Characterization of People Receiving 2-Drug Regimens (2DR) for HIV Management in Italy

Three-drug antiretroviral regimens (ARV) have long been the “gold standard” first-line therapy for adult people living with human immunodeficiency virus (PLHIV) ¹. However, concerns about long-term toxicities have prompted the investigation of two-drug regimens (2DR) as an alternative treatment option ², and current EACS guidelines also recommend 2DRs ³.

Preliminary trials on early 2DR combinations for treatment-naive populations produced inconclusive outcomes due to limited sample sizes, restricted treatment options, and short durations of therapy ⁴. NEAT001/ANRS143, perhaps the first true trial of dual strategy, concluded that treatment of treatment-naïve PLHIV with 400 mg raltegravir (RAL) twice daily plus 800 mg darunavir and 100 mg ritonavir (DRV/r 800/100 mg) once daily as Nucleoside Reverse Transcriptase Inhibitor (NRTI)-sparing regimen was not inferior to DRV/r 800/100 mg once daily plus tenofovir disoproxil-emtricitabine (TDF/FTC) in a 245 mg and 200 mg fixed-dose combination (FDC) ⁵.

Lamivudine (3TC) has demonstrated favorable efficacy and safety, positioning itself as a candidate for combination therapy ⁶. However, early studies involved the use of 3TC with ritonavir-boosted protease inhibitors (PIs), which have been associated with metabolic adverse reactions and drug interactions. These potential drawbacks may counteract benefits expected from reduced cumulative toxicity due to decreased drug exposure ⁷.

Phase 3 clinical trials have yielded evidence that dolutegravir (DTG) is a promising candidate as a central component in 2DRs. The GEMINI studies support DTG/3TC as a well-tolerated option in treatment-naive PLHIV ⁸.

The phase III SWORD trials evaluated the efficacy and safety of once-daily dolutegravir 50 mg plus rilpivirine 25 mg (DTG/RPV) versus current ART regimen (CAR), and found DTG/RPV to be not inferior, with 95% of PLHIV in both groups achieving undetectable viremia ⁹.

The Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) doravirine (DOR) is available both as single drug for combination and as 3-drug FDC with tenofovir disoproxil fumarate (TDF) and 3TC. Evidence for its safe and effective use is available from randomized trials ^{10, 11, 12}, and doravirine is now among the recommended drugs for first-line ART. Doravirine has little cross resistance to other NNRTI in addition to a relatively high resistance barrier ¹³ and can be an option for PLHIV with extensive ART history.

Sammet et al. conducted a prospective observational study of PLHIV treated with DOR + DTG as 2DR. The main reasons for choosing DOR + DTG were drug-drug interactions (DDI) (29%), tolerability (25%), and cardiovascular risk reduction (21%). DOR + DTG proved to be a durable treatment option even in extensively pretreated individuals ¹⁴.

DOR is currently under evaluation as an FDC with islatravir ¹⁵.

In Italy, a significant proportion of PLHIV is treated with 2DR, but the factors influencing this choice are still unclear ¹⁶, as well as whether the approval of 2DR FDC leads to changes regarding patient types and treatment decisions. A better understanding of patient characteristics would help to highlight residual unmet needs in modern HIV management strategies. Consequently, this study aimed to describe the baseline patient characteristics for approved FDC and free-combination dual therapies to recognize the drivers of therapeutic decisions for 2DR.

This study highlights the significance of considering the baseline characteristics of PLHIV while developing HIV management strategies. To the best of our knowledge, this is the first real-world study conducted in Italy to assess the baseline profiles of PLHIV who are on 2DR FDC compared to those on 2DR free-combination therapies. Statistically significant differences were observed between the two groups with respect to age, gender, time from AIDS-defining diagnosis to start/switch to 2DR, years of known HIV status at baseline, HIV VL, ART regimen and selected comorbidities.

Many PLHIV (n=416) initiated FDC therapy (DTG/RPV or DTG/3TC), and these participants were more likely white males. This is in line with previous evidence that reported the majority of people with HIV treated with FDC DTG/3TC being male and white ¹⁷. However, as per the report of Centre for Disease Control and Prevention (CDC), Black/African American and Hispanic/Latino communities are disproportionately affected by HIV compared to other racial/ethnic groups ¹⁸. Group 1 PLHIV were older, with an average age of 49.2±12.07 years compared to 32.5 years in the GEMINI 1 and 2 clinical trials conducted on treatment-naïve PLHIV ¹⁹, but of similar age compared to other real-world data; 48.6 years (EUROSIDA HIV) ²⁰ and 51 years ²¹.

Group 1 had significantly shorter time from AIDS-defining diagnosis to start of 2DR and fewer years of known HIV status than those in Group 2. In Group 1, the median time from AIDS-defining diagnosis to start of 2DR was 11.5 years, compared to 14 years in the LAMIDOL study ²² and 15 years in the DOLAMA study ²³.

