Late diagnosis of HIV-1 infection is not uncommon in Western countries.1 Highly active antiretroviral therapy (HAART) has been shown to control HIV-1 infection when started in HIV-1–infected individuals with a CD4+ T-cell count >200 per cubic millimeter.2 Current recommendations for antiretroviral treatment3 support initiating antiretroviral therapy with 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a nonnucleoside reverse transcriptase inhibitor (NNRTI; with efavirenz as the first-line drug) or a boosted protease inhibitor (PI) (atazanavir/ritonavir or darunavir/ritonavir as first-line drugs). Integrase inhibitor–based regimens are now considered first-line regimens. Conversely, lopinavir-/ritonavir-based treatment is now considered an alternative regimen.3 However, international guidelines do not specify which is the best antiretroviral treatment in patients with a very low CD4 T-cell count, although they do state that some drugs, such as abacavir/lamivudine and rilpivirine, should be avoided in patients with HIV RNA levels above 100,000 copies per milliliter. In the treatment of advanced patients, physicians tend to prefer boosted PI–based antiretroviral regimens because of their high genetic barrier to resistance and because treatment is started soon after diagnosis of HIV infection without waiting for genotypic resistance test results. The immunological, virological, and clinical outcomes of an NNRTI-based antiretroviral regimen with a boosted PI–based antiretroviral regimen in very immunosuppressed patients have been compared in few controlled studies. The Advanz trial4 revealed similar immune reconstitution but better virological response at 3 years for very immunosuppressed patients (CD4 T-cell count <100/mm3) starting an efavirenz-based regimen compared with those starting a ritonavir-boosted indinavir-based regimen. Sierra-Madero et al5 demonstrated the virological superiority of efavirenz over ritonavir-boosted lopinavir in combination with zidovudine and lamivudine in patients with a CD4 T-cell count <200/mm3.
The aim of this randomized clinical trial was to compare the immune reconstitution achieved using efavirenz-based HAART with that of a ritonavir-boosted PI–based regimen (atazanavir and lopinavir) in severely immunosuppressed antiretroviral-naive HIV-1–infected patients.
We performed an open-label trial in which HIV-1–infected patients with a CD4 T-cell count <100/mm3 were randomly assigned to receive an NNRTI-based antiretroviral regimen or a boosted PI–based regimen. Enrollment was between July 2007 and March 2010 (last visit for week 48 was on March 4, 2011). The study was approved by the Ethics Committees of the participating hospitals and the Spanish Agency for Medicines and Health Care Products and conducted in compliance with the Declaration of Helsinki, good clinical practice guidelines, and local regulations. Patients were adequately informed about the study objectives and signed a written informed consent form before enrollment.
Setting and Participants
This trial was conducted in 5 infectious diseases clinics in Catalonia, Spain. Investigators recruited participants among patients who attended at their centers after reviewing their medical records and completing screening procedures to assess eligibility. HIV-1–infected adults (age >18 years) were eligible if they were antiretroviral naive and had a baseline CD4+ T-cell count <100/mm3. Patients were excluded if they presented an active opportunistic infection requiring parenteral treatment or any contraindication to study drugs. Female patients were excluded if they were pregnant or breastfeeding.
Randomization and Interventions
Using a centralized computer-generated process, eligible patients were randomly assigned to 1 of 3 treatment arms in a 1:1:1 ratio, as follows: tenofovir (TDF, 300 mg daily) plus emtricitabine [FTC, 200 mg daily (Truvada, Gilead Sciences, Foster City, CA)] combined with efavirenz [EFV 600 mg daily (TDF + FTC + EFV, Atripla Bristol-Myers Squibb Company, Princeton, NJ USA & Gilead Sciences, Foster City, CA)] as the NNRTI or atazanavir–ritonavir [300/100 mg daily (Reyataz Bristol-Myers Squibb Company, Princeton, NJ/Norvir AbbVie Inc., North Chicago, IL)] or lopinavir–ritonavir [400/100 mg twice a day (Kaletra AbbVie Inc., North Chicago, IL)] as ritonavir-boosted PI.
