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

The Coming Crisis in HIV Drug Development

Excellent article by Paul Dalton

Project Inform
The Coming Crisis in HIV Drug Development
By Paul Dalton

June 16, 2008

The last few years have seen tremendous progress in treating people with advanced and drug-resistant HIV. Four powerful drugs became available that either overcame drug resistance (Prezista [darunavir, TMC-114], Intelence [etravirine, TMC-125]) or were from entirely new classes [Selzentry (maraviroc), Isentress (raltegravir)].

This marked an important and unique moment in HIV drug development. Never before have so many new and effective drugs come out so close together. People with extensive experience taking HIV drugs have been able to put together powerful regimens with two or more fully active agents -- often for the first time.

Project Inform took pains to highlight both the tremendous promise of these new drugs as well as the importance of using them correctly -- emphasizing that this moment, or anything resembling it, is unlikely to recur. Our message was clear: 'Seize this opportunity, use the new drugs carefully, and don't waste this once-in-a-lifetime chance'.

As good as some of these newer drugs have looked in studies, there are emerging signs of trouble in the real world. Dr. Steven Deeks, a prominent HIV physician and researcher says, "Although the current generation of drugs are generally doing great, many patients are not responding in a durable manner. We are now following about 25 individuals who have failed all six drug classes. The key now is to design regimens to maintain immunologic and clinical stability while we wait for more drugs. I am concerned, however, as it will likely be a few years before we have another shot at getting the virus under control. We desperately need a second generation integrase inhibitor that works against viruses resistant to raltegravir."

Dr. Deeks' experience is far from typical. He follows many of the most treatment experienced people in the San Francisco Bay Area, many of whom have been on therapy since 1987. Although not typical, his experiences have been reported elsewhere, if in smaller numbers.

This suggests a burgeoning problem of people beginning to run out of treatment options, as has happened a couple of times during the epidemic. Project Inform is concerned that the most vulnerable people living with HIV will be left with few or no viable treatment options, possibly for many years.

One of the unintended effects of the recent successes in drug development is that fewer people are available for studies of experimental drugs aimed at treatment experienced folks. We saw this coming and have been counseling drug companies and the Food and Drug Administration (FDA) that the era of 'TORO-like' studies was coming to a close. These studies give volunteers optimized background therapy (the best combination of HIV drugs chosen with resistance test results) with either the experimental drug or a placebo. The design allows regulators, scientists and activists to clearly see the benefit of the new drug. (Some call these studies 'TORO-like' after those that led to the approval of Fuzeon [enfuvirtide, T20]).

This contrasts with how studies of first line treatment are done. When studying HIV drugs as first line, the basic model is head-to-head non-inferiority studies, which are designed to tease out the relative contribution of the entire regimens rather than the individual drugs. (Non-inferiority means that one drug or regimen is equivalent or 'close enough' to another.)

The FDA has allowed non-inferiority studies for drugs being studied as first line, but has insisted on placebo controlled superiority studies for treatment experienced studies. This made a good deal of sense when there were many people signing up for these studies. The situation is now quite different.

While there aren't enough people signing up for these kinds of studies, there's still a sizeable need for studying new HIV drugs. This, combined with the thin drug pipeline and the current difficulty recruiting for studies, may add up to real trouble down the line.

In meetings with many drug companies Project Inform has warned of this impending problem and recommended that they adopt new ways of studying their drugs. The reaction has been mixed. While some companies have been quite open to new ideas, it's fair to say that most would prefer to stick with models that have proven successful.

We have struggled to argue -- to the companies and the FDA -- that ways of studying and developing drugs are both necessary and possible. Gilead Sciences is one of the first to grapple with this. When it came time to do large, pivotal studies of their experimental integrase inhibitor, elvitegravir, there simply were not enough people in the US to enroll a typical study for treatment experienced people. Project Inform had warned Gilead, and others, of this eventuality and argued for studies that would more closely resemble the head-to-head, non-inferiority studies used for studying first-line drugs.

Over time Gilead came to agree that this was the way forward and submitted such a plan to the FDA. The FDA eventually allowed Gilead to move forward with this study design for elvitegravir. This is a great victory for people living with HIV. There is a great need for new treatments to be developed and for the FDA and companies to think and act creatively to ensure this happens.




An Overview of the Current State of HIV Drug Development
The Industry
As a whole, pharma has done a tremendous job developing HIV drugs. However, many visible signs are showing their fading commitment to HIV. Fewer new companies are getting into HIV, and some well established ones are either cutting back or eliminating their drug development plans. The marketplace for HIV drugs is both crowded and competitive. The scientific hurdles for developing new HIV drugs have also grown more difficult, making it a less attractive market for companies.

The FDA
The FDA is responsible for ensuring that drugs are safe and effective before they become available outside clinical studies. Recent media stories that focused on drug safety, particularly on Vioxx and Heparin, have created a somewhat fearful climate inside the FDA where new ideas are met skeptically. Their recent decision to green light elvitegravir's development shows that at least its antiviral division is open to creative drug development plans.

The Current Pipeline
All in all, the pipeline is both thin and unimpressive. There are a few 'me too' drugs (slight changes in existing drugs) which are helpful but not game changing. A few novel compounds may prove promising down the line, but they're struggling right now, due to either study results or in one case the company being bought by a company that doesn't want to work in HIV.

As for those drugs in human studies, the closest to approval is rilpivarine (TMC-278), an NNRTI for first line treatment being studied against Sustiva. Vicriviroc, Schering's CCR5 drug, continues to flounder but is still viable. Bevirimat, a maturation inhibitor from Panacos, has been hamstrung by formulation problems. Other drugs we are following are Pharmasset's racivir, and Avexa's apricitabine.

The Bottom Line
The past two years have been a boon to people with extensive treatment experience. Four successful new drugs, including two new classes, have meant most people can put together powerful, effective and tolerable regimens, even if they've never been able to get to undectable before. However, this period is now over, and we're experiencing a major downturn in the number of promising drugs in the pipeline.

This reinforces the importance of using the current crop of new drugs correctly. Your best chance at getting to and staying undetectable is to start a regimen with at least two and hopefully three fully active drugs. If you're able to do this and get your HIV level to undetectable, good adherence is the best way of keeping it there.

This also points to the need for treatment activists, like Project Inform, to continue to work with the companies, scientists and regulators to ensure that new drugs are developed.
Lastly, this situation points toward the need for a cure. It is only going to become more difficult to keep the companies, their researchers and the general public interested in HIV drugs. There's a growing sense that HIV is not that much of a problem anymore, at least not in wealthy countries.

The only real solution is a cure. While some may discount its possibility, we do not. Many promising approaches are under study, as well as a resurgence in community activism aimed at cure research. A conscientious program mounted by academia, industry, government and community is necessary to reach this goal.

My Column at TheBody.com

TheBody.com is one of the most visited web sites in the world of HIV. It has many experts that answer health questions for free. I am honored to be part of this web site.

