Highly active antiretroviral therapy (HAART) has dramatically reduced HIV-1-associated mortality and morbidity.1 Despite evidence that starting HAART at a CD4 count as high as 500 cells/mm3 significantly reduces mortality risk2-4 and slows progression to AIDS,4-7 current guidelines recommend deferring therapy in patients with CD4 counts ≥350 cells/mm3 and HIV viral loads <100,000 copies/mL.8 This recommendation is based in part on concerns that the prolonged exposure to antiretrovirals resulting from earlier initiation of HAART may increase the risk for conditions such as peripheral neuropathy, anemia, renal insufficiency, lipoatrophy, dyslipidemia, and insulin resistance. Although these drugs have been shown to contribute to some of the risk for these conditions, many of the comorbidities attributed to antiretrovirals have also been reported in patients with little or no exposure to these medications, particularly patients with advanced disease. These observations suggest that inadequately controlled HIV infection with consequent chronic immune activation may contribute to such events and that antiretroviral-mediated control of viral replication could reduce the risk for their development.
We and other investigators have previously reported that in addition to antiretroviral therapy, low CD4 cell counts and various host factors such as age, race, and gender are associated independently with increased risk for developing peripheral neuropathy, anemia, and lipodystrophy (lipoatrophy and lipoaccumulation).9-16 In light of the survival benefit conferred by initiating HAART at higher CD4 cell counts,4,17-19 our objective was to determine in a large cohort of diverse patients (the HIV Outpatient Study [HOPS]) the risk for experiencing 3 comorbid conditions at these higher CD4 strata.
HIV Outpatient Study
The HOPS is an ongoing, prospective, observational cohort study of HIV-infected patients receiving care in 9 participating HIV clinics (1 public, 4 university, and 4 private) in 8 US cities (Chicago, IL; Denver, CO; Long Island, NY; Oakland/San Leandro, CA; Philadelphia, PA; Tampa, FL; and Washington, DC) since March 1993. Patient data, including sociodemographic characteristics, symptoms and signs, diagnoses, treatments, and laboratory values, are abstracted from medical charts and entered into an electronic database (Clinical Practice Analyst [CPA]; Cerner Corporation, Vienna, VA) by trained staff. These data are reviewed centrally for quality and analyzed centrally. To date, the HOPS has collected information on more than 8200 patients in more than 280,000 clinical encounters. The HOPS protocol has been reviewed annually and approved by the Centers for Disease Control and Prevention, Cerner Corporation, and each local site's institutional review board since its inception. Informed consent is obtained on an annual basis from all patients. The study protocol conforms to the guidelines of the US Department of Health and Human Services for the protection of human subjects in research.
Overview of Analyses
We examined the incidence of peripheral neuropathy, anemia, and renal insufficiency among antiretroviral drug-naive and-experienced patients who initiated their first HAART regimen while in the HOPS. We also investigated factors associated with risk for developing these incident conditions, including pre-HAART CD4 cell counts. We analyzed data collected prospectively between a patient's date of entry into the HOPS and September 30, 2006 as well as data collected from a patient's prior documented medical history. The period of analysis was defined as starting with the patient's first HAART regimen and ending with a diagnosis of 1 of the 3 conditions of interest or until the last recorded patient visit.
Of 8224 patients who were enrolled in the HOPS through September 30, 2006, we included persons who had at least 2 HOPS clinical visits, who had started their first HAART regimen after enrolling in the HOPS, and who had at least 90 days of cumulative HAART use during follow-up (n = 3634). We considered each patient's time on HAART to be the cumulative time on each HAART regimen during follow-up. A HAART regimen was considered to be 2 nucleoside analogues (NAs) plus 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) or at least 1 protease inhibitor (PI), at least 2 PIs and any number of drugs of other classes, or at least 1 drug from each of the 3 classes. We further restricted analyses to patients who had complete documented antiretroviral histories and who had CD4 cell counts available before initiating HAART (n = 2165).
Peripheral Neuropathy Cohort (n = 1969)
We defined a case of peripheral neuropathy as the first diagnosis of distal symmetric peripheral sensory neuropathy that was recorded in the patient's medical records. We excluded from analysis 196 patients who had been diagnosed with symmetric peripheral sensory neuropathy at baseline and patients subsequently found to have radiculopathy, proximal, or asymmetric symptoms. All cases of peripheral neuropathy so defined were confirmed in consultation with patients' treating physicians.
