Inflammatory biomarkers and soft tissue changes among patients commencing second-line antiretroviral therapy after first-line virological failure.

INTRODUCTION: We explored associations of inflammatory and immune activation biomarkers at baseline and percentage gain in peripheral and trunk fat and lean mass over 96 weeks in patients with confirmed virological failure initiating lopinavir-anchored second-line antiretroviral therapy (ART) regimens. METHOD: We measured baseline plasma concentration of interleukin (IL)-6, tumour necrosis factor (TNF), neopterin, IL-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, soluble cluster of differentiation 14 (sCD14), and soluble CD163 in 123 participants of the SECOND-LINE body composition substudy. Linear regression assessed the association between biomarkers and percentage gain in limb/trunk fat and lean mass, adjusting for age, nucleoside or nucleotide reverse transcriptase inhibitor (N(t)RTI) use, body mass index, ethnicity, smoking, viral load, CD4+ T-cell counts, smoking, duration of ART use, and cholesterol. RESULTS: Mean (standard deviation) age was 38 (7.3) years, CD4+ T-cell count was 252 (185.9) cells/µl, human immunodeficiency virus viral load was 4.2 (0.9) log10 copies/ml, 47% (58/123) were in the N(t)RTI arm (vs. raltegravir [RAL] arm in 53%); 56.1% (69/123) were females. In adjusted analyses, for every log10 increase in baseline levels of IL-6, neopterin, and D-dimer, the percentage gain in peripheral fat over 96 weeks was 11.8% (95% confidence interval [CI]: 0.9-22.6, P = 0.033); neopterin, 11.2% (95% CI: 3.2-19.2, P = 0.007); D-dimer 9.6% (95% CI: 3.1-15.9, P = 0.004), respectively. The associations remained significant when analysis was stratified by N(t)RTI vs. RAL and included only patients with viral suppression at week 48. A significant gradient in lean mass gain was seen across quartiles of IL-6, TNF, neopterin, hsCRP, D-dimer, and sCD14. CONCLUSION: Inflammatory biomarkers provide important mechanistic insights into the pathogenesis of limb fat and lean mass changes independently of ART.

Proctitis in gay and bisexual men. Are microscopy and proctoscopy worthwhile?

OBJECTIVES: We explored the association between nucleic acid amplification testing (NAAT) and rectal microscopy/proctoscopy findings and correlates of rectal STIs among 150 gay and bisexual men (GBM) diagnosed with proctitis at the Sydney Sexual Health Centre from March 2016 to October 2017. METHODS: From case files, we analysed risk behaviours, microscopy, proctoscopy and NAAT results for rectal STIs (Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, herpes simplex virus type 1/2, lymphogranuloma venereum and syphilis). χ2 test assessed the association between microscopy/proctoscopy findings and NAAT results. Linear regression assessed the association between NAAT positivity and correlates of rectal STIs. RESULTS: The mean age was 32.5 (9.8) years, 43% (65/150) were taking pre-exposure prophylaxis, 17% (26/150) were HIV positive and 24% (36/147) had multiple rectal STIs.Among GBM with documented proctoscopy findings (n=113), 58% (65/113) had discharge, 36% (41/113) had anorectal erythema and 25% (28/113) had bleeding. A quarter of GBM (28/113) had negative proctoscopy findings.Discharge found on proctoscopy (p=0.001), positive HIV status (p=0.030) and time since last receptive anal intercourse (p=0.028) were independently associated with NAAT positivity for any rectal STI. Discharge had a positive likelihood ratio of 1.6 (95% CI 1.0 to 2.4).Among those with documented microscopy findings (n=69), 59% (41/69) and 41% (28/69) were NAAT positive and negative, respectively. Among NAAT-positive GBM, 27 (66%) had polymorphonuclear cells (PMNs) (mean number of PMNs, 10 (SD 9) cells per oil immersion field), 1 (2%) had Gram-negative intracellular diplococci and 11 (27%) had negative findings. There was no significant association between microscopy findings and NAAT results (p=0.651) or the number of rectal STI (p=0.279). CONCLUSION: Microscopy does not reliably provide information necessary to tailor the management of GBM diagnosed with proctitis. Discharge found during proctoscopy may identify GBM with rectal STI. Services should consider recommendations to perform these investigations.

