Heart Disease and HIV- What to Do?

Some HIV+ people have emailed me worried about this report:

Heart Attacks Found Early and Frequently in HIV Positive People

Calculate your 5 year estimated cardiovascular risk: D-A-D Cardiovascular Risk Equation for HIV+ People

My suggestions to minimize heart disease (not in any other of importance):

1- Do not smoke

2- Keep your cholesterol and triglycerides within normal ranges (with exercise, diet, HIV medication change, fish oils, even medications)

3- Exercise 4 times a week for an hour

4- Take a baby aspirin every day (81 mg)

5- Take 200 mg of Coenzyme Q-10 and 2000 mg of carnitine per day

6- Get a stress test every two years 

7- Have one to two glasses a day of red wine, no more.

8- Controversial topic: avoid abacavir (Ziagen, Epzicom), D4T, AZT, Crixivan.

9- Control your HIV to under 50 copies all the time

10- Manage stress: meditate, take a hobby, do pleasurable things every day, let go of what you cannot control, etc

11- Avoid street drugs, except moderate pot for pain or appetite.

12- Get your blood pressure under control 

13- Keep your weight down

14- Keep your gums healthy

15- Eat cold water fish (salmon, sardines, etc) at least once a week

16- Have a hand full of nuts once a day

17- Keep your testosterone and thyroid hormones within healthy ranges.

18- Know the symptoms of a heart attack and call 911 immediately if you ever have them. Do not deny them or "sleep them off".  Do not have a friend take you to the hospital. Call 911 and paramedics will pre-treat you right when they are driving you to the hospital. Read about symptoms: Symptoms of a heart attack

Dolutegravir, Trii and new abacavir data- How it all ties together

By Nelson Vergel

Powerusa.org

Dr Joe Eron presented new dosing and efficacy phase 2b data on the new GSK integrase inhibitor dolutegravir (DTG, S/GSK1349572) using 50 mg twice a day in patients whose HIV virus has developed resistance to raltegravir (Isentress). Prior data presented in Vienna from a cohort (cohort 1) of patients who took 50 mg once a day showed that patients with one or more Q148+ associated integrase mutations had reduced activity to the drug, so GSK decided to recruit a second cohort (cohort 2)  of patients who took 50 mg twice a day in hopes that the increased blood levels would overcome some of this lower efficacy. Despite a long half life supporting once-daily dosing, the lack of dose proportional increase in exposure above 50 mg precluded using 100 mg once daily.

Adult patients with HIV-1 RNA ≥1000 copies/mL showing genotypic resistance to raltegravir and to ≥2 other ARV classes received 50 mg twice daily of DTG while continuing their failing regimen (without RAL) to day 11, after which the background regimen was optimized with another active agent. Unlike the previously presented 50 mg qd cohort I, eligibility required at least 1 fully active ARV for day 11 optimization.

All patients in this 50 mg bid cohort II with extensive raltegravir resistance (mutations Q148+ others) virus responded compared to 3 of 9 in the 50 mg qd cohort I. The mean reductions in plasma HIV-1 RNA (log10 copies/mL) at day 11 were –1.76  for  50 mg bid cohort II ( a lower but still attractive response of –1.57 for Q148+ virus) and –1.45 for  50 mg qd cohort I ( a reduced response of –0.72 for Q148+ virus). DTG was generally well tolerated:  mild to moderate diarrhea was the most common adverse event (n = 6), while 1 subject experienced 2 severe adverse events (demyelinating polyneuropathy, at day 23; diabetes mellitus, at day 79) considered unrelated to study drug.

 Although the day 11 responses were numerically better in cohort II, the baseline fold change range in virus susceptibility to DTG for cohort II was more limited due to extensive raltegravir related mutations.  46% of patients taking the 50 mg bid dose had one or more Q148 associated mutations that were associated with reduced response to the prior 50 mg qd dose cohort.  Longer-term (24 weeks) assessments in this phase 2b study are ongoing.

The data from cohort 2 provide promise for patients with extensive raltegravir resistance. However, many of these patients are in deep salvage with no remaining active ARVs to construct a viable regimen, so even if DTG works for them they will need another active agent.  Luckily, several companies are currently collaborating in an upcoming expanded access program that will allow these patients at higher risk of disease progression and death to obtain more than one active investigational drugs without waiting three years for all of them to be approved.  I will write about this project in future articles.

