Virological Outcome After Choice of Antiretroviral Regimen Guided by Proviral HIV-1 DNA Genotyping in a Real-Life Cohort of HIV-Infected Patients.

Issues have been raised concerning clinical relevance of HIV-1 proviral DNA genotypic resistance test (DNA GRT). To assess impact of DNA GRT on choice of antiretroviral therapy (ART) and subsequent virological outcome, we retrospectively reviewed decision-making and viral load (VL) evolution following DNA GRT performed in our center between January 2012 and December 2017, except those prescribed within the framework of a clinical trial. A total of 304 DNA GRTs were included, 185 (62%) performed in a context of virological success. Only 34% of tests were followed by ART change, more frequently in situation of virological success (39% vs. 26%, p = 0.02). In this situation, ART change guided by DNA GRT led to VL >20 copies/mL after 6 months in 5% of cases. In multivariate analysis, higher HIV DNA quantification (p = 0.01) was associated with occurrence of viremia. A higher nadir of CD4 count (p = 0.04) and a longer time with VL <20 copies/mL (p = 0.04) were independently associated with a lower risk of viremia. In situation of low-level viremia, ART change guided by DNA GRT led to VL <20 copies/mL after 6 months in 52% of cases, while decision to maintain the same treatment led to VL <20 copies/mL in 74% of cases. In multivariate analysis, longer time with VL >20 copies/mL (p = 0.02) was associated with persistence of virological replication. In conclusion, in situation of virological success, use of DNA GRT in addition to analysis of historical RNA GRT to guide ART optimization appears safe. Its prescription framework in situation of low-level viremia deserves to be better defined.

Clinical impact of tropism testing in a real-life cohort of HIV infected patients: a retrospective observational study.

BACKGROUND: The circumstances of prescription of tropism tests clinically relevant in treatment-experienced patients are unclear. METHODS: We performed a monocentric retrospective analysis of all tropism tests performed between 2006 and 2015 in HIV-infected patients on antiretroviral therapy (ART) without MVC. The motivation of tropism determination was collected. Factors associated with MVC prescription were determined using logistic regression analysis. RESULTS: Five hundred sixty-three tests were performed in experienced patients not receiving MVC. Reasons for tropism performance were: virological failure (44%), side effects or drug-interactions (37%), simplification or sparing strategies (11%), immunological failure (5%), and improvement of neurological diffusion (3%). MVC was prescribed in 110 cases (20%), though 366 tests (65%) revealed a tropism CCR5. MVC was more often prescribed before 2011 (OR 3.65, 95% CI 2.17-6.13) and in patients with multiple previous ART regimens (less than 4 ART regimens compare to more than 10 ART regimens (OR 0.34, 95% CI 0.15-0.74)). CONCLUSIONS: In experienced patients not receiving MVC, tropism test prescription should be restricted to patients with virological failure and limited therapeutic options such as patients already treated with a wide range of ART regimens.

Reduced bone mineral density among HIV-infected, virologically controlled young men: prevalence and associated factors.

OBJECTIVE: Reduced bone mineral density (BMD) is a frequent comorbidity observed in people living with HIV (PLHIV). We aimed to determine the prevalence of reduced BMD and its associated factors among young PLHIV men, virologically controlled by combination antiretroviral therapy (cART). DESIGN: A bicentric cross-sectional study. METHODS: We selected men, aged less than 50 years, treated by cART, with HIV-RNA less than 50 copies/ml. BMDs of lumbar spine and hip were measured by dual-energy X-ray absorptiometry (DXA). A Z-score at either site between -1.0 and -2.0 or -2 or less defined osteopenia or osteoporosis, respectively. Linear and polytomous logistic regression analyses were performed. RESULTS: Among 230 men with a median age of 43 [interquartile range (IQR), 36-47] years, BMI of 23.5 (21.3-25.3) kg/m(2) and median duration of cART of 4.2 (1.7-8.5) years, reduced BMD was diagnosed in 48.3%. In multivariate analyses, BMI decrease was associated with a risk of osteopenia [odds ratio (OR) = 1.17, P < 0.01] and osteoporosis (OR = 1.24, P < 0.01). Oestradiol levels decrease were associated with osteoporosis (OR = 1.32, P < 0.05) and lower lean mass with osteopenia (OR = 2.98, P < 0.01). There was a protective effect of the duration of cART (OR = 0.87, P < 0.01), which was even greater when the duration was more than 3 years (OR = 0.44, P = 0.02). CONCLUSION: There is a high prevalence of reduced BMD among young men, despite persistent virological control of HIV-infection. This observation raises the question of extending current recommendations for BMD assessment to PLHIV aged < 50 years for whom BMD has stabilized after cART initiation, i.e. treated for more than three years.

