Abstract

Introduction: Dual Antiretroviral Therapy (DT) has been evaluated as a successful treatment approach in various patient populations, including treatment-naïve and suppressed individuals. However, its effectiveness in experienced patients who become nonadherent due to pill burden, dosing frequency, and/or associated toxicities and develop resistance to it is uncertain.

Objectives and Methods: This study aimed to assess the therapeutic efficacy of DT involving dolutegravir (DTG), doravirine (DOR), and darunavir/ cobicistat (DRV/c) or darunavir/ritonavir (DRV/r 600/100 bid) in multi-experienced patients, both suppressed and unsuppressed. For patients experiencing treatment failure, genotypic resistance testing was conducted to evaluate drug efficacy. In cases without treatment failure, regimen selection was based on considerations such as previous toxicities, drug interactions, and clinical history.

Results: A total of 72 multi-experienced patients were studied (one with more than one treatment) between 2015 and 2023, mostly men (64%), with ages between 37 and 73 (average 54 ± 9) and a time of infection between 4 and 24 years (median or mean 16 ± 5). The major risk for infection was heterosexual (63%), followed by intravenous drug users (23%). All of them presented with more than one therapeutic drug class resistance, and the most previously used regime was RAL+LPV/R in 18 patients (24%). The most frequent reason for switching was the development of resistance in 30 (41%) of the patients, followed by simplification of the number of doses or tablets in 31 (42%) patients. At the switch, DTG+DRV/c were used in 46 (62%) patients, followed by DTG+DRV/R 600 in 19 (26%) patients. At the end of follow-up, 82% had a viral load of less than 200 cps/mL, 79% less than 100 cps/mL, and 67% had complete viral suppression. Twelve patients were lost for follow-up; seven patients were off medications; and of these, three died with AIDS-defining illnesses. Four additional patients died of non-HIV-related causes, all virally suppressed.

Conclusion: The extended evaluation period (6 years) demonstrated that the simplification for dual therapy in patients who were treatment experienced with prior adherence failure with consequent multi-resistant drug patterns is associated with a high degree of efficacy (82%). Many (18%) still dropped out, consistent with findings from other studies. The reduction of pill burden and toxicities are factors that, by promoting a higher adherence rate to treatment, may have contributed to this success.

Keywords

Dual Therapy (DT); Single-Tablet Regimen (STR); Dolutegravir (DTG); Darunavir/boosted (DRV/b); Low-Level Viremia (LLV)

Introduction

Since the early days of HIV treatment, patients with poor adherence have often been lost to follow-up and experienced multiple drug resistance patterns. Once reintroduced into treatment, the complexity of subsequent treatment regimens has been a major obstacle, with a delicate decision-making process for further treatment, followup, and survival. The need for simplification of therapies becomes apparent, yet the use of Dual Therapy (DT), while successful in treatment-naïve and suppressed patients, lacks extensive validation in experienced patients with prior resistance and suboptimal treatment histories. Many remain challenged by pill burden and drug-induced toxicities. Novel and simplified therapeutic regimens, including dual therapy, are an option.

While DT has been explored and accepted in certain scenarios in therapy guidelines, its effectiveness and tolerability have varied across studies, such as PROGRESS [1], exploring the combinations of RAL+DRV/r [2], DRV/r+3TC [3], and LPV/r+3TC [4,5]. However, recent advancements have changed this. High-potency DT, such as dolutegravir/rilpivirine (DTG/RPV) [6] and lamivudine/dolutegravir (3TC/DTG) [7], have shown promising outcomes for both naive and experienced patients. These treatments have been particularly successful when patients switch to simplified regimens (e.g., reducing pill burden and/or minimizing toxicities).

Since the introduction of DTG and DOR, treatment patterns have shifted, benefiting from accumulated experience with both drugs. Additionally, the co-formulation of DRV with cobicistat (DRV/c) in a Single-Tablet Regimen (STR) has enabled the use of high-genetic- barrier therapeutics in simplified regimens, often comprising only two drugs when cobicistat functions solely as a booster. Further studies focusing on multi-experienced patients, such as those seen in BenchmrK [8], Resist [9], Power [10], and more recently Capella [11] and Brighte [12], are essential for evaluating these new combinations and their efficacy in challenging patient populations.

Objectives

This study aims to evaluate the response to DT comprising Dolutegravir (DTG), either doravirine (DOR), or darunavir boosted by ritonavir or cobicistat (DRV/b) in multidrug-experienced patients with resistance to more than two therapeutic classes, often nucleoside (tide) reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. The evaluation will be based on achieving a negative or decreased viral load (quantitative HIV RNA), with a criterion of at least a 2_log10 decrease at the end of 8 weeks of therapy.

