Introduction

As of the end of 2021, HIV continues to pose a significant global challenge, affecting approximately 38.4 million individuals worldwide [1]. While there is still no cure for HIV, the early introduction of Antiretroviral Therapy (ART) has proven to be instrumental in significantly reducing mortality rates among HIV-infected individuals [2,3,4,5]. Moreover, ART has been found to reduce the viral load in genital secretions, which is closely linked to the sexual transmission of HIV to partners, potentially slowing the spread of the virus [6,7,8]. Consequently, initiatives such as the United Nations' 90-90-90 program have been introduced with the goal of reducing the number of new HIV cases to 500,000 per year. The program aims to diagnose 90% of people infected with HIV, ensure that 90% of diagnosed individuals receive ART, and achieve suppressed viral load in 90% of those on ART [9, 10].

Historically, the commencement of ART was delayed until CD4 counts dropped below 200, a level at which opportunistic infections may thrive [11]. However, current guidelines recommend starting ART as soon as possible after diagnosis [12, 13]. Despite the significant benefits of ART, not all individuals receiving treatment achieve viral suppression. Approximately 20% of individuals in contact with healthcare or receiving ART do not achieve viral suppression, highlighting the importance of addressing adherence challenges and virologic failure [14]. According to the World Health Organization (WHO), all individuals diagnosed with HIV should begin ART as soon as possible, and those at high risk of infection should receive pre-exposure therapy [15]. Adherence to the treatment regimen is crucial for successful treatment outcomes, as poor adherence can lead to the development of drug-resistant strains of the virus or virologic failure [16].

As new genotypes of HIV emerge, the importance of genetic diversity is more clear in the process of treatment, vaccine design [17] and drug-resistance strains [18]. The reason for this diversity is thought to be the high rate of errors while replicating [19]. As the data suggests, a combination therapy across the available ARTs is quite effective against most HIV-1 subtypes, however, there are differences between subtypes across the globe, hence, there are differences in their drug resistance [20]. To mention an example, subtype C can go through K65R mutation, related to tenofovir resistance, more than subtype B [21, 22]. HIV drug resistance is a genuine challenge in some countries trying to adhere to the goal of UNAIDS’ 90/90/90 goals [10].

Several factors influence adherence to ART and virologic outcomes in HIV-positive individuals. Patient-related factors, such as substance and alcohol abuse, unstable housing, financial difficulties, and psychiatric disorders, can all contribute to non-adherence [23, 24]. Additionally, the complexity of the treatment regimen, including the number of pills and side effects, can also impact adherence [25]. Thus, it is essential to address these determinants to improve treatment success and reduce virological failure among HIV patients on ART. Measuring virologic failure is vital in monitoring treatment effectiveness. Detectable viremia, measured by PCR, may not always indicate clinical significance, but ART is still recommended even when viremia levels are below 200 [26,27,28,29]. Factors such as poor adherence to the therapeutic regimen, gastrointestinal malabsorption, or drug interactions can contribute to detectable viremia [26,27,28,29]. By understanding and addressing the determinants of virologic failure, we can enhance the effectiveness of antiretroviral therapy and contribute to the global effort in tackling this public health issue. Therefore, this study aims to investigate the status of determinants for virologic failure and also predisposing factors by reviewing the current literature.

Methods

This comprehensive review investigates currently prescribed antiretroviral agents in the course of human immunodeficiency virus (HIV) infection. The primary focus is to explore evidence of determinants for virologic failure and its implications for drug resistance to antiretroviral therapy (ART) agents. To ensure transparent reporting, this review adheres to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Additionally, the methodological integrity of the included publications is assessed using the National Institutes of Health (NIH) quality and bias risk assessment tool.

Data sources

We conducted a systematic search on four major databases, namely PubMed/MEDLINE, Embase, Scopus, and Web of Science (WoS), up to May 26, 2023. To maximize the identification of relevant publications, we employed Boolean operators between the keywords and performed combined keyword searches. The search inquiry of PubMed/MEDLINE is as follows, with the inquiries for other databases provided as an Additional file 1.

