Protease Inhibitor-based Therapy Research Articles

Dolutegravir Resistance in African Programmatic Settings Among Patients With Failure of Dolutegravir-based ART.

Dolutegravir resistance is emerging in routine clinical contexts in southern Africa, primarily in patients with prior treatment experience failing dolutegravir-based antiretroviral therapy (ART). This potential issue was raised by The Nucleosides and Darunavir/Dolutegravir in Africa trial that compared dolutegravir and boosted protease inhibitor-based therapy as second-line ART, in which new dolutegravir resistance was observed at failure. However, recent data suggest that also at risk are patients who were transitioned to dolutegravir from non-nucleoside reverse transcriptase inhibitor-based ART while viremic. Identifying patients experiencing failure of dolutegravir with resistance will be difficult given current gaps in viral load monitoring and limited capacity for genotypic resistance testing. As a result, in the short term, most patients affected will go unrecognized, with particularly important implications for patients affected who have advanced HIV or who are pregnant/breastfeeding. Prospective research is needed to understand the scope of the problem, identify additional risk factors, and determine best management. In the short term, for most patients with dolutegravir resistance and prior non-nucleoside reverse transcriptase inhibitor exposure, the best option will be a timely switch to a regimen anchored by a boosted protease inhibitor, with a high genetic barrier to resistance.

Weight and Metabolic Outcomes in Naïve HIV Patients Treated with Integrase Inhibitor-Based Antiretroviral Therapy: A Systematic Review and Meta-Analysis.

The use of integrase inhibitor-based antiretroviral therapy could be associated with worse weight and metabolic outcomes in patients with HIV infection. PubMed, EMBASE, and Scopus were searched from inception to March 2022. We selected randomized controlled trials (RCTs) comparing integrase inhibitors with other antiretroviral classes (efavirenz-based or protease inhibitor-based therapies) in naïve HIV patients. Random effects meta-analysis was used to assess the effects of integrase inhibitors vs. controls on weight and lipid outcomes. Effects were described as mean differences (MD) and their 95% confidence intervals (CI). Certain pieces of evidence (CoE) were evaluated using the GRADE methodology. Six RCTs (n = 3521) were included, with patients followed up between 48 and 96 weeks. The use of integrase inhibitors in comparison with other antiretroviral classes was associated with an increase in weight (MD 2.15 kg, 95%CI 1.40 to 2.90, I2 = 0%, moderate CoE), and decreases in total cholesterol (MD -13.44 mg/dL, 95%CI -23.49 to -3.39, I2 = 96%, low CoE), LDL cholesterol (MD -1.37 mg/dL, 95%CI -19.24 to -3.50, I2 = 83%, low CoE), HDL cholesterol (MD -5.03 mg/dL, 95%CI -10.61 to 0.54, I2 = 95%, low CoE), and triglycerides (MD -20.70 mg/dL, 95%CI -37.25 to -4.15, I2 = 92%, low CoE). There was a high risk of bias in two RCTs and some concerns about bias in two RCTs. In HIV patients, the use of integrase inhibitor-based therapy in comparison with protease inhibitor- or NNRTI-based therapy was associated with a small increase in weight and small decreases in lipid serum levels.

Association between integrase strand transfer inhibitor use with insulin resistance and incident diabetes mellitus in persons living with HIV: a systematic review and meta-analysis

Whether integrase strand transfer inhibitors (INSTIs) are associated with a higher risk of incident type 2 diabetes mellitus (DM) than other antiretroviral therapies (ART) needs to be established.MEDLINE, Embase, Web...