Additionally, secondary analysis will assess the degree of recovery of the immune response measured by variations in total CD4+ T lymphocyte count (TCD4+), as well as the recovery of the immune system through analyzing variations in the percentage of CD4+ T lymphocytes and the CD4+/CD8+ ratio.

Furthermore, the study will assess the reasons for discontinuation or modification of therapy

Methods

Seventy-two patients were studied between 2015 and 2023, drawn from the database of the Infectious Diseases Service (IDS) of the Local Health Unit of Matosinhos, EPE-Pedro Hispano Hospital in Matosinhos, Portugal. The service closely monitors approximately 1200 patients with HIV/AIDS infection, 1141 of whom is undergoing treatment with various therapeutic regimens-first, second, or third line. These 72 patients were all multi-experienced individuals, exhibiting resistance to at least two therapeutic drug classes. They were receiving suboptimal regimens (characterized by a high number of pills and toxicities) based on genotypic tests and had been maintaining therapy due to the lack of robust solutions allowing simplification.

The choice for the switch based on combinations with dolutegravir (DTG), doravirine (DOR), and darunavir/cobicistat (DRV/c) or darunavir/ritonavir (600/100 bid) was made after a re-analysis of the patient’s history (past ART regimens and their clinical status), and in patients in failure, the choice of drugs was made according to the results of the genotyping test.

A close follow-up was maintained with quantitative HIV RNA, total T-CD4+ counts, and TCD4+/CD8+ ratio, initially every 3 months and then extended to every 6 months from the second year of follow-up.

The efficacy of ART was determined by the variation in the percentage of patients with suppressed HIV RNA <200 copies/mL (cps/mL) or the decrease of 2_log10 at the end of 8 weeks of therapy in patients with previous treatment failure, according to the FDA’s Snapchat algorithm [13,14] where missing = failure.

The immune response analysis was made by the variation of the TCD4+ and TCD8+ counts, their percentages, and the CD4+/CD8+ ratio before and at the end of follow-up. Microsoft Excel® 365 was used for correlation statistical analysis.

Results

Out of 1250 patients, 72 were undergoing complex and suboptimal therapies due to either a high pill burden or toxicity issues, prescribed based on genotypic resistance tests. Among these, 46 (64%) were males, aged between 37 and 73 years (mean age 54 ± 9 years), with 96% being of Portuguese nationality (Graph 1).

Graph 1: Distribution of the 72 patients by gender.

The risk for HIV infection was heterosexual intercourse in 63%, followed by intravenous drug addiction in 32%, and men who have sex with men (MSM) in 7%. In this group of patients, the duration of infection ranged from a minimum of 4 years to a maximum of 24 years (mean 16 ± 5 years). Analyzing the immunological status according to the criteria of the Centers for Disease Control and Prevention (CDC), 46% were in stage C (Graph 2).

Graph 2: Distribution of the 72 patients according to the CDC Staging at the beginning of the study.

The 72 patients had different ART regimens (one had two different regimens due to resistance), some in monotherapy, with the most represented regimen being RAL+LPV/r, in 18 patients (24%), followed by DTG+DRV/c, in 5 patients (7%) (Table 1).

ART Regimes prior to switch	Patients	%
ral+lpv/r	18	24%
dtg+drv/c	5	7%
abc/3tc/dtg	5	7%
tdf/ftc/efv	4	5%
ral+etr	4	5%
lpv/r	3	4%
tdf/ftc+drv/r	3	4%
ral+drv/c	2	3%
taf/ftc/drv/c	2	3%
abc/3tc+drv/r	1	1%
taf/ftc+dor	1	1%
abc/3tc+drv/c	1	1%
ral+etr+drv/r	1	1%
tdf+ral+drv/r	1	1%
etr+dtg+drv/r+mrv	1	1%
mvc+drv/r 600	1	1%
tdf/ftc+etr	1	1%
ral+lpv/r+3tc	1	1%
tdf+ral+etr	1	1%
dtg+etr+drv/r	1	1%
tdf/ftc+lpv/r	1	1%
drv/r+etr	1	1%
abc/3tc+ral+etr	1	1%
drv/r+etr+dtg	1	1%
tdf+etr+drv/c	1	1%
azt/3tc+ral+etr	1	1%
azt+ral+drv/r	1	1%
ral+drv/r	1	1%
tdf+etr+drv/r	1	1%
abc/3tc+atz/r	1	1%
abc/3tc+ral	1	1%
abc/3tc/azt+ral	1	1%
tdf/ftc+ral	1	1%
ral+drv/r+azt	1	1%
azt/3tc+efv	1	1%
dtg/rpv	1	1%

Table 1: ART Regimens previously to switch.