((“HIV”[mesh] OR “Human Immunodeficiency Virus”[Title/Abstract] OR “HIV”[Title/Abstract] OR “AIDS Virus*”[Title/Abstract] OR “Acquired Immune Deficiency Syndrome Virus”[Title/Abstract] OR “Acquired Immunodeficiency Syndrome Virus”[Title/Abstract] OR “aids associated virus”[Title/Abstract] OR “aids related virus”[Title/Abstract] OR “immunodeficiency associated virus”[Title/Abstract]) AND (“Antiretroviral Therapy, Highly Active”[mesh] OR “Antiretroviral Therapy, Highly Active”[Title/Abstract] OR “anti-retroviral therapy”[Title/Abstract] OR “ART (drug therapy)”[Title/Abstract] OR “antiretroviral therapy”[Title/Abstract] OR “HAART”[Title/Abstract]) AND (“Drug Resistance, Viral”[mesh] OR “Drug Resistance, Viral”[Title/Abstract] OR “Antiviral Drug Resistance”[Title/Abstract] OR “Drug Resistance”[Title/Abstract] OR “antiviral resistance”[Title/Abstract] OR “virologic failure”[Title/Abstract]).

As the searching of databases was finished and the relevant articles were obtained, we gathered them in a single file of EndNote to remove duplicates and further to steps of selection and data extraction.

Study selection

A two-prong approach was used for article screening and selection. In the first step, two researchers evaluated the relevance of articles based on their titles and abstracts. In the second step, three other researchers reviewed the full texts of the screened literature. Publications that met the following criteria were included for data extraction:


Inclusion criteria

  • Review articles addressing ART in HIV infection, virologic failure of ART, and resistance to ART in HIV-positive patients.

  • Articles written in English and published in peer-reviewed journals.

Exclusion criteria

  • Case series, and case reports, editorial letters, opinion letters, anecdotal records, and records published in non-academic sources like magazines, websites, and social media.

  • Non-human research studies, ongoing trial studies without published data, and abstracts without full texts.

Data extraction

Articles deemed relevant to the study objectives after the second step of selection and met the eligibility criteria were included for data extraction. Details of the extracted data are presented in Table 1. Three researchers were involved in this process, and the accuracy of the extracted data was double-checked by other team members to eliminate duplicates and address the inconsistencies in the reported results.

Table 1 Bias risk assessment of the studies by NIH QA Tool for systematic reviews and meta-analysis
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Bias risk assessment

To evaluate the bias risk of the included studies, we utilized the National Institute of Health (NIH) quality assessment (QA) tool. Two independent researchers completed the assessment. Table 1 displays the results of their assessment for each study. The 8 items of this tool are depicted underneath the table.

Results

The initial search strategy yielded a total of 652 papers. Following the first review of papers, 66 duplicates were removed, and two researchers independently assessed the titles and abstracts of the remaining 586 articles. Next, the remaining articles were subjected to a full-text screening where eligibility criteria were applied; 40 articles finally fulfilled the inclusion criteria and were included in this umbrella review (Fig. 1). The quality assessment of included studies was performed using the NIH quality assessment tool and is presented in Table 1.

Fig. 1
figure 1

PRISMA 2020 flow diagram of study retrieval process

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Of 40 eligible articles, 16 were review articles, 17 were meta-analyses with quantitative synthesis, and the remaining 7 were systematic reviews. More than 1250 studies were enrolled in our review; involving more than 427,058 patients with HIV infection. The number of included studies and the study population in ten and twenty reviews, respectively, were not clearly stated. The included studies were published between 2015 and 2023, covering a broad time frame.