Аdverse events underlying antiretroviral therapy in children with HIV infection

Introduction. Human immunodeficiency virus infection can alter properties of blood vessels in children and increase the risk of development of cardiovascular diseases in the future. Today the actual contribution of the effects of both HIV infection and antiretroviral therapy into such changes remains unknown. Objective. We seek to assess adverse events, including metabolic disorders (dyslipidemias), underlying antiretroviral therapy, and to determine the relation between metabolic disorders and intima injury in children receiving antiretroviral therapy (ART).Materials and methods. The adverse events were investigated within the framework of a prospective and retrospective study. The study included evaluation of biochemical parameters in relation to the therapeutic regimen; calculation of atherogenic index of plasma; and determination of incidence of dyslipidemia in children. In addition to standard tests, children on ART were evaluated for insulin resistance (using HOMA-IR) and submitted to diagnostic imaging including Doppler ultrasonography of brachiocephalic arteries and veins.Results. Children on protease inhibitor-based ART have higher total cholesterol, LDL and triglyceride levels in comparison to both children on NNRTI-based ART and children who do not receive ART. LDL levels in children on long-term ART remained within the tolerance range and were clearly higher than those in children who did not receive ART. Carotid IMT was higher in children on NNRTI-based ART in comparison to those who received protease inhibitor-based therapy; and the correlation analysis conducted revealed positive correlation between the age and carotid IMT: The later ART was prescribed, the greater IMT was, which most likely was attributable to HIV effects.Conclusion. Prescription of antiretroviral therapy at an older age results in changes in the intima-media complex, which may give evidence to vasoprotective effects of the therapy. Since HIV is directly involved in causing injury to the intima, it is advisable to start managing HIV infection in children as soon as they are diagnosed with the infection; and children to whom ART is prescribed at an older age and who develop dyslipidemia should be additionally evaluated by medical imaging with Doppler ultrasonography with carotid IMT measurement.

Disclosing the involvement of proteases in an eczema murine animal model: Perspectives for protease inhibitor-based therapies

Eczema is a skin condition characterized by itchy and inflammatory patches. The accumulation of neutrophils and the imbalance between enzymes and their inhibitors appears to be related to this condition. We proposed a neutrophil elastase (NE)-based eczema model in mice in order to verify histopathological features as well as the expression and activity of proteases and inhibitors. Mice skins were topically administered with human NE (0–2 pmol/cm2) for 24–168 h. It was observed thickening of epidermis, parakeratosis, spongiosis and leukocyte infiltration. Also, NE-treated skins presented high activity of epidermal kallikreins 5 and 7, and cathepsin B on synthetic substrates, and expression evaluated by RT-qPCR. The proteolytic activity was inhibited by soybean trypsin inhibitor, CA074 and Caesalpinia echinata kallikrein inhibitor (CeKI). The topic application of CeKI reversed eczema phenotype in NE-treated skins. Elafin expression was shown to be increased in NE-treated skins. These results suggest that the NE may trigger morphological and biochemical changes in skin similar to those observed in eczematous diseases. In addition to the establishment of this in vivo model, this work opens perspectives for the use of protease inhibitor-based drugs for the management of this skin condition.

1005. Comparison of Weight Changes in Treatment-Naïve, HIV-Infected Patients Receiving Integrase Inhibitor-Based Therapy Versus Protease Inhibitor-Based Therapy

BackgroundRecent data regarding integrase inhibitor (INSTI) therapy indicate possible association with weight gain. The incidence and degree of weight gain seems to vary by both patient-specific and regimen-related factors, such as nucleoside reverse transcriptase (NRTI) backbone.MethodsThis was a retrospective chart review of previously ART-naïve Indiana University Health LifeCare Clinic patients who started an INSTI- or PI-based regimens from 1/1/13 to 7/31/19. Adult patients without prior ART exposure receiving an INSTI- or PI-based regimen for at least 10 months were included. The primary objective was weight gain at 12 months after starting ART. Subgroup analyses were conducted by INSTI, PI, or NRTI backbone utilized. Statistical testing included Wilcoxon Rank-Sum Test and Chi Square analyses.ResultsThe patient population (N=162) was predominately male and African American with relative immunocompetence, generally achieving viral suppression after 12 months of ART. Patients receiving PI-based therapy were more likely to be Asian American or Hispanic (p=0.04), and to receive a tenofovir disoproxil fumarate (TDF)-based regimen (p=0.0034). No statistically significant difference in weight change was observed between INSTI- and PI-based regimens (median weight gain 5.1 kg vs 3.9 kg, p=0.52). The proportion of obese or overweight patients in the INSTI arm increased significantly as compared to baseline (p=0.00001). Subgroup analyses demonstrated significant increases in weight gain and clinically significant weight gain with tenofovir-based (tenofovir alafenamide and TDF) regimens compared to those with abacavir/lamivudine (p< 0.05).Primary Objective BMI Category Changes by INSTI or PI Agent NRTI Subgroup Analyses ConclusionLack of power makes meaningful interpretation of the results for the primary objective difficult. However, several of the prespecified secondary objectives and subgroup analyses demonstrated clinically significant results related to increased weight gain or BMI category changes with INSTI-, PI-, and tenofovir-based regimens. Checking the patient’s weight at every appointment is considered standard practice at IU Health clinics, but missing values despite qualifying encounters were observed. Further commitment to standardized weighing practices should be a priority at clinics caring for patients living with HIV.Disclosures All Authors: No reported disclosures

