More than the Infinite Monkey Theorem: NHP Models in the Development of a Pediatric HIV Cure.

PURPOSE OF REVIEW: An HIV cure that eliminates the viral reservoir or provides viral control without antiretroviral therapy (ART) is an urgent need in children as they face unique challenges, including lifelong ART adherence and the deleterious effects of chronic immune activation. This review highlights the importance of nonhuman primate (NHP) models in developing an HIV cure for children as these models recapitulate the viral pathogenesis and persistence. RECENT FINDINGS: Several cure approaches have been explored in infant NHPs, although knowledge gaps remain. Broadly neutralizing antibodies (bNAbs) show promise for controlling viremia and delaying viral rebound after ART interruption but face administration challenges. Adeno-associated virus (AAV) vectors hold the potential for sustained bNAb expression. Therapeutic vaccination induces immune responses against simian retroviruses but has yet to impact the viral reservoir. Combining immunotherapies with latency reversal agents (LRAs) that enhance viral antigen expression should be explored. Current and future cure approaches will require adaptation for the pediatric immune system and unique features of virus persistence, for which NHP models are fundamental to assess their efficacy.

Exercise in Dialysis: Ready for Prime Time?

It is widely acknowledged that patients with end-stage kidney disease receiving maintenance hemodialysis (HD) may benefit from increasing their physical activity levels. Decades of exercise-related clinical trials have demonstrated improvements in various metrics related to dialysis patient's health and quality of life. Yet, the implementation of exercise programs in dialysis clinics today is scarce, and physical inactivity and dysfunction remain a hallmark of the disease. To address this issue, many groups worldwide are beginning to rethink how physical activity and exercise are prescribed in HD patients, as well as how to evaluate the efficacy of these programs. The vast majority of exercise interventions in HD patients have included intradialytic cycling as the predominant or only exercise prescription. Moreover, efficacy has most often been evaluated using standard measures of strength, physical function, and/or traditional cardiovascular disease risk factors (e.g., blood pressure, lipids, etc.). More recently, there has been a greater emphasis on novel intervention approaches that are focused on providing patients with a greater variety of options for exercise and enhanced motivational tools. The benefits of exercise on patient reported outcome measures (PROMs) and other clinically important outcomes are also becoming more prevalent. The purpose of this review was to: (1) critically review the data from several recently published large randomized clinical trials of exercise in HD patients, (2) discuss some of the novel approaches that groups across the world are taking to improve implementation and efficacy of exercise-related interventions in HD, and (3) discuss policy prescriptions that may be needed to continue improving exercise prescriptions for this critically ill patient population. While it may be too early to declare that exercise in dialysis is ready for prime time, exciting advances have been made in recent years, yet more work is needed to realize its full potential.

Pilot study to reduce interdialytic weight gain by provision of low-sodium, home-delivered meals in hemodialysis patients.

INTRODUCTION: Patients with kidney failure undergoing maintenance hemodialysis (HD) therapy are routinely counseled to reduce dietary sodium intake to ameliorate sodium retention, volume overload, and hypertension. However, low-sodium diet trials in HD are sparse and indicate that dietary education and behavioral counseling are ineffective in reducing sodium intake. This study aimed to determine whether 4 weeks of low-sodium, home-delivered meals in HD patients reduces interdialytic weight gain (IDWG). Secondary outcomes included changes in dietary sodium intake, thirst, xerostomia, blood pressure, volume overload, and muscle sodium concentration. METHODS: Twenty HD patients (55 ± 12 years, body mass index [BMI] 40.7 ± 16.6 kg/m2 ) were enrolled in this study. Participants followed a usual (control) diet for the first 4 weeks followed by 4 weeks of three low-sodium, home-delivered meals per day. We measured IDWG, hydration status (bioimpedance), standardized blood pressure (BP), food intake (3-day dietary recall), and muscle sodium (magnetic resonance imaging) at baseline (0 M), after the 4-week period of usual diet (1 M), and after the meal intervention (2 M). FINDINGS: The low-sodium meal intervention significantly reduced IDWG when compared to the control period (-0.82 ± 0.14 kg; 95% confidence interval, -0.55 to -1.08 kg; P < 0.001). There were also 1 month (1 M) to 2 month (2 M) reductions in dietary sodium intake (-1687 ± 297 mg; P < 0.001); thirst score (-4.4 ± 1.3; P = 0.003), xerostomia score (-6.7 ± 1.9; P = 0.002), SBP (-18.0 ± 3.6 mmHg; P < 0.001), DBP (-5.9 ± 2.0 mmHg; P = 0.008), and plasma phosphorus -1.55 ± 0.21 mg/dL; P = 0.005), as well as a 0 M to 2 M reduction in absolute volume overload (-1.08 ± 0.33 L; P = 0.025). However, there were no significant changes in serum or tissue sodium (all P > 0.05). DISCUSSION: Low-sodium, home-meal delivery appears to be an effective method for improving volume control and blood pressure in HD patients. Future studies with larger sample sizes are needed to examine the long-term effects of home-delivered meals on these outcomes and to assess cost-effectiveness.

