These results illustrate that changes in triglyceride levels over 12 weeks of treatment were similar in subjects treated with DRV/r-based and ATV/r-based regimens. Additionally, small changes in lipids and insulin sensitivity, decreases in biomarkers, small changes in body fat, improvements in efficacy parameters, and a low incidence of AEs were seen over 48 weeks in both treatment arms. In the DRV/r arm, the increase in apoA1, the major component of HDL, indicates favorable lipid changes that support the return-to-health phenomenon observed in subjects with lower CD4+
cell counts initiating ARV therapy.38
The small changes in lipids seen in this trial with DRV/r are in agreement with results from the ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects) trial of 689 treatment-naive subjects, which showed that once-daily DRV/r had a more favorable metabolic profile compared with that of lopinavir (LPV)/r.39
Subjects infected with HIV-1 have increased levels of hs-CRP, TNF alpha (TNF-α), IL-6, d
-dimer, and other biomarkers compared with HIV-negative subjects.2,40–42
These elevations in biomarkers persist even after virologic suppression, likely due to HIV-induced activation of inflammation and coagulation pathways.2
Levels of TNF-α, IL-6, hs-CRP, and other proinflammatory cytokines are associated with HIV-1 viral load and may predict disease progression, as well as correlate with a higher risk of CVD and all-cause mortality.42–45
Our findings corroborate another recent analysis, which reported that only d
-dimer, and not IL-6 or hs-CRP, is reduced over the short term in those initiating ARV therapy.46
Additionally, the reductions in LPS observed here are similar in magnitude to those seen in a previous study47
; the similar reductions in the DRV/r and ATV/r arms suggest that these ARV agents do not result in differential levels of LPS, a trigger of persistent immune activation in ARV-treated individuals. In contrast, no decreases in hs-CRP were seen in either arm of this study over 48 weeks; this observation is in agreement with the ACTG (AIDS Clinical Trials Group) A5095 study, which demonstrated similar results in subjects receiving efavirenz-based regimens over 96 weeks.48
During HIV infection, chronic viremia induces progressive immune dysregulation characterized broadly by a decrease in CD4+
cells and an increase in CD8+
cells and specifically by elevated expression of CD38 and HLADR. This persistent immune activation yields rapid and elevated lymphocyte turnover and a shift to an immunosenescent phenotype (CD28−
As expected, based on the results of previous studies demonstrating the mitigating effect of ARV therapy on these processes,51–53
the current study found reductions in the proportion of activated T cells (CD38−
) in both the DRV/r and ATV/r arms. Furthermore, the decline in the proportion of cells with an immunosenescent phenotype (CD28−
) illustrates the relationship between immune activation and immunosenescence and a critical immunologic benefit of ARV therapy.
Individuals infected with HIV-1 have a higher risk of serious, non-AIDS conditions than do uninfected subjects.1
Given that HIV infection is now considered a manageable chronic disease, there is a growing level of attention focused on the need for identification of metabolically favorable ARVs. Atazanavir has generally been considered to have the most favorable metabolic profile among PIs34
and was, therefore, chosen as a comparator drug for this study. In the study presented here, changes in metabolic parameters and biomarkers from baseline with DRV/r were comparable to changes observed with ATV/r. These results are in agreement with those seen in the TMC114-C159 trial, which investigated metabolic changes in healthy subjects treated with DRV/r or ATV/r over 28 days and observed similar mean changes in lipid and glucose parameters between treatment groups.33
The TMC114-C159 trial did report significant differences in the changes between treatment arms for insulin and the TC/HDL ratio; these results, however, were not observed in METABOLIK, which noted differences between arms only in changes in TNF RII over 48 weeks.
The effect of some boosted PIs on insulin sensitivity remains controversial. In contrast to some other PIs,8,10,11
no clinically significant changes were seen in insulin sensitivity in either the DRV/r or ATV/r arm of this study. Treatment with indinavir and treatment with LPV/r have both been associated with the development of insulin resistance in healthy subjects9–11
; however, other studies have demonstrated that LPV/r does not affect insulin sensitivity in healthy subjects.12,13
Atazanavir has generally had little effect on insulin sensitivity in previous trials of HIV-negative subjects,10,12
and switching from other PI-based therapies to ATV/r has been shown to improve insulin sensitivity in HIV-1-infected subjects.54
The results from this trial suggest that DRV/r, likewise, has little impact on insulin sensitivity. It should be noted that unlike the other studies cited here, which used the euglycemic, hyperinsulinemic clamp technique, this study used HOMA-IR as a measure of insulin resistance. However, several studies have demonstrated that results obtained using HOMA-IR correlate well with results using the euglycemic, hyperinsulinemic clamp technique.36,55
Slight reductions in creatinine clearance were seen from baseline to week 12 in both treatment arms of this study; however, these reductions were no longer apparent after 48 weeks of treatment. A previous study suggested an association between the use of ATV, TDF, or indinavir and creatinine clearance, as indicated by a persistent reduction in glomerular filtration rate over time.56
The biological explanations for these findings are unclear, but may include glomerular dysfunction, high renal excretion rates, and/or crystalluria.56
Though the current study observed modest changes over 48 weeks, the ARTEMIS study did not show any changes in creatinine clearance over 96 weeks,39
suggesting that long-term use of DRV/r has little effect on creatinine clearance.