Perinatal outcomes on mortality and influencing factors among HIV-infected mothers in Sichuan province

Objective: To explore the influencing factors on perinatal mortality of pregnant women with HIV infection to reduce the mother-to-child transmission in Sichuan province. Methods: In this study, 4 786 perinatal infants of the HIV-infected pregnant women were included. Related data on perinatal epidemiology was reported by all the 183 medical and health care institutions where the HIV prevention of mother-to-child transmission program was initiated in 2005-2016. Univariate χ(2) test and multivariate logistic regression methods were used to analyze the perinatal mortality outcomes and influencing factors. Results: The overall perinatal mortality rate was 25.7‰ (123/4 786) among HIV-infected pregnant women, with annual downwarding trend (trend χ(2)=32.220, P=0.000). Perinatal mortality rate appeared the highest (χ(2)=4.130, P=0.042), with more fetal deaths and stillbirths and less early neonatal death within 7 days in Liangshan county (χ(2)=29.626, P=0.000). Results from the multivariate logistic regression analysis showed that fewer pregnant numbers would contribute to the, lower perinatal mortality rate (1-2 pregnancies OR=0.417, 95%CI: 0.184-0.943; 3-4 pregnancies OR=0.447, 95%CI: 0.223-0.895). Perinatal deaths were more likely to be prevented if LPV/r protease inhibitor-based triple antiviral therapy was provided (OR=0.530, 95%CI: 0.285- 0.986) or delivery was taken place in the hospital (hospital of municipal-level and above OR=0.222, 95%CI:0.098-0.499; county-level hospital OR=0.282, 95%CI: 0.166-0.480; township-level hospital OR=0.134, 95%CI: 0.031-0.586) among HIV-infected pregnant women. However, premature delivery or neonatal asphyxia would increase the risk of perinatal mortality (premature delivery OR=8.285, 95%CI: 5.073-13.533; neonatal asphyxia OR=9.624, 95%CI: 4.625-20.028). Conclusions: The perinatal mortality rate of HIV-infected pregnant women appeared significantly higher than that in the province or the whole country. Strategies involving LPV/r-based triple antiviral therapy, promotion of hospital delivery, reducing the incidence rates of premature deliveries and neonatal asphyxia, should be strengthened.

THU425 - Identification of patients with compensated cirrhosis who can safely use protease inhibitor-based therapy for HCV infection

THU425 - Identification of patients with compensated cirrhosis who can safely use protease inhibitor-based therapy for HCV infection

Brief Report: Sex Differences in Outcomes for Individuals Presenting for Third-Line Antiretroviral Therapy.

