Alternative Administration of Antiretroviral Therapy in People with HIV Unable to Swallow: A Scoping Review

Introduction

The Human Immunodeficiency Virus (HIV) pandemic has persisted for more than 40 years.¹ As of 2022, an estimated 39 million people worldwide were living with HIV, with approximately 1.3 million new infections that year.²

In the US, the CDC approximates that 50% of the US population with HIV is aged at least 50 years, which increases concerns related to the increased rates of common comorbidities associated with age, including intensive care admissions, as well as the increased risk of frequent hospitalizations.³ Consistent adherence to ART is essential for decreasing HIV-related morbidity and mortality, as well as in preventing the development of viral resistance to treatment as well as transmission.^4,5

Various formulations of ART exist with some being in tablet-form, capsules, powders, solutions, implants, and injectables. Oral tablets remain the most accessible formulation and have evolved from multiple daily doses to once-daily regimens, improving adherence.⁴ The most widely used regimen is BIC/FTC/TAF, which is a triple therapy single-tablet regimen of bictegravir (INSTI), tenofovir alafenamide (TAF), and emtricitabine (FTC) (2 NRTIs), representing 36.3% of the market share in 2022.⁶ Oral solutions are primarily formulated for pediatric use. Injectable formulations are limited and face unique challenges including the requirement for healthcare provider administration and high costs, particularly for uninsured patients.⁷

In general, oral medications often come with a “do not crush” label to prevent complications related to medication toxicity, ineffective treatment or safety hazards related to specialized release mechanisms, enteric coating or ingredient stability.⁸ When tube feeding is involved, post-pyloric feeding methods, drug absorption is altered as gastric acidity is bypassed. This can affect absorption of some antiretrovirals like dolutegravir or tenofovir.^9,10 This can lead manufacturing companies to avoid providing data on tablet crushing, avoiding liability.¹¹

Injectable ART have unique indications, such as the need to have a suppressed viral load and no documented resistance to any of its components in Cabotegravir/rilpivirine.⁷ However, the prevalence of rilpivirine-associated resistance mutations among PWH varies based on the population and analysis year, ranging from 2.2% to 14.6%. In a single-center study, 18% of PWH had one or more medical contraindications to CAB/RPV. Furthermore, risk factors such as the A6 subtype, high viral loads, low CD4 counts, and obesity increase the risk of virologic failure.^12–14 Other formulations like the subcutaneous lenacapavir is only indicated for multi-drug resistant HIV, alongside oral ART.¹⁵ Other factors limiting use include trypanophobia (fear of needles) and Hepatitis B co-infection, which affects 5% to 15% of PWH in the U.S.¹⁶

Multiple clinical circumstances may prevent patients from swallowing oral medications, including altered mental status, surgical procedures with nothing-by-mouth (NPO) status, facial trauma, critical illness requiring enteral feeding, and obstructive gastrointestinal malignancies. Other conditions can be esophageal strictures, achalasia, prolonged intubation, prior to and briefly after surgeries requiring general anesthesia.¹⁷ Besides, some chronic conditions like inflammatory bowel disease would decrease intestinal motility and absorption, altering drug pharmacokinetics.¹⁸ Although modern ART regimens demonstrate comparable efficacy after switching, regimen changes are typically reserved for managing tolerability issues or drug resistance rather than for addressing transient swallowing difficulties.¹⁹ Even so, there are limited formulations to turn to since tablets and capsules are the primary formulations in the market.⁴

When patients cannot swallow pills, there is minimal information to support administering ART in an alternative dosage form. Besides, there is minimal insight into the effectiveness and optimization of such methods. Although pharmacokinetic data on solid oral drug forms is available for some antiretroviral drugs, little information is published on crushed or altered forms. The last review, to our knowledge, performed by Patrick et al, was published in 2020.²⁰ We performed this scoping review to explore all possible published data around this topic, to give providers some insight on the feasibility of such an approach and the available options. This would offer heterogeneous, comprehensive and contemporary evidence on this topic, especially as a lot of advances have been made in the ART world in the last few years.

Methods

General

We performed an extensive search of literature to include everything published about alternative methods of administration of ART tablets from 2011 till 2025. We limited our search to tablet forms and not include injectable ART formulations. As there are many common keywords in common with other infectious diseases and/or medical conditions that cause inability to swallow, we used a complex search strategy, described in Table 1.

