Safety and efficacy of pharmacotherapy containing INSTIs and chemotherapy drugs in people living with HIV and concomitant colorectal cancer.

BACKGROUND: Previous clinical data have shown that raltegravir-based antiretroviral therapy (ART) with fewer drug-drug interactions (DDIs) and adverse events (AEs) is a good regimen in patients with HIV infection who need cancer chemotherapy. There are currently few data on ART regimens that include Integrase inhibitors (INSTIs) other than RAL among this patient subgroup. METHODS: We evaluated the safety and efficacy of different kinds of INSTI-based regimens among patients with HIV and concomitant colorectal cancer (CRC) who received antineoplastic agents. RESULTS: From January 2020 to November 2021, 66 patients were enrolled. The patients were divided into three groups: 20 patients treated with dolutegravir (DTG)/lamivudine (3TC)/tenofovir (TDF) (group I), 24 patients treated with DTG/albuvirtide (ABT) (group II), and 22 patients treated with bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) (group III). The majority of AEs during treatment were of grade 1-2. Treatment-related AEs of grade 3-4 occurred in 6 patients (9.09%), and no grade 5 AEs occurred. The most common AEs were nausea (100%) and neutrophils (84.85%) attributed to anticancer agents, and there was no significant difference in the incidence of these AEs among the three groups (P > 0.05). Viral load rebound was not observed among pretreated patients during chemotherapy. The viral load of untreated patients who started their ART concomitant with chemotherapy almost decreased to the lower limit of detection 6 months after ART initiation (only one patient in group III had a viral load of 102 copies/ml). At the 6th month, the CD4 count in group I decreased significantly from baseline (P < 0.05). However, the change in CD4 count was not significant in group II (P = 0.457) or group III (P = 0.748). CONCLUSIONS: DTG- or BIC-containing regimens are good options for patients with HIV and concomitant CRC.

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.

ABSTRACT: High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Inflammatory Myositis Secondary to Anti-Retroviral Therapy in a Child; Case Report and Review of the Literature.

Here, we describe a five year old girl with congenital HIV who had a six-week onset of rapidly deteriorating mobility and progressive proximal muscle weakness, associated with a raised Creatine Kinase (CK) level of 4330 U/L [25-200 U/L], subsequently diagnosed with an inflammatory myositis. Potential causes were investigated by paediatric neurology and immunology teams. Her viral load had been undetectable over the preceding two years, excluding a primary HIV myositis. While MRI scanning did not show evidence of definite myositis, a muscle biopsy showed evidence of an inflammatory process, comprising a moderate endomysial, perimysial and perivascular mononuclear (CD8 + T cell) infiltrate with increased MHC expression. No particular features of dermatomyositis or immune-mediated necrotising myopathy were identified and there were no features of an inclusion body myositis.Given the absence of active HIV infection, the role of anti-retroviral medications was considered. She had had a recent switch in medication, from twice daily Raltegravir (an Integrase Strand Transfer Inhibitor, INSTI) to once daily Dolutegravir (an INSTI) while continuing on an established daily protocol of Abacavir and Lamivudine (Nucleoside Reverse Transcriptase Inhibitors). Changing the Dolutegravir back to Raltegravir, in combination with continuing Lamivudine and Abacavir for two months made no difference to her weakness or CK levels. Moreover, this drug regimen had been well-tolerated over the preceding 19 month period. Changing the anti-retroviral regime completely to a single drug class (Protease Inhibitors) of Ritonavir and Darunavir, resulted in a dramatic improvement in her symptomatology. Within ten days she regained the ability to stand and walk, with a reduction in her CK from 1700 U/L at time of switch to 403 U/L [25-200]. This case highlights the potential risk of developing inflammatory myositis from anti-retrovirals even 19 months into treatment.

Pharmacokinetics and Safety of a Raltegravir-Containing Regimen in Children Aged 4 Weeks to 2 Years Living With Human Immunodeficiency Virus and Receiving Rifampin for Tuberculosis.

