Changes in the Incidence and Predictors of Wasting Syndrome Related to Human Immunodeficiency Virus Infection, 1987–1999

Ellen Smit1, Richard L. Skolasky2, Adrian S. Dobs3, Bridget C. Calhoun4, Barbara R. Visscher5, Frank J. Palella6 and Lisa P. Jacobson2

1 Department of Social and Preventive Medicine, School of Medicine and Biological Sciences, University at Buffalo, Buffalo, NY.
2 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
3 School of Medicine, Johns Hopkins University, Baltimore, MD.
4 Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
5 Schools of Public Health and Medicine, University of California, Los Angeles, CA.
6 Feinberg School of Medicine, Northwestern University, Evanston, IL.

Received for publication July 13, 2001; accepted for publication April 17, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The authors examined the impact of potent antiretroviral therapy (ART) on the diagnosis of wasting syndrome in the Multicenter AIDS Cohort Study. Study time was divided into the periods 1988–1990, 1991–1993, 1994–1995, and 1996–1999 to correspond to different treatment eras. The proportion of acquired immunodeficiency syndrome diagnoses in which wasting was present increased from 5% in 1988–1990 to 7.1% in 1991–1993, 7.7% in 1994–1995, and 18.9% in 1996–1999. The incidence of wasting per 1,000 person-years increased from 7.5 in 1988–1990 to 14.4 in 1991–1993 and 22.1 in 1994–1995; it decreased to 13.4 in 1996–1999. Fewer patients with wasting had low hemoglobin and hematocrit levels and reported oral thrush in 1996–1999 than in any other period. Analysis of change in body mass index (weight (kg)/height (m)2) after wasting showed a faster return to prewasting levels in 1994–1995 and 1996–1999 than in earlier periods. Case-control analysis showed that wasting prior to 1996 was weakly associated with fatigue (p = 0.10), low hemoglobin (p = 0.11), and CD4-positive T-lymphocyte count (p = 0.04). During 1996–1999, wasting was weakly associated with diarrhea (p = 0.05) and potent ART (p = 0.097). Predictors of wasting have changed with potent ART. Further research is needed to determine whether lipodystrophy may be misdiagnosed as wasting syndrome. Am J Epidemiol 2002;156:211–18.

acquired immunodeficiency syndrome; AIDS-related opportunistic infections; anti-HIV agents; body mass index; disease progression; HIV; HIV protease inhibitors; HIV wasting syndrome

Abbreviations: Abbreviations: AIDS, acquired immunodeficiency syndrome; ART, antiretroviral therapy; HIV, human immunodeficiency virus; NRTI, nucleoside reverse transcriptase inhibitor.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Current antiretroviral therapy (ART) has been very successful in improving the prognosis of persons infected with human immunodeficiency virus (HIV) (14). These potent treatment regimens have been shown to reduce the incidence of certain illnesses indicative of acquired immunodeficiency syndrome (AIDS), such as Kaposi’s sarcoma and other specific opportunistic infections (2, 3). They have also been effective in prolonging survival among persons with HIV type 1 (4, 5).

There are indicators that wasting syndrome, a condition diagnostic of AIDS, is still occurring in the United States, even with the availability of potent ART regimens. According to the Centers for Disease Control and Prevention, 7 percent of adults and adolescents diagnosed with AIDS had wasting syndrome as an AIDS indicator condition in 1997, and 8 percent had wasting in 1998 (6). These estimates may be conservative, since case reporting may be incomplete. It is not known whether individuals who develop wasting syndrome also use potent ART. In the past, wasting syndrome has been associated with poor survival (710). Thus, the persistence of wasting syndrome among users of potent ART would be of clinical concern.

Several studies on weight loss and wasting syndrome have provided data on predictors of wasting prior to the current era of potent ART (1113). Graham et al. (12) showed that ß2-microglobulin, fatigue, and anemia were early predictors of a 10 percent weight loss or a wasting diagnosis during the period 1985–1991. Lyles et al. (13) showed that higher HIV RNA levels were associated with an increased relative hazard of weight loss.