Risk factors for syphilis infection in men who have sex with men: results of a case-control study in Lille, France.

BACKGROUND: Substantial increases in syphilis have been reported since the early 2000s in northern countries, particularly among men who have sex with men (MSM). The authors aimed to identify risk factors for early syphilis in MSM in Lille, a large urban area of northern France. METHODS: A matched case-control study was conducted in MSM aged ≥ 18 years. Cases were diagnosed with primary, secondary or early latent syphilis between April 2008 and June 2010. Controls sought care in STIs clinics or were followed in an HIV clinic. Controls had no history of and no current syphilis. They were matched to cases for age and HIV status. Multivariate conditional logistic regression models were used to identify risk factors for early syphilis. RESULTS: 53 patients with early syphilis were enrolled. Average age was 37 years, and 47% were HIV-infected. For analysis, they were matched to 90 controls. Factors associated with syphilis were: low educational attainment (OR=5.38, 95% CI 1.94 to 14.94; p=0.001), receptive oral sex with casual male partners without a condom (OR=4.86, 95% CI 1.63 to 14.48; p=0.005) and anal sex toy use with casual male partners (OR=2.72, 95% CI 1.01 to 7.32; p=0.05). Seeking of sex partners online (OR=5.17, 95% CI 1.33 to 20.11), use of poppers (OR=2.2, 95% CI 1.1 to 4.3) and erectile dysfunction drugs (OR=1.9, 95% CI 1.0 to 13.2) were associated with syphilis only in the univariate analysis. CONCLUSIONS: Receptive oral sex without a condom and use of anal sex toys were identified as presenting a major risk of syphilis infection. Although these practices have been shown to present low risk of HIV transmission, the general public is unaware of their impact on transmission of other STIs.

Pharmacologic boosting of atazanavir in maintenance HIV-1 therapy: the COREYA propensity-score adjusted study.

BACKGROUND: Among HIV-1 infected patients who achieved virologic suppression, the use of atazanavir without pharmacologic boosting is debated. We evaluated the efficacy and tolerance of maintenance therapy with unboosted atazanavir in clinical practice. METHODS AND RESULTS: This multicenter retrospective cohort study evaluated the efficacy of switching HIV-1-infected patients controlled on triple therapy to unboosted (ATV(0), n = 98) versus ritonavir-boosted atazanavir (ATV/r, n = 254) +2 nucleos(t)ide reverse transcriptase inhibitors. The primary endpoint was time to virologic failure (VF, >200 copies/mL). ATV groups were compared controlling for potential confounding bias by inverse probability weighted Cox analysis and propensity-score matching. Overall and adjusted VF rates were similar for both strategies. Both strategies improved dyslipidemia and creatininemia, with less jaundice in the ATV(0) group. CONCLUSION: In previously well-suppressed patients, within an observational cohort setting, ATV(0)-based triple-therapy appeared as effective as ATV/r- based triple-therapy to maintain virologic suppression, even if co-administered with TDF, but was better tolerated.

Newer drugs and earlier treatment: impact on lifetime cost of care for HIV-infected adults.

OBJECTIVE: To determine the component costs of care to optimize treatment with limited resources. DESIGN: We used the Cost-Effectiveness of Preventing AIDS Complications Model of HIV disease and treatment to project life expectancy and both undiscounted and discounted lifetime costs (2010 €). METHODS: We determined medical resource utilization among HIV-infected adults followed from 1998 to 2005 in northern France. Monthly HIV costs were stratified by CD4 cell count. Costs of CD4, HIV RNA and genotype tests and antiretroviral therapy (ART) were derived from published literature. Model inputs from national data included mean age 38 years, mean initial CD4 cell count 372 cells/µl, ART initiation at CD4 cell counts less than 350 cells/µl, and ART regimen costs ranging from €760 to 2570 per month. RESULTS: The model projected a mean undiscounted life expectancy of 26.5 years and a lifetime undiscounted cost of €535,000/patient (€320,700 discounted); 73% of costs were ART related. When patients presented to care with mean CD4 cell counts of 510 cells/µl and initiated ART at CD4 cell counts less than 500 cells/µl or HIV RNA more than 100,000 copies/ml, life expectancy was 27.4 years and costs increased 1-2%, to €546,700 (€324,500 discounted). When we assumed introducing generic drugs would result in a 50% decline in first-line ART costs, lifetime costs decreased 4-6%, to €514,200 (€302 ,800 discounted). CONCLUSION: As HIV disease is treated earlier with more efficacious drugs, survival and thus costs of care will continue to increase. The availability in high-income countries of widely used antiretroviral drugs in generic form could reduce these costs.

