Birth Country Influences the Choice of Antiretroviral Therapy in HIV-Infected Individuals: Experience From a French HIV Centre.

OBJECTIVES: To assess whether antiretroviral therapy (ART) prescriptions differ between naive and virally suppressed HIV patients born in France (PBFs) and in Sub-Saharan Africa (PBSSAs). SETTING: Observational single-center study. METHODS: We included all PBFs and PBSSAs who entered into care at Pitié-Salpêtrière Hospital, Paris, France, from 01/01/2000 to 31/12/2018, with plasma HIV-RNA>200 copies/mL. We first compared the initial ART in naive PBFs and PBSSAs. Second, we compared the last-prescribed ART (including drug-reduced ART: daily 2-drug regimens, daily 1-drug regimens and intermittent 3-drug regimens) in virally suppressed PBFs and PBSSAs, by focusing on patients in care in 2018 with HIV-RNA <50 copies for at least 24 months. A univariable and multivariable logistic regression model was used to assess the impact of geographical origin on ART prescriptions. RESULTS: A total of 1944 naive patients were included (915 PBSSAs and 1029 PBFs). PBSSAs were more frequently women, hepatitis B coinfected, with a lower pretherapeutic CD4 T-cell count, and most had tuberculosis at HIV diagnosis. After adjustment for confounders, PBSSAs were more likely to receive a first-line protease inhibitor-based regimen (OR 1.61, 95% CI: 1.31 to 1.98), and less likely to receive an integrase inhibitor-based regimen (OR 0.61, 95% CI: 0.42 to 0.88). Of the 968 virally suppressed patients (431 PBSSAs and 537 PBFs), PBSSAs were less likely to receive drug-reduced ART, including 2-drug regimens and intermittent three-drug regimens (OR 0.48, 95% CI: 0.36 to 0.65). CONCLUSIONS: Differences in ART prescriptions between PBSSAs and PBFs were not only explained by different clinical and virologic situations. Personal motivations of doctors in choosing ART according to country of birth need to be explored.

Clinical, epidemiological and therapeutic characteristics of Mycoplasma genitalium infection in a French STI center.

OBJECTIVES: We report the characteristics of Mycoplasmagenitalium (MG) infection in patients from a STI center in Paris. We evaluated outcomes after treatment. METHODS: We included all patients tested for MG, Chlamydiatrachomatis (CT) and Neisseria gonorrhoeae (NG) infection in our center from January 2017 to December 2018, using multiplex PCR on urine specimen, vaginal or rectal swabs. We collected data regarding sex, age, HIV status, PrEP use, sexual behavior, NG and CT co-infection, symptoms and treatment. RESULTS: MG infection prevalence was 7% (397/5586) (95% CI 6.4-7.8). It ranged from 4.6% in patients consulting for routine STI testing (3.9% in women, 5% in men), to 16% in HIV-positive patients and 25% in PrEP users. Among the 397 MG infected patients, 351 (88%) were asymptomatic and 87 (22%) were co-infected with NG or CT. Among the 270 (68%) treated patients, 249 (92%) received azithromycin. Failure rate was 74% in the 103 patients tested post-treatment. Treatment failure tended to be higher with azithromycin single dose than with 5-day azithromycin (88% vs. 70%; P=0.07). Azithromycin and moxifloxacin were used as second-line treatment in 24 and 23 patients, respectively. Post-treatment PCR remained positive in 55% of the 44 tested patients with a better eradication rate with moxifloxacin than with azithromycin (70% vs. 33%; P=0.04). CONCLUSION: MG infection is highly prevalent in PrEP users and HIV-positive patients and is mostly asymptomatic. Management of MG infection should be tailored and adapted to the risk of antibiotic resistance and reinfection.

Intermittent two-drug antiretroviral therapies maintain long-term viral suppression in real life in highly experienced HIV-infected patients.

