Nicholas I. Paton

Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection

Background In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]). We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis. Methods and Findings Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively. Conclusions IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. Trial Registration: ClinicalTrials.gov (NCT00027352).

Inflammation, coagulation and cardiovascular disease in HIV-infected individuals.

Background The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors. Methods A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1st quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models. Results There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference). Conclusions In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.

Changes in Inflammatory and Coagulation Biomarkers: A Randomized Comparison of Immediate versus Deferred Antiretroviral Therapy in Patients With Hiv Infection

Objectives:Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naïve to antiretroviral therapy (ART) or off ART (6 months or longer) at study entry, risk of AIDS and serious non-AIDS events were increased for participants who deferred ART compared with those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART. Methods:Stored specimens for 254 participants (126 drug conservation [DC] and 128 viral suppression [VS]) who were naïve to ART or off ART (6 months or longer) were analyzed for interleukin-6, high sensitivity C-reactive protein, and D-dimer at baseline and Months 2 and 6. Results:At Month 6, 62% of the VS group had HIV RNA less than 400 copies/mL and median CD4 count was 190 cells/mm3 higher than for the DC group (590 versus 400 cells/mm3). Compared with DC, the VS group had 32% (95% confidence interval, 19%-43%) lower D-dimer levels at Month 6 (P < 0.001); differences were not significant for high sensitivity C-reactive protein or interleukin-6 levels. Conclusions:In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not interleukin-6 and high sensitivity C-reactive protein, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.

Lipoprotein particle subclasses, cardiovascular disease and HIV infection

OBJECTIVEnTo study the association of lipoprotein particles with CVD in a subgroup of HIV-infected patients who were enrolled in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. SMART was a trial of intermittent use of ART (drug conservation [DC]) versus continuous of ART (viral suppression [VS]).nnnMETHODSnIn a nested case-control study, lipoprotein particles (p) by nuclear magnetic resonance were measured at baseline and at the visit prior to the CVD event (latest levels) for 248 patients who had a CVD event and for 480 matched controls. Odds ratios (ORs) were estimated using conditional logistic models.nnnRESULTSnTotal, large and small HDL-p, but not VLDL-p nor LDL-p, were significantly and inversely associated with CVD and its major component, non-fatal coronary heart disease. The HDL-p associations with CVD were reduced after adjustment for high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer. Latest levels of total HDL-p were also significantly inversely associated with CVD; treatment interruption led to decrease of total HDL-p; adjusting for latest HDL-p did not explain the greater risk of CVD that was observed in the DC versus VS group.nnnCONCLUSIONSnLipoprotein particles, especially lower levels of small and large HDL-p identify HIV-infected patients at increased risk of CVD independent of other CVD risk factors.

Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial.

CONTEXTnTherapies to decrease immune activation might be of benefit in slowing HIV disease progression.nnnOBJECTIVEnTo determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline.nnnDESIGN, SETTING, AND PATIENTSnRandomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL.nnnINTERVENTIONnHydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks.nnnMAIN OUTCOME MEASURESnThe primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models.nnnRESULTSnThere was no significant difference in CD8 cell activation between the 2 groups (-4.8% and -4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, -0.6%; 95% CI, -4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (-85 cells/μL vs -23 cells/μL at week 48; difference, -62 cells/μL; 95% CI, -115 to -8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03).nnnCONCLUSIONnAmong HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication.nnnTRIAL REGISTRATIONnisrctn.org Identifier: ISRCTN30019040.

Inflammation Predicts Changes in High-Density Lipoprotein Particles and Apolipoprotein A1 Following Initiation of Antiretroviral Therapy

Background:The effects of HIV infection and antiretroviral therapy (ART) on usual lipid levels have been reported. The effects of initiating versus deferring ART on high-density and low-density lipoprotein particle (HDL-P and LDL-P, respectively) concentrations and apolipoprotein (Apo) levels are not well described. Methods:In a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) trial to immediately initiate ART (‘viral suppression group’) or to defer it (‘drug conservation group’), lipoprotein particle concentrations and ApoA1 and ApoB levels were measured at baseline and at 2 and 6 months following randomization. Results:Compared with drug conservation group (nu200a=u200a126), HDL-P and ApoA1 levels increased among viral suppression participants (nu200a=u200a128) after starting ART. At 6 months, viral suppression participants had 13% higher total HDL-P (Pu200a<u200a0.001) and 9% higher ApoA1 (Pu200a<u200a0.001). LDL-P, very low density lipoprotein particle, and ApoB did not differ significantly between the viral suppression and drug conservation groups. Among viral suppression participants, predictors of HDL-P and ApoA1 increases included baseline levels of high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6), but not HIV RNA level, CD4 cell count, or traditional cardiovascular disease risk factors. The effect of starting ART on changes in HDL-P and ApoA1 was greater for those with higher versus lower baseline levels of IL-6 (Pu200a=u200a0.001 and 0.08, respectively, for interaction) or hsCRP (Pu200a=u200a0.01 and 0.04, respectively, for interaction). Conclusion:HDL-P and ApoA1 increase following ART initiation, to a degree that depends on the degree of inflammation present at entry. These findings suggest that activation of inflammatory pathways contribute to HIV-associated changes in HDL.