Here is the link to my column
http://www.thebody.com/Forums/AIDS/Nutrition/index.html

Mortality Down 94% in HIV Among Diagnosed

NATAP http://natap.org/
_______________________________________________



Changes in the Risk of Death After HIV Seroconversion Compared With Mortality in the General Population
Krishnan Bhaskaran, MSc; Osamah Hamouda, MD; Mette Sannes, MLabTech;Faroudy Boufassa, MD; Anne M. Johnson, MD; Paul C. Lambert, PhD; Kholoud Porter, PhD; for the CASCADE Collaboration


JAMA. July 2, 2008;300(1):51-59.

".....To our knowledge, no study to date has made a comparison of mortality among HIV-infected and uninfected individuals adjusted for duration of HIV infection, and our results provide estimates, hitherto unavailable, of the cumulative excess probability of death as duration of HIV infection increases.....we found that by 2004-2006, the risk of death in the first 5 years following seroconversion was similar to that of the generalpopulation, with the excess probability of death becoming apparent only later in the course of infection, particularly evident in those infected for 10 years or more....Our long-term cumulative mortality estimates for 2004-2006 include data from individuals infected in the mid-1990s or earlier who may have started antiretroviral treatment later in the course of infection and with regimensinferior to those currently available; thus, such estimates may be pessimistic in terms of the long-term outlook for more recently infected individuals.....Indeed, we found a lower uptake of HAART among those exposed through IDU compared with other groups, while lower therapy adherence among such individuals has been described in the literature.....Although we matched by age, sex, calendar time, and country, it is likely that HIV-infected individuals in our study differ from the general population in other ways. Rates of smoking have been shown to be high among some HIV-infected populations30; other risk behaviors, socioeconomic factors, and race/ethnicity are also likely to differ among HIV-infected persons. Those exposed through IDU in particular are likely to be at higher risk of mortality than the general population regardless of HIV infection, and we have presented our estimates of the cumulative excess mortality proportion excluding this group. Nonetheless, our results are interpretable as estimates of the excess mortality among HIV-infected individuals, who may differ from a general population not only in being infected with HIV but also in other factors......A second limitation is that HIV seroconverters are not representative of the total HIV-infected population; mortality estimates derived from seroconverters, by definition diagnosed and monitored from an early stage, are likely to be optimistic compared with the experience of the wider HIV-infected population....

......We found that the gap in mortality rates between HIV-infected individuals in our study and the general population narrowed in every calendar period from 1996 onward. Considering the first years following the widespread introduction of HAART, we haveestimated an 88% reduction in excess mortality in 2000-2001 compared with pre-1996, corresponding closely to the 87% reduction in the standardized mortality ratio in 1997-2001 compared with pre-1996, as reported by the Swiss HIV cohort.7 Our more recentdata show that reductions have continued to 2004-2006, with excess mortality in this period 94% lower than pre-1996 levels. Corresponding to these reductions, the uptake of HAART increased, and though this leveled off after 2001, there followed an increasing use of NNRTI-based HAART as the first-line treatment regimen and a substantial increase in the boosting of PI-based regimens......Despite the major reductions in excess mortality, a significantly increased risk of death remained among individuals of all ages in 2004-2006.....we aimed to evaluate changes over calendar time in the excess mortality of HIV-infected individuals comparedwith expected mortality in the general uninfected population, adjusting for duration of HIV infection. We further aimed to assess changes over calendar time in the effects of prognostic factors and in the overall and excess probability of death at various stages of HIV infection. We also report corresponding changes over time in the uptake and use of HAART in our population.....excess mortality decreased dramatically from 1996 onward. By 2004-2006, there was no evidence of any excess mortality to 5 years from seroconversion in any age group. However, in the longer term, some excess mortality was still evident, with the cumulative excess probability of death in the first 10 years from seroconversion estimated to be 4.8% (95% CI, 2.5%-8.6%) in those aged 15 to 24 years and 4.3% (95% CI, 0.0%-10.5%) in those 45 years or older at seroconversion....The median time from HIV seroconversion to starting HAART was 1.6 (IQR, 0.7-3.5) years in 1996-1997 and 1.4 (IQR, 0.6-3.4), 1.8 (IQR, 0.7-5.6), 2.4 (IQR, 0.8-6.7), and 2.2 (IQR, 1.0-4.8) years in 1998-1999, 2000-2001, 2002-2003, and 2004-2006, respectively..."

ABSTRACT



Context Mortality among human immunodeficiency virus (HIV)–infected individuals has decreased dramatically in countries with good access to treatment and may now be close to mortality in the general uninfected population.

Objective To evaluate changes in the mortality gap between HIV-infected individuals and the general uninfected population.

Design, Setting, and Population Mortality following HIV seroconversion in a large multinational collaboration of HIV seroconverter cohorts (CASCADE) was compared with expected mortality, calculated by applying general population death rates matched on demographic factors. A Poisson-based model adjusted for duration of infection was constructed to assess changes over calendar time in the excess mortality among HIV-infected individuals. Data pooled in September 2007 were analyzed in March 2008, covering years at risk 1981-2006.

Main Outcome Measure Excess mortality among HIV-infected individuals compared with that of the general uninfected population.

Results Of 16 534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1000 person-years) decreased from 40.8 (95% confidence interval [CI], 38.5-43.0; 1275.9 excess deaths in 31 302 person-years) before the introduction of highly active antiretroviral therapy (pre-1996)to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14 703 person-years) in 2004-2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03-0.09] for 2004-2006 vs pre-1996). By 2004-2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%-8.6%] in the first 10 years among those aged 15-24 years).

Conclusions Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of highly active antiretroviral therapy. In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.



INTRODUCTION


Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
• Author information
• References





A number of studies have reported the dramatic decreases in mortality among individuals infected with human immunodeficiency virus (HIV) since the widespread introduction of highly active antiretroviral therapy (HAART) in industrialized countries.1-2 It is important to provide up-to-date and robust estimates of expected mortality as anti-HIV drugs and strategies continue to improve. Such estimates help policy makers and those planning health care to monitor the effectiveness of treatments at a population level and provide an indicator of the ongoing and likely future impact of HIV disease on health care needs.

With mortality among HIV-infected individuals decreasing to relatively low levels compared with the pre-HAART era and with patients living to older ages, it is also of increasing interest to assess how mortality rates of HIV-infected individuals compare with those of the general uninfected population, ie, the "excess mortality."3Overall mortality of HIV-infected individuals is likely to be increasingly influenced by deaths that would haveoccurred regardless of HIV infection, and mortality in the general uninfected population provides a natural reference point for taking this into account. This concept has been used in studies of other diseases in which successfully treated patients frequently live for many years, such as Hodgkin disease4 and thyroid5 and other6cancers.

A few studies have compared HIV-infected and uninfected populations in industrialized countries, reporting reductions in the standardized mortality ratio in the early years of HAART availability7 and estimating a reduced life expectancy of 17 years for HIV-infected individuals compared with that of the uninfected population.8 Two further studies specifically considering those with a good initial response to treatment found an increased mortality risk, even in this subgroup.9-10

These studies have not been able to adjust for duration of HIV infection, which is a key factor influencing mortality risk and could confound other relationships. Using a large data set of individuals with well-estimated HIV seroconversion dates—thus avoiding biases that can occur when duration of infection is unknown11—we aimed to evaluate changes over calendar time in the excess mortality of HIV-infected individuals comparedwith expected mortality in the general uninfected population, adjusting for duration of HIV infection. We further aimed to assess changes over calendar time in the effects of prognostic factors and in the overall and excess probability of death at various stages of HIV infection. We also report corresponding changes over time in the uptake and use of HAART in our population.


