The importance of the “how”: the case for differentiated service delivery of long-acting and extended delivery regimens for HIV prevention and treatment

Introduction

Long-acting and extended delivery (LAED) regimens for HIV treatment and prevention offer unique benefits to expand uptake, effective use and adherence. To date, research has focused on basic and clinical science around the safety and efficacy of these products. This commentary outlines opportunities in HIV prevention and treatment programmes, both for the health system and clients, that could be addressed through the inclusion of LAED regimens and the vital role of differentiated service delivery (DSD) in ensuring efficient and equitable access.

Discussion

The realities and challenges within HIV treatment and prevention programmes are different. Globally, more than 28 million people are accessing HIV treatment—the vast majority on a daily fixed-dose combination oral pill that is largely available, affordable and well-tolerated. Many people collect extended refills outside of health facilities with clinical consultations once or twice a year. Conversely, uptake of daily oral pre-exposure prophylaxis (PrEP) has consistently missed global targets due to limited access with high individual cost and lack of choice contributing to substantial unmet PrEP need. Recent trends in demedicalization, simplification, additional method options and DSD for PrEP have led to accelerated uptake as its availability has become more aligned with user preferences. How people currently receive HIV treatment and prevention services and their barriers to adherence must be considered for the introduction of LAED regimens to achieve the expected improvements in access and outcomes. Important considerations include the building blocks of DSD: who (provider), where (location), when (frequency) and what (package of services). Ideally, all LAED regimens will leverage DSD models that emphasize access at the community level and self-management. For treatment, LAED regimens may address challenges with adherence but their delivery should provide clear advantages over existing oral products to be scaled. For prevention, LAED regimens expand a potential PrEP user's choice of methods, but like other methods, need to be delivered in a manner that can facilitate frequent re-initiation.

Conclusions

To ensure that innovative LAED HIV treatment and prevention products reach those who most stand to benefit, service delivery and client considerations during development, trial and early implementation are critical.     

Dual blockade of the renin-angiotensin system: the ultimate treatment for renal protection?

The prevalence of chronic renal diseases is increasing worldwide. There is a great need to identify therapies that arrest disease progression to end-stage renal failure. Inhibition of the renin-angiotensin system both by angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists is probably the best therapeutic option available. Several large, multicenter studies have indeed shown a significant reduction in the risk for doubling baseline serum creatinine or progression toward end-stage renal failure in patients who do and do not have diabetes and have chronic nephropathies that are treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists. However, the number of patients who reach end-stage renal failure is still considerably high. Significant reduction of the incidence of ESRD is likely to be achieved in the near future for chronic nephropathies, provided that the degree of renoprotection can be improved. This goal may be attainable with a more complex strategy than with a single or dual pharmacologic intervention on the renin-angiotensin system. Strict control of BP and protein excretion rate, lowering of blood lipids, tight glucose control for individuals with diabetes, and lifestyle changes form part of the future multimodal protocol for treatment of patients with chronic nephropathies.     

Revascularization for atherosclerotic renal artery stenosis: the treatment of choice?

Atherosclerotic renal artery stenosis (ARAS) is an important cause of renal dysfunction and secondary hypertension, and is associated with adverse cardiovascular events and increased mortality. The natural history of ARAS is characterized by anatomic disease progression and/or renal dysfunction in only a minority of patients. Medical therapy for ARAS is directed primarily toward blood pressure control and cardiovascular risk factor reduction. Renal artery revascularization is an additional treatment option for ARAS associated with ischemic nephropathy or severe, poorly controlled hypertension despite aggressive medical therapy. Unfortunately, the benefits associated with revascularization versus medical therapy alone remain unproven. Renal artery revascularization may be accomplished through open surgical revascularization or angioplasty and stenting. Although surgical renal revascularization is associated with more durable results and relatively lower risk for postoperative renal function decline, the increased risk of death or major complications associated with this management approach limit its use in patients with significant comorbidities. Renal artery angioplasty and stenting is being utilized with increasing frequency but is of uncertain benefit and is associated with rates of post-intervention renal function improvement and deterioration that are approximately equal. Renal function outcomes associated with angioplasty and stenting may be improved through a selective treatment approach and utilization of distal embolic protection. Renal artery revascularization represents the only treatment alternative for patients unresponsive to medical management, and is therefore the 'treatment of choice' in this select group. Results of ongoing randomized trials are eagerly anticipated and may provide useful guidance for future management of ARAS.     

Novel techniques for the treatment of localized prostate cancer: Evidence of efficacy?

Radical retropubic prostatectomy and radiation therapy remain the mainstay of treatment for localized prostate cancer. However, with the advent of the Internet, more patients are arriving in physicians’ offices questioning novel techniques for their treatment that they otherwise would not have discovered. This paper discusses several of these techniques, including focal cryotherapy, high-intensity focused ultrasound, robotic-assisted laparoscopic prostatectomy, diets, supplements, and hormonal therapy. We also render our opinion on their efficacy for treatment based on the available published studies.     

