JAIDS Journal of Acquired Immune Deficiency Syndromes:
Initiation of Antiretroviral Therapy at CD4 Cell Counts ≥350 Cells/mm3 Does Not Increase Incidence or Risk of Peripheral Neuropathy, Anemia, or Renal Insufficiency
Lichtenstein, Kenneth A MD*; Armon, Carl MSPH†; Buchacz, Kate PhD‡; Chmiel, Joan S PhD§; Moorman, Anne C BSN, MPH‡; Wood, Kathleen C BSN†; Holmberg, Scott D MD, MPH‡; Brooks, John T MD‡; the HIV Outpatient Study (HOPS) Investigators
From the *University of Colorado Health Sciences Center, Denver, CO; †Cerner Corporation, Vienna, VA; ‡Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA; and the §Feinberg School of Medicine, Northwestern University, Chicago, IL.
Received for publication July 23, 2006; revised July 10, 2007; accepted September 10, 2007.
Supported by the Centers for Disease Control and Prevention (contract 200-2001-00133).
Preliminary results of this research were presented at the 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO, February 5-8, 2006 (abstract 769).
The investigation followed the guidelines of the US Department of Health and Human Services for the research protection of human subjects.
The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention.
K. A. Lichtenstein has served as a consultant for GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingleheim, Gilead, Abbott Laboratories, Tibotec, and Merck; has received research grants from Boehringer Ingleheim, Bayer, Serono, Bristol-Myers Squibb, and Merck; and serves on the speakers' bureaus of Abbott Laboratories, Bristol-Myers Squibb, Merck, and Gilead. All other authors have no conflicts.
Reprint requests to: John T. Brooks, MD, Division of HIV/AIDS Prevention, National Centers for HIV, Hepatitis, TB, and STD Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mailstop E-45, Atlanta, GA 30333 (e-mail: email@example.com).
Correspondence to: Kenneth A. Lichtenstein, MD, National Jewish Medical and Research Center, 1400 Jackson Street, G316, Denver, CO 80206 (e-mail: firstname.lastname@example.org).
Background: US guidelines recommend deferring initiation of highly active antiretroviral therapy (HAART) for most patients with CD4 counts >350 cells/mm3 in part because of concerns about antiretroviral toxicity.
Methods: Incidence rates of peripheral neuropathy, anemia, and renal insufficiency in a cohort of 2165 patients followed more than 3 years (mean) were analyzed in multivariate Cox proportional hazards models by CD4 cell counts at initiation of HAART. A nested cohort of 895 patients restricted to study participants who did or did not start HAART within a CD4 cell count stratum were also compared.
Results: Incidence and risks of all 3 comorbidities decreased with initiation of HAART at CD4 counts >200 cells/mm3 versus <200 cells/mm3. Incidence and risks of renal insufficiency were similar with HAART initiation at CD4 counts ≥350 cells/mm3 versus 200 to 349 cells/mm3, but risk of peripheral neuropathy and anemia were further decreased in persons starting HAART at a CD4 count ≥350 cells/mm3. The incidence of these conditions was highest during the first 6 months of treatment at any CD4 cell count and declined up to 19-fold with further therapy.
Discussion: Initiating HAART at CD4 cell counts ≥200 cells/mm3 reduced the incidence and risk of the 3 comorbid conditions and for anemia and peripheral neuropathy as well by starting at CD4 counts ≥350 cells/mm3. The incidence of each condition decreased rapidly and remained low with increasing time on HAART.
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.
1. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators [see comment]. N Engl J Med. 1998;338:853-860.
2. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies [erratum appears in Lancet 2002;360:1178]. Lancet. 2002;360:119-129.
3. Fahey JL, Taylor JM, Manna B, et al. Prognostic significance of plasma markers of immune activation, HIV viral load and CD4 T-cell measurements. AIDS. 1998;12:1581-1590.
4. Gougard C, Bonarek M, Meyer L, et al. CD4 cell count and HIV DNA level are independent predictors of disease progression after primary HIV Type 1 infection in untreated patients. Clin Infect Dis. 2006;42:709-715.
5. Deeks SG, Kitchen CM, Lie L, et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood. 2004;104:942-947.
7. Bacellar H, Munoz A, Miller EN, et al. Temporal trends in the incidence of HIV-1-related neurologic diseases: Multicenter AIDS Cohort Study, 1985-1992. Neurology. 1994;44:1892-1900.