METHODS


Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
• Author information
• References





Data were used from CASCADE (Concerted Action on Seroconversion to AIDS and Death in Europe), which has been described elsewhere.12 It is currently a collaboration of 23 cohorts of individuals with well-estimated dates of HIV seroconversion from Europe (20 cohorts from Denmark [1], France [4], Germany [1], Greece [1], Italy [1], the Netherlands [2], Norway [2], Spain [4], Switzerland [1], and the United Kingdom [3]), Australia (2 cohorts), and Canada (1 cohort). All eligible individuals are recruited, both prospectively and retrospectively, to the constituent cohorts through the clinical centers where they receive their HIV care, and an enrollment date is recorded for each participant. Of the 23 cohorts, 3 regional and 6 national cohorts collect data on individuals from a number of HIV clinical centers across the region or country, through the abstraction of medical records for all participants from routine clinic visits. These data are recorded on clinic report forms and then entered into the individual cohort database. Data are then extracted according to an agreed-on standardized data exchange protocol and submitted to the CASCADE coordinating center (Medical Research Council Clinical Trials Unit, London, United Kingdom) on an annual basis,where they are pooled. The remaining 14 single-clinic cohorts abstract data directly from their clinic database according to the same standardized data exchange protocol and forward the data to the coordinating center. Enrollment averaged 317 individuals per year overall from 1985-1987 and increased to 801 per year over the 19-year period 1988-2006. Six cohorts included in the analysis had ceased recruitment of new seroconvertersin 1992, 1997 (2 cohorts), 2000, 2002, and 2004. These 6 cohorts make up 7.7% of data included in the analyses. A subgroup of participants represented by the UK cohort data presented herein were evaluated in a previous study estimating changes in survival over calendar time after HIV seroconversion in a UK setting.13

All cohorts received approval from their individual ethics review boards except for the Danish cohort, which received approval from the National Data Registry Surveillance Agency because Danish law allowed collection and pooling of anonymized clinical data with approval from this agency alone. Two ethics review boards deemed their cohort participants exempt from providing signed informed consent. Signed informed consent was obtained from all others. Approval was also given by all ethics review boards to pool anonymized data for analyses and dissemination.

Estimates of HIV seroconversion dates are accurate to within 18, 12, and 6 months for 100%, 87%, and 63% of individuals, respectively, and are based on documented evidence of seroconversion. In 95% of cases, this evidence comprised a documented negative HIV antibody test result, which must be dated fewer than 3 yearsbefore the first positive result, and seroconversion date is estimated as the midpoint between the last negative and first positive test results. For the remaining 5% of cases, alternative documented laboratory evidence of seroconversion is available (real-time polymerase chain reaction positivity in the absence of HIV antibodies, or antigen positivity with <4 bands on a Western blot).

We included all individuals 15 years or older at seroconversion who had sexual or injection drug use (IDU) exposure to HIV and at least 1 day of follow-up since enrollment into the cohort. Individuals infected through hemophilia treatment (n = 234) and occupational exposure (n = 156) were excluded, as were 547 with unknown exposure type. To avoid survivorship bias, late-entry methods were used so that, in cases in whichseroconversion was identified retrospectively, time since seroconversion was only considered "at risk" from the date of enrollment into the cohort. Data were pooled in September 2007 and analyzed in March 2008, with follow-up available from May 1981 to June 2007. Follow-up time was censored on the date at which mortalitydata were assumed to be complete for each contributing cohort; death registration is compulsory in all countries represented in CASCADE, and for 14 of the 21 cohorts represented in the final analysis there is active cross-checking with national death registers for individuals lost to follow-up. As a further measure to avoid underascertainment of death due to reporting delays, we applied additional right-censoring on December 31,2006.

Statistical Analysis

Changes over time in the overall risk of death were calculated from a Cox model stratified by cohort and adjusted for age at seroconversion, sex, and HIV exposure category, with calendar period of follow-up as a time-updated covariate, categorized to represent the era before extensive availability of HAART (pre-1996) and at regular intervals thereafter (1996-1997, 1998-1999, 2000-2001, 2002-2003, and 2004-2006). We confirmed that there was no evidence against the proportional hazards assumption by a test based on the Schoenfeld residuals, where P < .05 would indicate problems with the assumption.14

For the analysis of excess mortality, the expected number of deaths was calculated by applying annual probability of death data from the general population to the study population, considering individuals to be at risk until their actual date of death or censoring.15 The general population mortality data were obtained from the Human Mortality Database in July 2007,16 stratified by age, sex, calendar year at risk, and country, and were matched to the study population on these factors. Race and ethnicity were not reported. The number of deaths among CASCADE individuals in each demographic stratum was then modeled using a Poisson process, offsetting the expected deaths. This is known as a relative survival model and provides adjustment for background mortality without the need for information on cause of death.3 Time since seroconversion was divided into 1-year intervals and included in the model as a categorical variable,17 thus effectively assuming a piecewise constant hazard of excess mortality in each 1-year interval following seroconversion. To check thesensitivity of our results to this assumption, we also repeated our analyses using 3-month and 6-month intervals in the first 2 years of infection, thus allowing the hazard function more flexibility close to seroconversion.

Within this relative survival model framework, we examined changes in the risk of excess mortality over calendar time of follow-up (time-updated), adjusting for age at seroconversion, sex, and HIV exposure category. The relative survival models provide estimates of excess hazard ratios (eHRs), the interpretation of which is similar to that of the familiar Cox hazard ratio. For example, an eHR of 1.5 for male/female would indicate that males have a 50% higher risk of dying compared with females, after accounting for expected background mortality. We then investigated the effects of age at seroconversion, sex, and HIV exposure category as potential prognostic factors for excess mortality. Interactions with calendar time were added to assess whether these effects had changed over calendar time. Two-sided P values for individual model parameters and interactions were produced using likelihood ratio tests of nested models, and for model-building purposes we considered P < .05 to indicate statistical significance.

Using subgroups based on the most important factors from the final model, we then calculated life-table estimates of the cumulative survival and relative survival function18 by duration of infection in each calendar period, by multiplying interval-specific probabilities. Hence the corresponding cumulative overall (1 – cumulative survival) and excess (1 – relative survival) probability of death at 5, 10, and 15 years of HIV infection duration were derived (as preplanned analyses). These intervals were chosen because we anticipated that reliable estimates could be derived up to 15 years from HIV seroconversion (in a prior report, stable estimates of overall survival to 10 years following HIV seroconversion were generated,1 and 5 additional years of follow-up data are now available), and we wished to describe changes in mortality patterns and allow comparison across subgroups at a small number of regular intervals of infection duration. Additional late entry and censoring were applied at the beginning and end, respectively, of the calendar period in question; thus,estimates for each period covered the entire duration of infection (incorporating short-term information from the recently diagnosed individuals and longer-term information from those diagnosed in the past). This approach is known as period analysis and has been commonly used in population-based studies.1, 19

Finally, in the same calendar periods, we described the time to starting HAART (defined as at least 3 antiretroviral drugs representing at least 2 drug classes or including abacavir or tenofovir20) using Kaplan-Meier methods and the proportion of time spent receiving HAART. The numerator for the latter was the amount of person-time spent receiving HAART as derived from the prescription start and stop dates recorded for individual drugs during routine clinical follow-up. Because therapy guidelines recommend the initiation of HAART before CD4 cell count decreases to 200 cells/µL and HAART is typically initiated at 200 to 350 cells/µL,20-21 we considered as the denominator only time at risk after the first CD4 cell count below 350 cells/µL or after HAART initiation, whichever came earlier.