Pharmacological interactions limit treatment options for children living with human immunodeficiency virus (HIV) and tuberculosis (TB). We found that 12 mg/kg twice daily raltegravir chewable tablets (administered after crushing) safely achieved pharmacokinetic targets in children living with HIV aged 4 weeks to <2 years receiving concurrent rifampin to treat TB. CLINICAL TRIALS REGISTRATION: NCT01751568.

Early changes in bone turnover and inflammatory biomarkers and clinically significant bone mineral density loss over 48 weeks among HIV-infected patients with virological failure of a standard first-line antiretroviral therapy regimen in the SECOND-LINE study.

OBJECTIVES: We assessed whether changes at week 12 in markers of bone turnover, inflammation, and immune activation were associated with clinically important (≥ 5%) bone mineral density (BMD) loss from baseline to week 48 at the proximal femur (hip) and lumbar spine in the SECOND-LINE study. METHODS: We measured concentrations of procollagen type 1 pro-peptide (P1NP), carboxyl-terminal collagen crosslinks (CTX), high-sensitivity C-reactive protein (hs-CRP), D-dimer, interleukin (IL)-6, tumor necrosis factor (TNF), neopterin, and soluble CD14 and 163 at weeks 0, 12, and 48 in 123 SECOND-LINE dual-energy X-ray absorptiometry (DXA) substudy participants. Linear regression was used to compare changes in biomarkers. Predictors of ≥ 5% BMD loss were examined using multivariable regression. RESULTS: The mean age was 38 years, the mean CD4 T-cell count was 252 cells/µL and the mean viral load was 4.2 log HIV-1 RNA copies/mL; 56% of participants were female and 47% were randomized to receive a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI]-based regimen [91% (53/58) were randomized to receive a tenofovir disoproxil fumarate (TDF)-containing regimen]. Over 48 weeks, 71% in the N(t)RTI arm experienced ≥ 5% hip BMD loss vs. 29% in the raltegravir arm (P = 0.001). Week 12 changes in P1NP and CTX were significantly greater among patients experiencing ≥ 5% hip BMD loss, patients randomized to N(t)RTI, and male patients. Predictors of ≥ 5% hip BMD loss at week 48 were P1NP increase [odds ratio (OR) 5.0; 95% confidence interval (CI) 1.1-27; P < 0.043]; N(t)RTI randomization (OR 6.7; 95% CI 2.0-27.1; P < 0.003), being African, higher baseline CD4 T cell count , and smoking. CONCLUSIONS: In a diverse cohort of viraemic HIV-infected patients, switching to second-line antiretroviral therapy (ART) was associated with clinically significant BMD loss, which was correlated with an early increase in P1NP. Measurement of P1NP may facilitate timely interventions to reduce rapid BMD loss among at-risk patients.

Association of raltegravir use with long-term health outcomes in HIV-infected patients: an observational post-licensure safety study in a large integrated healthcare system.

BACKGROUND: Raltegravir became the first integrase inhibitor to gain FDA approval; but with limited evidence documenting long-term risks in real world care, especially for major health outcomes of interest. OBJECTIVE: Assess raltegravir safety in clinical practice within an integrated health system. METHODS: We conducted a cohort study of HIV-infected adults within Kaiser Permanente California from 2005 to 2013. We compared patients initiating raltegravir during the study period with two groups; a historical cohort (started new antiretroviral regimen [ART] 2005-2007) and a concurrent cohort that did not initiate raltegravir (2007-2013). We used multivariate Cox proportional hazard regression to obtain hazard ratios (HR) for pre-specified incident health outcomes, employing propensity scores to adjust for potential confounding. RESULTS: The population included 8,219 HIV-infected adults (raltegravir cohort N = 1,757; 4,798 patient-years), with greater years known HIV-infected among raltegravir patients. The raltegravir cohort had increased HR for AIDS-defining (HR 2.69 [1.53-4.71]; HR 1.85 [1.21-2.82]) and non-AIDS-defining malignancies (HR 2.26 [1.29-3.94]; HR 1.88 [1.26-2.78]) relative to both comparison cohorts. Compared to the historical cohort we found no significant difference in all-cause mortality; the raltegravir cohort experienced increased HR for all-cause mortality compared to concurrent (HR 1.53 [1.02-2.31]). Raltegravir appeared protective of lipodystrophy when compared to the historical cohort but associated with increased incidence compared to concurrent. There were no significant differences in the incidence of hepatic, skin, or cardiovascular events. CONCLUSIONS: The potentially elevated risk for malignancy and mortality with raltegravir and residual confounding merits further investigation. We demonstrate the value of observational cohorts for monitoring post-licensure medication safety.