OBJECTIVES: To assess in real life whether two-drug regimens (2-DRs) given 4-5 days a week in virally suppressed patients can maintain viral suppression over 48 and 96 weeks. METHODS: This observational single-centre study enrolled all patients who initiated an intermittent 2-DR between 01/01/2016 and 30/06/2019. The primary outcome was the rate of virological failure (VF), defined as confirmed plasma viral load (pVL) ≥50 copies/mL or single pVL ≥50 copies/mL followed by ART change at week 48 (W48) and W96. Secondary outcomes were the 2-DR intermittent strategy success rate (pVL <50 copies/mL with no ART change), change in CD4 count, CD4/CD8 ratio and rate of residual viraemia. RESULTS: Eighty-five patients were included; 67/85 (79%) were men, median age = 57 years (IQR = 50-63), CD4 nadir = 233 cells/mm3 (110-327), ART duration = 21 years (13-24), duration of virological suppression = 6.5 years (3.7-10.8) and CD4 count = 658 cells/mm3 (519-867). Intermittent 2-DRs consisted of integrase strand transfer inhibitor (INSTI)/NNRTI (58%), INSTI/NRTI (13%), two NRTIs (11%), PI/NRTI (7%) and other combinations (11%). The median follow-up was 90 weeks (IQR = 64-111). Overall, four VFs occurred, leading to a virological success rate of 98.8% (95% CI = 93.6-100) at W48 and 95.3% (95% CI = 88.4-98.7) at W96. Resuming the same 2-DR 7 days a week led to viral resuppression in three patients, whereas the M184V mutation emerged in one patient, leading to ART modification. There was no significant change in the CD4 count or residual viraemia rate, but a small increase in the CD4/CD8 ratio (P = 0.009) occurred over the study period. CONCLUSIONS: This observational study shows the potential for intermittent 2-DRs to maintain a high virological success rate, which should be assessed in larger prospective randomized studies.

Efficacy of intermittent short cycles of integrase inhibitor-based maintenance ART in virologically suppressed HIV patients.

BACKGROUND: Several studies have shown that NNRTI/PI-based triple therapy could be safely administered as a 4 days (4D) or 5 days (5D) a week maintenance strategy. We report here our experience of using an integrase inhibitor (INSTI)-based 4D/5D regimen in virologically suppressed HIV patients. METHODS: This cohort study enrolled adult patients on ART with viral load (VL) <50 copies/mL for >1 year, who switched to an INSTI-based triple regimen given 4D/5D a week. The primary endpoint was the virological efficacy rate at Week (W) 48, with virological failure defined as confirmed VL ≥50 copies/mL. RESULTS: A total of 73 patients were included (n = 28 for 4D, n = 45 for 5D): 54 men (74%), median (IQR) age 51 (45-57) years, ART duration 10 (6-18) years and duration of viral suppression 5 (2-9) years at baseline. As of 25 March 2019, the median follow-up was 21 (14-35) months, with a total of 161 patient-years of follow-up; all patients had reached the W24 visit, 66 (90%) W48 and 34 (47%) W96. Four patients discontinued the strategy: virological failure (n = 2) at W60 and W67, respectively, switch for renal toxicity (n = 1) at W28 and switch to rilpivirine/dolutegravir (n = 1) at W65. Overall the rate of virological success (95% CI) was 100% (94%-100%) at W24 and W48 and 93.7% (79.8%-98.2%) at W96. CONCLUSIONS: While waiting for the final results of the large randomized QUATUOR ANRS-170 study, our real-life results suggest that the use of an intermittent maintenance triple-drug regimen given as a weekend (2 or 3 days) off is as effective with an INSTI-based regimen as with a PI or an NNRTI.

INSTI-Based Triple Regimens in Treatment-Naïve HIV-Infected Patients Are Associated With HIV-RNA Viral Load Suppression at Ultralow Levels.

