Striking differences in weight gain after cART initiation depending on early or advanced presentation: results from the ANRS CO4 FHDH cohort.

BACKGROUND: Many studies have reported weight gain in ART-naive people living with HIV (PWH) initiating an integrase strand-transfer inhibitor-based regimen. We studied the impact of early or advanced presentation and that of individual drugs in PWH initiating combined ART (cART) between 2012 and 2018. METHODS: From the French Hospital Database HIV cohort, we assessed factors associated with a weight gain  ≥10%, weight change after cART initiation or BMI increase  ≥5 kg/m2 up to 30 months. The analyses were conducted overall, and among PWH with early (primary infection or CD4 >350/mm3 and viral load  <100 000 copies/mL, without AIDS) and advanced presentation (AIDS or CD4 <200/mm3, not during primary infection). RESULTS: At 30 months, 34.5% (95% CI: 33.5-35.6) of the 12 773 PWH had a weight gain ≥10%, with 20.9% (95% CI: 19.6-22.2) among the 5794 with early presentation and 63.1% (95% CI: 60.9-65.3) among the 3106 with advanced presentation. Weight gain was 2.8 kg (95% CI: 2.0-3.7) for those with early presentation and 9.7 kg (95% CI: 8.4-11.1) for those with advanced presentation. Most weight gain occurred in the first 12 months. Underweight and obese PWH were at significantly higher risk of a BMI increase  ≥5 kg/m2 than normal-weight PWH. Results differed within classes and by outcome. Raltegravir and dolutegravir were consistently associated with greater weight gain than the other third agents. Tenofovir alafenamide was also associated with higher weight gain than tenofovir disoproxil or abacavir. CONCLUSIONS: After initiating cART, PWH with early presentation exhibited a small weight gain, whereas it was large among those with advanced presentation. The choice of ART should account for the risk of weight gain, especially for PWH who present with advanced disease and/or are obese.

Therapeutic Perspectives in the Systemic Treatment of Kaposi's Sarcoma.

In patients with Kaposi's sarcoma (KS), the therapeutic goal is to achieve a durable remission in the size and number of skin and visceral lesions. Although most patients show tumor regression in response to standard systemic chemotherapy regimens, alternative systemic treatments are needed for patients who develop refractory KS. Anti-angiogenic therapies represent attractive therapeutic targets in this context, due to the central role of angiogenesis in KS pathogenesis. Pomalidomide, which exhibits such anti-angiogenic activity through inhibition of VEGF, currently constitutes the most promising agent of this class and has been recently approved by the FDA. In addition, immune checkpoint blockade also represents an interesting alternative therapeutic approach through the restoration of immunity against HHV-8, the causative agent of KS, and improvement of tumor control. Although small series of cases treated successfully with these drugs have been reported, there is no marketing approval for anti-immune checkpoint antibodies for KS to date. In the present review, we will discuss potential therapeutic options for patients with recurrent or refractory KS, including systemic chemotherapies, immune checkpoint inhibitors, anti-herpesvirus agents, and anti-angiogenic drugs. Well-conducted clinical trials in this population are urgently needed to correctly address the efficacy of targeted agents and immunomodulators, while monitoring for adverse effects.

Immune Reconstitution Inflammatory Syndrome Associated Kaposi Sarcoma.

People living with HIV (PLWH) with advanced immunosuppression who initiate antiretroviral therapy (ART) are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS). Although ART is responsible for AIDS- associated Kaposi sarcoma (KS) improvement and resolution, new onset (unmasking KS-IRIS) or sudden progression of preexisting KS (paradoxical KS-IRIS) can occur after a time delay of between a few days and 6 months after the initiation or resumption of ART, even in patients with a low degree of immunocompromise. KS-IRIS incidence varies from 2.4% to 39%, depending on study design, populations, and geographic regions. Risk factors for developing KS-IRIS include advanced KS tumor stage (T1), pre-treatment HIV viral load >5 log10 copies/mL, detectable pre-treatment plasma-KSHV, and initiation of ART alone without concurrent chemotherapy. Both paradoxical and unmasking KS-IRIS have been associated with significant morbidity and mortality, and thrombocytopenia (<100,000 platelets/mm3 at 12 weeks) has been associated with death. KS-IRIS is not to be considered as ART failure, and an ART regimen must be pursued. Systemic chemotherapy for KS in conjunction with ART is recommended and, in contrast with management of IRIS for other opportunistic infections, glucocorticoids are contra-indicated. Despite our preliminary results, the place of targeted therapies in the prevention or treatment of KS-IRIS needs further assessment.