Anemia Cohort (n = 1398)
We defined a case of anemia as 2 consecutive laboratory measurements of hemoglobin ≤10 g/dL or a recorded diagnosis of anemia with a confirming hemoglobin value ≤10 g/dL We restricted analyses to patients who had at least 1 hemoglobin measurement within 2 years before baseline and 2 or more hemoglobin measurements during follow-up (n = 1782). We excluded 276 patients who had been diagnosed with anemia before baseline and 108 patients who had inherited anemia (eg, sickle cell disease) or other conditions that could induce anemia, such as renal failure or serum creatinine >2 mg/dL. Cases of anemia were not considered as outcomes in analysis if they occurred coincident with the diagnoses of the following conditions: thalassemia, sickle cell disease, G6PD deficiency, iron deficiency, pernicious anemia, bleeding (eg, upper or lower gastrointestinal tract, trauma, vaginal, tissue ulcerations), parvovirus B19 infection, leukemia/lymphoma, or any other comorbidity known to be associated with anemia.
Renal Insufficiency Cohort (n = 1152)
We defined a case of renal insufficiency as the first diagnosis of renal failure, end-stage renal disease, HIV-related nephropathy, chronic kidney disease, or glomerulonephritis in the patient's medical records and 2 consecutive measurements of creatinine clearance <60 mL/min (grade 3 or higher renal insufficiency) as calculated by the Cockcroft-Gault formula16 using weight and age closest to serum creatinine determination; most patients in the HOPS had weight measured within 8 days of serum creatinine determination. We restricted analyses to patients who had a creatinine measurement within 2 years before baseline and 2 or more creatinine measurements during follow-up (n = 1226). We excluded 74 patients who had renal insufficiency at baseline.
To address the problem of “lead-time bias” (ie, that persons with low CD4 cell counts may have unobserved events or conditions that would influence our analysis), we compared the incidence of the 3 toxicities in persons who were observed in the HOPS after they did or did not start HAART in 1 of 3 strata: 201 to 350 CD4 cells/mm3, 351 to 500 CD4 cells/mm3, and 501 to 750 CD4 cells/mm3 at the time of treatment initiation. We created this restricted cohort (n = 895) from patients who had at least 2 CD4 tests recorded in the HOPS before the start of their first HAART regimen and who started their first regimen no more than 1 month before their first HOPS visit. We excluded patients from each analysis who had the respective condition before or at baseline. Outcomes of patients who started HAART within a CD4 stratum were compared with those of patients who delayed HAART to a lower CD4 stratum.20
We identified variables that needed to be included in a Cox proportional hazards model by first analyzing data from the main cohort. We analyzed observation time from baseline (start of patient's first HAART regimen) until each patient's last HOPS visit, death, the first occurrence of the condition of interest, or September 30, 2006. We calculated incidence rates per 100 person-years (PY) for each of the 3 conditions stratified by pre-HAART CD4 cell count using 2 (0 to 199 cells/mm3 and ≥200 cells/mm3) and 3 (0 to 199 cells/mm3, 200 to 349 cells/mm3, and ≥350 cells/mm3) strata analyses. We then examined incidence rates of these 3 conditions by sociodemographic and clinical factors that were of a priori interest or that were identified as potential confounders because they were distributed differentially across the baseline CD4 cell count strata in the overall cohort of 2165 patients. These factors included gender, age, race/ethnicity, year of entry into the HOPS, year of starting first HAART regimen, type of medical insurance, history of intravenous drug use, alcohol use of >14 alcohol drinks per week at the time of HOPS entry, history of opportunistic infections or AIDS-defining malignancies, use of nephrotoxic agents, baseline HIV viral load, years since diagnosis of HIV infection, nadir CD4 cell count, history of diabetes or hypertension, percentage of time on (prescribed) HAART during follow-up, use of each class of antiretroviral agent, and select antiretroviral agents known to be associated with peripheral neuropathy (stavudine [d4T], zalcitabine, and didanosine [ddI]), anemia (zidovudine), and renal insufficiency (indinavir and tenofovir). In addition, we considered baseline hemoglobin in analyses of anemia and baseline creatinine clearance in analyses of renal insufficiency.
In our restricted cohort of 895 patients, we compared the incidence of the 3 outcomes among those who initiated HAART within a CD4 stratum with those among patients who delayed initiation to the next lower CD4 stratum.