DTG will also be tested in naïve patients in head-to-head with raltegravir  in phase 3 studies (using a background of Epzicom  (abacavir (Ziagen) + 3TC (Epivir) ) or Truvada. When I first saw this study design schema, I thought it curious about why GSK decided to include their nucleoside combination Epzicom in their upcoming studies with DTG.

This decision started to make sense when GSK recently made an announcement that they will coformulate dolutegravir with Epzicom (abacavir+epivir) in a pill called Trii.  This coformulation will be competing for treatment naïve market share with other once a day pills (BMS/Gilead’s Atripla, Gilead’s QUAD and Tibotec/Gilead’s TMC278+ Truvada).

The development of Trii for approval as a first line treatment seemed risky to me due  to some compelling but conflicting studies that linked abacavir to cardiovascular risks in patients with HIV.  These data compelled the DHHS guidelines panel to drop abacavir from its list of recommended first line nucleosides for the treatment of naïve HIV positive patients.  So how would GSK ensure that their future Trii coformulation has a prominent place in the recommended regimens for first line treatment of HIV-positive patients?

Shedding some more light on this abacavir-cardiovascular risk issue and GSK’s move to develop the Trii coformulation,  the US Food and Drug Administration (FDA)  presented  a surprising poster on  March 2 that reported  no evidence of an association between abacavir  and increased risk of myocardial infarction (heart attack) in a meta-analysis of 26 randomized trials of the drug.  The meta-analysis included 5028 patients on abacavir and 4804 patients not taking abacavir with a mean follow-up per person of 1.62 years.

It is yet unknown if this new FDA report will enable abacavir to regain its preferred position in first line treatment guidelines.  Whatever the outcome will be for this nucleoside ARV, GSK-ViiV’s decision to  pursue their new Trii coformulation for the treatment naïve indication will provide one more option in the growing arsenal of once daily pills.   Hopefully, this new competition among companies in the once daily market will generate better pricing and worldwide access.

As the abacavir story unfolds, we await for more efficacy and safety data in the next few months on DTG’s use in treatment naïve and experienced patients.

Sources:

DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II. Joseph Eron et al.Univ of North Carolina at Chapel Hill Sch of Med. Oral presentation 151LB

Ding X et al. No association of myocardial infarction with ABC use: an FDA meta-analysis.  Poster abstract 808.


More on:
http://www.retroconference.org/2011/Abstracts/42541.htm

http://www.thebodypro.com/content/art60708.html

More on CROI:
http://www.thebody.com/content/art60501.html

Is Exercise Important for People with HIV?

We need more programs around the Unites States and the world that provide supervised exercise programs for people with HIV!

Association between Exercise and HIV Disease Progression in a Cohort of Homosexual Men . Annals of Epidemiology , Volume 9 , Issue 2 , Pages 127 - 131 T . Mustafa



Having exercised was associated with slower progression to AIDS at 1 year (); hazard ratios (HR) at 2, 3, and 4 years were 0.96, 1.18, and 1.36, respectively. Having exercised was also associated with slower progression to death with AIDS at 1 year (HR = 0.37, 90% CI: 0.14–0.94) with hazard ratios at 2, 3, and 4 years of 0.68, 0.98, and 1.27, respectively, suggesting a protective effect close to the time exercise was assessed, but an increased risk after 2 years. Exercising 3–4 times/week had a more protective effect than daily exercise. Exercisers in the HIV positive group showed an increase in CD4 count during a year by a factor of 1.07.



Testosterone Replacement and Resistance Exercise in HIV-Infected Men With Weight Loss and Low Testosterone Levels

Shalender Bhasin, MD; Thomas W. Storer, PhD; Marjan Javanbakht, MPH; Nancy Berman, PhD; Kevin E. Yarasheski, PhD; Jeffrey Phillips, MD; Marjorie Dike, PhD; Indrani Sinha-Hikim, PhD; Ruoquing Shen, MD; Ron D. Hays, PhD; Gildon Beall, MD

JAMA. 2000;283:763-770.