Lopinavir/ritonavir resistance in patients infected with HIV-1: two divergent resistance pathways?

The HIV-1 protease L76V mutation has been described recently as conferring high-level resistance to lopinavir/ritonavir (LPV/r). The aim was to identify the factors and particularly protease mutations associated with the presence of L76V in treatment-experienced patients infected with HIV-1 who have failed virologically an LPV/r-based antiretroviral therapy regimen. This is a retrospective exploratory study. Patients were eligible if they were in care at the Northern France AIDS reference center between 2000 and 2009, failed virologically an LPV/r-based regimen, and infected with HIV-1 strains carrying LPV/r-resistant mutations (genotype resistance test after failure). Multivariate logistic regressions were used to compare LPV/r-resistant patients infected with virus harboring the L76V mutation or not (L76V positive/L76V negative). Twelve patients with virus L76V positive were identified and compared to 24 patients with virus L76V negative selected at random. Demographic and clinical data were not different significantly between the two groups. In univariate analyses, of the mutations found in ≥10% of patients, L89M and Q58E were more prevalent in viruses L76V positive than L76V negative (L89M, 42% vs. 0%, P = 0.0007; Q58E, 50% vs. 25%, P = 0.1). In contrast, I54V, G73S and L90M were less prevalent in viruses L76V positive than L76V negative (I54V, 42% vs. 83%, P = 0.01; G73S, 0% vs. 33%, P = 0.02; L90M, 25% vs. 83%, P = 0.0006). L90M, I54V and Q58E were associated with L76V in a multivariate analysis (P < 0.0001, P = 0.002, and P = 0.008, respectively). These results suggest two divergent pathways leading to LPV/r resistance. One contains the L76V and Q58E mutations and the other contains the L90M and I54V mutations.

Factors associated with presentation to care with advanced HIV disease in Brussels and Northern France: 1997-2007.

BACKGROUND: Our objective was to determine the frequency and determinants of presentation to care with advanced HIV disease in patients who discover their HIV diagnosis at this stage as well as those with delayed presentation to care after HIV diagnosis in earlier stages. METHODS: We collected data on 1,819 HIV-infected patients in Brussels (Belgium) and Northern France from January 1997 to December 2007. "Advanced HIV disease" was defined as CD4 count <200/mm3 or clinically-defined AIDS at study inclusion and was stratified into two groups: (a) late testing, defined as presentation to care with advanced HIV disease and HIV diagnosis ≤6 months before initiation of HIV care; and (b) delayed presentation to care, defined as presentation to care with advanced HIV disease and HIV diagnosis >6 months before initiation of HIV care. We used multinomial logistic regression to determine the factors associated with delayed presentation to care and late testing. RESULTS: Of the 570 patients initiating care with advanced HIV disease, 475 (83.3%) were tested late and 95 (16.7%) had delayed presentation to care. Risk factors for delayed presentation to care were: age 30-50 years, injection drug use, and follow-up in Brussels. Risk factors for late testing were: sub-Saharan African origin, male gender, and older age. HIV transmission through heterosexual contact was associated with an increased risk of both delayed presentation to care and late testing. Patients who initiated HIV care in 2003-2007 were less likely to have been tested late or to have a delayed presentation to care than patients who initiated care before 2003. CONCLUSION: A considerable proportion of HIV-infected patients present to care with advanced HIV disease. Late testing, rather than a delay in initiating care after earlier HIV testing, is the main determinant of presentation to care with advanced HIV disease. The factors associated with delay presentation to care differ from those associated with late testing. Different strategies should be developed to optimize early access to care in these two groups.

Incidence rate and risk factors for loss to follow-up in HIV-infected patients from five French clinical centres in Northern France - January 1997 to December 2006.

BACKGROUND: Our goal was to determine the incidence rate and risk factors for loss to follow-up (LTFU) of HIV-infected patients in Northern France. METHODS: We estimated the incidence rate of LTFU in 1,007 HIV-infected patients under care from January 1997 to December 2006. We then investigated potential risk factors for LTFU at inclusion and during follow-up. RESULTS: The incidence of LTFU was estimated to be 3.5 per 100 person-years. Risk factors for LTFU at enrolment in a multivariate Cox model were age <30 years (hazard ratio [HR] 1.66 versus >40 years, 95% confidence interval [CI] 1.04-2.64), transmission by injection drug use (HR 5.26 versus men who have sex with men, 95% CI 2.90-9.52), no phone number provided (HR 5.4, 95% CI 3.6-8.2), no primary care physician (HR 2.10, 95% CI 1.25-3.52) and sub-Saharan African origin (HR 2.09, 95% CI 1.36-3.22). Patients with CD4(+) T-cell counts <200 cells/mm(3) (HR 0.49 versus >/=350 cells/mm(3), 95% CI 0.32-0.76) and 200-349 cells/mm(3) at baseline (HR 0.63 versus >/=350 cells/mm(3), 95% CI 0.41-0.98) had a decreased risk of LTFU. During follow-up, the risk of LTFU increased when the most recent CD4(+) T-cell count was <200 cells/mm(3) (HR 2.06, 95% CI 1.16-3.66), the patient was not on highly active antiretroviral therapy (HAART; HR 4.20, 95% CI 2.66-6.61) and the patient was on HAART but had a detectable viral load (HR 1.92, 95% CI 1.19-3.01). CONCLUSIONS: Our findings will help clinicians recognize patients who require additional support for retention in care, including younger patients, injection drug users, people of sub-Saharan African origin, patients who are healthier at enrolment and patients who do not adhere to HAART during follow-up.

