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Epidemiology and Social: CONCISE COMMUNICATION

Effect of tuberculosis on the survival of HIV-infected men in a country with low tuberculosis incidence

López-Gatell, Hugoa; Cole, Stephen Rb; Margolick, Joseph Bc; Witt, Mallory Dd; Martinson, Jeremye; Phair, John Pf; Jacobson, Lisa Pb

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doi: 10.1097/QAD.0b013e32830e010c
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Abstract

Evidence regarding the effects of tuberculosis disease (TB) on the progression of HIV disease at the population level remains inconclusive [1]. An inverse-variance-weighted pooled estimate of data on 22 296 HIV-infected men and women with 11 044 deaths in eight papers published during the last decade [2–9] suggests that TB is associated with a slight increase in the risk of death of HIV-infected individuals, with a summary relative risk of 1.1 [95% confidence interval (CI): 1.0–1.2]. However, the analytical approaches used in those studies may have underestimated a harmful effect of TB on mortality [10]. Specifically, controlling confounding due to HIV stage by stratifying on time-varying markers of immunosuppression, such as CD4 cell count [7–9], may have provided, at best, only estimates of the effects of TB on mortality that are not mediated through such markers. Using appropriate analytic methods [11,12] that allow estimation of direct and indirect effects, we recently reported a four-fold increase in mortality associated with TB in HIV-infected women [10]. Here we estimate the effect of incident pulmonary and extra-pulmonary TB on AIDS-related mortality in a large prospective cohort of HIV-infected men.

Methods

Study population

The Multicenter AIDS Cohort Study (MACS) [13] is an ongoing prospective study of HIV-1 infection among men in four US cities: Baltimore/Washington DC, Chicago, Pittsburgh, and Los Angeles. Beginning in 1984, the MACS enrolled 2884 HIV-1 seropositive and 4089 HIV-1 seronegative homosexual men, 622 of whom subsequently seroconverted. Participants undergo semiannual physical examinations and provide specimens for laboratory measurements, including lymphocyte subset counts by flow cytometry at laboratories certified by the National Institute of Allergy and Infectious Diseases (NIAID) [14] and plasma HIV-1 RNA viral load by reverse transcriptase-polymerase chain reaction (Roche Molecular Systems, Branchburg, New Jersey, USA) with a lower limit of detection of 50 copies/ml. Participants also respond to interviewer-administered questionnaires about medical history and healthcare utilization, including use of antiretroviral therapy (ART). The present study is limited to 2882 (82%) of the 3506 (2884 + 622) MACS participants who were HIV infected by November 2005. Excluded were HIV-infected men with incomplete data for the variables of interest at study entry (n = 163, 5%), a history of TB at study entry (n = 4, <1%), and those with only a single study visit (n = 457, 13%).

Endpoint ascertainment

Men were followed from the first MACS semiannual visit at which they were HIV infected (hereafter known as study entry) until the first of death, dropout, or the date of analysis on 5 November 2005. Follow-up methods used in the MACS to ascertain vital status have been described elsewhere [15]. The endpoint of interest was AIDS-related mortality. Deaths were classified as AIDS-related if a cause listed on the death certificate was an AIDS-defining condition (ADC) according to the 1993 CDC classification system for HIV infection [16] or ‘AIDS’ or ‘HIV’ was listed as a cause, without further specification.

Assessment of tuberculosis

The exposure of interest was confirmed incident TB; defined as the first self-report of pulmonary or extra-pulmonary TB at any semiannual visit 6 months beyond study entry, confirmed by culture, cytology, or clinical or radiological assessment. Incident TB was modeled as a time-varying binary indicator that was set to zero for all men at study entry and changed to one after the onset of TB.

Assessment of covariates

Age, CD4 cell count, and viral load at study entry were modeled as time-fixed continuous covariates; white ethnicity was modeled as a time-fixed binary indicator. During follow-up, CD4 cell count and nadir, as well as viral load and peak, were modeled as time-varying continuous covariates. Also during follow-up, time-varying binary indicators were created for anti-Pneumocystis jiroveci pneumonia (PCP) prophylaxis (i.e., trimethoprim, co-trimoxazole, dapsone, or aerosolized pentamidine), use of ART, HIV-related symptoms (i.e., persistent fever or night sweats), incident PCP, incident Mycobacterium avium complex disease (MAC), and the remaining clinical ADCs excluding TB, PCP, and MAC. To assure a correct time sequence, all time-varying covariates were lagged one visit and therefore measured before TB onset. To allow a flexible (e.g., curvilinear) relation between continuous covariates and incident TB, censoring, and mortality, we used restricted cubic splines with knots at the 5th, 35th, 65th, and 95th percentiles.