More information on the characteristics of patients with wasting syndrome is needed (14). This is particularly important for cases that occur while people are receiving treatment with potent ART. The objective of this investigation was to evaluate the impact of potent ART on wasting syndrome among patients in the Multicenter AIDS Cohort Study, a large, well-characterized cohort study. The incidence of wasting in various time periods defined by type of therapy was calculated, and characteristics associated with wasting before and after the introduction of potent ART were determined.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population and independent characteristics
The Multicenter AIDS Cohort Study is an ongoing cohort study of 5,622 homosexual and bisexual men at four US sites. A total of 4,954 men were enrolled in 1984–1985, and 668 were enrolled in 1987–1991. The study sites are located in Baltimore, Maryland; Chicago, Illinois; Los Angeles, California; and Pittsburgh, Pennsylvania. Details on the study’s design and baseline characteristics of the cohort are provided elsewhere (15). Briefly, participants return to a study center every 6 months for follow-up visits that include a detailed interview regarding medical history, health care utilization, and health behaviors, a physical examination (including venipuncture), and completion of self-administered questionnaires. Concomitant laboratory measurements include a complete blood cell count and differential cell counts. Determination of T-lymphocyte subsets is carried out using standardized flow cytometric methods (16).

Self-reported information on oral candidiasis, fatigue, diarrhea, and weight loss was obtained from the visit questionnaires. Baseline height was used along with body weights from subsequent visits to determine body mass index (weight (kg)/height (m)2). A variable on change in body mass index was constructed to reflect the mean change in body mass index per 6-month period between visits. It was calculated using linear regression techniques to model body mass index for visits taking place prior to and after the diagnosis of wasting syndrome. Use of ART was classified as follows: no treatment; monotherapy consisting of one nucleoside reverse transcriptase inhibitor (NRTI); combination therapy consisting of two or more NRTIs; and potent ART consisting of two or more NRTIs plus a protease inhibitor or non-NRTI (17).

Wasting syndrome
As part of the ongoing cohort study, men who are diagnosed with AIDS (as defined by the 1993 criteria of the Centers for Disease Control and Prevention (18)) are contacted at least every 3 months, in addition to their 6-month follow-up study visits, for collection of information on new or recent clinical events. Medical records are obtained and reviewed to confirm reports of AIDS, cancer, wasting, and other specific diagnoses. Wasting syndrome is defined as involuntary weight loss of more than 10 percent of baseline body weight plus either chronic diarrhea (at least two loose stools per day for 30 days or more) or chronic weakness and documented fever (for 30 days or more, intermittent or constant), in the absence of a concurrent illness or condition other than HIV infection that could explain the findings (e.g., cancer, tuberculosis, cryptosporidiosis, or other specific enteritis) (18). The date of diagnosis of wasting syndrome is defined as the actual date of diagnosis listed in the medical records.

For the present study, only cases of wasting syndrome that had developed since 1987 were included in the analysis. Prior to 1987, wasting was not considered definitive of AIDS by the Centers for Disease Control and Prevention. Therefore, men diagnosed with wasting earlier in the study were excluded from the risk population.

Study design
There were three components in this study. First, we examined the proportion of AIDS diagnoses over time in which wasting syndrome was an AIDS indicator condition. Calendar time was divided into four periods corresponding to the availability and use of different therapeutic regimens by the cohort: 1988–1990 (representing mostly NRTI monotherapy), 1991–1993 (representing the introduction of NRTI combination therapy), 1994–1995 (representing combination therapy and initiation of the newest potent ART), and 1996–1999 (representing potent ART) (4). Only men who developed an AIDS-defining opportunistic infection, malignancy, or wasting syndrome were included in the population for examination of proportionate morbidity.