Table 1 Search Criteria

Study Design

We conducted a scoping review following the PRISMA Extension for Scoping Reviews (PRISMA-ScR) framework. A scoping review methodology was selected rather than a systematic review due to the heterogeneous nature of available evidence (case reports, case series, pharmacokinetic studies) and the broad research question about multiple antiretroviral agents and administration methods.

References used: Pubmed, Web of Science and Google Scholar. We additionally screened Google Scholar to capture conference abstracts and non-indexed reports.

Inclusion criteria: Human studies only (no animal or in vitro studies), published between 2011 and 2025, adult PWH (≥18 years), articles describing alternative administration methods (crushing, dissolving, dispersing, or enteral tube delivery) of antiretroviral medications, studies reporting at least one of: pharmacokinetic data, virologic outcomes, or safety data and English language publications.

Exclusion criteria: Animal or in vitro studies, non-English language publications, pediatric populations only (studies in patients <18 years), studies exclusively about injectable long-acting ART (cabotegravir/rilpivirine, lenacapavir), studies about pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), articles about medication adherence or pill-swallowing difficulties without alternative administration methods, studies about rectal administration of ART.

Search Criteria are provided in Table 1.

Search Strategy Synthesis: The three database searches were combined, yielding 1,509 total results (690 from Google Scholar, 798 from PubMed, 21 from Web of Science). All results were imported into Rayyan.ai for duplicate removal and screening.

Duplicates management: The search yielded 1509 results. Rayyan.ai²¹ was used to sort the publications and remove duplicates before the first screening. After removing 35 duplicate articles, 1474 remained.

Data management (Figure 1: PRISMA Flowchart):

Figure 1 PRISMA flowchart.

First Abstract screen: After duplication removal, the first screening was done, blinded and independently, by the authors: HA, WJ, CB, and KP.

Articles excluded by all 4 authors were directly excluded. Those included by at least one author were sought for retrieval.

This screen excluded 1392 articles, leaving 82 articles for the second screen.

Second Screen: 73 articles were retrieved for second full-text screening, and they were again assessed independently by the same 4 authors.

Any article not excluded by all four authors was discussed via a meeting until a consensus was reached. In cases where consensus could not be reached through discussion, a fifth author made the final inclusion decision.

The second screen yielded 12 articles that were included in this review.

Assessment of Bias

Selection bias: All articles that fit our selection criteria were included for review. The authors reviewing the articles were blinded and independent.

Publication Bias: We decided to perform a scoping review to include any published literature regarding our studied topic, including non-indexed reports and conference abstracts identified through Google Scholar.

Outcome reporting bias: Results that showed no benefit in administering tablets via alternative methods were also included.

Time lag bias: we included all published literature since 2011, when the contemporary ARTs became more available.

Data Extraction and combination: The results of the included studied were summarized into a review matrix table and the results section was written manually by CB, KP, and MK. No artificial intelligence was used in writing any part of this manuscript.

Quality Assessment: Due to the heterogeneous study designs (case reports, case series, cohort studies), we did not apply a single quality assessment tool. Instead, we extracted and reported the quality indicators for each study: sample size, duration of follow-up, virologic outcomes (viral load measurements), pharmacokinetic data availability, adverse events reporting and method of ART administration (specific crushing/dissolving technique).

Case reports and case series were assessed for completeness of reporting using the CARE guidelines checklist. We acknowledge that case reports provide lower-quality evidence than controlled trials but included them due to the paucity of higher-level evidence for this clinical question.

Results

Our search identified 12 studies meeting inclusion criteria: 8 case reports (67%), 2 case series (17%), 1 cohort study (8%), and 1 systematic review (8%). Studies were published between 2011 and 2025, with 6 studies (50%) published after 2020. The total number of patients described across case reports and series was 24, with the largest cohort study including 19 patients. Geographic distribution included studies from the United States (n=5), Europe (n=4), and multi-national analyses (n=3).