Sex differences in studies of antiretroviral (ART) drug exposure and treatment outcomes support the hypothesis that some ART combinations may not be well tolerated in women. We evaluated disparities in outcomes between men and women participating in ACTG A5288, an interventional strategy trial for individuals failing a protease inhibitor-based second-line ART regimen in low- and middle-income countries. Participants were assigned to one of 4 cohorts (A-D) based on resistance profiles and ART history. Cohort A had no lopinavir/ritonavir (LPV/r) resistance and stayed on their second-line regimen, and cohorts B, C, and D had increasing resistance and accessed novel ART regimens. In this secondary analysis, we evaluated sex differences in the primary endpoint, HIV-1 RNA ≤200 copies/mL at week 48; confirmed virologic failure ≥1000 copies/mL (VF); and clinical outcomes and adverse events (intent-to-treat). Women made up 258/545 (47%) of the study population. More women than men were assigned to cohort A. Median follow-up was 72 weeks. Fewer women than men had HIV-1 RNA ≤200 copies/mL at week 48: 39% vs. 49% in cohort A and 83% vs. 89% in cohorts B, C, and D combined. More women experienced VF, grade ≥3 signs and symptoms, but similar grade ≥3 diagnoses or laboratory abnormalities. More women than men entered the study with a resistance profile suggesting that their second-line regimen could have been effective in maintaining virologic suppression. The more frequent occurrence of grade ≥3 signs and symptoms in women suggests that tolerability issues were under recognized in women on protease inhibitor-based therapy.

HIV protease inhibitor ritonavir induces renal fibrosis and dysfunction: role of platelet-derived TGF-β1 and intervention via antioxidant pathways.

Chronic kidney disease (CKD) with tubular injury and fibrosis occurs in HIV infection treated with certain protease inhibitor-based antiretroviral therapies. The pathophysiology is unclear. We hypothesized that fibrosis, mediated by platelet-derived transforming growth factor (TGF)-β1, underlies protease inhibitor-associated CKD. We induced this in mice exposed to the protease inhibitor ritonavir (RTV), and intervened with low-dose inhaled carbon monoxide (CO), activating erythroid 2-related factor (Nrf2)-associated antioxidant pathways. Wild-type C57BL/6 mice and mice deficient in platelet TGF-β1, were given RTV (10 mg/kg) or vehicle daily for 8 weeks. Select groups were exposed to CO (250 ppm) for 4 h after RTV or vehicle injection. Renal disorder, fibrosis, and TGF-β1-based and Nrf2-based signaling were examined by histology, immunofluorescence, and flow cytometry. Renal damage and dysfunction were assessed by KIM-1 and cystatin C ELISAs. Clinical correlations were sought among HIV-infected individuals. RTV-induced glomerular and tubular injury, elevating urinary KIM-1 (P = 0.004). It enhanced TGF-β1-related signaling, accompanied by kidney fibrosis, macrophage polarization to an inflammatory phenotype, and renal dysfunction with cystatin C elevation (P = 0.008). Mice lacking TGF-β1 in platelets were partially protected from these abnormalities. CO inhibited RTV-induced fibrosis and macrophage polarization in association with upregulation of Nrf2 and heme oxygenase-1 (HO-1). Clinically, HIV infection correlated with elevated cystatin C levels in untreated women (n = 17) vs. age-matched controls (n = 19; P = 0.014). RTV-treated HIV+ women had further increases in cystatin C (n = 20; P = 0.05), with parallel elevation of HO-1. Platelet TGF-β1 contributes to RTV-induced kidney fibrosis and dysfunction, which may be amenable to antioxidant interventions.

Detectability of HIV Residual Viremia despite Therapy Is Highly Associated with Treatment with a Protease Inhibitor-Based Combination Antiretroviral Therapy.

HIV persistence despite therapy contributes to chronic immune activation and inflammation, increasing the risk of aging-associated events in HIV-infected individuals. We sought here to better understand the complex link between clinical and treatment features and HIV persistence despite therapy. A total of 11,045 samples from 1,160 individuals under combination antiretroviral therapy (cART) with an unquantifiable viral load (VL; limit of quantification, 20 copies/ml) were categorized as detectable or undetectable depending on the detection of a PCR signal using a commercially available assay. Generalized estimating equation (GEE) regression was used to model viral load detectability and to assess the determinants of residual viremia (RV; VL detected below 20 copies/ml) despite therapy. A high VL zenith was associated with a higher probability to have a detectable viremia under cART. Conversely, the probability to have a detectable viral load below 20 copies/ml decreased with time under therapy. Of therapy regimens, protease inhibitor (PI)-based cART was associated with a significantly higher probability of detectable RV compared to nonnucleoside transcriptase inhibitor- or integrase inhibitor-based cART. We found that a PI-based treatment regimen is highly associated with an increased frequency of RV, supporting previous evidence suggesting that PI-based cART regimens could favor ongoing viral replication in some individuals.