Prevalence and Spectrum of Second Primary Malignancies among People Living with HIV in the French Dat'AIDS Cohort.

BACKGROUND: We aimed to describe the prevalence and spectrum of second primary cancer (SPC) in HIV-positive cancer survivors. METHODS: A multicenter retrospective study was performed using longitudinal data from the French Dat'AIDS cohort. Subjects who had developed at least two primary cancers were selected. The spectrum of SPCs was stratified by the first primary cancer type and by sex. RESULTS: Among the 44,642 patients in the Dat'AIDS cohort, 4855 were diagnosed with cancer between 1 December 1983 and 31 December 2015, of whom 444 (9.1%) developed at least two primary cancers. The most common SPCs in men were non-Hodgkin lymphoma (NHL) (22.8%), skin carcinoma (10%) and Kaposi sarcoma (KS) (8.4%), and in women the most common SPCs were breast cancer (16%), skin carcinoma (9.3%) and NHL (8%). The pattern of SPCs differed according to first primary cancer and by sex: in men, NHL was the most common SPC after primary KS and KS was the most common SPC after primary NHL; while in women, breast cancer was the most common SPC after primary NHL and primary breast cancer. CONCLUSION: The frequency and pattern of subsequent cancers among HIV-positive cancer survivors differed according to the first primary cancer type and sex.

Determinants of Second Primary Cancer Type in Survivors of Virus-Related and Non-Virus-Related Cancer Living With HIV in the French Dat'AIDS Cohort.

OBJECTIVES: People who survive after primary cancer are at an increased risk for subsequent primary cancers. We aimed to investigate the possible determinants of second primary cancer (SPC) in HIV-positive cancer survivors. METHODS: This was a multicenter retrospective study using longitudinal data from the French Dat'AIDS cohort. Subjects who developed at least 2 primary cancers were selected. Cancer cases were identified using ICD10 codes and distributed in 3 cancer categories: AIDS-defining cancer (ADC), virus-related non-ADC (VR-NADC), and virus-unrelated-NADC (VU-NADC). The possible determinants considered were the first primary cancer category, sex, age, HIV transmission route, duration of HIV infection follow-up, duration of ART exposure, nadir CD4+ T cell count, and hepatitis C and hepatitis B serostatus. RESULTS: Among the 44642 patients in the Dat'AIDS cohort, 4855 were diagnosed with cancer between 1 December 1983 and 31 December 2015, of whom 444 (9.1%) developed at least 2 primary cancers: 130 ADCs, 85 VR-NADCs, and 229 VU-NADCs. A longer delay between the first primary cancer and the SPC was associated with an increased risk of occurrence of a VR-NADC rather than a secondary ADC. Having had a first primary VU-NADC, an older age, and a longer delay between the HIV diagnosis and the first primary cancer as well as between the first primary cancer and the SPC were associated with an increased risk of VU-NADC rather than ADC. CONCLUSION: SPCs are now a major concern in HIV-positive cancer survivors justifying the development of monitoring strategies after a first cancer.

[Survey on HIV, HBV and HCV screening practices in cancerology, France]. / Enquête sur la pratique du dépistage du VIH, VHB et VHC en cancérologie, France.