Statistical analysis

In the presence of time-varying confounders affected by previous TB, conventional methods (i.e., stratification or regression) may at best provide an estimate of the direct, rather than the total, effect of TB on mortality. In particular, TB may induce faster HIV replication [17] or subsequent reductions in CD4 cell counts [18], which, in turn, predict higher mortality [19] and also, lower CD4 cell counts or higher HIV RNA levels predict TB. As in women [10], we used a marginal structural Cox proportional hazards model, which appropriately controls for time-varying confounding by weighting each person's person-time contribution proportionally to the inverse probability of his observed incident TB status, estimated as a function of the history of time-varying covariates [11,20]. Assuming no unmeasured confounding, no informative censoring, and no model misspecification, this method allows estimation of the total effect of TB on mortality. The marginal structural model included as time-fixed regressors: white ethnicity, study entry date, age, CD4 cell count, and viral load; as well as time-varying regressors: incident TB and follow-up time. The inverse probability weights were stabilized and taken as the product of incident TB and censoring weights [11,21]. Inverse probability-of-incident-TB weights were estimated using time-fixed regressors: white ethnicity, study entry date, and CD4 cell count; as well as time-varying regressors: CD4 cell count, CD4 nadir, log10 viral load, peak viral load, PCP, anti-PCP prophylaxis, other ADC, HIV symptoms, and follow-up time. Inverse probability-of-censoring weights were estimated using time-fixed regressors: white ethnicity, study entry date, CD4 cell count, log10 viral load, ART, and PCP-prophylaxis; as well as time-varying regressors: incident TB, CD4 cell count, log10 viral load, PCP, MAC, other ADC, HIV symptoms, and follow-up time. The mean (SD) of the final weights was 1.00 (0.10). To ameliorate the impact of extremely influential values, weights were censored at the 1st and 99th percentiles, namely, 0.64 and 1.6, respectively [22].

The effect of TB on mortality was measured by the hazard ratio, and the 95% CI was used as a measure of precision. Robust CI [23] was used for the marginal structural model [21]. Neither a plot of log–log survival by time nor an interaction between incident TB and follow-up time (robust P for homogeneity = 0.86) suggested a strong departure from the proportional hazards assumption. Analyses were performed with SAS version 9 (SAS Institute, Cary, North Carolina, USA).

Results

At study entry, the 2882 HIV-1-infected men had a median age of 35 years [interquartile range (IQR): 31–41], 71% were white, 17% African–American, and 10% Hispanic. Median calendar year was 1985 (IQR: 1985–1988), median CD4 cell count was 533 cells/μl (IQR: 365–737), and median viral load was 12 953 copies/ml (IQR: 2453–48 540) (Table 1). Of the 2882 men, 2201 (76%) entered into the analysis before 1 January 1996, the date when highly active ART became widely available.

T1-22
Table 1:
Characteristics of 2882 HIV-infected men at study entry and averaged over a median of 5.4 years of follow-up.

During follow-up, 0.5% (15 of 2882) incurred incident TB, yielding an incident TB rate of seven (95% CI: 4–14) per 10 000 person-years. Culture or cytology confirmed 12 of 15 TB reports and either radiological or clinical criteria confirmed the remaining three; 10 TB reports were pulmonary and five were extra-pulmonary.

Accounting for ethnicity, calendar year, CD4 cell count, and viral load at study entry, the average CD4 cell count over follow-up was 341 cells/μl for the person-time with TB and 471 cells/μl for the person-time without TB; Δ = 130 cells/μl (95% CI: 68–192). The average viral load over follow-up was 4.5 log10 copies/ml for the person-time with TB and 3.8 log10 copies/ml for the person-time without TB; Δ = 0.76 log10 copies/ml (95% CI: 0.39–1.1). Presence of HIV-related symptoms (hazard ratio = 3.6; 95% CI: 1.0–13), PCP (hazard ratio = 1.9; 95% CI: 0.5–7.1), or anti-PCP prophylaxis (hazard ratio = 3.5; 95% CI: 0.9–15) were each associated with incident TB.

From November 1984 to November 2005, the 2882 men were followed for a median of 5.4 years (IQR: 2.4–11). Of the 2882 men, 1202 (42%) died and 502 (17%) were lost to follow-up before the date of analysis. Twelve of 15 men with TB died, all from AIDS-related causes. Among the 1190 deaths occurring in 2867 men without TB, 1060 were from AIDS-related causes other than TB.

In the marginal structural model (which accounts for the confounding variables listed in the methods and footnote of Table 2), the hazard of AIDS-related death was 2.4 times (95% CI: 1.2–4.7) more for the person-time with TB compared with the person-time without incident TB (Table 2). Adjustment for the same set of time-fixed and time-varying covariates using a standard Cox proportional hazards model yielded a hazard ratio for AIDS-related mortality of 1.3 (95% CI: 0.6–2.5), which is similar to the summary of prior evidence, whereas standard adjustment for only time-fixed covariates yielded a hazard ratio of 3.0 (95% CI: 1.6–5.9).

T2-22
Table 2:
Effect of incident tuberculosis on all-cause mortality among 2882 HIV-infected men followed for a median of 5.4 years.