8. Barohn RJ, Gronseth GS, LeForce BR, et al. Peripheral nervous system involvement in a large cohort of human immunodeficiency virus-infected individuals [erratum appears in Arch Neurol 1993;50:388]. Arch Neurol. 1993;50:167-171.
9. Lichtenstein KA, Ward DJ, Moorman AC, et al. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS. 2001;15:1389-1398.
10. Lichtenstein KA, Delaney KM, Armon C, et al. Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. J Acquir Immune Defic Syndr. 2003;32:48-56.
11. Lichtenstein KA, Armon C, Baron A, et al. Modification of the incidence of drug-associated symmetrical peripheral neuropathy by host and disease factors in the HIV outpatient study cohort. Clin Infect Dis. 2005;40:148-157.
12. Mocroft A, Kirk O, Barton SE, et al. Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe. EuroSIDA Study Group. AIDS. 1999;13:943-950.
13. Sarcletti M, Quirchmair G, Weiss G, et al. Increase of haemoglobin levels by anti-retroviral therapy is associated with a decrease in immune activation. Eur J Haematol. 2003;70:17-25.
14. Tagliati M, Grinnell J, Godbold J, et al. Peripheral nerve function in HIV infection: clinical, electrophysiologic, and laboratory findings. Arch Neurol. 1999;56:84-89.
15. Sterne J, Hernan MA, Ledergerber B, et al. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet. 2006;366:378-384.
16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.
17. Deeks SG, Walker BD. The immune response to AIDS virus infection: good, bad, or both? [see comment]. J Clin Invest. 2004;113:808-810.
18. Hazenberg MD, Stuart JW, Otto SA, et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood. 2000;95:249-255.
19. Hazenberg MD, Otto SA, van Benthem BH, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. 2003;17:1881-1888.
20. Palella FJ Jr, Deloria-Knoll M, Chmiel JS, et al. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata [see comment]. [Summary for patients in Ann Intern Med 2003;138:I1] Ann Intern Med. 2003;138:620-626.
21. Palella FJ Jr, Chmiel JS, Moorman AC, et al. Durability and predictors of success of highly active antiretroviral therapy for ambulatory HIV-infected patients. AIDS. 2002;16:1617-1626.
22. Mildvan D, Bosch RJ, Kim RS, et al. Immunophenotypic markers and antiretroviral therapy (IMART): T cell activation and maturation help predict treatment response. J Infect Dis. 2004;189:1811-1820.
23. Tilling R, Kinloch S, Goh LE, et al. Parallel decline of CD8+/CD38++ T cells and viraemia in response to quadruple highly active antiretroviral therapy in primary HIV infection. AIDS. 2002;16:589-596.
24. Benveniste O, Flahault A, Rollot F, et al. Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1-infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads. J Infect Dis. 2005;191:1670-1679.
25. Lange CG, Lederman MM, Medvik K, et al. Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS. 2003;17:2015-2023.
26. Lederman MM, Kalish LA, Asmuth D, et al. ‘Modeling’ relationships among HIV-1 replication, immune activation and CD4+ T-cell losses using adjusted correlative analyses. AIDS. 2000;14:951-958.
27. Papagno L, Spina CA, Marchant A, et al. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol. 2004;2:E20.
28. Doweiko JP. Hematologic aspects of HIV infection. AIDS. 1993;7:753-757.
29. Geraci AP, Simpson DM. Neurological manifestations of HIV-1 infection in the HAART era. Compr Ther. 2001;27:232-241.
30. Keswani SC, Pardo CA, Cherry CL, et al. HIV-associated sensory neuropathies. AIDS. 2002;16:2105-2117.
31. Martin C, Solders G, Sonnerborg A, et al. Antiretroviral therapy may improve sensory function in HIV-infected patients: a pilot study [see comment]. Neurology. 2000;54:2120-2127.
32. Childs EA, Lyles RH, Selnes OA, et al. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology. 1999;52:607-613.
33. Cohen AH, Cohen GM. Distinguished Scientists Lecture Series. HIV-associated nephropathy. Nephron. 1999;83:111-116.
34. Simpson DM, Haidich AB, Schifitto G, et al. Severity of HIV-associated neuropathy is associated with plasma HIV-1 RNA levels [see comment]. AIDS. 2002;16:407-412.
