Response from Varani et al. to “Comment on ‘the IS6 family, a clinically important group of insertion sequences including IS26’ by Ruth M. Hall”

The IS6 family of insertion sequences is a large but coherent group which was originally named to avoid confusion between a number of identical or nearly identical IS that were identified at about the same time and given different names (IS15D, IS26, IS46, IS140, IS160, IS176). The underlying common mechanistic feature of all IS6 family members which have been investigated is that they appear to transpose by replicative transposition and form pseudo compound transposons with the flanking IS in direct repeat and in which associated genes are simply transferred to the target replicon and lost from the donor.In the accompanying letter Hall raises a number of very serious and wide-ranging criticisms of our recent review article concerning the IS6 family of insertion sequences. She clearly feels that we have undervalued her work and that we question or ignore certain of her in vivo results. This impression is almost certainly the result of the standard of proof we generally apply to mechanistic aspects of transposition where we think it important to identify transposition intermediates including the types of synaptic, strand cleavage and strand transfer complexes involved.

Evolution in Real-World Therapeutic Strategies for HIV Treatment: A Retrospective Study in Southern Italy, 2014–2020

Changes in HIV treatment guidelines over the last two decades reflect the evolving challenges in this field. Our study examined treatment change patterns throughout a 7-year period in a large Italian cohort of HIV patients as well as the reasons and direction of changes. Treatment-naïve and -experienced HIV patients managed by Cotugno Hospital of Naples between 2014 and 2020 were analyzed. During the period, the proportion of single-tablet regimen treatment sharply increased for the naïve and experienced patients. Regimens containing integrase strand transfer inhibitors rapidly replaced those containing protease inhibitor and non-nucleoside reverse transcriptase inhibitors. The use of the tenofovir alafenamide fumarate/emtricitabine backbone increased rapidly after its introduction in the Italian pharmaceutical market, making up 63.7 and 54.9% of all treatments in naïve and experienced patients, respectively, in 2020. The main reason for treatment changes was optimization and/or simplification (90.6% in 2018; 85.3% in 2019; 95.5 in 2020) followed by adverse effects and virological failure. Our real-world analysis revealed that the majority of treatment-naïve and treatment-experienced patients received antiretroviral drugs listed as preferred/recommended in current recommendations. Regimen optimization and/or simplification is a leading cause of treatment modification, while virologic failure or adverse effects are less likely reasons for modification in the current treatment landscape.

Sustained HIV viral suppression with dolutegravir, tenofovir, and emtricitabine as initial therapy despite high-level transmitted multi-class resistance

Multi-class high-level transmitted HIV drug resistance is uncommon, and the selection of the optimal initial antiretroviral drug regimen may be challenging. We report a case of extensive transmitted multi-class resistance successfully treated with dolutegravir, tenofovir, and emtricitabine even though the baseline genotype demonstrated full susceptibility to only one drug class, the integrase strand transfer inhibitors. Our case highlights both the high resistance barrier of dolutegravir and the residual antiviral activity of nucleoside reverse transcriptase inhibitors despite extensive resistance on genotype.

INSTIs and NNRTIs Potently Inhibit HIV-1 Polypurine Tract Mutants in a Single Round Infection Assay

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral compounds that prevent the insertion of a DNA copy of the viral genome into the host genome by targeting the viral enzyme integrase (IN). Dolutegravir (DTG) is a leading INSTI that is given, usually in combination with nucleoside reverse transcriptase inhibitors (NRTIs), to treat HIV-1 infections. The emergence of resistance to DTG and other leading INSTIs is rare. However, there are recent reports suggesting that drug resistance mutations can occur at positions outside the integrase gene either in the HIV-1 polypurine tract (PPT) or in the envelope gene (env). Here, we used single round infectivity assays to measure the antiviral potencies of several FDA-approved INSTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) against a panel of HIV-1 PPT mutants. We also tested several of our promising INSTIs and NNRTIs in these assays. No measurable loss in potency was observed for either INSTIs or NNRTIs against the HIV-1 PPT mutants. This suggests that HIV-1 PPT mutants are not able, by themselves, to confer resistance to INSTIs or NNRTIs.

Integrase Strand Transfer Inhibitors & Weight Gain in Children with Perinatal HIV

Background: In the past, HIV infection was associated with weight loss due to metabolic wasting. Now with early initiation of antiretroviral therapy (ART) an increasing number of patients are being classified as overweight/ obese both prior to initiation and during the course of ART. Certain integrase strand transfer inhibitors (INSTIs) have been associated with weight gain in the adult population, but data in the pediatric population is lacking. This study explores the association of ART with an INSTI backbone and changes in weight and body mass index (BMI) in children with perinatal HIV who are followed in the HIV clinic at Riley Hospital. Methods: We performed a retrospective review of 59 patients with perinatally acquired HIV from 2016 to 2021. Weight, BMI, z-score, blood pressure (BP) percentiles, and lipid panels were recorded from the patients’ most recent visit. BMI and BP percentiles were compared between patients on Bictegravir, Dolutegravir, and Elvitegravir. For patients currently on an INSTI-backbone ART regimen, BMI was compared before and up to 5 years after INSTI initiation. Results: In our cross-sectional analysis between patients on Bictegravir, Dolutegravir, and Elvitegravir there was no significant difference in BMI (p=0.859), systolic BP percentile (p=0.188), or diastolic BP percentile (p=0.541). In our longitudinal analysis, we observed a significant increase in BMI over 3 years compared to pre-INSTI initiation (p=0.049). In addition, we observed an upwards trend with patients on Bictegravir (p=0.094) and Elvitegravir (p=0.121). Conclusion/Impact: Our study suggests that ART regimens with an INSTI backbone are associated with greater increases in BMIs. Our study is limited by a small n, but provides pilot data to direct future studies. It also illustrates that emphasis on healthy body weight maintenance may be necessary when patients are placed on ART regimens with INSTI backbones.