Two drugs regimens for HIV.

As the evidence for two-drug regimens (2DR) for HIV treatment accumulates and 2DR start to enter consensus guidelines, this review covers the history, rationale and current evidence for 2DR in first-line and switch settings. Until recently, most evidence for 2DR was for boosted protease inhibitor-based therapies but now we have large, randomized trials to support the use of dolutegravir (DTG)-based 2DR, both for initial therapy and suppressed switch, with high efficacy and no emergent resistance at failure. 2DR will increasingly form part of the choice we are able to offer people with HIV but we must consider some of the limitations to ensure these regimens are used in the most clinically appropriate manner.

Drug resistance and optimizing dolutegravir regimens for adolescents and young adults failing antiretroviral therapy

The integrase strand inhibitor dolutegravir (DTG) combined with tenofovir and lamivudine (TLD) is a single tablet regimen recommended for 1st, 2nd and 3rd-line public health antiretroviral therapy (ART). We determined drug resistance mutations (DRMs) and evaluated the predictive efficacy of a TLD containing regimen for viremic adolescents and young adults in Harare, Zimbabwe. We sequenced plasma viral RNA from HIV-1-infected adolescents and young adults on 1st and 2nd-line ART with confirmed virologic failure (viral load >1000 copies/ml) and calculated total genotypic susceptibility scores to current 2nd, 3rd line and DTG regimens. A total of 160 participants were genotyped; 112 (70%) on 1st line and 48 (30%) on 2nd line, median (interquartile range) age 18 (15-19) and duration of ART (interquartile range) was 6 (4-8) years. Major DRMs were present in 94 and 67% of 1st and 2nd-line failures, respectively (P < 0.001). Dual class resistance to nucleotide reverse transcriptase inhibitors and nonnucleotide reverse transcriptase inhibitors was detected in 96 (60%) of 1st-line failures; protease inhibitor DRMs were detected in a minority (10%) of 2nd-line failures. A total genotypic susceptibility score of 2 or less may risk protease inhibitor or DTG monotherapy in 11 and 42% of 1st-line failures switching to 2nd-line protease inhibitor and TLD respectively. Among adolescents and young adults, current protease inhibitor-based 2nd-line therapies are poorly tolerated, more expensive and adherence is poor. In 1st-line failure, implementation of TLD for many adolescents and young adults on long-term ART may require additional active drug(s). Drug resistance surveillance and susceptibility scores may inform strategies for the implementation of TLD.

Short Communication: Nucleoside Reverse Transcriptase Inhibitors with Reduced Predicted Activity Do Not Impair Second-Line Therapy with Lopinavir/Ritonavir or Darunavir/Ritonavir.