Natural polymorphisms in HIV-1 protease: impact on effectiveness of a first-line lopinavir-containing antiretroviral therapy regimen.

Mutations on HIV protease lead to resistance to protease inhibitors. However, resistance development may be different according to primary, secondary or polymorphic mutations. The present study was designed to assess the impact of natural protease mutations on the effectiveness of a first-line antiretroviral therapy (ART), and secondarily, their effect on the initial viral load (VL). The study was conducted in 175 HIV-1-infected patients, who initiated a first-line lopinavir/r-containing ART regimen and who had an available genotype resistance testing before initiating therapy. We assessed the association between mutations (prevalence > or = 10%) and the initial VL. We assessed the association between mutations and ART effectiveness using two surrogate markers: the slope of VL decrease at 1 month and the time to VL undetectability. For the 175 patients, the initial median VL was 4.94 log(10) copies/ml [interquartile range: 4.44-5.47] and the initial median CD4 lymphocyte count, 219/microl [129-296]. Eighteen mutations had a prevalence > or = 10%. At 1 month, the median VL decrease was 2.35 log(10) copies/ml [1.76-2.82]. The median time to VL undetectability was 128 days [91-196]. No mutation was associated significantly with the initial VL, the slope of VL decrease at 1 month or the time to VL undetectability. This study of antiretroviral-naive patients showed that protease polymorphisms had no impact on the effectiveness of a lopinavir/r-containing ART regimen. However, polymorphisms may affect ART effectiveness differently in other populations, such as ART-experienced patients and/or patients treated with protease inhibitors other than the one used here.

Expected response to protease inhibitors of HIV-1 non-B subtype viruses according to resistance algorithms.

The expected effectiveness of protease inhibitors was assessed according to the Agence Nationale de Recherches sur le SIDA (ANRS), Rega and Stanford 2007 resistance algorithms in 93 and 87 antiretroviral therapy-naive patients, respectively, infected with B and non-B subtype viruses. Either B or non-B subtypes were considered fully susceptible to protease inhibitors, except to tipranavir/ritonavir, for which the 2007 ANRS algorithm scored non-B subtypes as naturally resistant when this algorithm was extended to these subtypes.

Impact of human immunodeficiency virus type 1 subtype on first-line antiretroviral therapy effectiveness.

OBJECTIVE: The effectiveness of antiretroviral treatment (ART) was compared in 416 naive patients from a French clinical cohort infected with B and non-B HIV-1 subtypes. METHODS: Time to HIV viral load (VL) undetectability was calculated for each subtype group. Three other parameters were estimated 3, 6 and 12 months after enrolment: clinical progression (that is, AIDS-defining events or death), changes in CD4 cell counts from baseline and proportion of patients achieving an undetectable VL (<400 HIV-RNA copies/ml). RESULTS: In this cohort, 317 patients (76%) were infected with a B subtype and 99 (24%) with a non-B subtype. Median time to VL undetectability was similar in the B subtype group [147 days, 95% confidence interval (CI) 119-165] and non-B subtype group (168 days, 95% CI: 105-234; P=0.16). After adjusting for AIDS-defining events at enrolment, baseline CD4 cell counts and VL, and for the treatment on which patients were initiated, no association was found between HIV subtypes and time to VL undetectability (B subtype vs non-B subtype: hazard ratio=0.80, 95% CI: 0.62-1.02, P=0.07). In the 3, 6 and 12 months after enrolment, subtype had no impact on clinical progression, CD4 cell count or VL responses to ART. This suggests that B and non-B subtypes do not affect first-line therapy efficacy, which is encouraging in view of the worldwide spread of non-B HIV-1 subtypes and the increasing availability of ART in developing countries. However, in this study we did not take into account individual non-B subtype species, therefore further studies should be designed to evaluate the efficacy of these regimens in patients with particular non-B subtypes.