JAIDS Journal of Acquired Immune Deficiency Syndromes:
Increased Body Mass Index Does Not Alter Response to Initial Highly Active Antiretroviral Therapy in HIV-1-Infected Patients
Tedaldi, Ellen M. MD*; Brooks, John T. MD†; Weidle, Paul J. PharmD, MPH†; Richardson, James T. BA‡; Baker, Rose K. MS, MSHyg‡; Buchacz, Kate PhD†; Moorman, Anne C. BSN, MPH†; Wood, Kathleen C. BSN‡; Holmberg, Scott D. MD, MPH†; and The HOPS Investigators
From the *Temple University School of Medicine, Philadelphia, PA; †Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA; and ‡Cerner Corporation, Vienna, VA.
Received for publication February 9, 2006; accepted June 15, 2006.
The investigation followed the guidelines of the US Department of Health and Human Services regarding the protection of human subjects. The study protocol was approved and renewed annually by each participating institution's ethical review board. All study participants provided written, informed consent.
This work was supported by Centers for Disease Control and Prevention (contract no. 200-2001-00133).
Dr Tedaldi has received research funding from Pfizer Inc, GlaxoSmithKline, and Merck & Co, Inc.
The other authors have no conflicts of interest.
Preliminary results of this research have been presented as a poster at the 3rd International AIDS Society Conference, July 24-27, 2005, Rio de Janeiro, Brazil.
The findings and conclusions from this review are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Dr Holmberg is now with Research Triangle Institute, Atlanta, GA.
Reprints: Ellen M. Tedaldi, MD, Professor of Medicine, Temple University Hospital, General Internal Medicine, 1st Floor, Jones Hall, 1316 West Ontario St, Philadelphia, PA 19140 (e-mail: firstname.lastname@example.org).
Background: Body mass index (BMI) can influence drug metabolism, thus affecting efficacy and risk for toxicities. Hypothesizing that persons with an increased BMI and larger volumes of distribution may experience a suboptimal response to highly active antiretroviral therapy (HAART), we evaluated the effect of BMI on virologic and immunologic response in previously ART-naive patients initiating therapy.
Methods: Using data from the HIV Outpatient Study, we analyzed the statistical association of BMI and other selected demographic variables with achieving an undetectable viral load and experiencing a CD4 cell count increase of more than 100 cell/μL after 3 to 9 months of therapy among antiretroviral-naive patients initiating HAART.
Results: Among 711 patients included in analysis, 43% had a BMI of more than 25 (overweight-obese). Higher BMI was associated with being female, having black or Hispanic race/ethnicity, being heterosexual, and using injection drugs (all P < 0.001). The patients in BMI groups did not differ significantly by baseline CD4 cell count or the duration of the initial HAART regimen. Although median baseline viral loads were significantly lower in obese participants (P = 0.008), overweight or obese BMI did not significantly alter the likelihood of achieving an undetectable viral load and a CD4 cell count increase of more than 100 cells/μL compared with normal weight persons.
Conclusion: A substantial proportion of HIV-infected outpatients in this cohort were overweight or obese. Increased BMI was not associated with decreased virologic and immunologic responses to initial HAART. Responses were equivalent and within expected ranges between normal weight patients, overweight patients, and obese patients at 3 to 9 months of observation.
The influence of body mass index (BMI) on the virologic and immunologic response to antiretroviral treatment in HIV-1-infected persons is largely unknown. Overweight/obese BMI has been independently associated with delayed progression of HIV disease, but these reports have focused on antiretroviral-naive patients not receiving therapy.1-3 Differences in BMI can alter the volumes of drug distribution in tissue compartments and result in variable levels of drug exposure.4 A small number of studies have shown that in the case of some antiretrovirals, persons with larger body size given standard doses experienced decreased drug exposures.5-8 Treating overweight/obese patients with antiretrovirals at dosages recommended for normal weight patients could thus lead theoretically to suboptimal therapy manifest clinically as a slower, less vigorous virologic, and immunologic response to initiation of highly active antiretroviral therapy (HAART). Only 2 of the currently approved antiretroviral medications in the United States, stavudine (d4T) and didanosine (ddI), have dosing adjustments based on weight; the adjustment is a decrease to account for low weight.9 No recommendations exist to adjust doses of antiretrovirals based on increased weight. In the present study, we have sought to describe the relationship between BMI and the immune and virologic response to initial antiretroviral therapy, hypothesizing that overweight/obese patients may experience an inferior response to initial HAART compared with normal weight patients.