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals.

The use of antiretroviral (ARV) drugs with central nervous system (CNS) penetration effectiveness (CPE) may be useful in the treatment of HIV-associated neurocognitive disorder (HAND) as well as targeting a CNS reservoir in strategies to achieve a functional cure for HIV. However, increased cognitive deficits are linked to at least one of these drugs (efavirenz). As mitochondrial dysfunction has been found with a number of ARVs, and as such can affect neuronal function, the objective of this study was to assess the effects of ARV with high CPE for toxicological profiles on presynaptic nerve terminal energy metabolism. This subcellular region is especially vulnerable in that a constant supply of ATP is required for the proper maintenance of neurotransmitter release and uptake supporting proper neuronal function. We evaluated the effects of acute treatment with ten different high CPE ARVs from five different drug classes on rat cortical and striatal nerve terminal bioenergetic function. While cortical nerve terminal bioenergetics were not altered, striatal nerve terminals exposed to efavirenz, nevirapine, abacavir, emtricitabine, zidovudine, darunavir, lopinavir, raltegravir, or maraviroc (but not indinavir) exhibit reduced mitochondrial spare respiratory capacity (SRC). Further examination of efavirenz and maraviroc revealed a concentration-dependent impairment of striatal nerve terminal maximal mitochondrial respiration and SRC as well as a reduction of intraterminal ATP levels. Depletion of ATP at the synapse may underlie its dysfunction and contribute to neuronal dysfunction in treated HIV infection.

Changes in Liver Steatosis After Switching From Efavirenz to Raltegravir Among Human Immunodeficiency Virus-Infected Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND: Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues. METHODS: HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP. RESULTS: Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1-Q3, 221-277) dB/m and 286 (Q1-Q3, 269-314) dB/m for the EFV group (P = .035). The median decrease in CAP values was -20 (Q1-Q3, -67 to 15) dB/m for the RAL arm and 30 (Q1-Q3, -17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029). CONCLUSIONS: After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL. CLINICAL TRIALS REGISTRATION: NCT01900015.

Safety of raltegravir-based antiretroviral therapy in HIV-infected patients receiving multi-kinase inhibitors.

Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and anti-cancer systemic treatments. We aimed to evaluate the safety profile of raltegravir-based HAART in cancer patients receiving multi-kinase inhibitors (MKIs). Patients and Methods We conducted a retrospective medical record review of adult, HIV-infected cancer patients treated in our institutions from January 2010 to December 2015. Patients eligible for the present analysis were those receiving a raltegravir-based HAART at the time of the initiation of a MKI for the treatment of advanced solid tumors. Treatment-related toxicity, virological outcomes and pharmacokinetic profile of MKIs were examined. Results Twelve patients (7 males, median age 55 years) were identified. Seven had sarcoma/GIST, 3 had hepatocellular carcinoma, one had pancreatic neuroendocrine tumor, and one had NSCLC. Patients received the following MKIs: imatinib (n = 3), sorafenib (n = 3), pazopanib (n = 3), sunitinib (n = 2) and erlotinib (n = 1). The mean CD4+ count at baseline was 929 cells/mm3, and 860 cells/mm3 after completion of MKI treatment. In all patients, HIV viral loads remained below the limit of detection (40 copies/ mm3) during the whole MKI treatment. No virological failure occurred. No unexpected or serious adverse event related either to raltegravir-based HAART or to MKIs was observed. The trough plasma concentrations of MKIs were assessed in 8 patients, and were found normal in all but one case (not related to raltegravir-based HAART). Conclusions The present data represent the first documentation of the concomitant use of raltegravir-containing HAART and MKIs in HIV-infected adult patients with advanced non-AIDS defining malignancies, with a reassuring safety profile.

