The clinical development of rectal microbicides for HIV prevention

Introduction: Individuals practicing unprotected receptive anal intercourse are at particularly high risk of HIV infection. Men who have sex with men in the developed and developing world continue to have disproportionate and increasing levels of HIV infection. The last few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis, vaginal microbicides, and treatment as prevention but there has also been significant progress in the development of rectal microbicides. The purpose of this thesis is to summarise the status of rectal microbicide research, to identify opportunities, challenges, and future directions in this important field of HIV prevention, and to describe the results of a recently completed Phase 1 rectal microbicide study (MTN-007). Methods: MTN-007, a Phase 1, randomised, partially blinded, rectal safety study was undertaken to determine whether a reduced glycerin formulation of tenofovir 1% gel was safe and acceptable to men and women with a history of practicing receptive anal intercourse. The study was conducted at three clinical trial sites in the United States (Pittsburgh, Pennsylvania; Boston, Massachusetts; and Birmingham, Alabama). Study participants were randomized to one of three gel arms (tenofovir gel, a hydroxyethyl cellulose placebo gel, or a 2% Nonoxynol gel) or a no treatment arm and received a total of eight rectal daily doses of the study product. In addition to collecting conventional clinical safety and acceptability data, the study also included extensive mucosal safety assays to determine whether product administration was associated with changes in mucosal biology that might predispose to increased risk of HIV acquisition associated with unprotected receptive anal intercourse. Results: Sixty-five participants (45 men and 20 women) were recruited into the study. There were no significant differences between the numbers of ≥ Grade 2 adverse events across the arms of the study. Likelihood of future product use (acceptability) was 87% (reduced glycerin formulation of tenofovir 1% gel), 93% (hydroxyethyl cellulose placebo gel), and 63% (Nonoxynol-9 gel). Fecal calprotectin, rectal microflora, and epithelial sloughing, did not differ by treatment arms during the study. Suggestive evidence of differences was seen in histology, mucosal gene expression, protein expression, and T cell phenotype. These changes were mostly confined to comparisons between the Nonoxynol-9 gel and other study arms. Microarray analysis of the mucosal transcriptome provided preliminary evidence that topical application of tenofovir 1% gel was associated with decreased mitochondrial function within the rectal mucosa. Conclusions: The MTN-007 study demonstrated that, using conventional criteria, tenofovir gel is safe and acceptable and should be advanced to Phase 2 development as a potential rectal microbicide. However, microarray analysis of mucosal tissue suggested that use of tenofovir gel may modulate mucosal mitochondrial function. This observation will require further evaluation in future studies

Responses to an isometric leg-exercise test predicts sex-specific training-induced reductions in resting blood pressure after isometric leg training

Isometric training, using either isometric handgrip (IHG) or isometric bilateral-leg (IBL) protocols, is an effective method of lowering resting systolic blood pressure (SBPrest). However, the reductions in SBPrest seen after training vary widely between individuals. Predicting likely training-induced reductions in SBPrest could make it possible to optimise the effects of the training in all participants. It is known that post-IHG training reductions in SBPrest can be predicted by SBP responses to a 2 minute IHG task in both hypertensive and older normotensives (Millar et al., 2009; Badrov et al., 2013). However, the predictability of such a test in younger individuals and when using a comparable IBL task, has not been established. Furthermore, it is not known whether these simple isometric tests can predict reductions in ambulatory SBP (mean 24-hour, SBPamb) as well as SBPrest. Therefore, the purpose of this study was to determine whether an IBL test can be used to predict training-induced reductions in SBPrest and SBPamb following 10 weeks of IBL training in young men and women.Resting and ambulatory BP (SBPrest and SBPamb) were measured prior to and following 10 weeks of IBL training using an isokinetic dynamometer (4, 2-minute contractions at 20% MVC with 2 minute rest periods, 3/week) in 20 normotensive individuals (10 men, age=21 ± 4 years; 10 women, age=23 ± 5 years). SBP responses to the IBL test (single 2-minute period of IBL exercise) was derived by calculating the difference between peak SBP and mean baseline SBPrest. Pearson’s product moment correlation coefficient was used to assess the relationship between the blood pressure responses to a short 2-minute IBL test and the magnitude of the reductions in SBPrest and SBPamb after IBL training.ResultsThere were significant reductions in men and women’s SBPrest (7.4±5.1mmHg, p=0.0001 & 5.7±4.1mmHg, p=0.001) and SBPamb (4.0±1.9mmHg, p=0.011 & 6.1±5.8mmHg, p=0.0001) following training. These changes in SBPrest were strongly correlated with pre-training SBP response to the IBL test in both men (r=-0.83, p=0.003, SEE=3.03) and women (r = -0.81, p=0.004, SEE=2.56). However, the magnitude of the reductions in SBPamb were not correlated with SBP response to the IBL test (men, r=-0.44, p=0.199, SEE=1.76; women, r=-0.23, p=0.517, SEE=6.01).These results support previous research which has identified that IBL training is an effective tool for lowering both resting and ambulatory BP. Furthermore, a simple isometric exercise test can be used as a tool to predict reductions in resting SBP, but not ambulatory SBP, after IBL training in both men and women. This test could be used to optimise the effects of this type of training in a wider range of participants, perhaps through modification of the training, to suit the anticipated effects in different individuals