HIV testing is recommended at time of cancer diagnosis, HBV and HCV screening because of the risk of reactivation with certain anticancer drugs.This is a cross-sectional study. The objectives were to assess the screening practices in cancer patients and the satisfaction of professionals in the event of use of the CancerHIV network. A questionnaire drafted by the CancerHIV expert and the OncoPaca-Corse Regional Cancer Network (RCN) was distributed in the region at the end of 2018 (part 1: V1) before being extended to the national level via the CancerHIV network (part 2: V2). Participation reached 160 and 130 respondents (V1 and V2, respectively). At the initial cancer assessment, 23% of respondents declared that they systematically screened for HIV at V1 (V2: 17%), 25% for HBV (V2: 20%) and 24% for HCV (V2: 19%). Before immunotherapy, the rates were 54% for HIV in V1 (V2: 52%), 57% for HBV (V2: 60%) and 55% for HCV (V2: 57%). Among the respondents, satisfaction when requesting a regional or national remedy was high (almost 100%). Screening for HIV, HBV and HCV allows supervised prescription of immunosuppressive or cytotoxic treatment to a potentially immunosuppressed patient. This study, resulting of an original collaboration between a RCN and a national expert network, underlines the lack of screening at the 2 examined stages of patient care, and the need for raising practitioners' awareness to recommendations.

Spectrum and Incidence Trends of AIDS- and Non-AIDS-Defining Cancers between 2010 and 2015 in the French Dat'AIDS Cohort.

BACKGROUND: Cancer risk is higher in people living with HIV (PLWH) compared with the general population, and cancers related to age are expected to be most prevalent. METHODS: We determined the spectrum and incidence rates of AIDS-defining cancers (ADC) and non-AIDS-defining cancers (NADC) and of lung, Hodgkin lymphoma (HL), head and neck (HNC), colon-rectum, anal, liver, breast, prostate, and urinary bladder cancers between January 2010 and December 2015 in the French Dat'AIDS cohort. Incidence rates were calculated by year and compared using the χ 2 test for linear trend. Standardized incidence ratios [SIR (95% confidence interval)] were calculated relative to the French general population. RESULTS: Among 44,642 patients, corresponding to 180,216.4 person-years (PY), 1,440 cancer cases occurred in 1,314 patients. ADC incidence was 191.4 (172.3-212.7)/105 PY and declined over time overall and in men, whereas NADC incidence was higher [548.8 (515.6-584.1)/105 PY] and did not change. In men, non-Hodgkin lymphoma was the most common cancer, but prostate cancer had the highest incidence among NADCs. Breast cancer was the most common cancer in women. SIRs were higher for cervical cancer [1.93 (1.18-3.14)], HNC in women [2.4 (1.4-4.2)], liver [overall: 3.8 (3.1-4.6); men: 3.2 (2.5-4.0); women: 12.9 (8.3-20.0)], and HL [overall: 13.8 (11.1-17.1); men: 16.2 (12.9-20.4); women: 6.2 (3.22-11.9)] but lower for lung [overall: 0.7 (0.6-0.9); men: 0.7 (0.5-0.8)], prostate [0.6 (0.5-0.7)], and breast cancers [0.6 (0.4-0.7)]. CONCLUSIONS: Spectrum of NADCs has changed, with prostate and breast cancers becoming the most common despite their lower SIR. IMPACT: These results confirm the need to maintain regular epidemiologic cancer monitoring in order to update screening guidelines.

Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV-infected patients.

AIMS: The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine. METHODS: A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration. RESULTS: Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%). CONCLUSIONS: This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.

Multimorbidity in Elderly Persons According to the Year of Diagnosis of Human Immunodeficiency Virus Infection: A Cross-sectional Dat'AIDS Cohort Study.