35. Anderson PL, Kakuda TN, Kawle S, et al. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS. 2003;17:2159-2168.
36. Anderson PL, Kakuda TN, Lichtenstein KA. The cellular pharmacology of nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities [see comment]. Clin Infect Dis. 2004;38:743-753.
37. Cohen AH, Sun NC, Shapshak P, et al. Demonstration of human immunodeficiency virus in renal epithelium in HIV-associated nephropathy. Mod Pathol. 1989;2:125-128.
38. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment [see comment]. N Engl J Med. 2006;355:2283-2296.
39. Marras D, Bruggeman LA, Gao F, et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat Med. 2002;8:522-526.
40. Nagano I, Shapshak P, Yoshioka M, et al. Increased NADPH-diaphorase reactivity and cytokine expression in dorsal root ganglia in acquired immunodeficiency syndrome. J Neurol Sci. 1996;136:117-128.
41. Yoshioka M, Shapshak P, Srivastava AK, et al. Expression of HIV-1 and interleukin-6 in lumbosacral dorsal root ganglia of patients with AIDS [erratum appears in Neurology 1994;44:1504-15055]. Neurology. 1994;44:1120-1130.
This article has been cited 23 time(s).
Bmc MedicineWhen to start antiretroviral therapy: the need for an evidence base during early HIV infectionBmc Medicine
Plos OneAssociation of Thymidylate Synthase Polymorphisms with Acute Pancreatitis and/or Peripheral Neuropathy in HIV-Infected Patients on Stavudine-Based TherapyPlos One
Quality of Life ResearchThe associations among coping, nadir CD4+T-cell count, and non-HIV-related variables with health-related quality of life among an ambulatory HIV-positive patient populationQuality of Life Research
Manifestations of HIV infection in the peripheral nervous system
Lancet Neurology, 12(3):
Hiv Clinical TrialsSimplification of the Research Diagnosis of HIV-Associated Sensory NeuropathyHiv Clinical Trials
AIDS Patient Care and StdsHIV Testing Factors Associated with Delayed Entry into HIV Medical Care among HIV-Infected Persons from Eighteen States, United States, 2000-2004AIDS Patient Care and Stds
Jama-Journal of the American Medical Association
Antiretroviral treatment of adult HIV infection - 2008 recommendations of the International AIDS Society USA panel
Jama-Journal of the American Medical Association, 300(5):
Enfermedades Infecciosas Y Microbiologia ClinicaRecommendations from the GESIDA/Spanish AIDS Plan regarding antiretroviral treatment in adults with human immunodeficiency virus infection (update February 2009)Enfermedades Infecciosas Y Microbiologia Clinica
Nature Reviews MicrobiologyCD4 immunophenotyping in HIV infectionNature Reviews Microbiology
Journal of Infectious DiseasesHuman immunodeficiency virus-associated lipoatrophy: Letting the genome out of the bottleJournal of Infectious Diseases
Journal of VirologyAntiretroviral Therapy in the ClinicJournal of Virology
Clinical Infectious DiseasesWhen to Start Antiretroviral Therapy?Clinical Infectious Diseases
When to Start Antiretroviral Therapy? NA-ACCORD Stimulates the Debate
AIDS Reader, 19(2):
American Journal of GastroenterologyLessons From HIV Therapy Applied to Viral Hepatitis Therapy: Summary of a WorkshopAmerican Journal of Gastroenterology
New England Journal of MedicineEffect of Early versus Deferred Antiretroviral Therapy for HIV on SurvivalNew England Journal of Medicine
Journal of Infectious DiseasesThe search for data on when to start treatment for HIV infectionJournal of Infectious Diseases
Revista Chilena De Infectologia
Clinical guide HIV/AIDS acquired immunodeficiency syndrome
Revista Chilena De Infectologia, 27(3):
International Journal of Std & AIDSInitiating antiretroviral treatment in a resource-constrained setting: does clinical staging effectively identify patients in need?International Journal of Std & AIDS
Lancet Infectious Diseases
Successes, challenges, and limitations of current antiretroviral therapy in low-income and middle-income countries
Lancet Infectious Diseases, 9():
Clinical Infectious DiseasesCoronary Aging in HIV-Infected PatientsClinical Infectious Diseases
Current Opinion in Infectious DiseasesShould HIV therapy be started at a CD4 cell count above 350 cells/μl in asymptomatic HIV-1-infected patients?Current Opinion in Infectious Diseases
anemia; highly active antiretroviral therapy; peripheral neuropathy; renal insufficiency
© 2008 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.