Commentary on Aerobic versus isometric handgrip exercise in hypertension: a randomized controlled trial

We, members of the International Working Group on Isometric Exercise, read with great interest the article by Pagonas et al. on the comparative effects of aerobic and isometric handgrip exercise (IRT). However, we believe the finding, that aerobic exercise induces reductions in blood pressure (BP), whereas isometric exercise training (handgrip) does not, to be compromised for several reasons

Establishing Equivalent Training Intensities for Isometric Bilateral-Leg and Handgrip Exercise Using the Category Ratio Scale

Isometric handgrip (IHG) training is commonly undertaken at an exercise intensity of 30% of a subject’s maximum voluntary contraction (MVC) (McGowan et al., 2007). Matching this intensity with isometric bilateral-leg (IBL) exercise is difficult due to the different muscle mass involved. Comparative studies (Howden et al., 2002) have tended to use different exercise intensities without providing a strong rationale. Therefore, the purpose of this study was to use the Category Ratio Scale (CR-10) to establish equivalent exercise intensities for IHG and IBL, based on participant effort perception and to test the extent to which intensity can be matched, when using this method during training sessions. A total of 26 healthy participants (male, n = 18; female, n = 8) undertook two minutes of unilateral IHG to establish the mean CR-10 values. Then, performed IBL exercise at 15, 20 and 25%MVC. The IBL intensity at which CR-10 most-closely matched the values for IHG, was identified as 20%MVC. Subsequently, an IHG and IBL training session was used, to test the extent to which the intensities were matched, according to effort perception. Ten participants (male, n = 6; female, n = 4) undertook 4 x 2 minutes unilateral IHG (30%MVC) and IBL (20%MVC) training, with 2 minutes recovery between contractions with CR-10 measured at the end of each exercise bout. A one-way independent ANOVA was used to identify the IHG and IBL intensities that were most-closely matched. To determine whether CR-10 values were significantly different during the IHG and IBL training sessions, a two-way mixed-model ANOVA was used.The intensity at which CR-10 was most-closely matched between IHG and IBL was 20%MVC. There were significant differences in the CR-10 values between IHG contractions at 30%MVC and IBL at 25%MVC and 15%MVC (P > 0.05) but not at 20%MVC (P 0.05).These results suggest when performing IBL exercise, the intensity most closely matching the IHG intensity (30%MVC) is 20%MVC. Furthermore, it can be seen from the simulated training sessions that CR-10 does not significantly differ between the two intensities until the final 2-minute bout. Therefore, it may be advantageous when undertaking one-off IBL exercise or IBL training protocols with the purpose of comparing data to that from IHG, to use 20%MVC. However, when a 4 x 2 minute training protocol is used, it may be necessary to attenuate the intensity of the 4th bout of IBL