All statistical analyses were performed using Stata version 10 (StataCorp, College Station, Texas).


RESULTS


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Participants

The analysis included 16 534 individuals (Table 1) with median age at HIV seroconversion of 29 years (interquartile range [IQR], 24-36 years). The reported exposure category was sex between males for 9465 individuals (57%), IDU for 3047 (18%), and sex between males and females for 4022 (24%). For year ofseroconversion, the median was 1994 (range, 1980-2006). The study observation time ranged from May 1981 to December 2006, and all but 1 cohort (representing 0.5% of the data) contributed data to every calendar period considered in the analysis. The median duration of follow-up was 6.3 years (range, 1 day to 23.8 years), with 16 344 individuals (99%) having more than 1 month of follow-up. There were 21 cohorts represented in the final included data (after excluding 2 with only hemophilia patients), with 16 143 individuals (98%) belonging to European cohorts. The median number of individuals included per cohort was 388 (range, 56-7000). For 2 contributing cohorts the reported exposure category was exclusively IDU and for 1 cohort was exclusively sex between males; however, most individuals (16 256 [98%]) were enrolled in cohorts covering all 3 exposure categories.




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Table 1. Characteristics of the Study Population






Changes Throughout Calendar Time in Excess Mortality Risk and Prognostic Factors

A total of 2571 individuals had died as of December 2006, compared with an estimated 235 deaths that would have been expected in a matched general population cohort (Table 2). The excess mortality rate per 1000 person-years was 40.8 (95% confidence interval [CI], 35.8-43.0; 1275.9 excess deaths in 31 302 person-years)pre-1996, decreasing in each subsequent calendar period to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14 703 person-years) in 2004-2006.




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Table 2. Changes in Overall and Excess Mortality Rates






The overall adjusted hazard ratio of death compared with pre-1996 was 0.57 (95% CI, 0.51-0.64), 0.20 (95% CI, 0.18-0.24), 0.15 (95% CI, 0.12-0.17), 0.13 (95% CI, 0.11-0.15), and 0.09 (95% CI, 0.07-0.11) in 1996-1997, 1998-1999, 2000-2001, 2002-2003, and 2004-2006, respectively. In the relative survival model adjusted for background mortality, as well as duration of infection and prognostic factors, the eHR of death compared with pre-1996 was 0.54 (95% CI, 0.48-0.60), 0.17 (95% CI, 0.14-0.20), 0.12 (95% CI, 0.10-0.14), 0.10 (95% CI, 0.08-0.12), and 0.06 (95% CI, 0.05-0.08) in the same periods, respectively. Older age at seroconversion was associated with a higher risk of excess mortality (eHR, 2.54; 95% CI, 2.10-3.07 for age 45 years compared with age 15-24 years; P < .001), as was a reported exposure category of IDU (eHR, 1.52; 95% CI, 1.36-1.69 [P < .001] compared with sex between males). Females appeared to be at lower risk than males (eHR, 0.80; 95% CI, 0.70-0.91 [P = .001]).

There was strong evidence for a change over calendar time in the effects of age at seroconversion (P = .002), exposure category (P < .001), and sex (P < .001) when these interactions were added individually to our model, although when all 3 were added, only the exposure category interaction remained statistically significant (Table 3). There was no overall effect of exposure category in the pre-1996 period (P = .29). In each subsequent calendar period, exposure category was strongly predictive of excess mortality (P < .001 in each period), with those exposed through IDU at significantly higher risk than those exposed through sex between males (eHR, 3.71; 95% CI, 2.05-6.73 in 2004-2006). Those exposed via sex between males and females had a risk of excess mortality similar to that of those exposed via sex between males in every periodexcept 2000-2001, when they were at higher risk (eHR, 2.02; 95% CI, 1.18-3.45).




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Table 3. Excess Hazard Ratios (eHRs) Obtained Using a Multivariate Model for Excess Mortalitya






For age at seroconversion and sex there was no evidence of variation over calendar time in the final model (P = .40 and P = .45, respectively, for interaction). Over all calendar periods there was a clear gradient of increasing risk of excess mortality with increasing age at seroconversion. Females were at consistently lower risk than males.

All estimates were very similar in 2 sensitivity analyses in which time since seroconversion was split into smaller intervals (3 and 6 months) for the first 2 years of infection.

Estimated Excess Mortality by Duration of Infection

Considering those in the sexual HIV exposure groups, mortality among HIV-infected individuals decreased toward background mortality levels between pre-1996 and 2004-2006 (Figure). Because individuals in the IDU exposure category are likely to be at higher risk of mortality than the general population regardless of HIV infection, this category was initially excluded from estimates of the cumulative excess mortality. Comparing the cumulative overall and excess probability of death, we found that prior to 1996, excess mortality above that expected in the general population accounted for the vast majority of total observed mortality in CASCADE in all age groups and at all stages of infection (Table 4). However, excess mortality decreased dramatically from 1996 onward. By 2004-2006, there was no evidence of any excess mortality to 5 years from seroconversion in any age group. However, in the longer term, some excess mortality was still evident, with the cumulative excess probability of death in the first 10 years from seroconversion estimated to be 4.8% (95% CI, 2.5%-8.6%) in those aged 15 to 24 years and 4.3% (95% CI, 0.0%-10.5%) in those 45 years or older at seroconversion, though in the latter age group this excess mortality represented less than half of the total 10-year mortality of 12.2%.





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Figure. Reduction in All-Cause Mortality pre-1996 to 2006 and Comparison With That of the General Population, by Age Group
The general population curve for 2004-2006 was generated by applying general population mortality rates in each 1-year interval since seroconversion to a hypothetical cohort matched to the study population on age, sex, and country. HIV indicates human immunodeficiency virus.






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Table 4. Estimated Cumulative Overall Probability of Death by Duration of HIV Infection Among Sexual Exposure Groups in CASCADE and Cumulative Excess Probability of Death Compared With That of the General Populationa







Among individuals exposed through IDU, in contrast, mortality in 2004-2006 was higher than background levels, even early in infection (estimated cumulative excess probability of death in the first 5 and 10 years, 4.8% [95% CI, 1.4%-13.6%] and 6.2% [95% CI, 2.2%-14.3%], respectively, among those exposed throughIDU who were younger than 45 years at seroconversion).

To further explore the differences between HIV exposure groups, we considered causes of death in 2004-2006. Of the 127 individuals who died in this period, 95 had known cause of death (as recorded in clinic records or death certificates), the most common being AIDS for 27 individuals (28%), non-AIDS malignancy for 14 (15%),and suicide or intentional harm for 13 (14%). The pattern of causes of death among those exposed through IDU differed from that of other groups: no non-AIDS malignancies were reported, and there was a higher proportion of reported liver-related causes (7/22 [32%], compared with 2/73 [3%] among sexual exposure groups). The proportion of deaths reported as suicide among those exposed through IDU was only slightly higher than among those with reported exposure category of sex between males (4/22 [18%] vs 8/51 [16%]).