Bench-to-bedside development of agonists and antagonists of luteinizing hormone–releasing hormone for treatment of advanced prostate cancer

BackgroundAndrogen deprivation therapy (ADT) has been the standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for 3 decades. The agonists of luteinizing hormone–releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT.ADT and LHRH analogsThe application of agonists of LHRH has improved and modernized the treatment of advanced PCa; millions of patients have benefited from therapy with LHRH agonists as a preferred alternative to surgical castration, as the psychological effects and perpetuity of orchiectomy are undesirable for most men. Despite their efficacy, agonists of LHRH have several shortcomings, including initial surge in testosterone, producing exacerbation of clinical symptoms, and microsurges in testosterone that might occur after each administration. A new, alternate approach to ADT is emerging with the improvements in antagonists of LHRH. This class of LHRH analogues produces a direct and immediate blockade of pituitary LHRH receptors and leads to a more rapid suppression of testosterone without an initial surge or subsequent microsurges. Degarelix, a third-generation LHRH antagonist, is the only antagonist with a low histamine-releasing activity that is currently on the market for clinical use in advanced PCa with improved testosterone suppression, better control of follicle-stimulating hormone and prostate-specific antigen, and which offers a prolonged delay to progression and more favorable effects on serum alkaline phosphatase.ConclusionsAlthough LHRH agonists are still the mainstay for treatment of advanced PCa, antagonists of LHRH offer an alternative as a pharmacological approach.     

What is the outcome of treatment for osteolysis?

Periprosthetic osteolysis secondary to wear-induced particle generation is a common long-term complication of hip and knee replacement and frequently results in the need for revision surgery. Management of significant bone defects remains a surgical challenge. Surgical intervention must address the wear particle generator (usually, but not always, the bearing surface), the osteolytic defects, and implant-related issues, primarily fixation and alignment. Indications for surgical intervention in the absence of loosening and pain are not well established. In general, patient age and activity level, the location and size of the osteolytic defect, and the clinical record of the implant system will dictate treatment choices.     

Transurethral microwave thermotherapy for the treatment of BPH: still a challenger?

Minimally invasive therapies for treatment of benign prostatic hyperplasia (BPH) compete with the gold standard transurethral resection of the prostate (TURP). Comparisons of efficacy and safety have broadened the knowledge of different treatment modalities. Concerns of quality of life such as unaltered sexual function as well as cost considerations drive the market to develop techniques of lower level invasiveness. Among the competitors the office based transurethral microwave thermotherapy (TUMT) provides the broadest scale of scientific data. Numerous manufacturers sell various modifications of this technology. According to different clinical studies TUMT proved to be an effective, safe, and durable therapy for the treatment of lower urinary tract symptoms (LUTS) secondary to BPH. However, TURP still holds the steadier long-term results and is more effective to reduce obstruction as well as other LUTS.     

Open reduction for developmental dysplasia of the hip: failures of screening or failures of treatment?

Introduction

The aim of this study was to define the clinical indications and demographic characteristics of patients undergoing open reduction for developmental dysplasia of the hip (DDH), and determine the proportion due to preventable failures of contemporary clinical screening and early management.

Methods

Case notes were reviewed of consecutive primary open reductions performed for non-teratologic hip dislocation at the Great Ormond Street Hospital for Children over a five-year period. Forty-eight patients (64 hips) were suitable for inclusion. A telephone survey confirmed selective hip ultrasonography screening protocols were employed in all maternity hospitals in our referral base.

Results

There were no cases of open reduction for unilateral DDH following Pavlik treatment commenced by six weeks of age, highlighting the importance of early detection and treatment. Eleven cases (23%) may have been avoided by appropriate implementation of existing selective ultrasonography screening protocols. Thirty-four cases (71%) presented after four months of age, suggesting open reduction is associated with late diagnosis rather than failure of primary management. None of these patients had neonatal hip ultrasonography and only 12% (4 patients) had a risk factor that should have triggered a scan.

Conclusions

Compared with published results, the contemporary screening practices in our referral base are failing to eliminate late presenting DDH and the need for open surgical reduction. Changes in strategy and implementation are required to significantly improve screening efficacy.     

Transfer of pectoralis major for the treatment of irreparable tears of subscapularis: does it work?

Transfer of pectoralis major has evolved as the most favoured option for the management of the difficult problem of irreparable tears of subscapularis. We describe our experience with this technique in 30 patients divided into three groups. Group I comprised 11 patients with a failed procedure for instability of the shoulder, group II included eight with a failed shoulder replacement and group III, 11 with a massive tear of the rotator cuff. All underwent transfer of the sternal head of pectoralis major to restore the function of subscapularis. At the latest follow-up pain had improved in seven of the 11 patients in groups I and III, but in only one of eight in group II. The subjective shoulder score improved in seven patients in group I, in one in group II and in six in group III. The mean Constant score improved from 40.9 points (28 to 50) in group I, 32.9 (17 to 47) in group II and 28.7 (20 to 42) in group III pre-operatively to 60.8 (28 to 89), 41.9 (24 to 73) and 52.3 (24 to 78), respectively. Failure of the tendon transfer was highest in group II and was associated with pre-operative anterior subluxation of the humeral head. We conclude that in patients with irreparable rupture of subscapularis after shoulder replacement there is a high risk of failure of transfer of pectoralis major, particularly if there is pre-operative anterior subluxation of the humeral head.