A Comparison of Intradialytic versus Out-of-Clinic Exercise Training Programs for Hemodialysis Patients.

BACKGROUND: Physical inactivity is prevalent and linked with a variety of unfavorable clinical outcomes in hemodialysis patients. To increase physical activity (PA) and improve quality of life in this population, intradialytic and out-of-clinic exercise interventions have been implemented in many studies. However, there is still a lack of consensus in the literature on which type of exercise intervention is more feasible and effective. SUMMARY: This review provides a brief overview of intradialytic and out-of-clinic exercise protocols utilized in previous studies. We also examine data related to the feasibility of each approach, and their efficacy for improving cardiovascular health, muscle mass, strength, and physical function. Key Messages: The benefits from most intradialytic and out-of-center exercise training interventions published to date have been modest or inconsistent. Furthermore, neither appears to provide a significant advantage over the other in terms of benefits for cardiovascular health, muscle mass, strength, and physical function. A significant concern is that most intradialytic and out-of-center exercise interventions are mandated exercise prescriptions that include either endurance or resistance training exercises, performed at low-moderate intensities, for a total of 60-135 min of exercise/week. This volume, intensity, and variety of exercise are far less than what is recommended in most PA guidelines. This type of structured activity is also boring for most patients. To enhance the effectiveness of exercise interventions, we suggest using the intradialytic period to provide patients guidance on how they can best incorporate more activity into their lives, based on their individual needs and barriers.

Global strategies to reduce the price of antiretroviral medicines: evidence from transactional databases.

OBJECTIVE: To estimate the impact of global strategies, such as pooled procurement arrangements, third-party price negotiation and differential pricing, on reducing the price of antiretrovirals (ARVs), which currently hinders universal access to HIV/AIDS treatment. METHODS: We estimated the impact of global strategies to reduce ARV prices using data on 7253 procurement transactions (July 2002-October 2007) from databases hosted by WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria. FINDINGS: For 19 of 24 ARV dosage forms, we detected no association between price and volume purchased. For the other five ARVs, high-volume purchases were 4-21% less expensive than medium- or low-volume purchases. Nine of 13 generic ARVs were priced 6-36% lower when purchased under the Clinton Foundation HIV/AIDS Initiative (CHAI). Fifteen of 18 branded ARVs were priced 23-498% higher for differentially priced purchases compared with non-CHAI generic purchases. However, two branded, differentially priced ARVs were priced 63% and 73% lower, respectively, than generic non-CHAI equivalents. CONCLUSION: Large purchase volumes did not necessarily result in lower ARV prices. Although current plans for pooled procurement will further increase purchase volumes, savings are uncertain and should be balanced against programmatic costs. Third-party negotiation by CHAI resulted in lower generic ARV prices. Generics were less expensive than differentially priced branded ARVs, except where little generic competition exists. Alternative strategies for reducing ARV prices, such as streamlining financial management systems, improving demand forecasting and removing barriers to generics, should be explored.