Uptake of HAART

The median time from HIV seroconversion to starting HAART was 1.6 (IQR, 0.7-3.5) years in 1996-1997 and 1.4 (IQR, 0.6-3.4), 1.8 (IQR, 0.7-5.6), 2.4 (IQR, 0.8-6.7), and 2.2 (IQR, 1.0-4.8) years in 1998-1999, 2000-2001, 2002-2003, and 2004-2006, respectively. After excluding time at risk when HAART would not be indicated, the proportion of person-time spent receiving HAART increased from 17% in 1996-1997 to 54%, 66%, 69%, and 73% in the same calendar periods, respectively. As expected, the use of nonnucleoside reverse transcriptase inhibitor (NNRTI)–based regimens increased over time and by 2004-2006, the proportion of person-time receiving NNRTI-based HAART was approximately equal to that spent receiving protease inhibitor (PI)–based HAART (40% and 42% of person-time on HAART, respectively, compared with 18% and 71%, respectively, in 1998-1999, when the first NNRTIs were available). Ritonavir boosting of PI regimens also increased from 7.0% of person-time receiving PI-based HAART in 1996-1997 to 10.7%, 32%, 63%, and 79% in 1998-1999, 2000-2001, 2002-2003, and 2004-2006, respectively.


COMMENT


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We found that the gap in mortality rates between HIV-infected individuals in our study and the general population narrowed in every calendar period from 1996 onward. Considering the first years following the widespread introduction of HAART, we haveestimated an 88% reduction in excess mortality in 2000-2001 compared with pre-1996, corresponding closely to the 87% reduction in the standardized mortality ratio in 1997-2001 compared with pre-1996, as reported by the Swiss HIV cohort.7 Our more recentdata show that reductions have continued to 2004-2006, with excess mortality in this period 94% lower than pre-1996 levels. Corresponding to these reductions, the uptake of HAART increased, and though this leveled off after 2001, there followed an increasing use of NNRTI-based HAART as the first-line treatment regimen and a substantial increase in the boosting of PI-based regimens.

Despite the major reductions in excess mortality, a significantly increased risk of death remained among individuals of all ages in 2004-2006. A number of other studies comparing mortality in HIV-infected and uninfected populations have also found a significant remaining excess mortality,10 though we found a relatively low level of excess mortality among those 45 years or older compared with 1 study8; however, since that study considered time-updated acquired age rather than age at HIV seroconversion, it is likely that those contributing to the 45 years or older age groups had longer duration of infection, which was unknown in that study.

To our knowledge, no study to date has made a comparison of mortality among HIV-infected and uninfected individuals adjusted for duration of HIV infection, and our results provide estimates, hitherto unavailable, of the cumulative excess probability of death as duration of HIV infection increases. Interestingly, we found that by 2004-2006, the risk of death in the first 5 years following seroconversion was similar to that of the generalpopulation, with the excess probability of death becoming apparent only later in the course of infection. Our long-term cumulative mortality estimates for 2004-2006 include data from individuals infected in the mid-1990s or earlier who may have started antiretroviral treatment later in the course of infection and with regimensinferior to those currently available; thus, such estimates may be pessimistic in terms of the long-term outlook for more recently infected individuals. Nevertheless, it is likely that even with current standards of HIV management, some long-term excess mortality would remain because problems of toxicity, resistance, and therapy adherence are likely to increase with time receiving HAART.

We found that older age was highly predictive of excess mortality prior to 1996, and this effect broadly continued in later calendar periods, despite suggestions in the literature that increasing age is associated with better adherence to HAART.22 Another large study23 found an association between older age and overallmortality following HAART initiation. It is of interest that the effect persisted in our analysis adjusted for natural aging, which appeared to account for more than half of the total mortality in individuals 45 years or older in 2004-2006. Some studies have found that older individuals experience slower immune recoveryfollowing HAART initiation,24-25 which could reflect the state of thymic function and may in part account for their continuing excess risk of death.26

Individuals exposed through IDU had a higher excess risk of death throughout the HAART era, with a 4-fold higher risk compared with the reported exposure category of sex between males in 2004-2006. It is unlikely that HIV infection is the only factor leading to increased mortality rates among those exposed through IDU, who, as well as accounting for the direct risks of substance abuse, may be more likely to be diagnosed with mental health–related illnesses27 and coinfections,28 the effects of which may have been masked prior to 1997 by the mortality burden of HIV disease itself. On the other hand, the increasing separation of those exposed through IDU since 1997 as a group with higher excess mortality may point to differences in access and adherence to therapy. Indeed, we found a lower uptake of HAART among those exposed through IDU compared with other groups, while lower therapy adherence among such individuals has been described in the literature.29

Our study has some limitations. Ideally we would like to quantify the excess mortality associated with HIV infection. To this end, we have compared mortality in CASCADE with that in the general population. Although we matched by age, sex, calendar time, and country, it is likely that HIV-infected individuals in our study differ from the general population in other ways. Rates of smoking have been shown to be high among some HIV-infected populations30; other risk behaviors, socioeconomic factors, and race/ethnicity are also likely to differ among HIV-infected persons. Those exposed through IDU in particular are likely to be at higher risk of mortality than the general population regardless of HIV infection, and we have presented our estimates of the cumulative excess mortality proportion excluding this group. Nonetheless, our results are interpretable as estimates of the excess mortality among HIV-infected individuals, who may differ from a general population not only in being infected with HIV but also in other factors.

A second limitation is that HIV seroconverters are not representative of the total HIV-infected population; mortality estimates derived from seroconverters, by definition diagnosed and monitored from an early stage, are likely to be optimistic compared with the experience of the wider HIV-infected population. In particular,further research will be needed before our finding of no excess mortality in the first 5 years of infection in 2004-2006 can be generalized beyond those diagnosed early in infection.

Despite these limitations, seroconverters provide a unique opportunity to study and adjust for the effect of duration of HIV infection on mortality and excess mortality. Our results show the progress in reducing mortality among HIV-infected individuals toward the levels experienced by the general uninfected population. However, there is continuing excess mortality, particularly evident in those infected for 10 years or more. Ongoing monitoring of excess mortality will be important as new treatment advances are implemented in an attempt to further reduce mortality rates among HIV-infected individuals.


AUTHOR INFORMATION


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Corresponding Author: Kholoud Porter, PhD, MRC Clinical Trials Unit, 222 Euston Rd, London NW1 2DA, United Kingdom (kp@ctu.mrc.ac.uk).

Author Contributions: Mr Bhaskaran had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Bhaskaran, Johnson, Porter.

Acquisition of data: Bhaskaran, Hamouda, Sannes, Boufassa.

Analysis and interpretation of data: Bhaskaran, Lambert, Porter.

Drafting of the manuscript: Bhaskaran, Sannes, Porter.

Critical revision of the manuscript for important intellectual content: Hamouda, Boufassa, Johnson, Lambert, Porter.