Baseline sociodemographic and clinical factors that were associated (P < 0.20) with a given outcome were included in the initial multivariable Cox proportional hazards models. Based on early exploratory models and analyses, we additionally included as time-varying covariates the following antiretrovirals in the respective models: d4T and ddI for peripheral neuropathy, zidovudine for anemia, and tenofovir and indinavir for renal insufficiency. The binary variables were set to equal unity at the date the drug was started and for the duration of follow-up as intention to treat. There was insufficient use of zalcitabine during follow-up to maintain this variable in the multivariable models for peripheral neuropathy. Using a stepwise backward selection technique, we developed multivariable models for each adverse event that retained all independent predictors for that event as well as age, gender, race, and baseline CD4 cell count. We explored the risk of incident adverse events during HAART, stratifying the variable for baseline CD4 cell count into 3 categories and into 2 categories in separate but otherwise identical models.
Statistical Software Methods
Summaries of descriptive data, univariate analyses, and Cox proportional hazards regression modeling were conducted with SAS version 9.1 (SAS Institute, Cary, NC). Patient characteristics were compared by the Yates corrected χ2 test or the Fisher exact test for categoric variables and by the Wilcoxon rank sum test for continuous variables. Incidence rates were compared using the Yates corrected χ2 test, with StatCalc (EpiInfo 2000; Centers for Disease Control and Prevention, Atlanta, GA). Statistical associations with P values <0.05 were considered significant.
In all analyses, >80% of the persons were male, >60% were non-Hispanic whites, and approximately two thirds entered the HOPS between 1995 and 2001 with baseline CD4 cell counts ≥200 cells/mm3. The median PY of follow-up were 3.1 years in the peripheral neuropathy cohort (interquartile range [IQR]: 1.1 to 6.4 years), 4.3 years in the anemia cohort (IQR: 1.8 to 7.9 years), and 4.5 years in the renal insufficiency cohort (IQR: 2.1 to 7.4 years), with longer periods of observed follow-up and a greater median number of patient visits among persons in the higher CD4 cell count strata (Table 1).
In the univariate analyses, factors associated with greater incidence of peripheral neuropathy included older age, baseline viral load >35,000 copies/mL, and baseline CD4 count <200 cells/mm3 (Table 1). Factors associated with incident anemia included female gender, black non-Hispanic race, baseline CD4 count <200 cells/mm3, and baseline hemoglobin <14.4 g/dL, which was the median hemoglobin value for this cohort (Table 1). Factors associated with incident renal insufficiency included older age, black non-Hispanic race, Hispanic ethnicity, baseline CD4 count <200 cells/mm3, baseline creatinine clearance <108.9 mL/min (the median creatinine clearance value for this cohort) (Table 1), and use of aminoglycosides or trimethoprim-sulfamethoxazole.
Incidence rates for each adverse event were significantly lower among patients with baseline CD4 cell counts in the strata ≥200 cells/mm3 (200 to 349 cells/mm3 and ≥350 cells/mm3) compared with those with CD4 counts from 0 to 199 cells/mm3 and were highest during the first 6 months of follow-up. This was also true among persons with baseline CD4 counts ≥350 cells/mm3 compared with persons with baseline CD4 counts from 200 to 349 cells/mm3. Over 6 years of follow-up, incidence rates for each of the 3 conditions significantly declined over time for persons in all 3 CD4 strata (Figs. 1-3).
Because of the agents' known association with each outcome and the multivariable analyses described here, we examined the incidence rates of peripheral neuropathy among persons receiving d4T and ddI and of anemia among persons receiving zidovudine by length of time on treatment and by initial CD4 stratum. There were significant declining incidences of peripheral neuropathy (see Fig. 1) with time on d4T and ddI treatment and of anemia with zidovudine (see Fig. 2); the declining trend of both toxicities was also observed for higher CD4 cell count at time of HAART initiation.