Three studies were specifically conducted among adolescents with perinatally acquired HIV infection, while the remaining 37 involved adults. The umbrella review's primary focus was on the current understanding of determinants for virologic failure risks and implications for drug resistance in ongoing antiretroviral therapy (ART) strategies. Thus, the review examined and listed several key items, including the first author (reference), country, year of publication, study population, included articles, type of ART, implications for drug resistance, virological failure risk factors, and main findings of the studies. The comprehensive analysis of these items can be found in Table 2.

Table 2 Description of the findings reported in eligible studies
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A wide variety of countries were represented in the studies, with China (n = 5), South Africa (n = 4), UK (n = 4), USA (n = 3), Canada (n = 3), Ethiopia (n = 3), Brazil (n = 3), Switzerland (n = 3), Spain (n = 3), and Italy (n = 2) being the countries with the most involvement. Additionally, India (n = 2), Australia, Denmark, Lebanon, Romania, and Nigeria each contributed one article to the review.

Regarding the classes of ART, the non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) were the most commonly studied drugs in relation to drug resistance and determinants for virologic failure. Review of included studies demonstrated that poor medication adherence, high HIV viral load, low CD4 level at the baseline and during therapy, co-infection presence, and advanced clinical stage of infection were the most prevalent factors associated with drug resistance and virological failure. Notably, drug resistance related to NNRTIs was more frequently reported than resistance to other types of ART, based on the reviewed studies.

Discussion

The advent of Antiretroviral Therapy (ART) has revolutionized the management of HIV, transforming it from a fatal disease to a chronic condition. The availability and efficacy of ART have played a crucial role in suppressing HIV and improving the quality of life for millions of people living with HIV [70, 71]. However, despite the significant progress, a subset of individuals living with HIV still face virological failure, which remains a global public health challenge.

In this umbrella review, we sought to address virological failure and its risk factors by evaluating evidence from multiple studies. Our findings have shed light on several important factors that contribute to virological failure in people living with HIV. Poor adherence to treatment emerged as the most commonly reported contributing factor, as evidenced by multiple studies [31, 39, 42,43,44,45, 59, 63, 67]. This was followed by a lower CD4 count at the initiation of ART [31, 33, 42, 44, 45, 61]. Other reported factors include high viral load at the initiation of ART [33, 39, 45, 52, 61, 67], and the presence of co-infections [31]. Additionally, we noticed that several factors can lead to drug resistance in people living with HIV such as the long duration of ART.

Poor adherence to treatment can be caused by a variety of factors. Adherence to ART is crucial for its effectiveness, and factors such as difficulty following regimens, side effects of therapy, lack of health knowledge, and limited availability of ART due to formulary restrictions or costs were identified as barriers to adherence [72]. Moreover, stigma associated with HIV, substance use, low income, and the number of administered drugs were also associated with adherence issues [36, 46, 73, 74]. Several approaches have been suggested to enhance adherence to ART in people living with HIV. Agyeman-Yeboah J et al. suggested that education and counseling, adherence tools, health service delivery, and antiretroviral strategies could improve ART adherence [75]. Recognizing substance users in HIV primary care and developing, evaluating, and implementing integrated substance use-mental health-adherence therapies may also be clinically relevant goals for optimal disease management and secondary HIV prevention initiatives [74]. Additionally, various personal-level psychological interventions have been shown to improve ART adherence [76]. Treatment techniques, such as fixed-dose combinations of ART drugs to reduce dosing complexity, and educational activities, including pharmaceutical treatment management initiatives, have been shown to improve adherence to HIV therapy [72].

In individuals living with HIV, failure of antiretroviral therapy (ART) can result in increased medication toxicity and the development of drug resistance. Studies have shown that nearly half of those who fail first-line ART are at a higher risk of failing second-line treatment as well [77, 78]. Therefore, it is crucial to detect treatment failure at an early stage to prevent the emergence of further drug resistance. Plasma viral load monitoring is considered the gold standard for evaluating the success of ART [79]. In addition, lower CD4 cell count, an important factor in HIV replication, is another indicator of virological failure [80]. Immunocompromised patients with lower CD4 cell counts are at a higher risk of opportunistic infections, leading to increased viral replication and a higher risk of drug resistance [81, 82]. A study by Zoufaly A et al. showed that 12% of children with ART resistance had a CD4 cell count below 200 cells/μl [83]. Therefore, it is crucial to monitor CD4 cell count along with viral load regularly in people living with HIV to ensure effective treatment and prevent virological failure.