Our data suggest that testosterone and resistance exercise promote gains in body weight, muscle mass, muscle strength, and lean body mass in HIV-infected men with weight loss and low testosterone levels. Testosterone and exercise together did not produce greater gains than either intervention alone.



A pilot study of exercise training to reduce trunk fat in adults with HIV-associated fat redistribution.

AIDS. 13(11):1373-1375, July 30, 1999.
Roubenoff, Ronenn abc; Weiss, Lauren c; McDermott, Ann c; Heflin, Tanya ac; Cloutier, Gregory J. d; Wood, Michael ac; Gorbach, Sherwood ab


Exercise training may reduce trunk fat mass in HIV-positive men with fat redistribution.


Resistance Exercise and Supraphysiologic Androgen Therapy in Eugonadal Men With HIV-Related Weight Loss -A Randomized Controlled Trial


Alison Strawford, PhD; Theresa Barbieri; Marta Van Loan, PhD; Elizabeth Parks, PhD; Don Catlin, MD; Norman Barton, MD, PhD; Richard Neese, PhD; Mark Christiansen, MD; Janet King, RD, PhD; Marc K. Hellerstein, MD, PhD

JAMA. 1999;281:1282-1290.



A moderately supraphysiologic androgen regimen that included an anabolic steroid, oxandrolone, substantially increased the lean tissue accrual and strength gains from PRE, compared with physiologic testosterone replacement alone, in eugonadal men with HIV-associated weight loss. Protease inhibitors did not prevent lean tissue anabolism.



Supervised exercise training improves cardiopulmonary fitness in HIV-infected persons.

Medicine & Science in Sports & Exercise. 25(6):684-688, June 1993.
MACARTHUR, RODGER D.; LEVINE, SHELDON D.; BIRK, THOMAS J.



We attempted to measure cardiopulmonary effects, CD4 counts, and perceived sense of well-being in 25 individuals moderately to severely immunocompromised from HIV infection (mean entry CD4 count = 144-[mu]l-1) before and after a 24-wk program of exercise training. Only six subjects completed the 24-wk program. All six showed evidence of a training effect. Statistically significant improvements were seen in maximal oxygen consumption (VO2max), oxygen pulse, and minute ventilation. Submaximal exercise performance improved significantly by 12 wk in the 10 individuals available for testing: decreases were seen in heart rate, rate pressure product, and rate of perceived exertion. White blood cell counts and T-lymphocyte subsets were stable at 12 and 24 wk in the subjects available for testing. High depression/anxiety scores on a mental health inventory (General Health Questionnaire) correlated with low CD4 counts. Scores did not correlate with compliance with the exercise program. There was a trend (P < 0.10) for scores to improve over time among those individuals who attended >=80% of scheduled exercise sessions. We conclude that exercise training is feasible and beneficial for some HIV-infected individuals.





Aerobic exercise: effects on parameters related to fatigue, dyspnea, weight and body composition in HIV-infected adults. AIDS. 15(6):693-701, April 13, 2001.
Smith, Barbara A. a; Neidig, Judith L. b,d; Nickel, Jennie T. e; Mitchell, Gladys L. c; Para, Michael F. b; Fass, Robert J. b



We conclude that supervised aerobic exercise training safely decreases fatigue, weight, BMI, subcutaneous fat and abdominal girth (central fat) in HIV-1-infected individuals. It did not appear to have an effect on dyspnea.



Exercise intervention attenuates emotional distress and natural killer cell decrements following notification of positive serologic status for HIV-1
Applied Psychophysiology and Biofeedback


Volume 15, Number 3 / September, 1990

Arthur R. LaPerriere, Michael H. Antoni, Neil Schneiderman, Gail Ironson, Nancy Klimas, Panagiota Caralis and Mary Ann Fletcher

Abstract The impact of aerobic exercise training as a buffer of the affective distress and immune decrements which accompany the notification of HIV-1 antibody status in an AIDS risk group was studied. Fifty asymptomatic gay males with a pretraining fitness level of average or below (determined by predicted VO2 max) were randomly assigned to either an aerobic exercise training program or a no-contact control condition. After five weeks of training, at a point 72 hours before serostatus notification, psychometric, fitness and immunologic data were collected on all subjects. Psychometric and immunologic measures were again collected one-week postnotification. Seropositive controls showed significant increases in anxiety and depression, as well as decrements in natural killer cell number following notification whereas, seropositive exercisers showed no similar changes and in fact, resembled both seronegative groups. These findings suggest that concurrent changes in some affective and immunologic measures in response to an acute stressor might be attenuated by an experimentally manipulated aerobic exercise training intervention.





