and statistical analyses were used. RESULTS: A total of 1 939 surveys were analysed, with 22% from the private sector. Training on the dolutegravir guidelines was received by significantly fewer healthcare workers in the private sector v. the public sector: 42.4% (95% confidence interval (CI) 37 - 48) v. 67.5% (95% CI I 65 - 70), respectively. Significantly fewer healthcare workers in the private sector had access to the guidelines (63.8%; 95% CI 59 - 69 v. 78.8%; 95% CI 77 - 81). When asked if they were aware that dolutegravir has interactions, just over half (56.9%) of healthcare workers in the private sector responded 'yes', 24.6% responded 'no' and 18.5% did not answer. Of those who were aware that dolutegravir has interactions, 48.9% knew that dolutegravir interacts with calcium, 44.6% with iron and 82.0% with rifampicin. Private sector knowledge of dosing changes was lower for all interacting drugs, with the difference only significant for calcium and iron. Private sector healthcare workers reported significantly lower levels of counselling on dolutegravir use in all appropriate situations. CONCLUSION: Private sector healthcare worker access to HIV training and guidelines requires attention. In a high-burden HIV setting such as SA, it is vital that healthcare workers across all professions, in both the public and private sector, know how to adjust antiretroviral dosing due to clinically significant interactions. Without these adjustments, there is a risk of treatment failure, increased mother-to-child transmission and morbidity and mortality.

Cediranib in addition to chemotherapy for women with relapsed platinum-sensitive ovarian cancer (ICON6): overall survival results of a phase III randomised trial.

BACKGROUND: Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of 'platinum-sensitive' ovarian cancer and has been shown to improve progression-free survival (PFS). PATIENTS AND METHODS: ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here. RESULTS: After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch-Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: -0.09 to 9.74 months). CONCLUSIONS: Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken.

Adjuvant statin therapy for oesophageal adenocarcinoma: the STAT-ROC feasibility study.

BACKGROUND: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT. METHODS: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival. RESULTS: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference -0·83 (95 per cent c.i. -1·4 to -0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise. CONCLUSION: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com).

ANTECEDENTES: Las estatinas inhiben las señalizaciones proliferativas en el adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC) y su uso se asocia con mejor supervivencia en estudios observacionales. El presente estudio se llevó a cabo para examinar la viabilidad de evaluar el tratamiento adyuvante con estatinas en pacientes con OAC operable en un ensayo aleatorizado y controlado de fase III. MÉTODOS: En este ensayo de viabilidad controlado por placebo, aleatorizado, de grupos paralelos, doble ciego y multicéntrico, los pacientes adultos con OAC (incluyendo lesiones Siewert I/II) que fueron sometidos a esofaguectomía se asignaron de forma centralizada (1:1) a tratamiento con simvastatina 40 mg o placebo equivalente mediante aleatorización en bloques, estratificados por centro. Los participantes, los clínicos y los investigadores desconocían la asignación del tratamiento. Los pacientes recibieron el tratamiento hasta un año. Los resultados de viabilidad fueron reclutamiento, retención, absorción del fármaco, adherencia, seguridad, calidad de vida, generalización, y supervivencia. RESULTADOS: Un total de 120 pacientes fueron evaluados para elegibilidad en 4 centros, de los cuales 32 (26,7%) fueron aleatorizados, 16 en cada grupo. Siete pacientes abandonaron el ensayo. Los pacientes asignados a tratamiento con simvastatina tenían niveles de colesterol LDL más bajos a los 3 meses (diferencia media ajustada, −0,83 mmol/L, i.c. del 95% −1,4 a −0,22, P = 0,009). La mediana de la adherencia a la medicación fue mayor del 90% entre los 3-12 meses de seguimiento. Los eventos adversos fueron similares entre los grupos. Los datos de calidad de vida estaban completos en el 98,3% de las preguntas del cuestionario. Enfermedad cardiovascular, diabetes y uso de aspirina eran más prevalentes en el grupo no aleatorizado, mientras que la localización del tumor, el estadio y el grado fueron similares entre los grupos. Las estimaciones de supervivencia fueron imprecisas. CONCLUSIÓN: Este RCT apoya la realización e informa de las consideraciones de diseño para un futuro ensayo de fase III de tratamiento adyuvante con estatinas en pacientes con OAC.

No socioeconomic inequalities in ovarian cancer survival within two randomised clinical trials.