Second-line therapy randomized trials with lopinavir/ritonavir question the value of resistance testing to guide nucleoside reverse transcriptase inhibitor (NRTI) selection. In this study, we investigated the association between baseline drug resistance and treatment outcome after 104 weeks of second-line therapy with NRTIs and either darunavir/ritonavir or lopinavir/ritonavir in West-central Africa. We did an observational analysis of data from 387 individuals in a randomized, open-label 2LADY trial in Burkina Faso, Cameroon, and Senegal. We modeled the association between RTI drug resistance mutations (DRMs) and virological failure (VF) (viral load [VL] <50 copies/mL) at week 104 using logistic regressions. Covariates included baseline VL and CD4+ count, demographic, and adherence data. Overall, 193 (49.9%), 150 (38.8%), and 44 (11.4%) individuals had, respectively, low/none (genotypic susceptibility score [GSS] <1), intermediate (GSS = 1), and high predicted NRTI activity (GSS >1) in their prescribed second-line regimen. The average number of DRMs by drug class, the proportion of individuals by GSS category, and the duration of first-line therapy were not associated with VF (p > .05). High VL at switch was the only consistent prognostic factor for VF after multivariate adjustment (p < .01). Suboptimal adherence, high predicted RTI activity, or low NRTI mutations were associated with VF (p < .05) when using higher end points for VF or in the intention-to-treat analysis. In conclusion, the use of RTIs with predicted reduced activity does not impair second-line protease inhibitor-based therapy. Therefore, HIV care in resource-limited settings should prioritize strategies to improve adherence and targeted VL testing over drug resistance testing for selecting NRTIs during a protease-based second-line switch.

Budget impact of antiretroviral therapy in a French clinic cohort.

In this study, we first assessed costs associated with the use of antiretroviral therapy (ART) in an infectious diseases University Hospital Clinic; second, we evaluated characteristics associated with these costs and finally simulated the impact on the overall ART budget of switching first-line and second-line regimens to less-costly regimens (as effective and well tolerated). Cohort analysis including persons living with HIV (PLHIV) aged at least 18 years on ART to estimate ART costs during 2014. The current study was conducted in the Bichat-Claude Bernard University Hospital Clinic in Paris, France, where 4501 PLHIV consulted in 2014. We used the medical database Nadis to describe patients' ART, characteristics and estimated costs. When assessing the budgetary impact of potential switches, we considered patients' history of failure, CD4 cell count, plasma viral load, resistance mutations, hepatitis B surface antigen or HLAB5701 profile. A total of 4238 of 4501 patients were on ART (94%). The total annual cost of ART prescribed was estimated at &OV0556;48 280 200 in 2014; first/second (simplification)-line regimens represented 25% (1076/4238) of the treated PLHIV and 23% (&OV0556;11 209 000) of the annual cost. For these PLHIV, we considered switches from the most common ART regimens (protease inhibitor boosted by ritonavir or nonnucleoside reverse transcriptase inhibitor + two nucleoside reverse transcriptase inhibitors) to less-expensive regimens. We found savings ranging from &OV0556;36 100 to 1472 600/year. Savings were the highest when we considered switching to generic-based regimens or from protease inhibitor-based triple therapy to protease inhibitor monotherapy. Costs associated with ART prescriptions are very high. Switches to generic-based regimens are associated with large savings. However, those targeting protease inhibitor regimens are also associated with substantial savings and should be considered.

HIV Pharmacist's Impact on Inpatient Antiretroviral Errors.

Transitions in care between out-patient and in-patient settings provide ample opportunity for medication errors to occur in HIV-infected patients. The purpose of this study was to examine the effectiveness of an HIV pharmacist monitoring service in decreasing antiretroviral medication errors in a large south central teaching hospital in the USA. A retrospective, observational study was conducted to examine the frequency of antiretroviral medication errors in HIV-seropositive patients with hospital admissions between 1 September 2011 and 30 September 2013 at a single tertiary care centre in Oklahoma. Patient assignment to the 12-month pre-intervention and intervention study periods was determined by admission date. Demographic, laboratory, and in-patient medication data were collected. Bivariate analyses were conducted using χ2 analysis with the Yates correction factor for continuity to examine frequencies in specific antiretroviral classes and error categories. A multivariable Poisson regression was employed to examine the frequency of medication errors before and after initiation of the pharmacist service. Medication errors were examined in a total of 330 patient admissions during the 2-year study period. A multivariable-adjusted decrease of 73.9% in the number of errors was observed between the pre-intervention and intervention periods (P < 0.001). Patients on protease inhibitor regimens or with impaired renal function had 2.6-fold and 2.8-fold higher numbers of errors, respectively (P < 0.001). HIV pharmacist monitoring can decrease medication errors in HIV-infected patients as they transition between out-patient and in-patient care. Patients receiving protease inhibitor-based therapy or with renal insufficiency are at higher risk for medication errors upon admission.