BACKGROUND: We assessed prevalence of multimorbidity (MM) according to year of human immunodeficiency virus (HIV) diagnosis in elderly people living with HIV (PLWH). METHODS: This was a cross-sectional study of MM in PLWH aged ≥70 years from the Dat'AIDS French multicenter cohort. MM was defined as at least 3 coexistent morbidities of high blood pressure, diabetes mellitus, osteoporosis, non-AIDS cancer, chronic renal failure, cardiovascular and cerebrovascular disease, obesity, undernutrition, or hypercholesterolemia. Logistic regression models evaluated the association between MM and calendar periods of HIV diagnosis (1983-1996, 1997-2006, and 2007-2018). The secondary analysis evaluated MM as a continuous outcome, and a sensitivity analysis excluded PLWH with nadir CD4 count <200 cells/µL. RESULTS: Between January 2017 and September 2018, 2476 PLWH were included. Median age was 73 years, 75% were men, median CD4 count was 578 cells/µL, and 94% had controlled viremia. MM prevalence was 71%. HBP and hypercholesterolemia were the most prevalent comorbidities. After adjustment for age, gender, smoking status, hepatitis C and hepatitis B virus coinfection, group of exposure, nadir CD4 count, CD4:CD8 ratio, and last CD4 level, calendar period of diagnosis was not associated with MM (P = .169). MM was associated with older age, CD4/CD8 ratio <0.8, and nadir CD4 count <200 cells/µL. Similar results were found with secondary and sensitivity analyses. CONCLUSIONS: MM prevalence was high and increased with age, low CD4/CD8 ratio, and nadir CD4 count <200 cells/µL but was not associated with calendar periods of HIV diagnosis. Known duration of HIV diagnosis does not seem to be a criterion for selecting elderly PLWH at risk of MM.

Hepatitis C virus-microelimination program and patient trajectories after hepatitis C virus cure in an outpatient HIV clinical unit.

OBJECTIVE: Treatment recommendations for hepatitis C now make no distinction between HIV/HCV-coinfected and HCV-monoinfected patients. The largest challenge remained lack of effective models to eliminate HCV in people living with HIV. We report the results of a microelimination program evaluating the possibility of eradicating HCV in an HIV-outpatient clinical unit within 12 months. METHODS: This HCV-microelimination program began in February 2016 in an unit following approximately 1000 HIV-infected patients and combined screening and therapeutic components according to the French guideline. A nested cohort study evaluating the impact of HCV cure on different health outcomes was conducted through self-administered questionnaires and using generalized mixed models. RESULTS: Among 601 patients eligible for HCV serological testing, 445 were evaluated, and two HCV acute infections were diagnosed. Among the 151 patients eligible for HCV RNA quantification, 119 were evaluated, and one reinfection with HCV was diagnosed. Among the 110 patients eligible for direct-acting antiviral treatment, 51 (46.4%) initiated treatment within the 12 months program, and 35 (31.8%) after. Sustained virologic response (SVR) rate was 96.1%, and two treatments failed. At least one self-reported symptom was declared by 72.5% (n = 29) of patients. Positive impact of HCV cure was observed on various markers of physical and mental health as well as on health habits. CONCLUSION: Our program should be considered as a proof of concept, which confirmed the feasibility of a HCV-microelimination program at the scale of an HIV clinical unit. However, 12 months were not sufficient to achieve our objective despite the specific organization.

Is the Risk of Myocardial Infarction in People With Human Immunodeficiency Virus (HIV) Associated With Atazanavir or Darunavir? A Nested Case-Control Study Within the French Hospital Database on HIV.

BACKGROUND: The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study has reported an increased risk of cardiovascular diseases in people with human immunodeficiency virus who were exposed to darunavir (DRV) but not to atazanavir (ATV). Our objective was to evaluate associations between ATV or DRV exposures and the risk of myocardial infarction (MI) in a nested case-control study within ANRS-CO4 French Hospital Database on HIV (FHDH). METHODS: Cases were individuals who had a first validated MI between 2006 and 2012. Up to 5 controls were selected at random with replacement among individuals with no history of MI, followed at the time of MI diagnosis, and matched for age and sex. Conditional logistic regression models were used to adjust for potential confounders (MI risk factors and HIV-related parameters) and for cumulative exposure to each antiretroviral drug (ARV). RESULTS: Overall, 408 MI cases and 1250 controls were included: 109 (27%) cases and 288 (23%) controls had been exposed to ATV, and 41 (10%) cases and 107 (9%) controls had been exposed to DRV. There was no significant association between exposure to ATV (adjusted odds ratio [OR] = 1.54; 95% confidence interval [CI], .87-2.73) or DRV (adjusted OR = 0.51; 95% CI, .11-2.32) and the risk of MI. CONCLUSIONS: In FHDH, exposures to ATV or to DRV were not significantly associated with the risk of MI, adjusting for complete ARV history, contrary to the analysis in DAD.