Statistical analysis: Bhaskaran, Lambert.

Obtained funding: Porter.

Administrative, technical, or material support: Hamouda, Sannes, Boufassa, Porter.

Study supervision: Bhaskaran, Johnson, Porter.

Financial Disclosures: None reported.

Funding/Support: The CASCADE collaboration has been funded through grants BMH4-CT97-2550, QLK2-2000-01431, QLRT-2001-01708, and LSHP-CT-2006-018949 from the European Union.

Role of the Sponsor: The European Union had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.


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The First AIDS Treatment

Dear Marty

I am glad to see people honoring who you are and what you have done for us in the HIV community. As you know , you inspired me to get crazy about treatment information and give lectures when I first saw you in Houston in the 80's. I realized back then that a "non-doctor" could know as much or more than doctors in HIV, and that made me lose my fears about not having enough qualifications to educate patients. Because of you and your work on importing hopeful therapies for dying patients back then, I was also inspired to help create a buyers club in Houston that is now only one of the few left after years of operation. You have been a great mentor to me and I love how you always have a peaceful attitude even when some of us are losing our cool.

I am honored that I have worked with you and got to see you in action in the great work that you have done for all of us living with this bug. I really hope you have many years of health so that you can keep mentoring those of us who do not live in the east and west coast and that may not be networked enough to be truly effective in our activism. You are a endangered species and we need to clone you!

Thanks for all you have done for me and all of us.

Nelson


*********************************************


The First AIDS Treatment Activist

Last night, Marty Delaney was honored at an event in Washington, DC. Marty is one of my heroes. He was the founder of Project Inform, and has been an AIDS treatment activist longer than anyone I know.

Back in the late 80's, when ACT UPers like myself starting pushing the government and big pharma to move faster in finding treatments for people living with HIV/AIDS, we quickly discovered that a great deal of groundwork had already been laid by Marty and one or two other gay men (notably Jay Lipner, a Manhattan-based lawyer -- see his NY Times obit). They had the smarts and patience to teach themselves about the scientific process and the inner workings of the bureaucracies involved in AIDS research.

They created AIDS treatment activism. I’m alive today because of gay men like Marty.

In addition to AIDS bigwigs like Robert Gallo, AIDSmeds.com’s very own David Evans paid tribute to Marty last night, with these wonderful remarks:

They say if you want to get to know someone well, you should spend several hours in a car with them. Since 1993 I’ve taken hundreds of car trips, dozens of plane rides and even spent a few hours in an indigenous canoe in the Caribbean just off the coast of Panama with Marty. I’ve come to know him well. It would take 100 hours to go into even half of it, but I’ve only got a few minutes and I want to take this time to tell you a few things about him that others may not know or mention.
There is a political Marty. He’s definitely left leaning, but he’s rarely partisan -- particularly when it comes to HIV. He’s equally generous with his criticism and praise of both Republicans and Democrats. This isn’t Machiavellian political gamesmanship. Speaking the truth is very important to him, and damn the politics, and damn what’s expedient or polite. This hasn’t always made him popular with politicians, government officials, or pharmaceutical executives—or even other AIDS activists. In fact I’ve watched him get beat up over his work many times, both publicly and privately.

Marty is not a typical activist. He’s unlikely to get arrested in front of the New York stock exchange or the Capitol building. Yet he repeatedly risked arrest and prison in the late 1980s, smuggling in drugs from Mexico that we once hoped would effectively treat HIV. He helped with the founding of the first buyers clubs that worked on quasi-illegal generic formulations of AIDS drugs in development. Marty will gladly buck authority and break the rules when he believes that there’s no other rational way to accomplish his goals.

Marty isn’t much of a yeller and screamer. When he sees a problem his first instinct is usually to figure out who is the person with the most power to effect the change he wants and then to pick up the phone and call that person, and to keep calling until he gets what he wants. This means that his advocacy work is often private, rather than public, and that much of his work has gone unnoticed and unacknowledged.

When I first met Marty in 1991 I had no idea who he was. I was a Project Inform volunteer and he was a guy with a briefcase who swooped in and out of the office once or twice a week. I didn’t get to know him well until we went on a road tour together of town-hall style meetings in 1993. We hit about fifty cities a year over the next three or four years. I’d do the legwork - fly in, rent a car, find a map – this was way before online driving directions or GPS – and get things set up. I’d pick Marty up at the airport the next day and we’d spend the next two to five days together, sometimes doing meetings in three or four towns in a row.

All of this began soon after the depressing results of the Concord study, which found that AZT all by itself didn’t increase survival. They were lean years, with far too many funerals. But Marty, privy to the earliest exciting data on the protease inhibitors in development saw it as his personal mission to keep people hopeful and healthy long enough for the drugs to become available. From 1993, until protease inhibitors became available at the end of 1995, Marty spoke in front of thousands of people, some of them terribly ill, and urged them to hang on just a little longer. Though he’s not a religious man, and thinks with the intellectual discipline of a scientist, he’s often said that when hope is lost, the body usually follows. When all we had to offer was hope, that’s what he strived to give people.

But his roadshow was just the warm up to some of the most intense, private work that took much of his personal time. At the end of each town meeting people lined up to talk to Marty. Most just wanted to thank him, or follow up on something he’d said in his talk. But there were always a few who faced profound problems -- sometimes life threatening problems –everything from doctors who kept them on a failing and toxic regimen for too long, or who failed to catch an opportunistic infection early enough, or problems accessing a needed treatment. It was then, with each one of these people, when Marty went into action, usually giving people his private home number so that in the coming days, and nights and weekends, they could together navigate those problems and find solutions. I imagine there are a few of you in this room tonight who are alive because of the direct help Marty gave you.

Marty’s a complicated person, and like any human being he’s not always right, or even in the best mood. But he’s always, always tried to live by a set of principles that include compassion, honesty, responsibility, fairness and what’s right and true.

For each of one of us who’s born witness to the horror and tragedy of this microscopic virus, it’s hard to imagine what it would have been like without Marty’s guiding hand. He’s indirectly helped tens of thousands of people by shaping clinical trials, the development of HIV drugs, and policies affecting treatment access and the price of drugs. And much more personally he’s helped thousands of people one-on-one. He prophesized hope when there seemed none. And more important still he stood with one person after another, taking it on himself to solve problems, overcome obstacles and ensure care in such a way that many came to see him as a kind of healthcare guardian angel. It’s important to honor his achievements, but it’s also important to honor his humanity, and that’s what I hope you will do.

U.S. Should Lift HIV/AIDS-Related Travel Restrictions

U.S. Should Lift HIV/AIDS-Related Travel Restrictions, Opinion Piece Says
[Jun 25, 2008]
Since 2003, the U.S. through the President's Emergency Plan for AIDS Relief has "extended a helping hand to" HIV-positive people living outside the country, Sens. John Kerry (D-Mass.) and Gordon Smith (R-Ore.) write in a Washington Times opinion piece. "Unfortunately, as we open our wallets to fund lifesaving treatments to those living with HIV/AIDS overseas, we will not open our doors," the authors write, adding that HIV is the "only medical condition that renders people inadmissible" to the U.S. The U.S. is "just one of 12 countries" -- including Libya, Russia, Saudi Arabia and Sudan -- that "prohibit, almost without exception, HIV-positive noncitizens from entering the country," according to Kerry and Smith. They add that such a "discriminatory policy has no basis in public health, let alone common sense."