Renal effects of novel antiretroviral drugs.

Chronic kidney disease (CKD) is a critical comorbidity for patients living with HIV, with an estimated prevalence between 2.4 and 17%. Such patients are increasingly affected by diseases associated with ageing, including cardiovascular disease and CKD, and the prevalence of risk factors such as smoking and dyslipidaemia is increased in this population. Proteinuria is also now recognized as a common finding in individuals living with HIV. While combination antiretroviral (ARV) treatments reduce CKD in the HIV-infected population overall, some ARV drugs have been shown to be nephrotoxic and associated with worsening renal function. Over the last few years, several highly efficacious new ARV agents have been introduced. This brief review will look at the novel agents dolutegravir, raltegravir, elvitegravir, cobicistat, tenofovir alafenamide fumarate and atazanavir, all of which have been licensed relatively recently, and describe issues relevant to renal function, creatinine handling and potential nephrotoxicity. Given the prevalence of CKD, the wide range of possible interactions between HIV, ARV therapy, CKD and its treatments, nephrologists need to be aware of these newer agents and their possible effect on kidneys.

Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir.

OBJECTIVES: Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once-daily regimen (QD) at a dose of 1200 mg is under development. The effect of calcium carbonate and magnesium/aluminium hydroxide antacids on the pharmacokinetics of a 1200 mg dose of raltegravir was assessed in this study. METHODS: An open-label, four-period, four-treatment, fixed-sequence study in 20 HIV-infected patients was performed. Patients needed to be on raltegravir as part of a stable treatment regimen for HIV, and upon entry into the trial received 5 days of 1200 mg raltegravir as pretreatment, before they entered the four-period study: 1200 mg of raltegravir alone (period 1), calcium carbonate antacid as TUMS® Ultra Strength (US) 1000 and 1200 mg raltegravir given concomitantly (Period 2), magnesium/aluminium hydroxide antacid as 20 ml MAALOX® Maximum Strength substitute MS given 12 h after administration of 1200 mg raltegravir (period 3), and calcium carbonate antacid as TUMS® US 1000 given 12 h after administration of 1200 mg raltegravir (period 4). Patients received their dose of 1200 mg QD raltegravir during the intervals between periods to re-establish steady state. AUC0-24 , C24 , Cmax and Tmax were calculated from the individual plasma concentrations of 1200 mg QD raltegravir after administration alone or with a calcium carbonate antacid or with a staggered dose of a calcium carbonate antacid or magnesium/aluminium hydroxide antacid. Adverse events, in addition to laboratory safety tests (haematology, serum chemistry and urinalysis), 12-lead electrocardiograms and vital signs were assessed. KEY FINDINGS: All treatments were well tolerated in the study. Metal-cation antacids variably affected the pharmacokinetics of 1200 mg QD raltegravir. When calcium carbonate antacid was given with 1200 mg raltegravir concomitantly, the geometric mean ratio (GMR) and its associated 90% confidence interval (90% CI) for AUC0-24 , Cmax and C24 h were 0.28 (0.24, 0.32), 0.26 (0.21, 0.32) and 0.52 (0.45, 0.61), respectively. When calcium carbonate antacid and magnesium/aluminium hydroxide were given 12 h after raltegravir 1200 mg QD dosing, the GMR (90% CI) values for AUC0-24 and Cmax were 0.90 (0.80, 1.03), 0.98 (0.81, 1.17), and 0.86 (0.73, 1.03), 0.86 (0.65, 1.15), respectively. However, significant reduction in the trough concentrations of raltegravir was observed: C24 h 0.43 (0.36, 0.51) in the presence of calcium carbonate antacids and 0.42 (0.34, 0.52) in presence of magnesium/aluminium hydroxide, respectively. CONCLUSIONS: Overall, the use of metal-cation antacids with 1200 mg QD raltegravir is not recommended.

Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial.

BACKGROUND: Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen. METHODS: Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per µL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants. FINDINGS: Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group). INTERPRETATION: A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide. FUNDING: The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories.