Concentration-response model of rilpivirine in a cohort of HIV-1-infected naive and pre-treated patients.

BACKGROUND: Rilpivirine is widely prescribed in people living with HIV. Although trough plasma concentrations have been associated with virological response, the drug pharmacodynamics remain incompletely characterized. OBJECTIVES: To develop the first pharmacodynamic model of rilpivirine in order to establish the rilpivirine concentration-response relationship for future treatment optimization. METHODS: A retrospective observational study was conducted in patients receiving the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. Individual rilpivirine trough plasma concentrations over time were predicted using a previous pharmacokinetic model. An established susceptible, infected, recovered model was used to describe HIV dynamics without assuming disease steady-state. Population analysis was performed with MONOLIX 2018 software. Simulations of the viral load evolution as a function of time and rilpivirine trough plasma concentration were performed. RESULTS: Overall, 60 naive and 39 pre-treated patients were included with a follow-up ranging from 2 to 37 months. The final model adequately described the data and the pharmacodynamic parameters were estimated with a good precision. The population typical value of rilpivirine EC50 was estimated at 65 ng/mL. A higher infection rate constant of CD4 cells for HIV-1 was obtained in pre-treated patients. Consequently, the time to obtain virological suppression was longer in pre-treated than in naive patients. CONCLUSIONS: The concentration-response relationship of rilpivirine was satisfactorily described for the first time using an original population pharmacodynamic model. Simulations performed using the final model showed that the currently used 50 ng/mL rilpivirine trough plasma concentration efficacy target might need revision upwards, particularly in pre-treated patients.

Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort.

OBJECTIVES: To analyse the frequency and causes of treatment discontinuation in patients who were treated with an integrase strand transfer inhibitor (INSTI), with a focus on neuropsychiatric adverse events (NPAEs). METHODS: Patients in 18 HIV reference centres in France were prospectively included in the Dat'AIDS cohort. Data were collected from all patients starting an INSTI-containing regimen between 1 January 2006 and 31 December 2016. All causes of INSTI-containing regimen discontinuations were analysed, and patients' characteristics related to discontinuation due to NPAEs were sought. RESULTS: INSTIs were prescribed to 21315 patients: 6274 received dolutegravir, 3421 received elvitegravir boosted by cobicistat, and 11620 received raltegravir. Discontinuation was observed in 12.5%, 20.2% and 50.9% of the dolutegravir-, elvitegravir- and raltegravir-treated patients, respectively (P < 0.001). Discontinuation for NPAEs occurred in 2.7%, 1.3% and 1.7% of the dolutegravir-, elvitegravir-, and raltegravir-treated patients, respectively (P < 0.001). In the multivariate analysis, discontinuation for NPAEs was related to dolutegravir versus elvitegravir (HR = 2.27; 95% CI 1.63-3.17; P < 0.0001) and versus raltegravir (HR = 2.46; 95% CI 2.00-3.40; P < 0.0001), but neither gender (HR for women = 1.19; 95% CI 0.97-1.46; P = 0.09) nor age (P = 0.12) was related. The association with abacavir was not retained in the final model. CONCLUSIONS: Although discontinuation for side effects was less frequent with dolutegravir than with boosted elvitegravir, discontinuation for NPAEs, although rare (2.7%), was more frequent with dolutegravir. No patient characteristic was found to be associated with these side effects in this very large population.

Factors associated with social deprivation among older persons living with HIV.