The HIV Outpatient Study (HOPS) is an ongoing prospective observational cohort of HIV-infected patients seen at 10 HIV specialty clinics in 7 US cities: Tampa, FL; Washington, DC, Oakland, CA; Denver, CO, Chicago, IL, Stony Brook, NY; and Philadelphia, PA.10,11 Since 1993, more than 7800 patients have been enrolled and observed at more than 227,000 visits, contributing 26,671 person-years of observation. The present analysis is based on patients seen from January 1996 through December 2004. Data were abstracted from patients' medical records and entered directly into an electronic database by trained abstractors. Abstracted information includes basic demographics, risk factors for HIV infection, and all symptoms, diagnoses, medications, and laboratory results. The data were compiled centrally, regularly controlled for quality, and updated monthly. All enrollees signed written informed consent, and the study protocol was reviewed annually by all participating institutions' ethical review boards.
We included antiretroviral-naive patients initiating HAART who had at least 6 months of follow-up observation while on treatment. Highly active antiretroviral therapy was defined as prescription of at least 3 antiretrovirals that included at least 1 protease inhibitor (PI) and/or a nonnucleoside reverse transcriptase inhibitor (NNRTI), 3 nucleoside analogue reverse transcriptase inhibitors (NRTI) that included abacavir, or 2 full-dose PIs. Patient age was determined at the start of the initial regimen.
Body mass index was calculated as weight in kilograms divided by height in meters squared and categorized per the National Health and Nutrition Examination Survey criteria as the following: underweight, less than 18.5 kg/m2; normal, 18.5 to 24.9 kg/m2; overweight, 25 to 29.9 kg/m2; obese, more than 30 kg/m2.12 Body mass index measurements were based on heights and weights obtained before the start of the antiretroviral regimen. Underweight patients comprised less than 5% of the sample and were excluded from the analysis. Eligible patients were also excluded if they were pregnant or became pregnant during observation.
Duration of therapy was determined using regimen start and stop dates. Follow-up was censored at the date when the initial antiretroviral was changed or stopped, date of death, 90 days after last antiretroviral prescription if patient was lost to follow-up, or December 31, 2004, whichever occurred first.
Regimens were categorized by class of antiretroviral. Nonnucleoside reverse transcriptase inhibitor-based included regimens containing one or more NNRTIs with NRTIs but no PIs. Nucleoside reverse transcriptase inhibitor-only included regimens containing no antiretrovirals from other classes. Protease inhibitor-boosted or PI-nonboosted included any regimens containing a PI, subcategorized according to whether or not the regimen also contained ritonavir prescribed at the 100-mg dose to boost the effect of another PI in the regimen. Prescribed antiretroviral doses were compared against the standard dosing recommendations13,14 and were categorized as "all standard doses, "any low doses, and "any high doses. Dosing was determined to be standard if all the doses were at recommended levels. For the 1.3% of HAART regimens where the dosage of one or more antiretrovirals was unknown, the unknown dosages were categorized as standard. Ritonavir prescribed at the 100-mg dose was categorized as standard if it was used to boost another PI in the regimen. The category of "any low doses included regimens with fewer than 4 antiretrovirals and at least 1 antiretroviral prescribed at a dosage below the recommended standard. Conversely, "any high doses included any regimen with one or more antiretrovirals above the recommended standard dose.
Baseline viral load (HIV RNA copies/mL) and CD4 cell count were defined as the values closest in time to the start of the initial HAART regimen, from within 180 days before through 7 days after. Patients were considered to have achieved an undetectable viral load and/or a CD4 cell count increase of more than 100 cells/μL from baseline if these benchmarks were reached anytime 3 to 9 months after initiating HAART. Viral loads less than 400 copies/mL were considered undetectable. The CD4 cell response of 100 cells/μL over baseline was considered as immunologic success based on current treatment guidelines of antiretroviral-naive individuals.9
Univariate differences among BMI categories were evaluated by the χ2 test (discrete variables) or the Wilcoxon rank sum test (continuous variables). We included hepatitis C serostatus as a variable because prevalence in the study population exceeded 10% and coinfection has been variable implicated as a factor altering disease progression and possible, the response to HAART.15-22 HAART itself may alter the progression of liver pathology that could in turn affect drug metabolism.23-25 Multivariate analyses included those variables that were significant in univariate analysis or that were known to influence initial response to HAART.13,26-29 Either the log baseline viral load or baseline CD4 was used to adjust for a patient s clinical status at the start of HAART. Only 1 was chosen because they are highly correlated. The 1 resulting in the best overall model fit was chosen. Factors associated with achieving an undetectable viral load and a CD4 cell count increase of more than 100 cells/μL from baseline were evaluated using logistic regression models. Factors associated with the length of time patients remained on their initial HAART regimens were evaluated with a proportional hazards model.