Nucleoside Reverse Transcriptase Inhibitors

Nucleoside reverse transcriptase inhibitors (NRTIs) remain a cornerstone of antiretroviral therapy because of their potency, tolerability, and inclusion in nearly all first-line ART regimens. Tenofovir, emtricitabine, lamivudine, zidovudine, and abacavir are available as oral solutions, originally developed for pediatric use but adaptable for adult administration via nasogastric (NG) tubes.²² However, drug–drug interactions should be taken into account, such as abacavir and some NNRTIs such as nevirapine, leading to less efficacy.²² Abacavir is available in powder formulations, and could be crushed or sprinkled, followed by a full glass of water to ensure dose completion.²³

Multiple NRTIs including abacavir, tenofovir, zidovudine, and emtricitabine have been successfully administered after crushing and suspending in NG tubes, gastrostomies, and jejunostomies.²⁴ However, tenofovir has better suspension stability when mixed with viscous foods such as yogurt rather than water, which may cause clumping and enteral tube occlusion.²⁵

In a systematic review in 2020, the authors recommend oral solutions as an ideal alternative to solid oral dose forms whenever available on the market.²⁰ Emtricitabine was available as an oral solution and other NRTIs, such as zidovudine, abacavir, lamivudine, and tenofovir disoproxil fumarate (TDF) were available as powders or crushable tablets as per their package labels.²⁰

Non-Nucleoside Reverse Transcriptase Inhibitors

Etravirine, efavirenz, and nevirapine are available as pediatric oral solutions and can be administered via enteral tubes in adults. Several NNRTIs such as efavirenz and etravirine can be crushed or sprinkled in water or food, followed by water to ensure complete dosing.²² Nevirapine could be made into a solution or suspension or sprinkled on a small amount of soft food while etravirine could be dispersed in water to form a slurry.^23,25

Important pharmacokinetic considerations exist for NNRTIs. Efavirenz and rilpivirine are highly lipid-soluble and suggest improved absorption when administered with lipid-rich fluids rather than water. Drug–drug interactions require monitoring, especially when patients receive concurrent azole antifungals, which may increase efavirenz and nevirapine concentrations through hepatic enzyme inhibition.²² The systematic review by San et al emphasized that crushing medications outside manufacturer guidance constitutes off-label use and may increase medication errors and provider liability, recommending increased pharmacist involvement and therapeutic drug monitoring when standard formulations cannot be used.²⁰

Protease Inhibitors

A lot of the protease inhibitors were available in liquid formulations that could be given via enteral tubes, such as lopinavir/ritonavir, ritonavir, and atazanavir.²² However, some formulations such as atazanavir and darunavir were exclusively available as oral tablets that cannot be crushed.²³

A case report suggested that darunavir 600mg tablets could be crushed, suspended in water, and administered via gastric tube, achieving sustained viral suppression for 28 months²⁴ Additionally, oral solutions of ritonavir and lopinavir–ritonavir can also be administered through gastrostomy (G) tubes and jejunostomy without significant loss of therapeutic efficacy.²⁴ Ritonavir is also available as a liquid formulation as well as darunavir.²⁵

Integrase Inhibitors

Integrase strand transfer inhibitors (INSTIs) are currently preferred anchor drugs for most first-line ART regimens. Raltegravir, the first INSTI approved, was initially available only as tablets with no data on crushing.²³ Subsequent studies documented successful administration via NG, nasogastric-duodenal (NGD), gastrostomy, and jejunostomy tubes after crushing.²⁴ Raltegravir chewable tablets designed for pediatric patients weighing <20kg provide an alternative for patients requiring alternative administration.²⁵

Dolutegravir presents unique challenges when administered enterally. A 2025 ICU case series with therapeutic drug monitoring (TDM) revealed that dolutegravir plasma concentrations were significantly reduced in patients receiving concurrent enteral nutrition feeds, likely due to chelation by polyvalent cations (calcium, magnesium, iron) present in nutritional formulations.²⁶ Despite reduced drug levels, therapeutic concentrations and virologic suppression were achievable when dolutegravir administration was carefully separated from enteral feeds by 2–4 hours and guided by TDM. This finding has important implications for critically ill patients requiring both dolutegravir-based ART and continuous enteral nutrition.²⁶

Elvitegravir is water-insoluble and requires dissolution in lipid-based preparations rather than aqueous solutions for optimal absorption.²⁰ Other integrase inhibitors, including bictegravir, are available only as components of fixed-dose combination tablets.

Combination ART Tablets

Fixed-dose combination tablets represent the most prescribed ART⁶ and pose the greatest clinical dilemma when patients cannot swallow, as switching from an effective combination to individual components may require using agents from different manufacturers with varying pharmacokinetic properties. Several case reports and series have documented successful crushing or dissolving of combination tablets.

Two-Drug NRTI Backbone Combinations

Lamivudine/zidovudine and emtricitabine/tenofovir are water-soluble and can be administered via nasogastric, nasoduodenal, gastrostomy, or jejunostomy tubes, although no published data exists regarding their stability after tube administration.²⁴ These older two-drug combinations were more commonly used prior to the availability of single-tablet regimens.

