Antiretroviral therapy response: exploring the potential influence of SARS-CoV-2

KEYWORDS:

• Antiretroviral therapy
• immunological factors
• SARS-CoV-2
• HIV
• immunological amnesia

1. Introduction

Antiretroviral therapy (ART) has profoundly transformed the prognosis of human immunodeficiency virus (HIV) over the past decades, achieving not only virologic suppression but also substantial improvements in immune function and clinical health. While the primary goal of ART has been to achieve undetectable viral loads, the therapy’s success is also measured by immunologic improvements (e.g. CD4 cell count recovery) and enhanced clinical outcomes (e.g. reduced morbidity and mortality), highlighting the comprehensive efficacy of ART Once considered a death sentence, HIV is now a manageable chronic condition, with access to antiretrovirals increasing from 24% in 2010 to 76% by 2022 [1]. This advancement has significantly enhanced the quality of life and decreased mortality rates, marking improved clinical outcomes. Additionally, a noteworthy virologic outcome is that 71% of those treated achieved suppressed viral loads at some point during their therapy, indicating effective virologic suppression [2].

The SARS-CoV-2 virus, which caused the coronavirus disease 2019 (COVID-19) pandemic, has prompted concerns about its potential effects on the efficacy of ART and the health outcomes for people living with HIV/AIDS (PLWHA) [3]. The available evidence is conflicting; some studies suggest higher risks for PLWHA with lower CD4 counts or those not on ART, while other reports indicate that HIV-associated immunosuppression might offer some protection against the severe hyperinflammatory responses seen in critical COVID-19 cases [3]. In other areas, reports suggest that SARS-CoV-2 May affect the epidemiology and pathogenesis of other respiratory infections [4,5].

A comprehensive systematic review and meta-analysis concluded that PLWHA do not face a significantly increased risk of contracting SARS-CoV-2 compared to the HIV-negative population [3]. However, those co-infected with COVID-19 faced higher mortality risks, particularly if they had low CD4 counts or were not on antiretroviral therapy [3]. The study also assessed various antiretroviral drugs, noting outcome variations linked to factors such as viral load and comorbidities, suggesting that overall, PLWHA were not adversely affected [3].

Nevertheless, the precise impact of SARS-CoV-2 on the effectiveness of ART remains uncertain. There is ongoing debate about whether SARS-CoV-2 might change how patients respond to ART, which could necessitate modifications to current treatment plans or the development of specialized clinical guidelines for managing people living with HIV/AIDS during the pandemic. Unraveling this mystery is crucial, as it could reveal broader implications for the influence of viral infections on ART responsiveness in the future.

This editorial aims to synthesize the current research, offer a nuanced view on the interaction between SARS-CoV-2 and ART, and highlight the urgent need for additional research to inform clinical strategies.

2. Current evidence

The current studies did not explicitly address whether SARS-CoV-2 influences the efficacy of HIV therapy; instead, they examined how PLWHA are at risk of severe COVID-19.

A systematic review of 44 studies has revealed that individuals who are HIV-positive have a significantly increased likelihood of hospital admission due to COVID-19 compared to those who are HIV-negative. Adjusted analyses also demonstrated a link between HIV and a rise in mortality risk among COVID-19 patients [6]. However, in unadjusted odds ratio analyses, HIV was not correlated with the severity of disease or mortality. A retrospective matched cohort study reported a trend toward increased ICU admissions, use of mechanical ventilation, and mortality in HIV-positive patients, though these differences were not statistically significant. HIV-positive individuals had notably higher C-reactive protein (CRP) values, which indicate inflammation, yet no significant differences were found in other inflammatory markers, or in the rates of myocardial infarction or thrombotic events between the groups [7].

Nonetheless, to grasp the potential relationship between the efficacy of HIV therapy and SARS-CoV-2, a deeper analysis of the elements that influence responsiveness to this therapy is imperative. The success of HIV therapy is contingent upon various immunological factors, and the emergence of SARS-CoV-2 adds further complexity to this scenario. HIV treatment often entails persistent chronic immune activation or inflammation, even with effective ART [8]. The timing of ART initiation is critical, as it influences the degree of immune restoration [9]. Genetic factors also play a certain role in the rates of disease progression and patients’ reactions to ART [10]. Enhancing innate immune responses, such as those driven by dendritic cells and natural killer cells, may improve HIV therapy outcomes. In pediatric cases, early life immunity is crucial for the effectiveness of ART due to factors associated with mother-to-child transmission, which contribute to rapid disease progression from ineffective HIV-specific CD8+ T-cell responses [11].

When PLWHA contract SARS-CoV-2, their immunological status may deteriorate further. Coinfection with SARS-CoV-2 May elevate the risk of HIV-1 viral rebound in severe COVID-19 cases, while seemingly exerting minimal impact on CD4+ cell counts [12]. This suggests that SARS-CoV-2 can modify the chronic immune activation associated with HIV. SARS-CoV-2 infection prompts an immune response that generates class I interferons and neutralizing antibodies in abundance, which are crucial in determining the clinical trajectory of COVID-19 in PLWHA [13]. Moreover, severe COVID-19 cases often involve underlying medical conditions, such as low CD4+ T-cell counts or high viral loads, issues that could be intensified by a SARS-CoV-2 coinfection [14].