Among the 711 patients included in analysis, 29.3% were overweight and 14.2% were obese. Women, who comprised 19.7% of the total sample, were significantly more likely than men to be overweight or obese (P < 0.001), as were black and Hispanic patients compared with whites (P < 0.001), and high-risk heterosexuals and injection drug users compared with men who have sex with men (P < 0.001). There were no significant differences in BMI observed between patients according to HCV coinfection status. Although neither age nor baseline CD4 cell count was associated with differences in BMI, median baseline viral load was modestly but significantly lower in obese patients compared with overweight and normal weight patients (4.49 log10 vs 4.83 log10 and 4.84 log10, respectively, P = 0.008) (Table 1A). Stratified analysis of sex and obesity demonstrated that baseline median viral loads were significantly lower only among obese women, but not for obese men. Obese women also had significantly greater median BMI (34.6, interquartile range [IQR] 32.3-38.6) compared with obese men (31.7, IQR 30.7-33.3).
The median duration of the initial HAART regimen did not differ significantly among BMI groups. Among initial HAART regimens prescribed, 36% were NNRTI based, 6% were NRTI only, 49% were PI nonboosted, and 9% were PI boosted. There was no significant difference in the type of initial prescribed regimen according to BMI category (P = 0.151). Although 83% of patients were prescribed HAART at standard drug dosages, those patients prescribed nonstandard doses were more likely to be normal weight (P = 0.002). Overweight and obese patients were less likely to have been prescribed ddI or d4T in their initial HAART regimen (P = 0.015) (Table 1B).
Approximately 66% of patients had a viral load documented within 3 to 9 months after HAART initiation, and 60% had both a baseline CD4 and a 3- to 9-month follow-up CD4 value documented. Overall, 84.4% achieved an undetectable viral load, and 66.4% achieved a CD4 cell count increase of more than 100 cells/μL. Although the percentage of patients achieving an undetectable viral load or a CD4 cell count increase of more than 100 cells/μL decreased with increasing BMI, these differences were not statistically significant (Table 2). These subsets of patients having virologic and immunologic outcomes documented were found to have demographic and clinical characteristics similar to the overall study cohort of 711 patients.
Logistic regression models that adjusted for statistically significant demographic, clinical, and treatment factors demonstrated that obese or overweight BMI did not alter the risk of achieving an undetectable viral load or of achieving an increase in CD4 cell count of more than 100 cells/μL increase from baseline (Table 3A). Factors associated with achieving an undetectable viral load were age, sex, and baseline viral load, with greater likelihoods associated with increasing age, being male, and having a lower baseline viral load. The only factor significantly associated with achieving an increase in CD4 cell count of more than 100 cells/μL was baseline viral load.
Proportional hazards analysis demonstrated no differences in the duration of the initial HAART regimen among obese and overweight patients compared with normal weight patients (Table 3B). This analysis indicated that PI-based regimens were discontinued significantly sooner than non- PI--based regimens (P < 0.001) and that with every 10-year increment in advancing age, patients remained on their initial HAART regimens significantly longer (P = 0.010).
More than 40% of treatment-naive patients in the HOPS cohort initiating HAART between 1996 and 2004 were overweight or obese. We found that BMI (normal, overweight, or obese) did not affect virologic and immunologic response to HAART among treatment-naive patients in the HOPS. The proportions of patients achieving undetectable viral loads and an increase in CD4 cell count of more than 100 cells/μL after 3 to 9 months of treatment were within expected ranges.30-33 As might be expected, baseline viral load was a significant predictor of improvements in these values posttreatment.
It is interesting to note that multivariable analyses found age and sex to be associated with achieving an undetectable viral load, but not with achieving an increase in CD4 cell count of more than 100 cells/μL. This was consistent with a finding from bivariate, unadjusted analyses which indicated that men were significantly more likely to achieve an undetectable viral load. There was also a greater likelihood of achieving an undetectable viral load with increasing age, but this was not statistically significant in an unadjusted analysis. It is unclear why age and sex were not similarly associated with increases in CD4, given that CD4 increases track with viral load decreases. Age and sex differences in viral load suppression may reflect factors such as adherence to initial antiretroviral therapy. The magnitude of the immune response to initial HAART, however, may depend on other variables, for example, time with viral load of 400 copies.33 In either randomized clinical trials or observational cohorts, there has not been a consistent association with CD4 response by age or sex.33-35
The large fraction of overweight and obese patients we observed (43.5%) has been noted in other recent reports36 but is lower than the 61.5% of overweight and obese adults reported in the general US population.37 It is reasonable to expect that the proportion of overweight and obese HIV-infected persons will continue to grow. The US HIV/AIDS epidemic increasingly affects demographic groups at greater risk for obesity (eg, women, racial/ethnic minorities).38 Earlier diagnosis and improvements in therapy delay the progression of disease and wasting. Despite the enormous success of HAART improving patients' immune status, obesity increases the risk for diabetes, hyperlipidemia, and cardiovascular disease, all conditions that increasingly complicate the management of HIV infection.39,40 As HIV-infected persons enjoy the benefits of longer survival conferred by HAART, their clinical management demands greater attention to the traditional risk factors for morbidity and mortality. It is possible that the benefits of effective HIV therapy may be offset by the long-term complications of obesity and other controllable risks.