Progesterone supplementation for HIV-positive pregnant women on protease inhibitor-based antiretroviral regimens (the ProSPAR study): a study protocol for a pilot randomized controlled trial.

BackgroundIn Canada, the majority of HIV-positive pregnant women receive combination antiretroviral therapy that includes a ritonavir-boosted protease inhibitor to prevent mother-to-child HIV transmission. However, protease inhibitor-based combination antiretroviral therapy has been associated with increased rates of preterm, low birth weight, and small for gestational age births. Our previous experimental findings demonstrate that protease inhibitor use during pregnancy is associated with decreased progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve protease inhibitor-induced fetal growth restriction. We hypothesize that HIV-positive pregnant women who receive protease inhibitor-based combination therapy may also benefit from progesterone supplementation during pregnancy.Methods/designIn order to test this hypothesis, we have designed an open-label, multi-centre, randomized controlled (parallel group) pilot trial. The initial goal of this trial is to test feasibility and acceptability of our intervention. Forty HIV-positive pregnant women who are either on, or intending to start or switch to a boosted protease inhibitor-based combination antiretroviral regimen will be enrolled from six sites across Ontario, Canada. Twenty-five women will be randomized to self-administer natural progesterone (Prometrium, 200 mg) vaginally every night starting between gestational week 16 and 24 until week 36, and 15 women will be randomized to no intervention. While the participants and treating physicians will not be blinded, the laboratory personnel performing the biochemical and morphological evaluations will be blinded to ensure unbiased evaluation. The primary outcome of the pilot study is the feasibility of enrolment as measured by the recruitment rate and patient-reported reasons to decline participation. Secondary outcomes in participants include safety, acceptability, and adherence to progesterone supplementation.DiscussionGiven the safety of intravaginal progesterone and its current use in the general obstetrical population to prevent recurrent preterm delivery, this pilot study will provide data to determine the feasibility of a larger randomized controlled trial to assess the impact of this intervention on improving neonatal health in the context of HIV-positive pregnancies.Trial registrationClinicalTrials.gov, NCT02400021

Efficacy of the Combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in Treatment-Naïve or Previously Treated Patients With Hepatitis C Virus Genotype 1 or 3 Infections

We performed a phase 2 trial of the efficacy and safety of 4, 6, and 8 weeks of sofosbuvir, given in combination with the NS5A inhibitor velpatasvir and the NS3/4A protease inhibitor GS-9857, in patients with hepatitis C virus (HCV) infection. We enrolled 161 treatment-naïve or previously treated patients infected with HCV genotypes 1 or 3 with or without compensated cirrhosis at 2 centers in New Zealand, from September 2014 through March 2015. All patients received sofosbuvir (400 mg) and velpatasvir (100 mg) plus GS-9857 (100 mg) once daily. The primary efficacy end point was sustained virologic response at 12 weeks after therapy (SVR12). The duration of therapy was determined by baseline patient characteristics: 4 or 6 weeks for treatment-naïve patients without cirrhosis, 6 weeks for treatment-naïve patients with cirrhosis, and 6 or 8 weeks for treatment-experienced patients with or without cirrhosis. Four weeks of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in 4 of 15 (27%) treatment-naïve patients with HCV genotype 1 without cirrhosis. Six weeks of this combination produced a SVR12 in 14 of 15 (93%) treatment-naïve patients with HCV genotype 1 without cirrhosis, in 13 of 15 (87%) treatment-naïve genotype 1 patients with cirrhosis, in 15 of 18 (83%) treatment-naïve patients with HCV genotype 3 with cirrhosis, and in 20 of 30 (67%) patients with HCV genotype 1 who had failed an all-oral regimen of 2 or more direct-acting antiviral agents. Eight weeks of the drug combination produced an SVR12 in 17 of 17 (100%) patients with HCV genotype 1, in 19 of 19 (100%) patients with HCV genotype 3 and cirrhosis who had failed pegylated interferon plus ribavirin, in 25 of 28 (89%) patients with HCV genotype 1 who had failed protease inhibitor-based triple therapy, and in 4 of 4 (100%) patientswith HCV genotype 3 who had failed an all-oral regimen of ≥2 direct-acting antiviral agents. The most common reportedadverse events were headache, nausea, and fatigue. Eight weeks of treatment with the combination of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in most treatment-naïve or previously treated patients with HCV genotype 1 or 3 infections, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT02202980.