HIV Pretreatment Drug Resistance Trends in Mexico City, 2017–2020

In response to increasing pretreatment drug resistance (PDR), Mexico changed its national antiretroviral treatment (ART) policy, recommending and procuring second-generation integrase strand-transfer inhibitor (INSTI)-based regimens as preferred first-line options since 2019. We present a four-year observational study describing PDR trends across 2017–2020 at the largest HIV diagnosis and primary care center in Mexico City. A total of 6688 baseline protease-reverse transcriptase and 6709 integrase sequences were included. PDR to any drug class was 14.4% (95% CI, 13.6–15.3%). A significant increasing trend for efavirenz/nevirapine PDR was observed (10.3 to 13.6%, p = 0.02). No increase in PDR to second-generation INSTI was observed, remaining under 0.3% across the study period. PDR was strongly associated with prior exposure to ART (aOR: 2.9, 95% CI: 1.9–4.6, p < 0.0001). MSM had higher odds of PDR to efavirenz/nevirapine (aOR: 2.0, 95% CI: 1.0–3.7, p = 0.04), reflecting ongoing transmission of mutations such as K103NS and E138A. ART restarters showed higher representation of cisgender women and injectable drug users, higher age, and lower education level. PDR to dolutegravir/bictegravir remained low in Mexico City, although further surveillance is warranted given the short time of ART optimization. Our study identifies demographic characteristics of groups with higher risk of PDR and lost to follow-up, which may be useful to design differentiated interventions locally.

Potential drug–drug interactions in the era of integrase strand transfer inhibitors: a cross-sectional single-center study in Japan

Background Potential drug–drug interactions (PDDIs) commonly occur because of aging and comorbidities in people living with human immunodeficiency virus (HIV; PLWH). Protease inhibitors and non-nucleoside reverse transcriptase inhibitors have been reported to cause PDDIs in these patients. However, there are few reports of PDDIs in the era of treatment using integrase strand transfer inhibitors. Therefore, we investigated PDDIs in Japanese PLWH receiving antiretroviral drugs (ARVs). Methods This was a cross-sectional observational study conducted in Japanese outpatients. All eligible patients who had received ARV therapy for at least 48 weeks were enrolled. The primary endpoint was the incidence of PDDIs detected using the Lexicomp® interface. Results Of the 71 eligible patients, 51 (71.8%) were prescribed concomitant non-ARV medications. In 21 patients (29.6%), PDDIs with the potential to reduce the effects of ARVs occurred, although the HIV load was suppressed in all cases. Polypharmacy (the use of ≥5 non-ARVs) was observed in 25 patients (35.2%). There was a significantly higher median number of non-ARV medications in the PDDI group than in the non-PDDI group (6 vs. 3, P < 0.001). Furthermore, the proportion of patients on polypharmacy was significantly higher in those with PDDIs than in those without PDDIs (81.0% vs. 26.7%, P < 0.001). Conclusions The incidence of PDDIs is relatively high in Japanese PLWH, even in the era of treatment using integrase strand transfer inhibitors. Therefore, it is important for patients and health care providers to be constantly aware of PDDIs associated with ARV treatment.

Trends in Antiretroviral Regimen Complexity Among Medicare Beneficiaries With HIV, 2014-2018

Little is known about antiretroviral therapy (ART) patterns among Medicare beneficiaries with Human Immunodeficiency Virus (HIV). ART has significant implications for spending in Medicare Part D as use of single-tablet regimens (STR) grows, generic availability remains low, and price increases for branded therapies consistently exceed inflation. The objective of this study is to detail patterns of STR utilization among Medicare beneficiaries with HIV. We conducted a retrospective trend analysis using a 5% sample of Medicare Chronic Conditions Data Warehouse, 2014-2018. We included each person-month that fee-for-service beneficiaries with HIV had Parts A, B, and D coverage. Trends in annual prevalence of STR overall, by ART class, and by age, sex, and race subgroups were estimated. The study included 9,509 beneficiaries who contributed 345,708 person-months to the analysis. The prevalence of STR increased from 21.8% (95%CI, 21.5-22.1) in 2014 to 44.6% (95%CI, 44.3-45.0) in 2018 (p &lt;0.0001), an increase of 104.6%. Integrase strand transfer inhibitors (INSTI) saw the largest increase in utilization between 2014 (4.4% [95%CI 4.2-4.5]) and 2018 (35.1% [95%CI 34.8-35.4]) (p&lt;0.0001), a 701.8% increase. All sociodemographic subgroups experienced similar growth in STR use between 2014 and 2018. STR and INSTI utilization increased significantly over the study period, suggesting increased ART spending under Part D. Although increasing availability of generic multi-tablet ART regimens (MTR) may offer cost-savings, further research is needed comparing generic MTR to branded STR with regards to patient preferences, adherence, healthcare resource utilization, and total costs in the growing population of Medicare beneficiaries with HIV.