Resistance exercise training reduces hypertriglyceridemia in HIV-infected men treated with antiviral therapy
J Appl Physiol 90: 133-138, 2001; Vol. 90, Issue 1, 133-138, January 2001
Kevin E. Yarasheski1, Pablo Tebas2, Barbara Stanerson1, Sherry Claxton1, Donna Marin2, Kyongtae Bae3, Michael Kennedy2, Woraphot Tantisiriwat2, and William G. Powderly2



Hypertriglyceridemia, peripheral insulin resistance, and trunk adiposity are metabolic complications recently recognized in people infected with human immunodeficiency virus (HIV) and treated with highly active antiretroviral therapy (HAART). These complications may respond favorably to exercise training. Using a paired design, we determined whether 16 wk of weight-lifting exercise increased muscle mass and strength and decreased fasting serum triglycerides and adipose tissue mass in 18 HIV-infected men. The resistance exercise regimen consisted of three upper and four lower body exercises done for 1-1.5 h/day, 4 days/wk for 64 sessions. Dual-energy X-ray absorptiometry indicated that exercise training increased whole body lean mass 1.4 kg (P = 0.005) but did not reduce adipose tissue mass (P = NS). Axial proton-magnetic resonance imaging indicated that thigh muscle cross-sectional area increased 5-7 cm2 (P < 0.005). Muscle strength increased 23-38% (P < 0.0001) on all exercises. Fasting serum triglycerides were decreased at the end of training (281-204 mg/dl; P = 0.02). These findings imply that resistance exercise training-induced muscle hypertrophy may promote triglyceride clearance from the circulation of hypertriglyceridemic HIV-infected men treated with antiviral therapy.



Effects of exercise training and metformin on body composition and cardiovascular indices in HIV-infected patients.

AIDS. 18(3):465-473, February 20, 2004.
Driscoll, Susan D ; Meininger, Gary E ; Lareau, Mark T ; Dolan, Sara E ; Killilea, Kathleen M ; Hadigan, Colleen M ; Lloyd-Jones, Donald M c; Klibanski, Anne ; Frontera, Walter R ; Grinspoon, Steven K



Exercise training in combination with metformin significantly improves cardiovascular and biochemical parameters more than metformin alone in HIV-infected patients with fat redistribution and hyperinsulinemia. Combined treatment was safe, well tolerated and may be a useful strategy to decrease cardiovascular risk in this population.



The effect of acute exercise on lymphocyte subsets, natural killer cells, proliferative responses, and cytokines in HIV-seropositive persons.Ullum H, Palmø J, Halkjaer-Kristensen J, Diamant M, Klokker M, Kruuse A, LaPerriere A, Pedersen BK. J Acquir Immune Defic Syndr. 1994 Nov;7(11):1122-33.



Copenhagen Muscle Research Center, Department of Infectious Diseases, Rigshospitalet, Denmark.

Eight healthy men infected with human immunodeficiency virus, type 1 (HIV) and eight HIV seronegative age- and sex-matched controls exercised on a bicycle ergometer (75% of VO2max, 1 h). The percentages of CD4+, CD4+45RA+, and CD4+45RO+ cells did not change, whereas the absolute number of CD4+ cells increased twofold during exercise and fell below prevalues 2 h after. The neutrophil count increase was more pronounced after exercise in the controls compared with in HIV-seropositive subjects. The percent CD16+ cells, and the natural killer (NK) and lymphokine activated killer (LAK) cell activity increased during exercise, but this increase was significantly less pronounced in the HIV-seropositive group. The results suggest that in response to physical stress, HIV-seropositive subjects have an impaired ability to mobilize neutrophils, NK and LAK cells to the blood. Furthermore, because the total number of CD4+ cells, but not the percentage of CD4+ cells, changed in response to exercise, this study further strengthens the idea that the percentage of CD4+ cells is preferable to the number of CD4+ cells in monitoring patients seropositive for HIV.