Microbicides 2006 conference

Current HIV/AIDS statistics show that women account for almost 60% of HIV infections in Sub-Saharan Africa. HIV prevention tools such as male and female condoms, abstinence and monogamy are not always feasible options for women due to various socio-economic and cultural factors. Microbicides are products designed to be inserted in the vagina or rectum prior to sex to prevent HIV acquisition. The biannual Microbicides conference took place in Cape Town, South Africa from 23–26 April 2006. The conference was held for the first time on the African continent, the region worst affected by the HIV/AIDS pandemic. The conference brought together a record number of 1,300 scientists, researchers, policy makers, healthcare workers, communities and advocates. The conference provided an opportunity for an update on microbicide research and development as well as discussions around key issues such as ethics, acceptability, access and community involvement. This report discusses the current status of microbicide research and development, encompassing basic and clinical science, social and behavioural science, and community mobilisation and advocacy activities

The Mechanism Underlying the Hypotensive Effect of Isometric Handgrip Training: Is it Cardiac Output Mediated?

Isometric handgrip (IHG) training lowers blood pressure (BP) in normotensive individuals yet the mechanisms remain equivocal, and some evidence suggests that men and women respond differently to training. To date, non-sex specific mechanisms influencing total peripheral resistance, either in response to a single IHG bout or with training, have been a primary research focus, and the effects of acute and chronic IHG on cardiac output (Q) in either sex are under-explored. The purpose of the current study was two-fold: 1) to investigate the effects of IHG training (4, 2-minute sustained bilateral isometric contractions at 30% of maximal contraction, 1-minute rest between, 3X/week for 10 weeks) on resting Q, and 2) to examine the Q response to an IHG bout, and the effects of training on this response. Resting BP (Dinamap Carescape v100, Critikon) was measured after 10 minutes of seated rest in twenty-two normotensive participants (10 women; mean age= 24 ± 5.0 years). To assess Q, aortic root diameter (ARD; 3S-RS probe; Vivid I, GE Healthcare), velocity-timed integral (VTI; P2D probe; Vivid I), and HR (Dinamap) were measured pre- and post- an IHG bout. Both variables were re-assessed post-training. Reductions in resting systolic BP of a similar magnitude (p>0.05) were observed in both men (2.4 ± 6.2 mmHg) and women (2.9 ± 4.6 mmHg) following 10 weeks of training (p=0.04). This was accompanied by reductions in resting Q (p=0.007) in both men (6.6 ± 2.2 to 6.3 ± 1.8 L/min) and women (5.8 ± 0.7 to 5.1 ± 0.8 L/min) and reductions in HR (p=0.036), both of which were similar between sexes (all p>0.05). In both groups, no changes in Q were observed in response to an IHG bout, and this response was similar pre- and post- training (all p>0.05). In conclusion, resting Q is reduced with training, potentially implicating it as a mechanism of post-training BP reductions. The acute response to an IHG bout remains unchanged with training

Reductions in ambulatory blood pressure in young normotensive men and women after isometric resistance training and its relationship with cardiovascular reactivity

Background: There has been very little published work exploring the comparative effects of isometric resistance training (IRT) on blood pressure (BP) in men and women. Most of the previously published work has involved men and used resting BP as the primary outcome variable. Early evidence suggests that IRT is particularly effective in older women and has a positive influence on ambulatory BP, a better predictor of disease risk. Objectives: With the WHO now placing global emphasis on the primary prevention of hypertension, the goals of this proof-of-concept study were to (i) examine whether sex differences exist in the ambulatory BP-lowering effects of IRT in young, normotensive men and women and (ii) determine whether these reductions can be predicted by simple laboratory stress tasks (a 2-min sustained isometric contraction and a math task involving subtracting a two-digit number from a series of numbers). Results: There were no differences in the IRT-induced reductions in 24-h (men: Δ4 mmHg, women: Δ4 mmHg), daytime (men: Δ3 mmHg, women: Δ4 mmHg), or night-time (men: Δ4 mmHg, women: Δ3 mmHg) ambulatory BP in men (n=13) and women (n=11) (P0.05). Conclusion: Our data suggest that lower ambulatory BP can be achieved, to a similar magnitude in young healthy women as well as men, with IRT; however, the BP-lowering effectiveness cannot be predicted by systolic BP reactivity. Taken together, this work heralds a potentially novel approach to the primary prevention of hypertension in both men and women and warrants further investigation in a larger clinical outcome trial