In Cox multivariable proportional hazards analyses (Table 2), factors associated with an increased hazard of incident peripheral neuropathy (P < 0.05) included baseline age as a continuous variable in 10-year intervals, baseline CD4 count <200 cells/mm3, and taking d4T or ddI during follow-up. Factors associated with an increased hazard of incident anemia included female gender, baseline CD4 count <200 cells/mm3, baseline hemoglobin ≤median value, and zidovudine use during follow-up. Factors associated with an increased hazard of incident renal insufficiency included baseline age as a continuous variable in 10-year intervals, female gender, nonwhite race, baseline CD4 count <200 cells/mm3, creatinine clearance as a continuous variable in 10-unit intervals, and use of zidovudine at baseline. In our study, neither use of indinavir or tenofovir nor use of aminoglycosides or trimethoprim-sulfamethoxazole during follow-up was associated with incident renal insufficiency. After adjusting for significant multivariable predictors of each outcome, patients with baseline CD4 counts from 0 to 199 cells/mm3 compared with patients with CD4 counts ≥200 cells/mm3 had a hazard ratio of developing peripheral neuropathy of 1.54 (P < 0.001), a hazard ratio of developing anemia of 1.68 (P = 0.030), and a hazard ratio of developing renal insufficiency of 2.22 (P < 0.001). The hazard of developing peripheral neuropathy and anemia among patients with baseline CD4 counts ≥350 cells/mm3 compared with patients with CD4 counts from 200 to 349 cells/mm3 was also decreased, although not statistically significantly.
In the nested cohort restricted analysis, when HAART was initiated or deferred at any CD4 cell count range, those individuals who initiated therapy at each range had a lower incidence per 100 PY of each comorbidity than those who deferred therapy, with the exception of anemia in the stratum with a CD4 count from 200 to 349 cells/mm3 compared with the stratum with a CD4 count <200 cells/mm3; however, these findings were not statistically significant (Table 3).
In the present study, we found that the incidence rates and risk of peripheral neuropathy, anemia, or renal insufficiency were decreased in patients who initiated HAART at CD4 counts from 200 to 349 cells/mm3 compared with patients initiating at <200 cells/mm3 and, in a subanalysis, compared with individuals who deferred therapy at the same CD4 range. The incidence of peripheral neuropathy and anemia, although lower, and that of renal insufficiency did not differ significantly between patients initiating at CD4 counts ≥350 cells/mm3 compared with CD4 counts from 200 to 349 cells/mm3. Incidence rates for all 3 conditions were greatest in the first 6 months of treatment and decreased up to 19-fold during subsequent follow-up.
Current US guidelines recommend offering combination HAART to all symptomatic HIV-infected patients and to patients with CD4 counts <200 cells/mm3 and to consider offering treatment to patients with CD4 counts between 201 and 350 cells/mm3 regardless of their HIV viral load and to patients with CD4 counts >350 cells/mm3 if their HIV viral load exceeds 105 copies/mL.21 These guidelines recommend deferring HAART in patients with CD4 counts >350 cells/mm3 and with plasma viral loads <105 copies/mL, however, with the rationale that the long-term benefit of early treatment in such patients is outweighed by the theoretic risks of greater toxicity and of potential difficulties with adherence that could fuel antiretroviral resistance.
Any discussion concerning guidelines and recommendations includes consideration of other issues, such as the impacts of earlier initiation on prevention of HIV transmission and of long-term adherence and consequent risk of inducing antiretroviral resistance. We are concerned that current recommendations may lead to therapy being withheld from patients when it is most beneficial, while, at the same time, placing them at increased risk of developing avoidable complications of HIV infection once they do start treatment. The problem is potentially greater in more resource-limited settings, where most of the world's HIV-infected populations live and where local public health policies may restrict provision of antiretrovirals to patients with the lowest CD4 cell counts.
Numerous studies have now demonstrated that using effective antiretroviral therapy at increasingly higher CD4 cell counts leads to correspondently greater reductions in death and progression to AIDS2-4,15,19-23 and that the expansions in CD4 cell counts, decreases in HIV viral loads, and preservation of specific immune function in treated patients are maintained.23-27 Data are lacking to support the hypothesis that there is greater risk of adverse events from longer term cumulative exposure to antiretrovirals when sustained treatment is initiated at higher CD4 cell counts, however. Are the risks of adverse effects actually worse than the untreated long-term exposure to viral replication and sustained chronic inflammation?