Outcomes and Follow-up
Screening included a clinical assessment and laboratory evaluations (plasma HIV-1 RNA, T-cell subsets, hematology, and clinical biochemistry). After randomization, on-study evaluation included clinical visits at baseline and at weeks 4, 12, 24, 36, and 48. Plasma HIV-1 RNA was assessed at each visit using the local HIV-1 assay. Qualitative immunological studies were performed (immune activation, immune senescence, and apoptosis markers), and markers of inflammation, coagulation, and bacterial translocation were determined at baseline and at week 48. Viral resistance at the time of virological failure was tested for all patients who met the criteria for virological failure. Adherence to therapy and changes in body fat distribution were not assessed. Patients were followed for the entire trial regardless of whether they prematurely discontinued the assigned therapy.
Outcomes and Measurements
The primary outcome measure was the median increase in the number of CD4+ T cells at 48 weeks in the 3 arms. The secondary outcome measures were the proportion of patients with a plasma HIV-1 viral load <50 copies per milliliter, the incidence of side effects, disease progression, and death. An exploratory analysis of immune activation and senescence, apoptosis, inflammation, bacterial translocation, and coagulation was also performed.
In the intention-to-treat analysis, treatment was considered to have failed in patients who died, had a new category C event, withdrew consent, were lost to follow-up, had virological failure, or changed the antiretroviral drug class or treatment arm because of an adverse event.
In the on-treatment analysis, treatment failure was defined as death, appearance of a new category C event, or virological failure; data on patients who withdrew consent, were lost to follow-up, changed treatment arm, or discontinued study medication were censored. For the primary end point, only the results of the on-treatment analysis are reported.
Immune Activation and Apoptosis
Peripheral blood mononuclear cells were obtained by separation on a Ficoll–Hypaque centrifugation gradient (Biomedics-Biomérieux, Madrid, Spain). Subpopulations of CD3+, CD4+, and CD8+ cells were determined using 3-color flow cytometry at baseline and at months 6, 12, and 24, essentially as previously described.4 Data were analyzed using FlowJo software. Apoptosis was studied using annexin V-PE (BD PharMingen, San Jose, CA). Staining was performed in the presence of 5 mM CaCl2 after 18 hours of cultivation of peripheral blood mononuclear cells at 1 × 106 cells per milliliter in 24-well plates in the presence and absence of 1% phytohemagglutinin.
Inflammation, Bacterial Translocation, and Coagulation
Inflammation was assessed by quantifying serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin 6, and tumor necrosis factor alpha. The marker used for coagulation was D-dimer. All these markers were measured using available commercial kits following the manufacturer's instructions. CD14+ monocyte/macrophages secrete soluble CD14 (sCD14), which binds lipopolysaccharides (LPS) and proinflammatory cytokines, such as tumor necrosis factor and interleukin 1, on LPS stimulation. Thus, to establish evidence for direct chronic LPS stimulation in vivo and its correlation with bacterial translocation, we measured plasma sCD14 levels using a commercially available enzyme-linked immunosorbent assay (Human sCD14 Quantikine ELISA Kit, R&D Systems, Abingdon, UK).
Virological Studies and Resistance Tests
Plasma HIV-1 RNA was evaluated using Ultra Direct Assay (Roche Molecular Systems, Alameda, CA) with a lower limit of quantification of 50 copies per milliliter. In cases of virologic failure, serum samples were obtained and stored at −80°C until genotypic resistance tests were performed.
Adverse events were evaluated by means of spontaneous patient reports, open-ended questioning by the physician, physical examination, and assessment of laboratory test abnormalities. The severity of toxic effects was assessed using the AIDS Clinical Trial Group toxicity grading scale.6
Sample Size and Statistical Analysis
Sample size was calculated based on the immunological end point; immune response was assessed based on a study that investigated the effectiveness of triple combination therapies in antiretroviral-naive patients who did not have advanced infection7 and in a retrospective case–control study in patients who did.8 Sample size was computed to detect differences of 50/mm3 in the CD4+ T-cell count at week 48, assuming a mean increase of between 168/mm3 (95% confidence interval (CI): 145 to 191)7 and 185/mm3 in the best performing8 arm. A total of 36 patients per group were required for the noninferiority assessment, with a 2-sided alpha of 0.05 and a statistical power of 80%. For the calculation of change from baseline of the CD4+ T-cell count, patients who discontinued early due to virological failure were deemed to be failures (observed failure approach) and to have returned to their baseline level at subsequent visits (ie, baseline value carried forward). This approach has been used elsewhere.9 Continuous variables were expressed as median (interquartile range). Categorical variables were expressed as an absolute value and percentage. Fisher exact test was used to compare dichotomous variables. Differences in continuous variables were analyzed using the Mann–Whitney or Kruskall–Wallis tests for comparisons between the groups and the Wilcoxon signed-rank test for comparisons among the same group. The time to disease progression and death was estimated using the Kaplan–Meier method. The equality of the distributions of the times to an event between the groups was estimated using the generalized log-rank test. The statistical analysis was performed using Stata software (Stata Statistical Software, Release 9.2; StataCorp 2009, College Station, TX).