According to the authors, they have introduced a bill that would "overturn this unfair policy." There is "no excuse for a law that goes out of its way to stigmatize a particular disease and separate parents from children, sisters from brothers, and people of all stripes from their work, travel and dreams of a better life," they add. "Actions matter," Kerry and Smith write, adding, "Leading by example in the fight against HIV/AIDS has left millions in the developing world grateful to America for our lifesaving help." It is "time we sent the same message by finally ending our needlessly discriminatory laws penalizing those with HIV/AIDS," the authors conclude (Kerry/Smith, Washington Times, 6/25).

Michael Mooney Speaks About Steroids in Deleted Scene from Bigger Stronger Faster

You can watch the video here:
http://www.mesomorphosis.com/blog/2008/06/14/hiv-activist-speaks-about-steroids-in-bigger-stronger-faster


Michael Mooney Speaks About Steroids in Deleted Scene from Bigger Stronger Faster
Posted on 02:26 June 14th, 2008 by Millard Baker

HIV activist Michael Mooney speaks about the therapeutic applications of testosterone and anabolic steroids for HIV wasting in a deleted scene from “Bigger Stronger Faster.” Mooney is the co-author of Built to Survive (along with Nelson Vergel) and wrote about steroids and HIV for the anabolic steroid and bodybuilding magazine Muscle Media 2000.

I still meet people who obviously have a serious problem with testosterone deficiency who have all the old AIDS symptoms and the doctor will not give them testosterone because their doctor is so afraid of the legal implications. Thousands of people have died because their doctor wouldn’t prescribe testosterone or anabolic steroids for their HIV.

Even though Mooney’s segment was regrettably not included in the final version of the film, Bigger Stronger Faster did include a very powerful segment with long-term HIV+ survivor Jeff Taylor about the life-saving medical applications of steroids. Al Benson wrote an excellent review of this segment for Nelson Vergel’s HIV Blog.

The angle I was most interested in was of course the application of these drugs to people living with AIDS, but I had not actually believed that it would be covered except in the most general way.

Was I wrong! About a half hour into the film , who should I see but the handsome, Smith Bros. bearded face of our friend and long term HIV survivor, Jeff Taylor.

Jeff spoke at length on two segments of his initial experience with the life saving effects of his steroid use, noting that he was able to rise up out of his death-bed, gain 30 pound in 6 weeks and gain 300 T-cells in the same 6 weeks.

[…]

I decided to question the director why they chose to spend so much time on ‘the Jeff Tailor segments”. And they said that they had read Built To Survive by Nelson Vergel and Michael Mooney and elaborated that Steroids were powerful lifesaving medications and that needed to be shown.

Please take the opportunity to check play dates for Bigger Stronger Faster and support this highly recommended steroid documentary.

Taking Care of Men

Taking Care of Men
Noted physician and author Frank Spinelli, who speaks in Houston this month, has plenty to say on gay men’s health.

By Nelson Vergel

Nelson Vergel, well-known local AIDS educator, advocate, and author, speaks to Frank Spinelli, M.D., by telephone, in advance of Spinelli's June 30 Houston appearance at an event hosted by Legacy Community Health Services. Spinelli, who maintains a private practice in the Chelsea neighborhood of New York City, is the author of the recently published Advocate Guide to Gay Men's Health and Wellness (Alyson) and writes a health column for Instinct , the gay man's answer to Cosmo.

Nelson Vergel: Could you give us a very brief background of who you are and what you do in New York?

Dr. Frank Spinelli: I've been living in the city for over 12 years. I'm from New York, originally. I'm a Brooklyn boy. And I was raised in Staten Island. I ended up in private practice in Manhattan, in New York, about eight years ago. So I've been in solo private practice in internal medicine with a sub-specialty of HIV in the gay community.

And what made you decide to write a book about gay men's health?

I've always wanted to write. I've always kept journals. Even when I was in practice, even in early periods, I would write into the local gay magazines. I would write in questions and answers, and see if they had many health columnists, and if they were interested, and how would I apply. They were very receptive. So I was attached to certain publications, like New York Blade and then HX. Then finally, I ended up with Instinct magazine, and I've been doing a Q&A for them.

Ultimately, I was feeling the same thing would keep coming up. It was these feelings of isolation and depression and loneliness. I thought, even though we are speaking now in 2008, it's amazing to me how we can still feel so isolated from our community, even being within our community. So I started to look beyond that and say, “What's going on? What are these key points that I want to address?” And that was internalized homophobia, HIV, and what that meant as a gay man. And why would gay men's health be different than men's health?

Nobody wants to talk about a few things that really concern gay men, especially aging gay men. In your book, you mention the higher suicide rates and depression and issues with GLBT youth. I really wonder what we can do as the older generation to mentor the younger generation of gay and lesbian and transgender youth to make their lives a little easier.

What I wanted to do is organize ourselves as a group and to reach out to the younger gay men, and even the older gay men, because we have a real big disparity there. The HIV epidemic really did inflict itself upon us, and it did wipe out a generation. There has been that devastation that occurred, and I think we're all kind of just wallowing in the aftermath of that. I want to say to the younger guys—because there are so many issues with complacency, where they think there [are] these new one-pill, once-a-day [treatments], and HIV is not so bad. They don't remember what the epidemic was like at the height of the epidemic. So you have to be able to address them without scaring them, because you don't want to become frightening. You want to attract your audience.

The other thing is how we deal with the older population, especially those over 50 who are breaking up with boyfriends and then going back and doing crystal meth or going back into the life of singlehood and dating. There are so many opportunities. I wanted to really explore them on a case-by-case basis. That's one of the things I'm going to do when I come to Houston. I really want to talk about these personal stories that I think are indicative of what's going on across the country.

You mention in your book that 800,000 men per year are raped or assaulted by their partner. I was really shocked by that number.
This week, I had a patient who had been attacked viciously outside his apartment, and he's in the ICU. He almost lost a kidney from being kicked and the result of what we thought was maybe a gay bashing . . . well, we researched further with the police and the investigators. We found out that it was his partner, his lover. Domestic violence—it still exists.

And you say it's very under-reported because of shame issues.


Because of shame and guilt of isolation. Because as gay men, we feel we don't have the cause to say, “Oh, I've been violated” or “I've been attacked.” There's a lot of disparity when we talk about men being attacked—like we should take care of ourselves. It's really sad, because men can be victimized, and that needs to be addressed, definitely.

Something that you also talk about a lot is our over-compulsion, our body consciousness. We get bombarded by the media — not only gays but straights, women, men — to consume more and then feel a lot more inadequate so we can consume more. How do we take care of our bodies while keeping the balance?

I was like a chubby kid when I was in school. I wasn't good at sports, and I hated to go to gym. So here I was, a gay kid. I was fat. I didn't want to go to school because I didn't want to have to play sports. . . . In the gay community, we do it to ourselves. It's like high school all over again. When I went to the bars, everybody was like, “Oh, you've got to be pretty. You've got to look good.” And I was thinking, Oh, my God. I gotta go to the gym! It comes right back down to your sense of self, who you are, and who you want to be in the community—and not just some image or some stereotype that's depicted on television, or to the camera in magazines.