Many of the adverse events described as occurring in association with antiretroviral use have been observed in untreated persons with advanced disease. Although d4T and ddI use has been associated with peripheral neuropathy and zidovudine use has been associated with anemia, antiretroviral treatment can also improve each of these conditions.12,13,28-31 Notably, our data demonstrate that with respect to peripheral neuropathy and anemia, although use of d4T and zidovudine was associated with a slightly increased risk for each condition, respectively, earlier initiation of HAART that included these agents conferred comparatively greater protection against the adverse event. In other words, our data indicate that a strategy of delaying treatment to avoid peripheral neuropathy and anemia would have increased the risk for these adverse events once treatment was initiated. After approximately 6 to 12 months of treatment, the likelihood of remaining free of each of these events plateaued; had the effect of exposure been cumulative, one might have also expected a progressive steady decline in the proportion of person remaining free of each event. Although the likelihood of remaining free of renal insufficiency steadily decreased during follow-up after HAART initiation, persons who initiated HAART in the higher CD4 strata were significantly more likely to remain free of the condition than persons initiating at CD4 cell counts <200 cells/mm3.
Biologic plausibility for our findings has yet to be fully elucidated. We hypothesize that the phenomenon we have observed may result, at least in part, from antiretroviral-mediated reduction in the chronic immune activation associated with uncontrolled HIV viral replication. Persistent production of proinflammatory factors seems to increase risk for developing certain HIV-associated comorbidities; this risk may in turn be augmented and ameliorated by antiretroviral treatment.13,32-34 For instance, the intracellular concentrations of zidovudine in peripheral blood mononuclear cells are increased inversely with lower pretreatment CD4 cell counts,35,36 a phenomenon attributed to greater intracellular phosphorylation of the drug fueled by a chronic inflammatory state that abates with suppression of HIV viral replication and resultant CD4 cell count increase.
This same phenomenon may occur in other tissues affected by adverse events attributed to antiretrovirals (eg, neurons, red blood cell precursors), where cytokines such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) and proinflammatory cells have been observed in higher concentrations.28,37-41
Our study has several important limitations. We restricted analyses to patients who had completely documented antiretroviral histories and known pre-HAART CD4 cell counts and who started their first HAART regimen during observation in the HOPS. We could not ensure complete ascertainment of incident adverse events before patients' entry into the HOPS. Nonetheless, the median times between HIV diagnosis and HOPS entry and between HOPS entry and initiation of first HAART were comparable among patients in the 3 CD4 cell count strata (data not shown), such that we do not believe there was major differential exclusion by history of preexisting conditions among the 3 CD4 cell count strata. Because we do not know when most subjects were infected with HIV, we cannot determine the true independent effect of the length of HIV infection on the risk for the adverse events we described. To account for this, we performed a restricted analysis to compare individuals who initiated versus deferred HAART at each CD4 range. In that nested cohort, despite the lack of statistical significance and with the exception of anemia in the stratum from 200 to 349 cells/mm3 compared with the stratum <200 cells/mm3, the incidence ratios for each of the conditions studied were consistently greater than 1 for persons who delayed treatment at any CD4 stratum to the next lower stratum, a finding consistent with our larger cohort analysis.
As with all prospective cohort studies, although we attempted to account for all relevant risk factors for the adverse outcomes of interest that could confound the relation between pre-HAART CD4 cell count and incidence of adverse events, there may have been factors for which we were unable to account that affected the associations observed. We did not report the independent effect of initiating HAART at CD4 counts >500 cells/mm3; the number of such patients in this CD4 cell count stratum was comparatively few, resulting in less reliable risk estimates with greater variance. Although we defined a unique study population for analysis of each outcome and analyzed risk factors for each outcome in the corresponding cohort separately, it is possible that individuals included in multiple cohorts may have experienced more than 1 of the outcomes; for such persons, exposure to single drugs or regimens may have been associated with 2 or more outcomes at a frequency potentially substantial enough to overestimate individual effect sizes and confidence intervals. We believe, however, that the outcomes we observed were for the most part biologically independent and unrelated events and that to the extent they may have been related to antiretroviral exposure, they were each associated with different and unique agents.
In summary, our data demonstrate that initiating effective antiretroviral therapy at CD4 counts ≥200 cells/mm3 ameliorates the risk of 3 important adverse conditions associated with HIV infection frequently attributed to toxicity-related side effects of antiretrovirals and that there was no increased risk for these conditions when treatment was initiated at CD4 counts ≥350 cells/mm3. Considered together with the evidence of decreased mortality and slower progression to AIDS among patients initiating therapy at progressively higher CD4 cell counts, our findings may be particularly relevant as recommendations to defer treatment in patients with CD4 counts ≥350 cells/mm3 are reviewed and reconsidered.
The authors are indebted to generous voluntary contribution of our dedicated patients.
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