BACKGROUND: During antiretroviral therapy (ART), HIV-1-infected patients may present with ultralow (UL) HIV-RNA viral loads (VLs) below quantification levels of current assays. Reasons for UL-VL detection and its relation to virological rebound (VR) are unclear. METHODS: HIV-1-infected, ART-naïve patients followed at 2 university hospitals were included. All participants had an HIV-RNA >200 copies/mL at ART initiation and achieved a VL <50 copies/mL during ART. UL-VL was determined by the presence/absence of polymerase chain reaction signal detected using a commercially available assay (COBAS, TaqMan, Roche). Random-effects Poisson regression was used for assessing determinants of UL-VL not detected overtime and conditional risk set analysis for VR (1 VL > 200 copies/mL or 2 VL > 50 copies/mL) while accounting for frequency of VL measurements. RESULTS: Between 2009 and 2013, 717 patients initiated ART containing 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTIs) plus a non-NRTI (29.4%), a protease inhibitor (58.4%), or an integrase-strand transfer inhibitor (INSTI; 12.1%). During a median (interquartile range) 3.4 (2.3-4.6) years, 676 (94.3%) patients achieved UL-VL not detected. In multivariable analysis, UL-VL not detected overtime was associated with younger age (P < .001), female gender (P = .04), lower baseline VL (P < .001), baseline CD4+ >500 vs <350/mm3 (P < .001), and INSTI-containing ART (P = .009). One hundred thirty-one (18.3%) patients had VR during follow-up, which was independently associated with a CD4/CD8 ratio <0.8 during follow-up (P = .01) and time spent with UL-VL not detected (P < .001). When UL-VL not detected occurred for ≥50% of the follow-up duration (n = 290), faster time to reach UL-VL not detected (P < .001), faster CD4+ T-cell count increase (P = .03), and faster CD4/CD8 ratio increase (P = .001) were observed. CONCLUSIONS: VL suppression at an ultralow level is associated with INSTI-class ART initiation. Extensive VL suppression below ultralow detection could improve immune reconstitution.

Determinants of a Low CD4/CD8 Ratio in HIV-1-Infected Individuals Despite Long-term Viral Suppression.

BACKGROUND: A low CD4/CD8 ratio in human immunodeficiency virus (HIV)-infected individuals despite effective antiretroviral therapy (ART) reflects ongoing immune activation and has been linked to a higher risk of non-AIDS morbidity and mortality. Our aim was to describe the proportion of individuals with a persistent CD4/CD8 ratio <1 despite long-term viral suppression and to determine associated risk factors. METHODS: This cross-sectional study was conducted in 2012 in a single clinical center. HIV type 1 (HIV-1)-infected individuals were eligible if they had a plasma HIV-1 RNA level <50 copies/mL for at least 2 years on a stable ART regimen. Logistic regression was used to identify risk factors for a persistent CD4/CD8 ratio <1. RESULTS: We enrolled 719 individuals with a median CD4/CD8 ratio of 0.8 (interquartile range [IQR], 0.6-1.1), CD4 and CD8 T-cell counts of 565 (IQR, 435-742) cells/µL and 727 (IQR, 530-991) cells/µL respectively, and viral suppression for 5.4 (IQR, 3.3-9.1) years. Cytomegalovirus (CMV) serology was positive in 564 of 645 individuals (87%). Persistent CD4/CD8 ratio <1 was observed in 471 patients (66%). The following factors were independently associated with a CD4/CD8 ratio <1: CMV seropositivity (odds ratio [OR], 1.9 [95% confidence interval {CI}, 1.1-3.1]), ART initiation before 1997 (OR, 1.9 [95% CI, 1.2-3.0] compared with 2002 or later), a lower CD4 T-cell nadir (OR, 0.7 [95% CI, .7-.8] per log2 increment), and shorter duration of viral suppression (OR, 0.6 [95% CI, .5-.8] per 5 years). CONCLUSIONS: Most HIV-infected individuals with long-term viral suppression still had a CD4/CD8 ratio <1. Early initiation and long-term effective ART appear to improve this ratio. CMV coinfection, which represents a potential target for therapeutic intervention, was strongly associated with a persistently suboptimal CD4/CD8 ratio.

Dual raltegravir/etravirine combination in virologically suppressed HIV-1-infected patients on antiretroviral therapy.

