Monthly Archives - July 2008

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.

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

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 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.

Mortality Down 94% in HIV Among Diagnosed


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…”


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.


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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.


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