Baseline Patient Characteristics
Between July 2007 and March 2010, a total of 112 patients were screened for inclusion in the study. Of these, 89 were eligible and were randomized to the treatment arms. One patient in the atazanavir/ritonavir arm and 1 patient in the efavirenz arm did not start the study medication (Fig. 1) and were excluded from the final analysis. The baseline characteristics of the patients were homogeneous between the groups (Table 1).
According to the on-treatment analysis, the median (interquartile range) increase in CD4+ T-cell count after weeks 12, 24, 36, and 48 was as follows: +118 (66–168), +146 (89–189), +165 (115–242), and +193 (129–349) cells per cubic millimeter in the efavirenz arm; +146 (92–251), +182 (119–219), +211 (147–267), and +197 (146–238) cells per cubic millimeter in the boosted atazanavir arm; and +117 (78–170), +141 (115–222), +204 (126–274), and +206 (178–327) cells per cubic millimeter in the boosted lopinavir arm (P = nonsignificant for all time points by the Mann–Whitney test). The immune reconstitution induced by an efavirenz-based regimen in very advanced HIV-1–infected patients was similar to that induced by a ritonavir-boosted PI–based regimen (median difference of −18 cells per cubic millimeter with a 95% CI of −75 to 65.2 compared with the lopinavir arm; 4.5 cells per cubic millimeter with a 95% CI of −49.4 to 65.8 compared with the atazanavir arm; −2.9 cells per cubic millimeter with a 95% CI of −55.4 to 54 compared with both the atazanavir arm and the lopinavir arm).
Figures 2A, B show the trend for median CD4 cell increase in the 3 arms during the study and the proportion of patients reaching a CD4 T-cell count >200/mm3, respectively.
Immune Activation, Apoptosis, Inflammation, and Coagulation
According to the results of the on-treatment analysis, from baseline to week 48, a significant reduction in markers of immune activation, apoptosis, bacterial translocation, and inflammation (but not coagulation) was observed in this very immunosuppressed population, with no significant differences between the treatment arms at week 0 or at week 48.
Table 2 summarizes the trend for qualitative analysis of immunologic markers, as well as markers of inflammation, bacterial translocation, and coagulation at baseline and at week 48 for the 3 treatment arms.
Virologic and Resistance Outcomes
According to the intention-to-treat analysis, the percentage (95% CI) of patients who had reached the protocol-defined outcome measure of plasma viral load <50 copies per milliliter at week 48 was 64.3% (95% CI: 45.8 to 79.3), 56.7% (95% CI: 39.2 to 72.6), and 51.7% (95% CI: 34.4 to 68.6), in the efavirenz, atazanavir, and lopinavir arms, respectively (P = 0.63). According to the on-treatment analysis, the percentage of patients reaching a plasma viral load <50 copies per milliliter at 12 months by the time to loss of virological response algorithm was 85.71% (95% CI: 68.5 to 94.3), 80% (95% CI: 62.7 to 90.5), and 82.8% (95% CI: 65.5 to 92.4) (P = 0.88), respectively, for the efavirenz, atazanavir, and lopinavir arms. Figures 2C, D show the proportion of patients achieving plasma HIV-1 RNA plasma levels <50 copies per milliliter by the intention-to-treat analysis and on-treatment analysis. Unfortunately, as most virological failures presented low-grade viremia (between 51 and 400 copies per milliliter), genotypic resistance testing was attempted but none of the samples were amplified.