Discussion

In this prospective study of 2882 HIV-1-infected men, we estimated incident TB to be associated with more than a two-fold increase in the hazard of AIDS-related mortality. This finding is in contrast to a summary hazard ratio of 1.1 based on prior evidence [2–9]. However, using statistical methods similar to those used in prior work, we also produced a hazard ratio of 1.3, which we believe is an underestimate of the true association due to over-control for biomarkers on the pathway between TB and mortality. Moreover, prior work treating TB and covariates as time-fixed in analyses [3,7,8] has borne out a positive association between TB and mortality; we also replicate this result but believe that the three-fold hazard ratio overestimates the true association because of uncontrolled time-varying confounding. Our primary result of greater than a two-fold association does not block pathways between TB and mortality nor does it allow uncontrolled time-varying confounding by measured variables.

We previously reported a four-fold increase in the hazard of AIDS-related death (95% CI: 1.2–14) associated with TB among HIV-1-infected women [10]. Here, in men, we found TB is associated with a 2.4 times (95% CI: 1.2–4.7) increase in the hazard of AIDS-related death. This is 40% (1–2.4/4) smaller than the hazard ratio reported for women, but the fact that each CI overlaps to include the other hazard ratio [24] cautions against over-interpreting this difference. Assuming that random error explains the difference in the two hazard ratios, the resultant inverse-variance-weighted average of hazard ratio for AIDS-related mortality is 2.7 times greater (95% CI: 1.5–4.9) with incident TB in HIV-1-infected men and women.

The present work has limitations. First, we could not examine whether highly active ART modifies the effect of incident TB on mortality because only three men incurred TB during the era of highly active ART. Second, the small number of men who incurred TB precluded the determination of whether CD4 cell count at study entry modifies the effect of incident TB on mortality [8]. Third, as with all observational studies, it is possible that unmeasured or residual confounding exists. Specifically, rather than a cause of mortality, incident TB may be a surrogate for immune suppression not captured by CD4 cell count and viral load, or a marker of social or behavioral conditions that predispose to increased mortality. In such a scenario, intervening on TB would not decrease subsequent mortality.

The strengths of this work include relatively modest attrition given 21 years of follow-up and comprehensive use of active and passive methods for determining vital status, making emigrative selection bias and information bias due to misclassification of endpoints, respectively, unlikely explanations for the findings. Additionally, serial collection of blood specimens allowed longitudinal control for markers of HIV disease progression. In conclusion, among these HIV-1-infected men, incident TB was associated with more than a two-fold increase in the hazard of AIDS-related mortality. Assuming a causal association, these results underscore the importance of avoiding TB by using preventive interventions such as treatment of latent TB infection, particularly in populations like those in sub-Saharan Africa, with a large prevalence of HIV/TB co-infected individuals.

Acknowledgement

All coauthors provided input to the design and analysis; Lopez-Gatell and Cole conducted analysis and drafted the manuscript; all coauthors provided input to the revision of the manuscript.

The Multicenter AIDS Cohort Study includes the following: Baltimore: The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick (Principal Investigator), Haroutune Armenian, Barbara Crain, Adrian Dobs, Homayoon Farzadegan, Joel Gallant, John Hylton, Lisette Johnson, Shenghan Lai, Ned Sacktor, Ola Selnes, James Shepard, Chloe Thio. Chicago: Howard Brown Health Center, Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: John P. Phair (Principal Investigator), Joan S. Chmiel (Co-Principal Investigator), Sheila Badri, Bruce Cohen, Craig Conover, Maurice O'Gorman, David Ostrow, Frank Palella, Daina Variakojis, Steven M. Wolinsky. Los Angeles: University of California, UCLA Schools of Public Health and Medicine: Roger Detels (Principal Investigator), Barbara R. Visscher (Co-Principal Investigator), Aaron Aronow, Robert Bolan, Elizabeth Breen, Anthony Butch, Thomas Coates, Rita Effros, John Fahey, Beth Jamieson, Otoniel Martínez-Maza, Eric N. Miller, John Oishi, Paul Satz, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, Zuo Feng Zhang. Pittsburgh: University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (Principal Investigator), Lawrence Kingsley (Co-Principal Investigator), James T. Becker, Robert W. Evans, John Mellors, Sharon Riddler, Anthony Silvestre. Data Coordinating Center: The Johns Hopkins University Bloomberg School of Public Health: Lisa P. Jacobson (Principal Investigator), Alvaro Muñoz (Co-Principal Investigator), Stephen R. Cole, Christopher Cox, Gypsyamber D'Souza, Stephen J. Gange, Janet Schollenberger, Eric C. Seaberg, Sol Su. NIH: National Institute of Allergy and Infectious Diseases: Robin E. Huebner; National Cancer Institute: Geraldina Dominguez; National Heart, Lung and Blood Institute: Cheryl McDonald. UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041. Website located at http://www.statepi.jhsph.edu/macs/macs.html.

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Keywords:

models; mortality; Multicenter AIDS Cohort Study; opportunistic infections; tuberculosis

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