Three-Drug Combinations: NNRTI-Based Regimens

Efavirenz/emtricitabine/tenofovir was historically available only as a whole tablet with manufacturer guidance against crushing.²³ Early reports indicated this combination was water-insoluble and crushing was not recommended.²⁴ Similarly, emtricitabine/rilpivirine/tenofovir was reported to be insoluble with crushing ill-advised.²⁴ However, this guidance predates recent clinical reports suggesting successful use of modified rilpivirine formulations.

Three-Drug Combinations: INSTI-Based Regimens

Dolutegravir/Abacavir/Lamivudine (DTG/ABC/3TC)

Chrdle et al (2018) reported successful administration of crushed dolutegravir/abacavir/lamivudine via nasogastric tube in a patient with esophageal candidiasis and gastric outlet obstruction.²⁷ Despite therapeutic drug monitoring showing slightly lower drug absorption compared to whole tablets, the patient achieved rapid virologic suppression from a baseline viral load of 330,000 copies/mL to 115 copies/mL within 14 days, 81 copies/mL at 28 days, and undetectable viral load after 10 months.²⁷ This case shows that even with suboptimal pharmacokinetics, clinically meaningful viral suppression can be achieved with crushed formulations.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF)

Kaplun et al (2019) reported sustained virologic response after administration of crushed E/C/F/TAF via percutaneous endoscopic gastrostomy (PEG) tube.²⁸ The preparation method involved crushing tablets, mixing with 30 mL water, administering via syringe, and following with 500 mL of nutritional support.²⁸ The patient maintained undetectable HIV-1 viral load (<20 copies/mL) from baseline through 14 weeks of crushed tablet administration.²⁸

Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF)

Multiple recent reports support the use of B/F/TAF in patients requiring enteral feeding. A 2022 case report described successful use of crushed B/F/TAF via PEG tube in a patient with pancreatic head cancer, maintaining undetectable viral load for 7 months after switching from oral to crushed enteral administration.²⁹

Moreover, a 2025 cohort study by Mercure et al provided the largest dataset on modified B/F/TAF administration.³⁰ Among 19 hospitalized patients receiving crushed or dissolved B/F/TAF via enteral tube, 89% (17/19) achieved or maintained viral suppression (<200 copies/mL) within one year of follow-up.³⁰ This study showed that B/F/TAF administration via enteral tube is a viable alternative to switching regimens in critically ill patients.

Pharmaceutical manufacturer data indicates that dissolving B/F/TAF tablets in water is preferred over crushing.³¹ Bioequivalence studies showed that dissolved tablets achieved equivalent drug exposure to intact oral tablets, whereas crushing resulted in slightly reduced bioavailability of emtricitabine and tenofovir alafenamide.³¹ Despite these reductions, clinical viral suppression was maintained in the majority of patients, suggesting that the reductions remained within the therapeutic window.^30,31

Multi-Drug Intensified Regimens

Ragonnet et al (2024) reported successful use of crushed rilpivirine combined with emtricitabine and dolutegravir, intensified with darunavir, administered via percutaneous endoscopic gastrostomy tube to maintain virologic suppression.³² This case suggests the feasibility of crushing multiple individual agents when fixed-dose combinations are not suitable Rilpivirine requires co-administration with food or enteral nutrition due to acid-dependent solubility and significantly improved bioavailability in the presence of dietary fats.²⁰

General Principles for Combination Tablet Administration

Across all combination tablet reports, common themes emerged: (1) Rapid crushing and immediate administration minimizes drug degradation. (2) Adequate flushing with water (typically 30–50 mL) before and after administration prevents tube clogging. (3) Separation from polyvalent cation-containing feeds by 2–4 hours optimizes absorption for certain agents, especially dolutegravir. And (4) therapeutic drug monitoring, while not always performed, may guide dosing adjustments when suboptimal clinical response occurs.