Aging persons living with HIV may develop multiple health problems, including comorbidities, and altered physical and mental health, earlier than non-infected people. They may also experience social deprivation. We assessed the prevalence of social deprivation and its relationship with health indicators in older persons living with HIV. An 18-month, multicenter, cross-sectional study was carried out between 2013 and 2014 focusing on patients ≥50-years of age followed-up in 12 dedicated HIV medical hospital units located in the South of France and involved the VISAGE study group. Social deprivation was measured with the EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centers) score (ES) and defined as ES ≥30.17. The following data were recorded: health indicators (gender, age, body mass index), comorbidities, frailty markers, socioeconomic, behavioral and age-related variables. Among 509 patients recruited, 494 completed the ES social deprivation evaluation. Mean age was 58.5 ± 7.0 years and 72.9% were male. The prevalence of social deprivation was 49.0%. Multivariable logistic regression analysis showed that higher social deprivation was significantly linked to alcohol consumption (OR = 4.07 [95%CI: 1.23-13.48]), risk of depression (OR = 3.59 [95%CI: 2.26-5.70]), chronic obstructive pulmonary disease (OR = 3.10 [95%CI: 1.36-7.09]), hepatitis C (OR = 1.96 [95%CI: 1.10-3.52]), and chronic pain (OR = 1.11 [95%CI: 1.01-1.21]). Social deprivation was not related to HIV status. Our study showed that not only did older patients with HIV suffer from social deprivation, but they also received little support from social workers. Physicians should be aware of this situation and should systematically evaluate social deprivation in order to provide comprehensive targeted care involving global, social, and psychological support to reduce the burden of social deprivation.

Risk factors associated with overweight and obesity in HIV-infected people: Aging, behavioral factors but not cART in a cross-sectional study.

Identifying risk factors associated with overweight and obesity in HIV-infected patients.A cross-sectional study analyzing data from patients attending an HIV outpatient unit. Overweight was defined as body mass index (BMI) ≥25 kg/m; <30 kg/m, obesity was ≥30 kg/m. Patients' characteristics contemporary to BMI assessment were collected. Multivariate logistic regression identified risk factors associated with overweight/obesity.Eight hundred sixty-two patients, median age 51 years, 21.5 years of HIV infection follow-up, 585 (68%) male, 829 (96%) receiving combined antiretroviral therapy (cART) for median 16.7 years, 768 (91%) HIV load <40 copies/mL, 618 (73%) CD4 ≥500 cells/mm; 266 (31%) HCV serology, 110 (13%) had detectable HCV-RNA. Overweight affected 191 (22%) patients and obesity 46 (5%). Overweight and obesity were associated with age, HIV follow-up duration, and HIV transmission risk group. Overweight was also associated with gender and HCV status. In patients with substance use data, overweight was associated with alcohol and nonsmoking status. Obesity was associated with nonsmoking and ex-smoker status. Overweight/obesity were not found associated with cART or immune cell counts.In HIV-infected people, aging, alcohol consumption, nonsmoking, and ex-smoker status, the absence of HCV coinfection and to have cleared HCV infection are associated with overweight and/or obesity. Clinicians should be aware of these trends and consider introducing weight management programs as part of routine HIV care.

Emergence of uncommon HIV-1 non-B subtypes and circulating recombinant forms and trends in transmission of antiretroviral drug resistance in patients with primary infection during the 2013-2015 period in Marseille, Southeastern France.

Primary HIV-1 infections (PHI) with non-B subtypes are increasing in developed countries while transmission of HIV-1 harboring antiretroviral resistance-associated mutations (RAMs) remains a concern. This study assessed non-B HIV-1 subtypes and RAMs prevalence among patients with PHI in university hospitals of Marseille, Southeastern France, in 2005-2015 (11 years). HIV-1 sequences were obtained by in-house protocols from 115 patients with PHI, including 38 for the 2013-2015 period. On the basis of the phylogenetic analysis of the reverse transcriptase region, non-B subtypes were identified in 31% of these patients. They included 3 different subtypes (3A, 1C, 4F), 23 circulating recombinant forms (CRFs) (CRF02_AG, best BLAST hits being CRF 36_cpx and CRF30 in 7 and 1 cases, respectively), and 5 unclassified sequences (U). Non-B subtypes proportion increased significantly, particularly in 2011-2013 vs in 2005-2010 (P = .03). CRF02_AG viruses largely predominated in 2005-2013 whereas atypical strains more difficult to classify and undetermined recombinants emerged recently (2014-2015). The prevalence of protease, nucleos(t)ide reverse transcriptase, and first-generation nonnucleoside reverse transcriptase inhibitors-associated RAMs were 1.7% (World Health Organization [WHO] list, 2009/2.6% International AIDS Society [IAS] list, 2017), 5.2%/4.3%, and 5.2%/5.2%, respectively. Etravirine/rilpivirine-associated RAM (IAS) prevalence was 4.3%. Men who have sex with men (MSM) were more frequently infected with drug-resistant viruses than other patients (26% vs 7%; P = .011). The recent increase of these rare HIV-1 strains and the spread of drug-resistant HIV-1 among MSM in Southeastern France might be considered when implementing prevention strategies and starting therapies.