A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice.

BACKGROUND: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of high-dose integrase inhibitors. METHODS: C57BL/6 mice were fed standard water (CTRL, n = 6), raltegravir-containing water (40 mg/kg/day, n = 6), or dolutegravir-containing water (2.7 mg/kg/day, n = 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. RESULTS: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p < 0.05) compared to control (raltegravir = 0.25 mg/dl, dolutegravir = 0.30 mg/dl versus CTRL = 0.17 mg/dl). Blood urea nitrogen, cystatin C, and urine microalbumin were unchanged. Kidney injury molecule-1 tissue expression in raltegravir and dolutegravir groups was nonsignificantly elevated compared to control (1.2-fold compared to control). Renal histopathology by periodic acid-Schiff staining failed to reveal glomerular or tubular renal injury in any group. CONCLUSION: These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy.

Changes in Bone Mineral Density After Initiation of Antiretroviral Treatment With Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir.

BACKGROUND: Specific antiretroviral therapy (ART) medications and the severity of human immunodeficiency virus (HIV) disease before treatment contribute to bone mineral density (BMD) loss after ART initiation. METHODS: We compared the percentage change in BMD over 96 weeks in 328 HIV-infected, treatment-naive individuals randomized equally to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL). We also determined whether baseline levels of inflammation markers and immune activation were independently associated with BMD loss. RESULTS: At week 96, the mean percentage changes from baseline in spine and hip BMDs were similar in the protease inhibitor (PI) arms (spine: -4.0% in the ATV/r group vs -3.6% in the DRV/r [P = .42]; hip: -3.9% in the ATV/r group vs -3.4% in the DRV/r group [P = .36]) but were greater in the combined PI arms than in the RAL arm (spine: -3.8% vs -1.8% [P < .001]; hip: -3.7% vs -2.4% [P = .005]). In multivariable analyses, higher baseline concentrations of high-sensitivity C-reactive protein, interleukin 6, and soluble CD14 were associated with greater total hip BMD loss, whereas markers of CD4(+) T-cell senescence and exhaustion (CD4(+)CD28(-)CD57(+)PD1(+)) and CD4(+) T-cell activation (CD4(+)CD38(+)HLA-DR(+)) were associated with lumbar spine BMD loss. CONCLUSIONS: BMD losses 96 weeks after ART initiation were similar in magnitude among patients receiving PIs, ATV/r, or DRV/r but lowest among those receiving RAL. Inflammation and immune activation/senescence before ART initiation independently predicted subsequent BMD loss.

Sustained increase of serum creatine phosphokinase levels and progressive muscle abnormalities associated with raltegravir use during a 32-week follow-up in an HIV-1 experienced patient on simplified HAART regimen, intolerant to protease inhibitors and abacavir: a case report / Aumento sostenido de los niveles de creatina fosfoquinasa sérica y las anormalidades musculares progresivas asociadas con el uso de raltegravir durante un seguimiento de 32 semanas en un paciente de VIH-1 experimentado en régimen de terapia TAAA simplificada, con intolerancia a los inhibidores de proteasa y abacavir: un reporte de caso

Sustained increase of serum creatine phosphokinase (CPK) concentrations and muscle abnormalities have been reported in patients taking raltegravir (RAL). In this report, we describe a case of sustained and asymptomatic increase of serum CPK concentrations associated with raltegravir, zidovudine, and lamivudine in an HIV-1 experienced patient with intolerance to protease inhibitor, abacavir and pencillin during 32 weeks of continuous drug monitoring.

Un aumento sostenido de las concentraciones de creatina fosfoquinasa sérica (CPK) y las anormalidades musculares ha sido reportado en relación con pacientes que toman raltegravir (RAL). En este reporte, describimos un caso de aumento sostenido y asintomático de concentraciones séricas de CPK asociadas con raltegravir, zidovudina y lamivudina en un paciente experimentado de VIH-1 con intolerancia al inhibidor de la proteasa, al abacavir y la penicilina durante 32 semanas de monitoreo farmacológico continuo.