During the study, 1 patient developed a new CDC category B event (infection by varicella zoster virus). Data for new category C events and IRIS are shown in Table 3. The Kaplan–Meier curve for new CDC category C events and death did not show any significant difference between the study arms (data not shown). Ten patients stopped their assigned HAART. Seven patients were lost to follow-up or withdrew consent. Table S1 (see Supplemental Digital Content, http://links.lww.com/QAI/A644) shows in detail the clinical outcomes by both the intent-to-treat and on-treatment analyses.
The overall incidence of adverse events was similar in the 3 treatment arms. Table 3 summarizes reported adverse events by study arm. Seven patients changed their assigned treatment because of adverse events. At week 48, a lower level of triglycerides and total cholesterol was observed for atazanavir than for lopinavir (P = 0.03 for both comparisons). A trend toward lower triglyceride and total cholesterol levels at week 48 was observed when the atazanavir arm was compared with efavirenz (P = 0.1 and 0.08, respectively). No significant differences in levels of plasma glucose were detected between the treatment arms at any time point (data not shown). Tenofovir/emtricitabine was switched in 3 patients (2 in the atazanavir arm and 1 in the lopinavir arm).
The risk of death or disease progression is significantly higher in patients starting HAART with a CD4+ T-cell count <200 per cubic millimeter.2 Very few controlled trials have targeted treatment-naive HIV-1–infected individuals with advanced disease because a low CD4+ T-cell count and clinical AIDS are often considered exclusion criteria. Boosted PI–based regimens have good virological control and immune reconstitution in many CD4 T-cell count strata and are a favorable treatment option in patients with advanced HIV-1 disease because they ensure a stronger genetic barrier against the development of viral resistance. However, an efavirenz-based regimen could prove useful in some clinical settings (eg, a concomitant opportunistic infection such as tuberculosis) by enabling a lower pill burden (and therefore easier adherence) and fewer pharmacological interactions.10 When the Advanz-3 trial was started, very few data were available on the best antiretroviral treatment in HIV-1–infected individuals with a very low CD4+ T-cell count. In both the Advanz trial4 and a study by Sierra-Madero et al,5 efavirenz performed better than a boosted PI in terms of virological suppression but similarly in terms of immune reconstitution in patients with a CD4 T-cell count of <100/mm3 and 200/mm3, respectively. Both studies used zidovudine and lamivudine as the NRTI backbone. A post hoc analysis in the CASTLE trial11,12 demonstrated better virological suppression for ritonavir-boosted atazanavir than for ritonavir-boosted lopinavir in patients with a CD4+ T-cell count <50/mm3. In the A5142 study,13 which compared the efficacy of efavirenz and ritonavir-boosted lopinavir, efavirenz was significantly associated with a lower rate of virologic failure at 96 weeks, whereas lopinavir showed a higher CD4+ T-cell increase than efavirenz. The A5202 trial14 demonstrated similar viral activity for efavirenz and ritonavir-boosted atazanavir; no specific results were reported for patients with very low CD4+ T-cell counts.
In advanced patients, rapid virologic suppression and short-term immune reconstitution at CD4 T-cell counts of ≥200/mm3 would be desirable,15 since viremic patients with a lower CD4 T-cell count are exposed to a higher risk of disease progression and death during the first 6 months.16 For this reason, antiretroviral treatments able to achieve faster virologic control and immune reconstitution should be prescribed in very immunosuppressed patients.