BACKGROUND: The combination of raltegravir (RAL) and etravirine (ETR) represents a novel antiretroviral treatment option in patients with toxicity or long-term exposure to standard therapies including protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI). The objective of this study was to evaluate the capacity of dual RAL/ETR therapy to maintain virological suppression in HIV-1 patients under effective antiretroviral therapy (ART). METHODS: Using the Nadis database we retrospectively identified all patients in our centre who were switched from different ART regimens to ETR 200 mg twice daily plus RAL 400 mg twice daily prior to February 2010, having a suppressed HIV-1 plasma viral load (pVL<200 copies/ml) at the moment of switch. Patients already on RAL or ETR at baseline were not excluded from the study. Treatment failure was defined as two consecutive pVL>50 copies/ml or discontinuation of RAL/ETR for any reason. RESULTS: A total of 18 patients were included. Median baseline characteristics were: age 48 years (IQR 45-56), duration of ART 14 years (IQR 13-16), duration of viral suppression 6 years (IQR 5-9), duration of NRTI exposure 11 years (IQR 8-14) and PI exposure 6 years (IQR 3-9). In intent-to-treat analysis, the efficacy at 6 months of follow-up was 94.4% (n=17/18, 95% CI 74.2, 99%) and 83.3% (n=15/18, 95% CI 60.7, 94.1%) at 12 months. In per-protocol analysis, the efficacy at 12 months was 100% (n=15/15, 95% CI 80.6, 100%). No tolerability-related treatment discontinuation was recorded. CONCLUSIONS: This study, although on a limited number of patients, suggests that raltegravir plus etravirine represents a potential option of NRTI/PI-sparing strategy, deserving further investigation in randomized studies.

Antiretroviral therapy with a twice-daily regimen containing 400 milligrams of indinavir and 100 milligrams of ritonavir in human immunodeficiency virus type 1-infected women during pregnancy.

We evaluated the safety and efficacy of a twice daily regimen containing 400 mg of indinavir and 100 mg of ritonavir in 32 human immunodeficiency virus (HIV)-infected women during pregnancy. The median indinavir trough concentration was 208 ng/ml during the third trimester. At delivery, 26 of 28 women on indinavir-ritonavir had HIV RNA levels of <200 copies/ml. No infant was HIV infected. These data are encouraging for the use of this combination for prevention of mother-to-child transmission of HIV.

Factors associated with the selection of mutations conferring resistance to protease inhibitors (PIs) in PI-experienced patients displaying treatment failure on darunavir.

The objective of this study was to characterize the mutations selected by darunavir (DRV) use in protease inhibitor (PI)-experienced patients and the associated factors. We analyzed treatment failure in 54 PI-experienced human immunodeficiency virus (HIV)-infected patients on a DRV- and ritonavir-containing regimen. Viral genotyping was carried out at the baseline, at between 1 and 3 months of treatment, and at between 3 and 6 months of treatment to search for the selection of mutations conferring resistance to PIs. The median baseline HIV RNA level was 4.9 log(10) copies/ml, and the median CD4 count was 87 cells/mm(3). At the baseline, the median numbers of resistance mutations were as follows: 3 DRV resistance mutations, 4 major PI resistance mutations, and 10 minor PI resistance mutations. The most common mutations that emerged at rebound included V32I (44%), I54M/L (24%), L33F (25%), I84V (21%), and L89V (12%). Multivariate analysis showed that higher baseline HIV RNA levels and smaller numbers of nucleoside reverse transcriptase inhibitor simultaneously used with DRV were associated with a higher risk of DRV resistance mutation selection. By contrast, L76V, a known DRV resistance mutation, was found to decrease the risk of selection of another DRV resistance mutation. The occurrence of virological failure while a patient was on DRV was associated with the selection of mutations that increased the level of DRV resistance without affecting susceptibility to tipranavir (TPV). In these PI-treated patients who displayed treatment failure while they were on a DRV-containing regimen, we confirmed the set of emerging mutations associated with DRV failure and identified the factors associated with the selection of these mutations. TPV susceptibility does not seem to be affected by the selection of a DRV resistance mutation.