You also address the sexual addiction and compulsion. We're always wondering, How much sex is too much sex? What is a healthy sexual appetite versus an unhealthy one? That's always a hot topic.

A healthy sexual appetite is great. I think sex is great. I recommend it highly. But I think anything can become an addiction when it interferes with your regular, routine life, when it just really becomes part of your routine and you cannot function without it. So when men are on the phone, texting men to arrange for sex, and they are not even talking to you at the table because they're arranging for sex afterwards, then there's a problem.

Sexual addiction speaks to something deeper. Is there underlying depression? Or is there isolation? There again, what is the void you're filling? We speak of the necessity to fill the void with sex or food or drugs or alcohol or smoking. The addictive potential for gay men is incumbent upon the fact that maybe they just feel really hollow inside because they don't accept who they are. So I wanted this to be an inspirational book for men to say, “We're gay and we should be very proud that we are here.” I hope that I put a face to gay men's health and we can just be here for one another.

In talking about meth addiction . . . I'm seeing a lot of problems not only in 20-somethings, but like you said, older gay men.

Oh, it's a huge concern. I'm going to actually speak at the Gay and Lesbian Center in New York next week. And we're talking about crystal meth. You know, crystal meth has not gone away. It's here. And it's actually very pervasive because of the way it's made and the fact of what it does to you. We talk about the effects it has on the reward system, and that it's like 50 times more powerful than cocaine. The addiction potential is so high, and what that leads to ultimately is unprotected sex and HIV. We don't talk about it enough. And I think it's like one of those things where we have to approach it in different ways, because it just gets tiresome—because everybody's like, Well, I don't want to talk about crystal meth anymore. But it still exists, and it's still around.

Something else I'm concerned about — because I've been working in the HIV field for a long time as an educator — the fact that we're still not talking enough about anal cancer, and issues with the human papilloma virus. People are not getting themselves checked. Fortunately, we now have two doctors now trained in Houston for anoscopies. Hopefully, you can talk to us about this when you come to Houston.

Yeah, well, who wants to talk about that? It's scary. I mean, I'm scared just to hear the word anus. Now, everybody is scared. You say the word anus —everybody runs. But you know what? We have got to talk about the anus. You have got to be in touch with your body. People think I'm crazy because I'm, like, You have to get a mirror. I grew up with women, so I feel very in touch with the feminine side. Do you remember in an episode of Sex and the City when they tell her [the character Charlotte] to look at her vagina in the mirror? I recommend that men look at their anuses in the mirror! Look at your body. You really have to know everything there is to know about your body.

If I had it my way, I'd have a bathroom with mirrors on every wall, so I can see everything that's going on, all over me. Because I want to know what's on my back, on my tushy, on my foot—everything. And instinctively, I examine myself all the time. But when you don't know what you're looking for, you're afraid and you ignore it. So how scary is it to find something going on in your butt? That would be frightening. So I just give in the book some tips on how to take care of yourself, because obviously this is being used as a sexual organ. We're not talking about it enough, but it is.

I don't think a lot of primary-care doctors are well-trained on doing Pap smears in men. Sometimes even the gay doctors don't want to deal with it. So it's kind of embarrassing and a problem that when it is diagnosed, it is usually in later stages that require chemotherapy or radiation.
Wait till I come to Houston with a big picture of an anus.

You are funny! Can't wait to listen to your lecture! Let me see what else I have here. Can you tell us more about what dysthymia means? Because I think a lot of us may be walking around with that underlying depression and not really know it.

I think there's a lot of underlying depression and anxiety across America period. People neglect to think that we're going through a war right now, and this has an effect on us, the economy, and everything. Add to the fact that you might be a minority, or gay, and how that influences your life, your decisions. It's a lot just to get up in the morning. That's tough.

I think addressing one's health is breaking it down into “How do I just find me? What works for me?” What I really wanted in this book was for someone to just look through it and say, “Look, I read this book and I have some questions.” That's what I wanted—to provoke a discussion between you and your doctor.

Frank Spinelli speaks on June 30, 6–8 p.m., at the Ensemble Theatre (3535 Main). There is no admission charge for the event, which is underwritten by Abbott Laboratories. Legacy will serve complimentary hors d'oeuvres, soft drinks, wine, and beer at the event.

Nelson Vergel is the co-author of Built to Survive! (with Michael Mooney) and edited the book How to Manage Side Effects, published by the Houston Buyers Club. He writes frequently on health and HIV/AIDS issues for the media, including for TheBody.com , the New York-based HIV information website. Vergel is the founder of PoWeR, the Program for Wellness Restoration, a nonprofit organization that provides educational information for HIV-positive people, and the founder and moderator of Yahoo.com PozHealthGroup, an HIV listserve.

Bigger, Stronger, Better

From Al Benson


Last night, my partner and I went to the film Bigger, Stronger, Better. The story of steroid use in America as refracted off the lives of an American family from Poughkeepsie ,NY. Its core belief is that steroid use is rampant in the US because it is an essential component of the American mentality of being a winner. It was a very well done documentary that surprised me by its open forthrightness in discussing the subject from every angle.

The science was correct and explained in a way that was useful to everyone watching, from the total indi/IFC buff to educated consumers like my partner and myself.

The angle I was most interested in was of course the application of these drugs to people living with AIDS, but I had not actually believed that it would be covered except in the most general way.

Was I wrong! About a half hour into the film , who should I see but the handsome, Smith Bros. bearded face of our friend and long term HIV survivor, Jeff Taylor.

Jeff spoke at length on two segments of his initial experience with the life saving effects of his steroid use, noting that he was able to rise up out of his death-bed, gain 30 pound in 6 weeks and gain 300 T-cells in the same 6 weeks.

Since we went on opening weekend, there was a Q&A with the 3 principle filmmakers. The crowd at the movie house was mainly indi types with a scattering of industry people. I thought it was odd that Tony and I were the only ‘big guys’ with the AIDS, there on opening Saturday Night.

I decided to question the director why they chose to spend so much time on ‘the Jeff Tailor segments”. And they said that they had read Built To Survive by Nelson Vergel and Michael Mooney and elaborated that Steroids were powerful lifesaving medications and that needed to be shown.

They eviscerated the congressional hearing and made Waxman look like a dottering idiot and Joe Biden look like an irrational angry man. Although, Joe Biden was the only actual congressman who attended the DC screening and said it was an excellent film.

I told them that they had made an excellent film and the only problem I say was the advertising for it. I had only known about the film from a conversation I had almost two years ago with somebody that they had interviewed and was lying on the cutting room floor, I guess.

In short it’s a film worth seeing, especially since it treats the issue of HIV and takes on some of the demonizing myths surrounding steroid use in America. Changes are that it will come to your town during the rollout, but you won’t hear about it, so you need to make the effort to search it out. It won’t be out in DVD for a long time so I recommend that everyone who can should make an effort to see it.

Al Benson

Buttock Wasting Options

I just wanted to let everyone know that a revised buttock wasting page is up at facialwasting.org

This is the only page out there that focuses on this undressed issue.

http://facialwasting.org/buttock_wasting.htm