Second, we examined the incidence of wasting syndrome over calendar time and compared characteristics of men diagnosed with wasting in the different time periods. All HIV-infected men without a prior diagnosis of wasting were considered to have been at risk for wasting since baseline (if HIV-seroprevalent since study entry) or since their date of seroconversion. Each individual contributed person-years to the analysis until January 1999, unless he developed wasting syndrome, died, or withdrew from the study prior to January 1999. In those cases, contributions to the number of person-years at risk stopped at the time the event occurred. Unless otherwise stated, information on such characteristics as weight, CD4-positive T-lymphocyte (CD4 cell) count, treatment, and self-reported symptoms was obtained from the prior study visit closest to and within 9 months of the actual date of wasting diagnosis.

Third, we sought to determine predictors of wasting among men developing AIDS, using a nested case-control design. Cases were defined as HIV-positive men diagnosed with wasting syndrome. Controls were selected from the HIV-positive men who developed an AIDS indicator condition other than wasting. Controls were matched to cases by AIDS-free time, such that the elapsed time to AIDS from either HIV infection (for seroconverters) or study entry (for the HIV-seroprevalent) was within 1 year of the case’s AIDS-free time. For cases who developed wasting syndrome subsequent to another AIDS-defining illness, the controls were also required to have survived their AIDS diagnosis for at least the amount of time the case took to develop wasting following AIDS. For cases who were HIV-seroprevalent upon enrollment in the Multicenter AIDS Cohort Study, a seroprevalent control was matched according to CD4 cell count (±50 cells/mm3) at the third visit. Cases and controls were compared with regard to factors assessed at the prior visit closest to and within 9 months of AIDS diagnosis.

Statistical analysis
The incidence of wasting was calculated as the number of new cases per 1,000 person-years of observation in each time period. Participants were considered to have been at risk for wasting starting in January 1988 (for HIV-seroprevalent men recruited during 1984–1985), at the baseline visit (for HIV-seroprevalent men recruited during 1987–1991), or on the date of seroconversion (for HIV seroconverters). Poisson regression was used to model the incidence of wasting and to determine the significance of the observed trends. Box plots were used to graphically illustrate contrasts between wasting cases with regard to change in body mass index and other characteristics associated with wasting. Nonparametric one-way analysis of variance and {chi}2 tests were used to test for significant differences.

For the nested case-control study, conditional logistic regression was used to evaluate determinants of wasting. Separate models were constructed according to calendar time. Subsequently, we incorporated factors found to be associated with wasting in univariate analysis into multivariate models to assess whether the association was independent and remained significant (p < 0.05). Only the results from the final models are presented here.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Incidence of wasting syndrome
Between 1988 and 1999, 170 cases of wasting syndrome developed among the 2,502 HIV-infected study participants who were free of wasting as of January 1988. The percentage of AIDS diagnoses attributed to wasting syndrome increased from 5 percent during the period 1988–1990 to 7.1 percent in 1991–1993, 7.7 percent in 1994–1995, and 18.9 percent in 1996–1999. As figure 1 shows, the incidence of wasting syndrome per 1,000 person-years increased consistently from 1988–1990 to the most recent time period (1996–1999), when it decreased to 13.4 per 1,000 person-years (p = 0.06).



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FIGURE 1. Incidence of wasting syndrome among homosexual and bisexual men, by calendar time (per 1,000 person-years), Multicenter AIDS Cohort Study, 1988–1999. Bars, 95% confidence interval.

 
Characteristics of men with wasting syndrome as assessed within 9 months prior to the time of diagnosis are shown in table 1. The increased use of potent ART by calendar time was expected and is consistent with reported use by the underlying cohort (4). With regard to clinical immune status, the cases diagnosed in the most recent study period (1996–1999) appeared to be less compromised than the cases diagnosed earlier (prior to 1996). In comparison with the wasting cases diagnosed prior to 1996, the rate of CD4 cell loss prior to AIDS was lower (p = 0.001) in the 1996–1999 time period, and the mean CD4 cell count prior to wasting diagnosis was higher, though not statistically significant (p > 0.05). Smaller proportions of the wasting cases had a low hemoglobin (<140 g/dl) or hematocrit (<40 percent) level in 1996–1999 than in any other time period. Weight loss of more than 10 pounds (>4.5 kg) was reported less often in 1996–1999 than prior to 1996, although this difference did not reach statistical significance. Similarly, the proportions reporting fatigue and oral thrush were lower in 1996–1999 than in the earlier time periods, with data reaching statistical significance only for oral thrush. In contrast, the reporting of diarrhea was similar or slightly higher in 1996–1999 than in the 1991–1993 and 1994–1995 time periods.