Association of Gag cleavage sites to protease mutations and to virological response in HIV-1 treated patients.

OBJECTIVES: The sequence variability in the protease and in the 5 Gag cleavage sites (CS) were explored to look for eventual associations between the mutations. Moreover, we have evaluated associations between the Gag region sequence and the virological response to Protease Inhibitors (PI). METHODS: The protease and the 5 Gag CS sequences from 98 PI-experienced patients were sequenced and compared to the HXB2 reference sequence. Sixty patients, treated by Saquinavir plus Ritonavir, were studied to evaluate the clinical impact of the Gag region variability. RESULTS: The relationship between 63 protease mutations and 21 Gag CS mutations were explored. Two patterns of mutations in the protease were identified: (M46I/L, I54V, V82A/T/F) was associated to the A431V and (K20I/R/M, L89M/I) to the S373Q and L449P. None of the Gag CS mutations resulting from PI treatment was associated to the virological response to SQV/r. On the other hand, the S373P mutation had a negative impact on the virological response that remained statistically significant in a multivariate analysis after adjustment on the number of PI resistance mutations. CONCLUSIONS: These results evoke the pertinence to introduce some mutations found in the Gag CS in the algorithms used for the interpretation of resistance testing.

Clinically relevant interpretation of genotype and relationship to plasma drug concentrations for resistance to saquinavir-ritonavir in human immunodeficiency virus type 1 protease inhibitor-experienced patients.

It has been shown that virological protease inhibitor (PI) resistance mutations present at the initiation of saquinavir (SQV) plus ritonavir (RTV) therapy in PI-experienced patients are the strongest predictors of virological response. But most of the current resistance algorithms are adapted for unboosted SQV regimens. We applied a stepwise methodology for the development and validation of a clinically relevant genotypic resistance score for an SQV (800 mg twice per day [b.i.d.]) plus RTV (100 mg b.i.d.)-containing regimen. PI-experienced patients treated by this regimen achieved a human immunodeficiency virus plasma viral load (VL) of <200 copies/ml at months 3 to 5 for 41.7% of subjects. Adjusted in a multivariate analysis, taking into account all the confounding factors, such as the nucleoside used, five mutations were combined in a resistance score associated with a reduced virological response to an SQV-plus-RTV regimen: L24I, I62V, V82A/F/T/S, I84V, and L90IM. Patients with isolates harboring 0 to 1 mutation among the score achieved -2.20 log10 and -1.23 log10 copies/ml of VL reduction, respectively, while it was -0.27 log10 copies/ml for those with at least two mutations, classifying the isolates as "no evidence of resistance" (0 or 1 mutation) or "resistance " (> or =2 mutations). The minimum concentration in plasma (Cmin) of SQV alone was not associated with the virological response. However, the combination of the SQV Cmin and the genotypic score, expressed as the genotypic inhibitory quotient, was predictive of the virological response, suggesting that the interpretation of SQV concentrations in plasma should be done only in the context of the resistance index provided by viral genotype for PI-experienced patients.

Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients.

OBJECTIVE: To evaluate the pharmacokinetics, efficacy and tolerability of a low-dose boosted indinavir (IDV)/ritonavir (RTV) regimen [100 mg RTV/400 mg IDV twice daily (bid)] in patients previously receiving a standard IDV regimen [800 mg three times a day (tid)]. METHODS: In a prospective, open-label, cross-over trial, patients with plasma HIV RNA < 200 copies/ml receiving an IDV-containing regimen (800 mg tid) were switched to an RTV/IDV (100/400 mg bid)-containing regimen. Minimal and maximal IDV plasma concentrations ( Cmin and Cmax ) were determined before the switch (day 0), at week 2 and week 4 after the switch. The CD4 cell count and plasma HIV RNA were determined at day 0, week 2 and week 4, then every 8 weeks. The primary end-point was the percentage of patients with plasma HIV RNA below 200 copies ml at week 48. RESULTS: Twenty patients were enrolled. At baseline, on IDV 800 mg tid, median IDV Cmin was 194 ng/ml and median IDV Cmax was 8449 ng/ml. On RTV/IDV (100/400 mg), median IDV Cmin increased to 536 ng/ml at week 2 and 475 ng/ml at week 4, while Cmax decreased to 2983 ng/ml at week 2 and 2997 ng/ml at week 4 ( P < 0.001). The median area under the IDV plasma concentration-time curve measured in seven patients was 25 126 ng.h/ml, and the IDV half-life (t1/2 ) was 4.4 h. All patients had plasma HIV RNA remaining < 200 copies/ml at week 48. Tolerability of RTV/IDV was excellent. CONCLUSION: RTV/IDV (100/400 mg bid) yields significantly higher IDV plasma Cmin and lower IDV Cmax values relative to the standard IDV regimen, thereby improving both tolerability and efficacy.