Episodic antiretroviral therapy increases hiv transmission risk compared with continuous therapy: Results of a randomized controlled trial

Objective:To compare the HIV transmission risk among patients randomized to episodic versus continuous antiretroviral therapy. Design:This was a substudy of the Strategies of Management of Antiretroviral Therapy study, in which patients were randomized to continuous versus CD4+-guided episodic antiretroviral therapy. Participants were surveyed about sexual activity and needle sharing and had laboratory testing for gonorrhea, chlamydia, and syphilis. Results:A total of 883 patients were enrolled in this study, the mean age of the patients was 45 years, 25% were women, and 78% were on antiretroviral therapy. At baseline, 136 participants (15.4%) had high-risk behavior (vaginal or anal sex without a condom, needle sharing, or incident bacterial sexually transmitted infection). After randomization, the proportion of participants reporting high-risk behavior was stable and did not differ by randomized arm (P = 0.39). Among participants off therapy at baseline, high-risk behavior was less common 4 months after randomization among those who were randomized to start antiretroviral therapy (P = 0.03). HIV transmission risk (high-risk behavior while HIV RNA level >1500 copies/mL) with partners perceived to be HIV uninfected was higher in the episodic therapy arm (P = 0.02). Conclusions:Patients on episodic antiretroviral therapy did not decrease high-risk behavior, and because HIV RNA levels were higher, this strategy may result in increased HIV transmission.

Changes in facial fat in HIV-related lipoatrophy, wasting, and weight gain measured by magnetic resonance imaging.

Abstract Background: Changes in facial fat occurring over time in patients with HIV-related lipoatrophy have not been properly quantified. We aimed to define the longitudinal changes in facial fat compartments in patients with lipoatrophy and to compare these with changes accompanying wasting or weight gain. Method: Facial MRI scans were performed at baseline and repeated after a median of 10 months in 24 patients, of whom 12 had moderate to severe lipodystrophy continuing antiretroviral therapy, 5 lost weight, and 7 gained weight (more than 10% weight change). Results: Superficial facial fat decreased by a median of 5.2 mL (p = .03) in patients with lipoatrophy, and 8 of 12 individuals showed more than 15% decrease (all of whom were taking stavudine). The decrease was mainly cheek fat. Superficial facial fat decreased by 6.0 mL in patients with weight loss (p = .04) and increased by 20.2 mL (p = .02) in patients with weight gain, and changes occurred in cheek fat, temporal fat, and masseter muscle and temporalis muscle compartments. Conclusion: MRI can detect substantial ongoing changes in facial fat in patients with facial lipoatrophy. A characteristic pattern of compartmental change distinguishes lipoatrophy from wasting and weight recovery. MRI should be considered for use in clinical trials of interventions to prevent or treat lipoatrophy and may be useful for documenting changes in individual patients during clinical follow-up.

The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial: a randomised controlled trial of a protease inhibitor monotherapy strategy for long-term management of human immunodeficiency virus infection

BACKGROUNDnStandard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain.nnnOBJECTIVEnTo compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial.nnnDESIGNnOpen-label, parallel-group, randomised controlled trial.nnnSETTINGnForty-three HIV clinical centres in the UK NHS.nnnPARTICIPANTSnHIV-positive adults taking standard combination ART with a suppressed VL for ≥u20096 months.nnnINTERVENTIONSnPatients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-mono), with prompt return to combination therapy in the event of VL rebound.nnnMAIN OUTCOME MEASURESnThe primary outcome was reduction of future drug options, defined as new intermediate-/high-level resistance to one or more drugs to which the patients virus was considered to be sensitive at trial entry (non-inferiority comparison, 10% margin). Secondary outcomes included confirmed virological rebound, serious drug- or disease-related complications, total grade 3 or 4 adverse events (AEs), neurocognitive function change, cluster of differentiation 4 (CD4) cell count change, change in health-related quality of life, cardiovascular risk change, health-care costs and health economic analysis.nnnRESULTSnIn total, 587 participants were randomised (77% male, 68% white) to OT (nu2009=u2009291) or PI-mono (nu2009=u2009296) and followed for a median of 44 months, of whom 2.7% withdrew/were lost to follow-up. One or more episodes of confirmed VL rebound were observed in eight patients (Kaplan-Meier estimate 3.2%) in the OT group and 95 patients (35.0%) in the PI-mono group [absolute risk difference 31.8%, 95% confidence interval (CI) 24.6% to 39.0%; pu2009<u20090.001]. PI-mono patients who changed to ART after VL rebound all resuppressed (median 3.5 weeks). The proportions with loss of a future drug option at 3 years were 0.7% in the OT group and 2.1% in the PI-mono group (difference 1.4%, (95% CI -0.4% to 3.4%); non-inferiority demonstrated). There were no significant differences in serious disease complications between groups or in the frequency of grade 3 or 4 clinical AEs (16.8% OT group vs. 22% PI-mono group; absolute risk difference 5.1%, 95% CI -1.3% to 11.5%; pu2009=u20090.12). Overall, the PI-mono strategy was shown to be cost-effective compared with OT under most scenarios explored. PI-mono was cost saving because of the large savings in ART drug costs while being no less effective in terms of quality-adjusted life-years in the within-trial analysis and only marginally less effective when extrapolated to lifetime outcomes.nnnCONCLUSIONSnPI monotherapy, with prompt reintroduction of combination therapy for VL rebound, was non-inferior to combination therapy in preserving future treatment options and is an acceptable and cost-effective alternative for long-term management of HIV infection.nnnTRIAL REGISTRATIONnCurrent Controlled Trials ISRCTN04857074.nnnFUNDINGnThis project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 21. See the NIHR Journals Library website for further project information.