The small increases in TAT and SAT seen in this study are similar to those seen in previous trials of boosted PIs and nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-naive subjects.19–22,24
Increases in abdominal fat and waist size have been associated with increased cardiovascular risk factors in HIV-1-infected subjects, suggesting a need to monitor even small changes in fat distribution in this population. The increase in PAT seen with DRV/r treatment in this study was in contrast to data from other studies, which have reported decreases in PAT in HIV-1-infected individuals receiving other ARVs.19,20,22
Although some studies have demonstrated an association between lipoatrophy and use of specific PIs or NRTIs,19,22
others have shown no ARV-specific effects,20
and it has been observed that HIV-1-infected subjects, in general, have lower levels of PAT compared with uninfected control subjects.57
The increase in PAT in the DRV/r arm of this study, which had more advanced disease at baseline compared with the ATV/r arm, can be considered as potentially favorable; however, the small sample size and short duration of this trial limit clinical interpretation of these data.
In this study, despite slight increases in VAT and SAT, subjects' perceptions of their body changes generally improved or remained constant over time. The results from the ABCD questionnaire are in line with those from a previous study, which demonstrated improvements in ABCD scores over 48 weeks of DRV/r-based therapy.30
In both treatment arms, the question “In the past 4 weeks has your belt or waist size increased?” had the greatest increase in subjects answering “yes” at 48 weeks compared with baseline; this result is consistent with the increases in VAT and SAT seen during the trial. Although changes in adipose tissue distribution over the study period were similar between arms, more DRV/r subjects reported increases in waist and chest size compared with ATV/r subjects. This discrepancy may indicate subtle differences in lipodystrophy and lipoatrophy between the two treatment regimens, or may have been partially due to the differences in racial distribution between the two study arms.
Both regimens had favorable safety profiles, with low incidences of AEs and laboratory abnormalities; the increased incidence of grade 2–4 hyperbilirubinemia or grade 2–4 increased total bilirubin in the ATV/r arm was expected, as they are known side effects of ATV/r-based therapy.34,58
Similar to the results obtained here, safety results from ARTEMIS suggested low rates of grade 2–4 AEs, including gastrointestinal and renal AEs, in subjects receiving DRV/r over 96 weeks.39
Subjects receiving DRV/r in ARTEMIS had a significantly lower rate of diarrhea compared with LPV/r subjects (4% vs. 11%, respectively) and, in line with results from this trial, no clinically relevant changes were seen in creatinine clearance in either treatment arm.
Interpretation of the data reported in this pilot study may be limited by the small sample size, as well as the fact that the trial was not powered to test for statistical significance, but was rather intended to be an exploratory analysis. The variation seen between arms in certain baseline characteristics, despite the randomized study design, is likely related to the small sample size. Somewhat larger changes in TC and apoA1 with DRV/r versus ATV/r, particularly at week 12, are likely due to lower baseline values of these parameters in the DRV/r arm. Likewise, the larger reduction in TNF RII is likely due to the higher baseline value in the DRV/r arm. Additionally, it should be noted that subjects with abnormal lipid or glucose levels were excluded from the trial and may not, therefore, be reflective of the overall HIV-1-infected population. Despite these limitations, the equally favorable metabolic profile observed with DRV/r-based therapy when compared with ATV/r-based therapy warrants further investigation. It is noteworthy that the ACTG is conducting a large study of approximately 1800 treatment-naive, HIV-1-infected subjects receiving DRV/r, ATV/r, or raltegravir (all receiving fixed-dose FTC/TDF in the background regimen); end points from this study include changes in metabolic parameters over 144 weeks (clinicaltrials.gov identifier: NCT00811954). This study is statistically powered to definitively evaluate whether DRV/r-based therapy and ATV/r-based therapy are characterized by similarly favorable metabolic profiles.