One of the significant factors that influences the HIV therapeutic choice is HIV VL at treatment initiation. In our cohort, 399 PLHIV had a median HIV VL<50 copies/mL at baseline. There was a significant difference in mean baseline HIV VL between the two groups, with Group 1 having a higher average than Group 2. From the results, it can be interpreted that the PLHIV were under viral suppression and presented a lower risk of disease progression, irrespective of the combination therapies. The efficacy and safety of DTG plus 3TC for treating PLHIV without resistance mutations were settled by the TANGO randomized trial ²⁴. These findings support the use of 2DR as a switch option for PLHIV with viral suppression on a 3- or 4-DR who wish to receive fewer ARTs due to treatment complexity, avoidance of potential drug-associated toxicity, risk of drug–drug interactions, or cost. Clinicians should consider viral loads at baseline for tailoring HIV management strategies to ensure optimal viral suppression and prevent the emergence of drug-resistant strains. Of note, the greater prevalence of resistant mutations in Group 2 suggests that clinical needs have not yet been fully addressed with approved 2DR FDC, and warrants investigation of potential further 2DR strategies such as DOR/ISL, which has demonstrated high potency even in the presence of drug-resistance mutations ²⁵.

PLHIV in both cohorts were medically complex, with diagnoses of hypertension, hypercholesterolemia, dyslipidemia and vitamin D deficiency. Another study also indicated that multi-comorbidities were higher in PLHIV who switch from 2DR compared with 3DR ²⁶.

The average duration of the ART regimen after switching differed significantly between the groups, with shorter duration in Group 1. According to the ICONA report, gender, type of treatment and time spent on HIV management were independent factors associated with discontinuation of ART regimens ²⁷. However, our current study did not explore the reason behind switching ART.

PLHIV who switched from 2DR were found to be significantly older, more experienced at the index date, and less likely to be male when compared to individuals on a 3DR. These findings are consistent with those reported by Ruzika et al ²⁶.

Our study highlights that individuals who switch to 2DR may be difficult to treat, particularly if they were on free combination therapies due to the presence of resistant mutations. The need for more effective and tailored treatment options is increasingly recognized, particularly for individuals who may not respond optimally to standard triple therapy. Currently approved FDC may not adequately address the clinical complexities of various patient populations, thereby reinforcing the unmet need for more innovative therapeutic options. Ongoing clinical development of novel 2DR seeks to fill this gap. The combination of doravirine and islatravir (DOR/ISL) and bictegravir and lenacapavir (BIC/LEN) administered once daily are under investigation for their potential to provide robust virologic suppression with a favorable tolerability profile ^{28, 29}. Furthermore, the weekly dosing option of ISL in combination with LEN is being explored to enhance patient adherence while maintaining viral suppression ³⁰. These advancements in 2-drug regimens will address the significant unmet needs associated with current treatment paradigms, reducing treatment burden and thereby advancing the overall management of HIV.

Although our study's retrospective data are not fully representative of the general Italian PLHIV population, it aimed to describe the baseline characteristics of PLHIV on 2DR FDC and free combination therapies, with DOR as the last NNRTI launched on the market at the time of enrollment. We assume that a similar relationship between the two comparison groups would hold in the general population as well.

This medical chart review renders the study results representative of real-world clinical practice. The study was performed in Italy, suggesting that the results may be more representative of European countries and not of the broader population and are specific to the stratification groups mentioned. The enrolment of a low percentage of women under both combination therapies suggests that the study demographics do not fully represent the Italian population of PLHIV. Data on patient adherence and virological failure with previous HIV drug use at baseline and reasons for switching to 2DR were not collected at baseline, hence the study was unable to evaluate treatment patterns based on the aforementioned variables. The majority of PLHIV had a HIV-VL<50 copies/mL, which did not allow any baseline consideration for PLHIV with very high viral loads.

This study was the first step in understanding the baseline profiles and medical needs of PLHIV who started 2DR in Italy. It provides a foundation for future studies to further analyze reasons for switching therapy, as well as to identify those PLHIV that may most benefit from current and future 2DR therapies. In conclusion, PLHIV in Italy on currently approved FDC 2DR therapies were younger, virologically suppressed individuals at baseline with shorter time from prior AIDS-defining diagnosis, lower prevalence of resistance, and lower comorbidities rates compared to individuals on free dual combination therapies. This highlights existing unmet needs of PLHIV with currently approved FDC, indicating a pressing need for ongoing research and the development of tailored treatment strategies that cater to the diverse clinical profiles of this population.

The study protocol was reviewed by the local Health Authority. Approvals were obtained from the Ethics Committee of participating sites. Informed consent, as appropriate per local regulations, was obtained from all participants. Data is available upon request.

All authors conceptualized, critically revised the manuscript for important intellectual content, and approved the final manuscript.

Funding for this research was provided by MSD Italia Srl.

Medical writing and statistical analyses were provided by OPIS srl. This assistance was funded by MSD Italia.

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