Cardiopulmonary and CD4 cell changes in response to exercise training in early symptomatic HIV infection. Med. Sci. Sports Exerc., Vol. 31, No. 7, pp. 973-979, 1999.

Approximately 61% of exercise-assigned participants complied (> 50% attendance) with the exercise program, and analyses of exercise relapse data indicated that obesity and smoking status, but not exercise-associated illness, differentiated compliant from noncompliant exercisers. Compliant exercisers significantly improved peak oxygen consumption ( O2peak; 12%), oxygen pulse (O2pulse; 13%), tidal volume (TV; 8%), ventilation ( E; 17%), and leg power (25%) to a greater degree than control participants and noncompliant exercisers (all P < 0.05). Although no group differences in health status were found, a significant interaction effect indicated that noncompliant exercisers' CD4 cells declined (18%) significantly, whereas compliant exercisers' cell counts significantly increased (13%; P < 0.05).



Moderate and high intensity exercise training in HIV-1 seropositive individuals: a randomized trial. Int J Sports Med. 1999 Feb;20(2):142-6. Terry L, Sprinz E, Ribeiro JP.

HIV-infected individuals are frequently active, but guidelines for exercise in this population lack scientific support, since studies on the effects of exercise training on immunologic variables of HIV-1 positive individuals have shown conflicting results. Exercise capacity, immunologic markers (CD4, CD8 and CD4:CD8 ratio), anthropometric measurements, and depression scores were evaluated to compare the effects of two intensities of aerobic exercise on HIV-1 seropositive individuals. Twenty-one healthy subjects (14 men, 7 women), carriers of the HIV-1 virus (CD4>200 cells x mm(-3)), and inactive for at least 6 months, completed a 12 week exercise training program (36 sessions of 1 h, 3 times per week), in a moderate intensity group (60+/-4% of maximal heart rate) or a high intensity group (84+/-4% of maximal heart rate). Exercise capacity estimated by treadmill time was increased significantly in both moderate intensity (680+/-81 s before; 750+/-151 s after) and high intensity (651+/-122 s before; 841+/-158 s after) groups, but the high intensity group presented a significantly larger increment (p<0.01). There were no significant changes in the immunologic variables, anthropometric measurements or depression scores. Thus, HIV-seropositive individuals that participate in moderate and high intensity exercise programs are able to increase their functional capacity without any detectable changes in immunologic variables, anthropometric measurements or depression scores.



Aerobic Exercise Training for Depressive Symptom Management in Adults Living With HIV Infection . Journal of the Association of Nurses in AIDS care , Volume 14 , Issue 2 , Pages 30 - 40 J . Neidig , B . Smith , D . Brashers



Aerobic exercise training may help prevent or reduce depressive symptoms experienced by persons living with HIV infection. However, the psychological effects of aerobic exercise have not been studied extensively. This study evaluated the effects of an aerobic exercise training program on self-reported symptoms of depression in HIV-infected adults and examined the convergent validity of two widely used depressive symptom scales. Sixty HIV-infected adults participated in a randomized, controlled trial of a supervised 12-week aerobic exercise training program. As compared to study controls, exercise participants showed reductions in depressive symptoms on all indices, and total depressive symptoms scores were highly correlated. Additional study of the psychological effects of aerobic exercise programs in the target population is recommended.





The effect of exercise training on aerobic fitness, immune indices, and quality of life in HIV+ patients.

Medicine & Science in Sports & Exercise. 30(1):11-16, January 1998.
STRINGER, WILLIAM W.; BEREZOVSKAYA, MARINA; O'BRIEN, WILLIAM A.; BECK, C. KEITH; CASABURI, RICHARD



Exercise training resulted in a substantial improvement in aerobic function while immune indices were essentially unchanged. Quality of life markers improved significantly with exercise. Exercise training is safe and effective in this patient group and should be promoted for HIV+ patients