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TABLE 1. Characteristics of human immunodeficiency virus-positive men with a diagnosis of wasting, according to time period of wasting diagnosis, Multicenter AIDS Cohort Study, 1988–1999
 
Although there were differences in self-reported weight loss, mean body mass indices for the cases were similar across the time periods. To examine changes in body mass index before and after a diagnosis of wasting syndrome, we calculated change in body mass index before and after diagnosis. Figure 2 shows the changes in body mass index for each diagnostic calendar period. Time zero (x-axis) reflects the 6-month period between the visit prior to wasting diagnosis and the visit after wasting diagnosis. A body mass index change of zero (y-axis) reflects the initial body mass index; thus, a value of –2 on the y-axis reflects a decrease in body mass index of 2 units. The change (decrease) in body mass index before wasting was lower in the 1996–1999 period than in earlier time periods, though not significantly. After diagnosis of wasting syndrome, the change (increase) in body mass index differed by time period (p = 0.05), with greater increases being seen in 1994–1995 and 1996–1999 than in earlier periods.



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FIGURE 2. Change in body mass index (weight (kg)/height (m)2) among homosexual and bisexual men before and after diagnosis of wasting syndrome, by calendar time, Multicenter AIDS Cohort Study, 1988–1999.

 
Predictors of wasting syndrome
To examine predictors of wasting as compared with the development of other AIDS-defining illnesses, we matched 131 cases to 131 controls. Although 170 cases of wasting were initially identified, 39 matched pairs were excluded because either the case or the control lacked data from a visit that had taken place within 9 months of and prior to the AIDS diagnosis.

The results of the univariate analysis are shown in table 2. Across all time periods, the cases with wasting were more likely to have a lower body mass index than the controls. When we collapsed the time periods to increase statistical power, the overall odds ratio was 0.87 (p = 0.007). Men with wasting were also more likely than controls to have a lower CD4 cell count at diagnosis (overall odds ratio = 0.94, p = 0.004). For other HIV-related symptoms, there appeared to be heterogeneity by year of diagnosis. More of the men with the most recently diagnosed cases (1996–1999) reported having diarrhea prior to AIDS than the men diagnosed with other AIDS-defining conditions in the same time period. There was a nonsignificant (p = 0.097) association of wasting syndrome with use of potent ART in 1996–1999, with 38 percent of the cases reporting prior use of potent ART versus 17 percent of their matched controls. Thus, univariately, predictors of wasting syndrome in all time periods included lower body mass index and lower CD4 cell count. In the 1996–1999 time period, diarrhea was an additional predictor.


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TABLE 2. Predictors of wasting syndrome in univariate analyses comparing cases with a diagnosis of wasting with controls with another diagnosis indicative of acquired immunodeficiency syndrome,* Multicenter AIDS Cohort Study, 1988–1999
 
Because of similar univariate trends in 1988–1990, 1991–1993, and 1994–1995, we combined these time periods for the multivariate analysis. Table 3 shows results from the final multivariate model for each time period. Each model was limited to those factors found to contribute to the model (for 1988–1995, covariates were fatigue, low hemoglobin level, and CD4 cell count; for 1996–1999, covariates were diarrhea and potent ART). Wasting syndrome prior to 1996 was weakly associated with symptoms of more advanced HIV disease, including fatigue (p = 0.10), low hemoglobin level (p = 0.11), and lower CD4 cell count (p = 0.04). There was no independent association with any of these symptoms after 1996. Thus, predictors of wasting syndrome based on multivariate analysis for the 1988–1995 time period, though weak, included fatigue, low hemoglobin level, and CD4 cell count. In the 1996–1999 time period, predictors of wasting included diarrhea (p = 0.05) and potent ART (p = 0.097). An examination of predictors of wasting using data from the visit approximately 2 years prior to wasting diagnosis showed no significant associations across any of the time periods (data not shown).