Frail and pre-frail phenotype is associated with pain in older HIV-infected patients.

As HIV-infected patients grow older, some accumulate multiple health problems earlier than the noninfected ones in particular frailty phenotypes. Patients with frailty phenotype are at higher risk of adverse outcomes (worsening mobility, disability, hospitalization, and death within three years).Our study aimed to evaluate prevalence of frailty in elderly HIV-infected patients and to assess whether frailty is associated with HIV and geriatric factors, comorbidities, and precariousness in a French cohort of older HIV infected.This 18-month cross-sectional multicenter study carried in 2013 to 2014 had involved 502 HIV-infected patients aged 50 years and older, cared in 18 HIV-dedicated hospital medical units, located in South of France.Prevalence of frailty was 6.3% and of pre-frailty 57.2%. Low physical activity and weakness were the main frailty markers, respectively 49.4% and 19.9%. In univariate models, precariousness, duration of HIV antiretroviral treatment >15 years, 2 comorbidities or more, risk of depression, activities of daily living disability, and presence of pain were significantly associated with frail and pre-frail phenotype. Multivariate logistic regression analyses showed that only pain was significantly different between frail and pre frail phenotype versus non frail phenotype (odds ratio = 1.2; P = .002).Our study is the first showing a significant association between pain and frailty phenotype in older patients infected by HIV. As frailty phenotype could be potentially reversible, a better understanding of the underlying determinant is warranted. Further studies are needed to confirm these first findings.

Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine.

PURPOSE: Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. METHODS: We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. RESULTS: We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50 ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9 L/h and 321 L, respectively, resulting in a half-life of 25.2 h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. CONCLUSIONS: Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from "real-life" conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.

Ledipasvir and tenofovir drug interaction in human immunodeficiency virus-hepatitis C virus coinfected patients: Impact on tenofovir trough concentrations and renal safety.

We evaluate the impact of ledipasvir on both tenofovir plasma trough concentration and estimated glomerular renal function in human immunodeficiency virus-hepatitis C virus coinfected patients receiving a tenofovir-based antiretroviral regimen and treated with ledipasvir/sofosbuvir. Twenty-six patients [81% male, median age: 51 years; hepatitis C virus genotype 1(75%)/4(15%)] were included. Tenofovir trough concentration (interquartile range) increased from 78 ng ml-1 (53-110) at baseline to 141 ng ml-1 (72-176) at 1 month (P = 0.003). No significant difference on estimated glomerular renal function using both Cockroft-Gault and Modification of Diet in Renal Disease formulae, respectively, [median (interquartile range)] was observed between baseline [101.3 ml min-1 (91.1-114.1); 95.6 ml min-1 (86.5-111.2)], 1 month [102.4 ml min-1 (89.8-112.9), P = 0.26; 92.5 ml min-1 (88.1-114.3), P = 0.27], end-of-treatment [96.5 ml min-1 (82.4-115.4), P = 0.39; 95.4 ml min-1 (84.2-105.4), P = 0.16] and 12 weeks after the end of treatment [100.5 ml min-1 (83.3-111.9), P = 0.24; 93.4 ml min-1 (82.2-103.5), P = 0.16]. Three patients progressed from chronic kidney disease stage 1 to stage 2 at 12 weeks post-treatment. A significant increase in tenofovir exposure through P-glycoprotein inhibition by ledipasvir was confirmed without significant impact on glomerular renal function in our population with normal renal function or mild renal impairment.