Additionally, the duration of ART use has implications for treatment success and drug resistance. Longer duration of ART use was associated with loss of information, poor adherence, and increased drug interruption, leading to virological failure [31, 33, 84,85,86]. In a study conducted by Zoufaly A et al., 53% of the children who experienced virological failure were on ART for an average of 3.5 years [83]. In contrast, in another study by Chen RY et al., the median duration of ART and successful ART regimens in 405 ART-naive individuals reported to be 1.6 years, indicating that successful treatment outcomes can be achieved with shorter durations of ART use, highlighting the importance of optimizing treatment regimens [87]. The occurrence of TB/HIV co-infection increases the likelihood of patients experiencing virological failure [88]. The consequences of TB/HIV co-infection are mutual, with TB accelerating the progression of HIV infection to AIDS, resulting in an increased risk of virological failure and death [89]. Additionally, the combination of TB and HIV infections lowers the CD4 cell count, leading to a weakened immune system [86].

Drug resistance is an inevitable concern in the treatment of HIV due to the virus's genetic diversity. However, using new strategies to produce medications may reduce the occurrence of drug resistance. Since the discovery of ARTs as a viable therapeutic medication, tremendous progress has been achieved, resulting in the FDA’s approval of five integrase strand transfer inhibitors (INSTIs): Dolutegravir (DTG), Raltegravir (RAL), Elvitegravir (EVG), Bictegravir (BIC), and Cabotegravir (CAB). INSTIs have been demonstrated to successfully block HIV-1 replication and have a more robust genetic threshold to resistance than nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Extensive studies have provided a thorough understanding of the resistance patterns of DTG in recent years. It has been demonstrated that DTG exhibits a prolonged binding half-life to HIV integrase (IN) compared to both RAL and EVG. This characteristic likely contributes to DTG's ability to remain effective against the majority of first-generation INSTI-resistant variants [90,91,92,93]. More intriguingly CAB is the first long-acting drug in HIV-1 therapy [94]. In this umbrella review, NNRTIs demonstrated the highest resistance and INSTIs the lowest. NNRTIs have exhibited more risk of resistance than NRTIs and DTG has a low risk of resistance [43, 53, 59]. DTG and lamivudine (3TC) can lower the viral load even in triple to dual regimen changes [56, 66, 69].

It is worth noting that regional differences play a role in the occurrence of ART resistance and virological failure. Sub-Saharan Africa, for example, faces a high prevalence of HIV treatment failure, partly due to factors such as inadequate nutritional assistance, delayed HIV testing, and treatment failure [86, 95,96,97] [98,99,100]. In China, resistance to ART has increased since 2012, primarily driven by NNRTI resistance [101].

Conclusion

In conclusion, resistance to HIV drugs and virologic failure is a significant issue that affects the quality of life and well-being of HIV-infected individuals. This article has highlighted several primary causes of treatment failure, including poor adherence to medication, low CD4 T-cell counts, high viral levels, and specific types of regimens used. Interventions such as drug use, educational counseling, psychological support, and changes in management can help address these causes. With proper adherence to ART regimens, virologic failure without mutation is rare. However, considerations such as drug interactions must be taken into account and can be managed using online tools. Notably, Sub-Saharan Africa remains a region with high rates of virological failure, mainly due to delayed testing and diagnosis and the delayed initiation of ART. These challenges emphasize the urgent need for improved strategies to detect resistance in HIV patients and reduce the likelihood of viral failure by addressing its underlying causes. Further research is needed to improve the detection of resistance in HIV patients and reduce the likelihood of viral failure by identifying and addressing its underlying causes.