(NOTE: the total is 73- as one patient was on two regimens prior due to side effects).
ral – raltegravir; lpv/r-lopinavir/ritonavir; dtg-dolutegravir; drv/cdarunavir/cobicistat 800/100mg; abc-abacavir; 3tc- lamivudine; efvefavirenz; etr-etravirine; tdf-tenofovir DF; taf-tenofovir alafenamide; drv/r-darunavir/ritonavir 600/100mg; dor-doravirine; ftc-emtricitabine; mrv-maraviroc; azt-zidovudine; rpv-rilpivirine; atz/r- atazanavir/ritonavir.

The most frequent reason for switching was resistance in 30 (41%) patients, followed by simplification of pill burden in 31 (42%), and Low-Level Viremia (LLV) (persistence of HIV RNA between 100 and 200 cps/mL) in 9 (12%). Toxicity was the reason for change in 4 (5%) patients, although it is conceivable that in some cases of simplification, there were also concerns to prevent future toxicities. In one case, DT was changed due to gastrointestinal effects-the patient was on DTG+DRV/c and changed to DTG+DOR with the resolution of the effects. Regarding regimens, the most used regimen was DTG+DRV/c 800/100mg in 45 (62%) patients, followed by DTG+DRV/r 600/100mg twice daily in 19 (26%). The remaining is shown in graph 3.

Graph 3: ART after switching (N = 73 ART regimens changed).

These regimens were used for a minimum of 4 weeks up to 443 weeks, with average treatment duration of 175 weeks.

At the beginning of the new treatment, HIV RNA varied from <200 cps/mL to 787,973 cps/mL, with 30 (36%) patients negative and 12 (16%) with levels compatible with LLV. At the end of the evaluation, 82% were suppressed with HIV RNA <200 cps/mL, and 79% had levels <100 cps/mL, with 49 (67%) patients testing negative. Regarding immune status, 32 (43%) patients had TCD4+ counts <350 cells/ μL, and of these, 8 (25%) had counts <100 cells/μL. However, there was substantial recovery of immunity at the end of the evaluation, as presented in table 2.

Table 2: Data regarding the Virological and Immune status of the 73 cases before and after switching to dual therapy.
Data i: DATA initial; DATA f: DATA final; Var: variation; T ART: Time after switch.

At the end of the evaluation period, 12 patients were lost to followup, all abandoning treatment after periods of poor adherence. Among these, 3 died from AIDS-defining illnesses. Additionally, 4 patients died, but they were negative at the time of death and their deaths were not related to HIV/AIDS.

Discussion and Conclusion

This study underscores the complexity of managing HIV patients with diverse treatment histories. Despite facing challenges such as resistance and medication toxicity, the implementation of dual therapy regimens has shown promising results in improving treatment outcomes. The observed reduction in viral loads and improvement in immune status reflect the efficacy of these regimens in suppressing HIV replication and restoring immune function.

However, the study also highlights the persistent issue of treatment adherence, as evidenced by the loss of follow-up of 12 patients, as presented in other studies. This underscores the ongoing need for interventions to support patient adherence and retention in care.

Furthermore, the occurrence of AIDS-related deaths among the lost-to-follow-up patients emphasizes the critical importance of continuous monitoring and support for HIV-positive individuals, particularly those with advanced disease stages. While dual therapy offers a valuable treatment option, comprehensive care strategies addressing both medical and psychosocial needs remain essential for optimizing patient outcomes.

Overall, this study contributes valuable insights into the real-world application of dual therapy regimens and emphasizes the importance of individualized treatment approaches and holistic patient care in the management of HIV/AIDS.

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Article Information

Article Type: RESEARCH ARTICLE

Citation: de Abreu RC, Duarte F (2024) Long-Term Experience with Dual Therapy in Multi-Experienced Patients. Combine Study. J HIV AIDS 8(1): dx.doi.org/10.16966/2380-5536.188

Copyright: © 2024 Correia de Abreu R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication history: 

Received date: 20 May, 2024

Accepted date: 12 Jun, 2024

Published date: 19 Jun, 2024