We observed significantly lower baseline viral loads among obese patients in our cohort. Although lower pretreatment viral loads have been reported in women,40-43 other studies have demonstrated that increased BMI is associated independently with lower viral load and with a slower progression of HIV disease.1-3 In our study, the association of significantly lower viral load observed with sex in obese patients may have been because of the greater obesity of women compared with men. It has not been determined whether the phenomenon of better virologic control with greater BMI holds true in treated patients; however, with such an effect, we might have expected the obese and overweight patients in the present study to have demonstrated a superior response (eg, more patients achieving an undetectable viral load and a CD4 cells count >100 cells/μL) if antiretroviral dosing were pharmacokinetically equivalent in the 3 BMI groups. Research to explain the interplay among obesity, viral dynamics, immune response to therapy, and progression of clinical disease suggests that adipocytes may play a key regulatory role through the production of adipokines (eg, leptin, adiponectin) and other interactions with immune cells.44,45
We do not have pharmacokinetic data; therefore, we cannot correlate our observations with antiretroviral drug concentrations to determine if overweight and obese patients' treatment (eg, drug dosing) resulted in drug exposure comparable to normal weight patients. Our median length of follow-up was approximately a year, and we are unable to comment on the effect of BMI on long-term durability of treatment. We could not assess the effects of pill burden and adherence as independent factors affecting antiretroviral response in this analysis, although we have no reason to believe either pill burden or adherence would be significantly different across the 3 BMI categories. Less than 10% of HAART regimens included a ritonavir-boosted PI, which is an increasingly frequent component of initial therapy. We did not have viral load or CD4 cell count data at 3 to 9 months on 34% and 40% of patients, respectively, but the persons included in this analysis were comparable to the entire cohort and the proportions of missing values were equally spread across the 3 groups, and thus, we expect that similar findings would be found in an intent-to-treat (missing = failure) analysis. Lastly, the number of underweight patients in our cohort was too few to permit the assessment of the effect of low weight on response to HAART.
In summary, a large proportion of HIV-infected patients in the HOPS cohort are overweight and obese. Our findings that BMI did not influence the response to treatment and that the virologic and immunologic improvements we observed at 3 to 9 months of treatment were within expected ranges are reassuring. Although evidence from other sources suggests that untreated overweight and obese persons might be expected to respond better than normal weight patients, we were unable to detect any further improvement among overweight and obese patients over the excellent responses achieved by normal weight patients. These data suggest that the potency of current HAART regimens is adequate for normal weight to obese persons, although additional pharmacokinetic and clinical data among overweight and obese patients would be desirable.
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The HOPS Investigators include the following investigators and sites: Anne C. Moorman, Tony Tong, John T. Brooks, and Kate Buchacz, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention (NCHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, GA; Scott D. Holmberg, Research Triangle Institute (formerly of CDC); Kathleen C. Wood, Rose K. Baker, Carl Armon, James T. Richardson, Cerner Corporation, Vienna, VA; Frank J. Palella, Joan S. Chmiel, Janet Cheley, and Tiffany Murphy, Feinberg School of Medicine, Northwestern University, Chicago, IL; Kenneth A. Lichtenstein, University of Colorado Health Sciences Center, Denver, CO; Kenneth S. Greenberg, Benjamin Young, Barbara Widick, Cheryl Stewart, and Peggy Zellner, Rose Medical Center, Denver, CO; Bienvenido G. Yangco, Kalliope Halkias, and Arletis Lay, Infectious Disease Research Institute, Tampa, FL; Douglas J. Ward and Charles A. Fiorentino, Dupont Circle Physicians Group, Washington, DC; Jack Fuhrer, Linda Ording-Bauer, Rita Kelly, and Jane Esteves, State University of New York (SUNY), Stony Brook, NY; Ellen M. Tedaldi, Ramona A. Christian, and Linda Walker-Kornegay, Temple University School of Medicine, Philadelphia, PA; Joseph B. Marzouk, Roger T. Phelps, and Mark Rachel, Adult Immunology Clinic, Oakland, CA; Silver Sisneros and Mark Rachel, Fairmont Hospital, San Leandro, CA; Richard M. Novak, Jonathan P. Uy, and Andrea Wendrow, University of Illinois at Chicago, Chicago, IL.
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