Efficacy and safety of ritonavir/indinavir 100/400 mg twice daily in combination with two nucleoside analogues in antiretroviral treatment-naive HIV-infected individuals.

OBJECTIVE: To evaluate the efficacy and tolerability of indinavir/ritonavir (IDV/RTV) 400/100 mg twice daily in combination with two nucleoside reverse transcriptase inhibitors in antiretroviral-naive patients. DESIGN AND METHODS: Antiviral therapy-naive patients with plasma HIV-1 RNA > 5000 copies/ml were enrolled in this pilot, single-arm study. CD4 cell count and viral load were evaluated at weeks (W) 4, 12, 24 and every 3 months until W48. The primary end-point was the percentage (%) of patients with viral load < 400 copies/ml at W48. Intent-to-treat (ITT) (missing values or change in treatment equalled failure) and on-treatment (OT) analyses were performed. RESULTS: Forty patients were enrolled. Baseline median viral load was 5.36 log10 copies/ml, median CD4 count was 84 cells/mm3. At W48 by ITT analysis, the % patients with viral load < 400 copies/ml was 65% (95% CI: 48-79) and 50% (95% CI: 35-65) with viral load < 50 copies/ml, and 96% (26/27) (95% CI: 89-100) and 74% (95% CI: 57-91], respectively, by OT analysis. The median decrease in viral load at W48 was -3.83 log10 copies/ml (-0.1; -5.19) and the median increase in CD4 was +167 cells/mm3 (6-474 cell/mm3). At W4 (34/40), the median IDV C(min) was 500 ng/ml (range 5-8100) with 91% of patients with an adequate IDV C(min) > 150 ng/ml. Ten patients discontinued the study treatment before W48: adverse events (eight), patient's will (one) and simplification of therapy (one). Three patients were lost to follow-up. Only one virological failure occurred and was associated with poor compliance and sub-optimal concentrations of IDV/RTV. CONCLUSIONS: IDV/RTV 400/100 mg twice daily is an effective and safe first-line antiretroviral therapy. The simplicity and the low cost of IDV/RTV is of major interest particularly in countries with limited resources.

Discontinuation of secondary prophylaxis against disseminated Mycobacterium avium complex infection and toxoplasmic encephalitis.

We retrospectively studied outcomes for patients infected with human immunodeficiency virus who received highly active antiretroviral therapy (HAART) and had stopped receiving secondary prophylaxis against toxoplasmic encephalitis (TE) or disseminated Mycobacterium avium complex (MAC) infection. Nineteen patients had a history of TE, and 26 had a history of disseminated MAC infection. The median duration of secondary prophylaxis was 27 months, and the median duration of HAART before discontinuation of secondary prophylaxis was 22 months. Median CD4(+) cell counts at the time of cessation of secondary prophylaxis against TE or disseminated MAC infection were 404 and 105 cells/mm(3), respectively. Plasma virus load was undetectable in 68% of the patients who had a history of TE and in 31% of patients who had a history of disseminated MAC infection. Patients were followed up for a median of 29 months after discontinuation of secondary prophylaxis; no relapses occurred in patients with a history of TE, and 3 relapses occurred in patients with a history of disseminated MAC infection (incidence, 4 relapses per 100 person-years).