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TABLE 3. Predictors of wasting syndrome in multivariate analyses comparing cases with a diagnosis of wasting with controls with another diagnosis indicative of acquired immunodeficiency syndrome,* Multicenter AIDS Cohort Study, 1988–1999{dagger}
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this analysis, we assessed changes in characteristics associated with wasting syndrome over calendar time in a large cohort of homosexual and bisexual men. Wasting syndrome as a proportion of all AIDS diagnoses more than doubled during the 1996–1999 time period in comparison with all previous time periods. The incidence of wasting increased until 1994–1995 and decreased somewhat thereafter. Although Moore and Chaisson (3) did not find a significant change in the incidence of wasting, the trend was similar to our findings: They reported the incidence of wasting per 1,000 person-years to be 12 in 1994, 14 in 1996, and 11 in 1998. Mocroft et al. (2) also found an increase in the incidence of wasting between 1992–1993 (12/1,000 person-years) and 1994–1996 (30–32/1,000 person-years), with a subsequent decrease in 1997 (4/1,000 person-years). Despite the decrease in the incidence of wasting syndrome, clearly it is still being diagnosed, and its diagnosis has increased as a proportion of all AIDS-related outcomes.

Characteristics of persons diagnosed with wasting syndrome have changed over calendar time. Men who were diagnosed in 1996–1999 had higher CD4 cell counts than men diagnosed during the previous time periods; fewer had a low hemoglobin or hematocrit level; and fewer reported having symptoms related to wasting, including fatigue, oral thrush, and weight loss. In contrast, a similar proportion reported diarrhea in 1996–1999 as in the previous time periods. Thus, all symptoms are still being reported in the era of potent ART, but at a lower rate. Diarrhea continues to be reported at a similar rate as before the introduction of potent ART, which suggests that it has an ongoing role in current wasting syndrome.

Trends in body mass index prior to wasting showed a slower decrease in 1996–1999 than in all other diagnosis years. Postwasting body mass index trajectories showed a faster return to prewasting levels in 1994–1995 and 1996–1999 than in earlier time periods. These body mass index trends and characteristics suggest that the men diagnosed with wasting syndrome more recently are less immunocompromised than men diagnosed earlier. The more rapid improvement in body mass index following wasting may also represent general health benefits derived from potent ART.

When we examined factors associated with wasting given an AIDS diagnosis using a nested case-control approach, we noted that symptoms such as fatigue, oral thrush, low hemoglobin level, and lower body mass index were associated with the development of wasting prior to the era of potent ART. With the introduction of potent ART, only diarrhea was reported more often by men with wasting than by men diagnosed with other AIDS illnesses. These results also indicate that more recently diagnosed wasting cases do not reflect a lack of potent ART use. This is in agreement with the results of Wanke et al. (19), who found that weight loss and wasting occurred in patients using potent ART as well as in patients not using potent ART.

Lyles et al. (13) reported on the possible relation between viral load and wasting. We examined viral load at the baseline visit and found no association with wasting (data not shown). We currently do not have viral load measurements for visits occurring prior to and within 2 years of wasting diagnosis, and thus we cannot assess the importance of more recent viral load measurements at this time.