Evaluation of advanced fibrosis measured by transient elastography after hepatitis C virus protease inhibitor-based triple therapy.

Few studies have investigated the course of liver stiffness after treatment with protease inhibitors. We evaluated the impact of this therapy on liver fibrosis measured by transient elastography. This multicenter observational, cohort, prospective study included 90 patients with hepatitis C genotype 1 treated with telaprevir or boceprevir who had advanced fibrosis evidenced by liver stiffness (≥9.5 kPa). Liver stiffness was measured at baseline and 24 weeks after treatment ended, and was compared with virological responses at week 12. Liver stiffness decreased in 89% of patients who achieved sustained virological response. The median intrapatient liver stiffness value at the end of follow-up decreased by 5.1 kPa (35%) from baseline compared with 0.1 kPa (0.5%) in those who did not achieve a sustained virological response (P<0.001). The liver stiffness level fell below 9.5 kPa in 58% of patients with sustained virological response, and 71% of those with sustained virological response and cirrhosis evidenced by liver stiffness at baseline achieved regression below 12.5 kPa by the end of follow-up. Sustained virological response was the only variable associated with improved liver stiffness in multivariate analysis (odds ratio: 17.3; 95% confidence interval: 4.4-67.6; P<0.001). In patients with advanced fibrosis measured by transient elastography at the beginning of protease inhibitor-based therapy with sustained virological response, liver stiffness was significantly reduced 24 weeks after treatment. This suggests the possibility of liver cirrhosis evidenced by liver stiffness regression after sustained virological response in a significant proportion of patients.

Contribution of Gag and Protease to HIV-1 Phenotypic Drug Resistance in Pediatric Patients Failing Protease Inhibitor-Based Therapy.

Protease inhibitors (PIs) are used as a first-line regimen in HIV-1-infected children. Here we investigated the phenotypic consequences of amino acid changes in Gag and protease on lopinavir (LPV) and ritonavir (RTV) susceptibility among pediatric patients failing PI therapy. The Gag-protease from isolates from 20 HIV-1 subtype C-infected pediatric patients failing an LPV and/or RTV-based regimen was phenotyped using a nonreplicativein vitroassay. Changes in sensitivity to LPV and RTV relative to that of the matched baseline (pretherapy) sample were calculated. Gag and protease amino acid substitutions associated with PI failure were created in a reference clone by site-directed mutagenesis and assessed. Predicted phenotypes were determined using the Stanford drug resistance algorithm. Phenotypic resistance or reduced susceptibility to RTV and/or LPV was observed in isolates from 10 (50%) patients, all of whom had been treated with RTV. In most cases, this was associated with protease resistance mutations, but substitutions at Gag cleavage and noncleavage sites were also detected. Gag amino acid substitutions were also found in isolates from three patients with reduced drug susceptibilities who had wild-type protease. Site-directed mutagenesis confirmed that some amino acid changes in Gag contributed to PI resistance but only in the presence of major protease resistance-associated substitutions. The isolates from all patients who received LPV exclusively were phenotypically susceptible. Baseline isolates from the 20 patients showed a large (47-fold) range in the 50% effective concentration of LPV, which accounted for most of the discordance seen between the experimentally determined and the predicted phenotypes. Overall, the inclusion of thegaggene and the use of matched baseline samples provided a more comprehensive assessment of the effect of PI-induced amino acid changes on PI resistance. The lack of phenotypic resistance to LPV supports the continued use of this drug in pediatric patients.