Conversely, some authors suggested that ART regimens may offer protection against SARS-CoV-2 coinfection, indicating a complex interaction where elements of HIV treatment might have beneficial effects regarding SARS-CoV-2 coinfection [15,16]. Observational studies have highlighted that PLWHA on certain ART regimens may experience lower incidence and mortality rates from COVID-19. While it has been suggested that these benefits could stem from the chemoprophylactic properties of specific ART combinations, it is important to note that the observed reductions in severe COVID-19 cases among this population might not solely relate to chemoprophylactic effects. Other potential mechanisms, such as immunomodulatory effects or a nonspecific reduction in the nucleoside pool, may also play a significant role. These ART regimens could potentially offer protection against COVID-19 by a variety of means, including disrupting crucial functional proteins of SARS-CoV-2 or through other yet to be fully understood mechanisms, thereby possibly reducing the severity or likelihood of COVID-19 infection [17]. The potential protective effects of ART and the risk of immunosuppression highlight the dual nature in which SARS-CoV-2 May simultaneously diminish and enhance the efficacy of HIV therapies.

Immunological amnesia, commonly associated with viral infections such as measles that erase immune memory, may offer a valuable perspective on how SARS-CoV-2 might affect the efficacy of HIV therapy. This phenomenon occurs when an infection disrupts the immune system’s memory, leading to a diminished ability to respond to previously encountered pathogens. This can result in a more susceptible state to other infections, as the immune system’s historical record of pathogens, necessary for rapid and effective response, is partially or completely wiped out. In the context of HIV, where the immune system is already compromised, the additional burden of SARS-CoV-2-induced immunological amnesia could further hinder the effectiveness of ART by compromising the body’s ability to manage HIV and other opportunistic infections efficiently [18].

In HIV, the immune system is compromised by the gradual depletion of CD4+ T cells, the pivotal orchestrators of the immune response, culminating in exacerbated immune dysregulation when an individual is also infected with SARS-CoV-2 [19]. This may intensify immunodeficiency and undermine therapies designed to maintain or restore immune competence. Studies have shown that the loss of CD4+ T cells attributed to both viruses contributes to disease outcomes and levels of immunodeficiency; such depletion could aggravate the conditions and lessen the effectiveness of therapies aimed at bolstering immune competence. Moreover, the inflammatory milieu of advanced HIV infection, characterized by significant T-cell activation, could be modified by simultaneous SARS-CoV-2 infection [20]. This might inadvertently prevent the pathological immune responses typically observed in acute COVID-19 due to an ‘immune exhaustion’ or tolerance engendered by chronic HIV infection. While this could blunt the immune system’s overreaction to SARS-CoV-2, often leading to adverse outcomes, it might also hinder the success of antiretroviral therapy in HIV patients.

Evidence also suggests that SARS-CoV-2 infection impairs the CD8+ T cell response, mirroring the long-term immune damage seen with infections like hepatitis C or HIV [21]. This impact on the memory T cell pool, essential for immune surveillance against chronic HIV infection, could be compromised. Immunological amnesia, induced by SARS-CoV-2 May 2001elevate the risk of opportunistic infections or resurgence of HIV replication. A multicenter observational study of 3,451 COVID-19 patients in Italy found no mortality benefit from using lopinavir/ritonavir (LPV/r), while darunavir/cobicistat (DRV/c) was associated with an increased risk of death, particularly among high-risk groups. These results suggest the use of LPV/r and DRV/c does not improve, and may even worsen, outcomes for COVID-19 patients [22].

3. Expert opinion

This editorial outlines the complexities of ART amidst the SARS-CoV-2 pandemic, highlighting the resilience of HIV and its intricate interplay with new viral challenges. Research points to a complex relationship between HIV, ART, and SARS-CoV-2. PLWHA are not at an increased risk of contracting SARS-CoV-2; however, those who are infected may face worse outcomes if their CD4 counts drop or if ART is interrupted. Regrettably, there are significant knowledge gaps regarding the impact of SARS-CoV-2 on immune system components critical to the success of ART.

The primary goal of this research domain is to refine ART outcomes in the face of evolving viral pathogens, to ensure strong immune responses and quality of life for PLWHA. This area of study is promising: it could lead to customized ART approaches that consider the burden of COVID-19 co-infection. To achieve this, research must delve into the dynamics of immune responses to concurrent HIV and SARS-CoV-2 infection; understanding how SARS-CoV-2 May affect the chronic immune activation or inflammation associated with HIV is crucial.

Realizing this objective relies on conducting thorough studies that examine the immunological shifts caused by SARS-CoV-2 in conjunction with HIV, a daunting task due to the complex nature of both viruses and the host’s response. A significant challenge is developing methods to decipher the immune interactions in co-infected individuals, necessitating advancements in immunological assays and sustained longitudinal studies.

The field is poised to explore the intersection of virology and host immunity, focusing on developments such as how ART modulates immune responses during SARS-CoV-2 co-infection, and potentially mitigating the severe inflammatory responses observed in COVID-19. There is growing interest in whether specific ART regimens might offer protection against SARS-CoV-2, opening new avenues where HIV therapies intersect with antiviral strategies for emerging pathogens.

Currently, the area stirring considerable interest is the concept of ‘immunological amnesia’ and its implications for ART effectiveness. SARS-CoV-2 might induce alterations in the immune system, diminishing its response to previously encountered pathogens, including HIV. This poses significant challenges in managing HIV infection following a COVID-19 diagnosis, necessitating researchers to stay vigilant and adapt rapidly to evolving challenges in HIV care and treatment.

4. Conclusion

In summary, the interplay among HIV, ART, and SARS-CoV-2 is complex and continuously evolving; it necessitates a deeper understanding of the immune system’s response to co-infection. The development of COVID-19 treatments relies on targeted research that studies these intricate interactions to optimize the effectiveness of ART. As technology advances, new strategies must be developed and continuously employed to adapt HIV management plans to emerging viral threats like SARS-CoV-2. Further research in this field is crucial for enhancing ART efficacy against SARS-CoV-2 and for anticipating and preparing for novel pathogens. Investigating immune responses and viral interactions will be key in developing more resilient and adaptive treatment protocols in response to global health crises.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The paper was not funded.