Differences in predictors of wasting before and during the era of potent ART suggest a difference in either mechanisms of wasting or definitions used in the diagnosis of wasting, or both. Suggested mechanisms of the development of wasting syndrome include increased metabolic rate, abnormal protein and lipid metabolism (14, 20, 21), decreased food intake, alteration in metabolic hormones, increased production of cytokines (e.g., tumor necrosis factor {alpha}) (2225), and change in small intestinal mucosa (26). We did not collect information on dietary intake and metabolic rate, and thus we could not determine the impact of those factors. Oral candidiasis can cause difficulties with chewing or swallowing, a decrease in food intake, and a subsequent negative energy balance. We found an association between oral thrush and wasting in the era before potent ART but not in the era of potent ART. Diarrhea was not associated with wasting in the pre-potent-ART era, yet in the potent-ART era it was positively associated with wasting, possibly as a side effect of ART treatment. If diarrhea were associated with wasting independently of treatment, we would have expected to see an association of diarrhea with wasting syndrome in both the pre-potent-ART and potent-ART time periods. Since we found an association between diarrhea and wasting syndrome only in the potent-ART era, it may be that some wasting cases in the current era result indirectly from the use of HIV treatments.

We found an association between potent ART and wasting syndrome. Recent studies have reported changes in body habitus associated with potent ART use, including thinning of the arms and legs, sunken cheeks, an increase in the size of the abdomen, and development of a dorsocervical fat pad—signs often collectively referred to as lipodystrophy (2729). Perhaps some individuals with lipodystrophy-like symptoms are being misdiagnosed with wasting syndrome.

In summary, predictors of wasting that were considered reliable during the pre-potent-ART era may no longer be exclusive predictors of wasting. Studies on wasting syndrome should include detailed body composition measurements, biochemical measures, and dietary intake assessments. Using these tools, researchers should focus on changes in predictors of wasting in the potent-ART era and evaluate the possibility of lipodystrophy syndrome’s being misdiagnosed as wasting syndrome.


    ACKNOWLEDGMENTS
 
The Multicenter AIDS Cohort Study includes the following centers and investigators: Baltimore, Maryland—Johns Hopkins Bloomberg School of Public Health: Joseph B. Margolick (Principal Investigator), Haroutune Armenian, Barbara Crain, Adrian Dobs, Homayoon Farzadegan, Nancy Kass, Shenghan Lai, Justin McArthur, Steffanie Strathdee, and Ellen Taylor; Chicago, Illinois—Howard Brown Health Center and Northwestern University Feinberg School of Medicine: John P. Phair (Principal Investigator), Joan S. Chmiel, Bruce Cohen, Maurice O’Gorman, Daina Variakojis, and Steven M. Wolinsky; Los Angeles, California—University of California Schools of Public Health and Medicine: Roger Detels and Beth Jamieson (Principal Investigators), Barbara R. Visscher (Co-Principal Investigator), Anthony Butch, John Fahey, Otoniel Martínez-Maza, Eric N. Miller, John Oishi, Paul Satz, Elyse Singer, Harry Vinters, Otto Yang, and Stephen Young; Pittsburgh, Pennsylvania—University of Pittsburgh Graduate School of Public Health: Charles R. Rinaldo (Principal Investigator), Lawrence Kingsley (Co-Principal Investigator), James T. Becker, Phalguni Gupta, John Mellors, Sharon Riddler, and Anthony Silvestre; Data Coordinating Center—Johns Hopkins Bloomberg School of Public Health: Alvaro Muñoz (Principal Investigator), Lisa P. Jacobson (Co-Principal Investigator), Linda Ahdieh, Stephen Cole, Stephen Gange, Cynthia Kleeberger, Steven Piantadosi, Ellen Smit, Sol Su, and Patrick Tarwater; National Institutes of Health, Bethesda, Maryland—National Institute of Allergy and Infectious Diseases: Carolyn Williams and Paolo Miotti; National Cancer Institute: Sandra Melnick.

The Multicenter AIDS Cohort Study website is located at http://www.statepi.jhsph.edu/macs/macs.html.


    NOTES
 
Correspondence to Dr. Ellen Smit, 273 Farber Hall, School of Medicine and Biological Sciences, University at Buffalo, 3435 Main Street, Buffalo, NY 14214–3000 (e-mail: esmit{at}buffalo.edu). Back


    REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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