Relationship between untimed plasma lopinavir concentrations and virological outcome on second-line antiretroviral therapy.

BACKGROUND: Resource constraints in low and middle-income countries necessitate practical approaches to optimizing antiretroviral therapy outcomes. We hypothesised that an untimed plasma lopinavir concentration (UPLC) at week 12 would predict loss of virological response in those taking lopinavir as part of a second-line antiretroviral regimen. METHODS: We measured plasma lopinavir concentration at week 12 on stored samples from the SECOND-LINE study. We characterized UPLC as: detectable and optimal (≥1000 µg/l); detectable but suboptimal (≥25 to < 1000 µg/l); and undetectable (<25 µg/l). We used Cox regression to explore the relationship between UPLC and loss of virological response over 48 weeks and backwards stepwise logistic regression to explore the relationship between UPLC and other predictors of virological failure at week 48. RESULTS: At week 48, we observed virological failure in 15/32 (47%) and 53/485 (11%) of patients with undetectable and detectable UPLC, respectively, P < 0.001. Both suboptimal [adjusted hazard ratio (HR) 2.94; 95% confidence interval (CI) 1.54-5.62; P = 0.001], and undetectable (adjusted HR 3.55; 95% CI 1.89-6.64; P < 0.001) UPLC were associated with higher rates of loss of virological response over 48 weeks. In multivariate analysis, an independent association with virological failure at week 48 and undetectable UPLC was observed after adjustment (odds ratio 5.48; 95% CI 2.23-13.42; P < 0.01). CONCLUSION: In low and middle-income countries implementing a public health approach to antiretroviral therapy treatment, an untimed plasma drug concentration may provide a practical method for early identification of patients with inadequate medication adherence and facilitate timely corrective interventions to prevent virological failure.

Efficacy and safety of contemporary dual-drug antiretroviral regimens as first-line treatment or as a simplification strategy: a systematic review and meta-analysis.

BACKGROUND: Some guidelines recommended two-drug antiretroviral therapies as alternative regimens to triple therapy in selected patients with the aim of reducing drug burden and toxicity and preserving future treatment options. We aimed to assess the efficacy and safety of dual-therapy versus triple therapy as first-line treatment or in treatment simplification. METHODS: For this systematic review and meta-analysis, we searched Medline, Embase (via OVID), the Cochrane Trial Registry, and major conference proceedings for randomised trials published between Jan 1, 2008, and Dec 31, 2015. We included studies comparing dual-therapy (from two independent classes) antiretroviral regimens as a first-line or a switch strategy (in virologically suppressed individuals) with standard triple-drug regimens. Our primary outcome was the risk of virological failure (non-completion=failure) at the 48 week timepoint. We did a random-effect meta-analysis to pool the relative risk (RR) or odds ratio (OR) for each of the outcomes. FINDINGS: For the primary outcome, we included 21 studies (11 first-line and ten switch studies), providing data for 4821 individuals (2478 in dual-therapy groups and 2343 in control groups). Overall, the RR of failure with dual-therapy compared with triple-therapy (control) groups was 1·14 (95% CI 0·91-1·43). In first-line studies, the RR of failure for dual-therapy versus control groups was 1·17 (0·94-1·47; I(2)=51%), which reduced to 1·05 (0·86-1·28; I(2)=26%) on exclusion of maraviroc-containing studies. In switch studies, the RR of failure for dual-therapy versus control groups was 1·21 (0·72-2·02; I(2)=67%), which reduced to 1·13 (0·64-1·99; I(2)=61%) after exclusion of maraviroc-containing studies. In patients with a baseline viral load of more than 100 000 copies per mL, RR of failure for dual-therapy versus control groups was 1·24 (1·03-1·49), which reduced to 1·18 (0·94-1·47) on excluding maraviroc-containing studies. We recorded the ORs for dual-therapy versus control groups for serious adverse events (1·16 [0·92-1·48]), adverse events (0·82 [0·52-1·28]), and mutations (2·11 [1·32-3·36]). INTERPRETATION: Dual therapy, especially with regimens excluding maraviroc, could be safe and efficacious, particularly in patients with baseline viral loads of less than 100 000 copies per mL. However, dual therapy seems to have a greater risk of selecting resistance mutations compared with standard triple therapy. FUNDING: None.