We found that the immune reconstitution and virological suppression induced by an efavirenz-based regimen were similar to those induced by a boosted PI–based regimen (atazanavir/ritonavir or lopinavir/ritonavir) at 48 weeks. In the efavirenz and atazanavir groups, the proportion of patients reaching the threshold CD4+ T-cell count of 200/mm3 at 3 months was significantly higher than in the lopinavir arm; the percentage of patients reaching viral suppression at 12 months was similar in the 3 arms by both the intention-to-treat and the on-treatment analyses (Fig. 2C, D), although in the intention-to-treat analysis at 6 and 9 months, there was a nonsignificant trend toward higher rates of suppression for efavirenz and atazanavir than for lopinavir (P = 0.07) (Fig. 2C). Progression to AIDS and incidence of IRIS were similar in the 3 treatment arms. No deaths were recorded, although a potential selection bias should be taken into account because clinicians tend to exclude patients with more severe clinical conditions in this type of trials. Observational studies conducted in Western countries reported a mortality rate of 11%–16% in advanced patients at 1 year, with a poorer prognosis for those diagnosed with lymphoma at baseline, older patients, and patients with higher viral loads and lower CD4 T-cell counts.17,18
As for safety, efavirenz was tolerated as well as atazanavir and lopinavir. In contrast with the study by Sierra-Madero et al5 and the CASTLE trial,11 we used the newer formulation of lopinavir/ritonavir, which made it possible to reduce the pill burden and probably improved tolerability; in fact, the main reason for switching from the lopinavir arm was to avoid drug–drug interactions rather than side effects. The incidence of grades 3–4 side effects was similar in all 3 treatment arms. Consistent with the findings of previous studies,11,14 our results showed that atazanavir had a better lipid profile than that of lopinavir and efavirenz.
The correlation between immune activation, inflammation, bacterial translocation, and disease progression and death in patients with HIV infection has become increasingly evident in the last few years.19–23 Almost all currently available data on markers of immune activation, inflammation, coagulation, and bacterial translocation in very advanced patients are available in the context of observational studies.23–25 Very few authors have explored the impact of different antiretroviral regimens on these markers.4,26 Our study partly fills the gap in available data in this field. In our population, the median value for markers of immune activation, inflammation, coagulation, and bacterial translocation—but not D-dimer—were significantly higher than normal levels at baseline and decreased significantly after 1 year of effective HAART. We found that patients experienced a marked reduction in the expression of markers of immune activation, inflammation, and bacterial translocation at 1 year.
Our study is limited by its open-label design and insufficient statistical power to detect differences in secondary outcome measures between the 3 arms, although it did have sufficient power to detect noninferiority for the immunological outcome measure. Therefore, the conclusions we drew from the virological, clinical, and qualitative studies on immune activation, inflammation, coagulation, and bacterial translocation should be considered tentative. Another limitation is that we have not included an integrase inhibitor–based regimen as a comparator arm because integrase inhibitors were not available when the study was designed.
In conclusion, our study confirms previous data on the use of an NNRTI-based regimen in very advanced HIV-1–infected patients. Therefore, efavirenz-based treatments can be used reliably in HIV-1–infected patients with very low CD4 T-cell counts and high plasma HIV-1 RNA levels, at least in those who are expected to have good adherence and do not present transmitted mutations. With currently available data, lopinavir/ritonavir should be used with caution in patients with very advanced disease, since the results of our study and those of other trials indicate a trend toward slower virologic control. No significant differences in the decreased levels of markers of inflammation, coagulation, and bacterial translocation were observed between the treatment arms. Further controlled data are needed for other first-line regimens such as those comprising darunavir or integrase inhibitors in patients with very advanced HIV-1 infection.
The authors are indebted to the study participants.
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Members of the Advanz Study Group
- Trial Chairs.
- Jose M. Miro, Montserrat Plana, and José M. Gatell.
- Trial Coordinators and Monitors.
- Ana Cruceta and Helena Beleta
- Trial Statistician.
Participating Centers and Investigators (in alphabetical order):
(1) Hospital de Bellvitge-IDIBELL, University of Barcelona, Barcelona (Elena Ferrer, Daniel Podzamczer, Nerea Rozas); (2) Hospital Clínic—IDIBAPS, University of Barcelona, Barcelona (Fernando Agüero, Alberto C Guardo, Teresa Gallart, Felipe García, José M Gatell, Montserrat Loncà, Francisco Lozano, Christian Manzardo, Josep Mallolas, José M. Miró, Montserrat Plana, Laura Zamora); (3) Hospital Universitari Germans Trias i Pujol, Badalona (Isabel Bravo, Bonaventura Clotet, Roger Paredes, Joan Romeu); (4) Hospital Universitari de la Santa Creu i Sant Pau, Barcelona (Pere Domingo, Montserrat Fuster, Mar Gutiérrez, Gracia Mateo, Jessica Muñoz); and (5) Hospital Universitari Vall d'Hebron, Barcelona (Esteban Ribera, Marjorie Diaz, Adrian Curran).