BACKGROUND: Ovarian cancer is the leading cause of death among cancers of the female genital tract, with poor outcomes despite chemotherapy. There was a persistent socioeconomic gradient in 1-year survival in England and Wales for more than 3 decades (1971-2001). Inequalities in 5-year survival persisted for more than 20 years but have been smaller for women diagnosed around 2000. We explored one possible explanation. METHODS: We analysed data on 1406 women diagnosed with ovarian cancer during 1991-1998 and recruited to one of two randomised clinical trials. In the second International Collaborative Ovarian Neoplasm (ICON2) trial, women diagnosed between 1991 and 1996 were randomised to receive either the three-drug combination cyclophosphamide, doxorubicin and cisplatin (CAP) or single-agent carboplatin given at optimal dose. In the ICON3 trial, women diagnosed during 1995-1998 were randomised to receive either the same treatments as ICON2, or paclitaxel plus carboplatin.Relative survival at 1, 5 and 10 years was estimated for women in five categories of socioeconomic deprivation. The excess hazard of death over and above background mortality was estimated by fitting multivariable regression models with Poisson error structure and a dedicated link function in a generalised linear model framework, adjusting for the duration of follow-up and the confounding effects of age, Federation of Gynecology and Obstetrics (FIGO) stage and calendar period. RESULTS: Unlike women with ovarian cancer in the general population, no statistically significant socioeconomic gradient was seen for women with ovarian cancer treated in the two randomised controlled trials. The deprivation gap in 1-year relative survival in the general population was statistically significant at -6.7% (95% CI (-8.1, -5.3)), compared with -3.6% (95% CI (-10.4, +3.2)) in the trial population. CONCLUSIONS: Although ovarian cancer survival is significantly lower among poor women than rich women in England and Wales, there was no evidence of an association between socioeconomic deprivation and survival among women with ovarian cancer who were treated and followed up consistently in two well-conducted randomised controlled trials. We conclude that the persistent socioeconomic gradient in survival among women with ovarian cancer, at least for 1-year survival, may be due to differences in access to treatment and standards of care.

A prognostic nomogram to predict overall survival in patients with platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. PATIENTS AND METHODS: The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). RESULTS: The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65-0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). CONCLUSIONS: This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.

Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer.

BACKGROUND: Cediranib is a potent oral vascular endothelial growth factor (VEGF) signalling inhibitor with activity against all three VEGF receptors. The International Collaboration for Ovarian Neoplasia 6 (ICON6) trial was initiated based on evidence of single-agent activity in ovarian cancer with acceptable toxicity. METHODS: The ICON6 trial is a 3-arm, 3-stage, double-blind, placebo-controlled randomised trial in first relapse of platinum-sensitive ovarian cancer. Patients are randomised (2 : 3 : 3) to receive six cycles of carboplatin (AUC5/6) plus paclitaxel (175 mg m(-2)) with either placebo (reference), cediranib 20 mg per day, followed by placebo (concurrent), or cediranib 20 mg per day, followed by cediranib (concurrent plus maintenance). Cediranib or placebo was continued for 18 months or until disease progression. The primary outcome measure for stage I was safety, and the blinded results are presented here. RESULTS: Sixty patients were included in the stage I analysis. A total of 53 patients had received three cycles of chemotherapy and 42 patients had completed six cycles. In all, 19 out of 60 patients discontinued cediranib or placebo during chemotherapy because of adverse events/intercurrent illness (n=9); disease progression (n=1); death (n=3); patient decision (n=1); administrative reasons (n=1); and multiple reasons (n=4). Grade 3 and 4 toxicity was experienced by 30 (50%) and 3 (5%) patients, respectively. No gastrointestinal perforations were observed. CONCLUSION: The addition of cediranib to platinum-based chemotherapy is sufficiently well tolerated to expand the ICON6 trial and progress to stage II.

Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study.

BACKGROUND: Hysterectomy and bilateral salpingo-oophorectomy (BSO) is the standard surgery for stage I endometrial cancer. Systematic pelvic lymphadenectomy has been used to establish whether there is extra-uterine disease and as a therapeutic procedure; however, randomised trials need to be done to assess therapeutic efficacy. The ASTEC surgical trial investigated whether pelvic lymphadenectomy could improve survival of women with endometrial cancer. METHODS: From 85 centres in four countries, 1408 women with histologically proven endometrial carcinoma thought preoperatively to be confined to the corpus were randomly allocated by a minimisation method to standard surgery (hysterectomy and BSO, peritoneal washings, and palpation of para-aortic nodes; n=704) or standard surgery plus lymphadenectomy (n=704). The primary outcome measure was overall survival. To control for postsurgical treatment, women with early-stage disease at intermediate or high risk of recurrence were randomised (independent of lymph-node status) into the ASTEC radiotherapy trial. Analysis was by intention to treat. This study is registered, number ISRCTN 16571884. FINDINGS: After a median follow-up of 37 months (IQR 24-58), 191 women (88 standard surgery group, 103 lymphadenectomy group) had died, with a hazard ratio (HR) of 1.16 (95% CI 0.87-1.54; p=0.31) in favour of standard surgery and an absolute difference in 5-year overall survival of 1% (95% CI -4 to 6). 251 women died or had recurrent disease (107 standard surgery group, 144 lymphadenectomy group), with an HR of 1.35 (1.06-1.73; p=0.017) in favour of standard surgery and an absolute difference in 5-year recurrence-free survival of 6% (1-12). With adjustment for baseline characteristics and pathology details, the HR for overall survival was 1.04 (0.74-1.45; p=0.83) and for recurrence-free survival was 1.25 (0.93-1.66; p=0.14). INTERPRETATION: Our results show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women with early endometrial cancer. Pelvic lymphadenectomy cannot be recommended as routine procedure for therapeutic purposes outside of clinical trials.

Why i.p. therapy cannot yet be considered as a standard of care for the first-line treatment of ovarian cancer: a systematic review.

A National Cancer Institute (NCI) clinical announcement recommended i.p. therapy for women with optimally debulked ovarian cancer. Its basis was a summary of eight randomised controlled trials and two systematic reviews, which appear to indicate benefit of i.p. therapy. However, the systematic reviews that inform the recommendations have been inappropriately presented and interpreted. The systematic reviews inappropriately pooled results from 'confounded' trials in which different drugs and different doses of drugs were given in the control and i.p. treatment arms. Therefore, it is not possible to assess which component of treatment is responsible for improving outcome. In addition, none of the trials use a control arm of the internationally accepted standard of care. Using just the unconfounded trials, indirect comparisons show that the magnitude of benefit observed when i.p. regimens are compared with older i.v. regimens [hazard ratio (HR) for overall survival (OS) 0.75; 95% confidence interval (CI) 0.60-0.92, P = 0.006] is smaller than the magnitude of benefit achieved with modern day standard of i.v. treatment compared with the same i.v. regimen used as control in the unconfounded i.p. trials (HR for OS 0.68; 95% CI 0.58-0.80, P < 0.001). A further difficulty is that the reviews cannot recommend an i.p. regimen for standard use. Drug-related toxicity and catheter complications that occur with i.p. therapy are considerable. The NCI recommendations have major implications for the treatment of women with ovarian cancer and for the next generation of clinical trials. We do not believe that the body of evidence currently available supports the recommendation that i.p. therapy should form part of routine care. The choice of treatment of women with newly diagnosed, optimally debulked, ovarian cancer, where therapy has the best chance of influencing OS, is too important to be left with this uncertainty. A clinical trial that investigates a practical and acceptable regimen which gives some or all chemotherapy by the i.p. route and compares this with standard i.v. chemotherapy should be a priority for those who wish to promote its use.

Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial.

BACKGROUND: Despite improvements in the treatment of ovarian cancer, most patients develop recurrent disease within 3 years of diagnosis. There is no agreed second-line treatment at relapse. We assessed paclitaxel plus platinum chemotherapy as such treatment. METHODS: In parallel international, multicentre, randomised trials, between January, 1996, and March, 2002, 802 patients with platinum-sensitive ovarian cancer relapsing after 6 months of being treatment-free were enrolled from 119 hospitals in five countries. Patients were randomly assigned paclitaxel plus platinum chemotherapy or conventional platinum-based chemotherapy. Analysis was by intention to treat, except for toxic effects. FINDINGS: With a median follow-up of 42 months, 530 patients have died. Survival curves showed a difference in favour of paclitaxel plus platinum (hazard ratio 0.82 [95% CI 0.69-0.97], p=0.02), corresponding to an absolute difference in 2-year survival of 7% between the paclitaxel and conventional treatment groups (57 vs 50% [95% CI for difference 1-12]), and median survival of 5 months (29 vs 24 months [1-11). 717 patients developed progressive disease or died. The progression-free survival curves show a difference in favour of paclitaxel plus platinum (hazard ratio 0.76 [0.66-0.89], p=0.0004), corresponding to an absolute difference in 1-year progression-free survival of 10% (50 vs 40% [4-15]) and in median progression-free survival of 3 months (13 vs 10 months [1-5]). INTERPRETATION: Paclitaxel plus platinum chemotherapy seems to improve survival and progression-free survival among patients with relapsed platinum-sensitive ovarian cancer compared with conventional platinum-based chemotherapy.

Management of the very weak pelvic floor. Is there a point?

Conservative treatment in the form of pelvic muscle exercises is effective in the treatment of stress urinary incontinence. There are no studies specifically looking at women who have extremely weak pelvic muscles and their response to conservative treatment. This study looks at the effectiveness of pelvic muscle therapy in women with very weak pelvic muscles. Out of 965 women attending the bladder clinic at Kirwan Hospital, 219 were assessed to have weak pelvic muscles by digital palpation. All patients were subjected to a detailed urogynecological questionnaire, a frequency/volume chart, and clinical assessment. All patients were then given detailed verbal and written instructions on good bladder habits, including posture, dietetic habits and pelvic muscle exercises. Of the 219 women, 163 were able to complete their treatment and presented for review. Out of 163 women 118 (72%) reported a subjective improvement; 89 (54%) demonstrated an objective improvement in pelvic muscle strength.

Zidovudine pharmacokinetics in zidovudine-induced bone marrow toxicity.

1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV-positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2. Twelve HIV-positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3-10 mg kg-1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half-life of ZDV was 1.10 +/- 0.16 h with an oral clearance of 2752 +/- 1031 ml min-1 compared with values of 1.06 +/- 0.18 h and 2843 +/- 730 ml min-1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.