Crushing or dispersing antiretroviral tablets can alter pharmacokinetic exposure depending on excipient composition, release mechanisms, and absorption requirements. Drugs that rely on gastric acidity or lipid-mediated uptake may experience reduced absorption when crushed, while immediate-release formulations that dissolve readily in water often maintain therapeutic exposure.²⁵ Dolutegravir absorption is reduced when co-administered with enteral nutrition because polyvalent cations in feeds chelate the drug, requiring separation of dosing and consideration of therapeutic drug monitoring.²⁶ Rilpivirine requires the presence of food or enteral nutrition to achieve adequate bioavailability due to acid-dependent solubility.²⁰ Bictegravir/emtricitabine/tenofovir alafenamide maintains virologic suppression when dissolved and administered enterally, and dissolving is preferred over crushing to avoid reduced intracellular tenofovir alafenamide activation.³¹ Healthcare providers should consult pharmacists experienced in HIV pharmacotherapy when preparing crushed or dissolved ART formulations to optimize drug exposure and minimize risks of tube occlusion or drug degradation.

Table 2 synthesizes all the data we found in our review.

Table 2 Summary of Our Study Findings

Discussion

As an undetectable viral load means an untransmissible virus (U=U), effective uninterrupted ART is important in decreasing viral transmission.³³ Besides, therapy interruptions are known to raise the risk of treatment resistance, which further highlights the need to ensure an uninterrupted ART administration to all PWH, even when they cannot swallow oral treatment.³⁴

Swallowing difficulties PWH can arise from physiologic dysphagia, pill aversion, or both, and may be chronic or acute. Pill aversion alone affects up to 25–40% of PWH and is influenced by pill size, shape, and sensory characteristic.^35,36 Physiologic dysphagia may result from neuromuscular and neurodegenerative conditions (such as Parkinson’s disease, Alzheimer’s disease, ALS, myasthenia gravis, and multiple sclerosis), structural or malignant processes in the oropharynx or esophagus, and mucosal inflammation from infection or medication injury.³⁷ Some chronic reasons for esophageal dysphagia include eosinophilic esophagitis, gastroesophageal reflux disease, esophageal or peptic stricture, malignancy, and systemic sclerosis.³⁷ Acute dysphagia may also occur post-intubation, post-surgical NPO status, or during severe gastrointestinal illness.^17,37 In these situations, where the patient’s ability to swallow whole tablets is compromised, risk of treatment interruption and virologic rebound increases, making alternative administration routes clinically relevant. In a palliative care setting, the possibility of enteral ART administration prevents the need for IV lines and maximizes patient comfort while maintaining viral suppression.

While some of these acute reasons may be preventable and resolved with time and behavior modifications, the chronic reasons may be more difficult for patients to be adherent to their oral ART regimens. For example, ICU admissions, especially for acute respiratory failure, limit the ability for patients to swallow medications.²⁰ As such, depending on the admission length, patients may difficulties controlling their HIV viral load and CD4+ counts due to inability for oral pills to be taken. Patients who have medical conditions that require nasogastric tubes and percutaneous endoscopic gastrostomy tubes due to impaired intestinal passage may also find themselves in similar situations, with some of their medications not being able to be taken via a different route of administration.²⁰ Overall, it is important to consider patients’ reasons behind their inability to take oral pill regimens as this can impact compliance and their HIV status, whether detectable or undetectable.

For PWH undergoing surgery, it is not recommended to interrupt ART except when needed due to drug–drug interactions or the need for strict nothing per os (NPO).³⁸ Even then, the timing of interruption is minimal, rarely extending beyond 1 day, which is still considered safe. Other reasons for short-term interruptions such as severe gastrointestinal illness are usually less than 2 days, which, while usually safe, has to be minimized.³⁹ As treatment continuation is always advised, many providers attempt to crush pills and administer them parenterally via NG, G, jejunostomy, or other methods without clear literature backup. This review serves to collect such published data to establish a consensus, offering providers in such a situation a evidence suggesting the possibility of an alternative use of such medications.

Based on 2025 data, practical considerations have emerged. If available, clinicians should prioritize dissolving rather than crushing B/F/TAF tablets to maximize drug exposure. For dolutegravir, strict separation from cation-containing enteral feeds and consideration of TDM are advised to avoid sub-therapeutic levels. Furthermore, the European AIDS Clinical Society (EACS) 2025 guidance cycle acknowledges these special administration scenarios, signaling a shift from strict “do not crush” labels to case-by-case management with monitoring.^26,40 Together, these developments suggest a growing consensus, led by EACS, that antiretroviral administration in patients with swallowing dysfunction should be managed on the individual level, prioritizing pharmacokinetic optimization, clinical monitoring, and continuity of HIV suppression over rigid adherence to tablet integrity.⁴⁰

In an ideal scenario, patients can be switched to injectable formulations when possible, but in many cases where this is not an option, this review serves to offer a literature-based approach to use oral ART in alternative methods. It is worth noting, however, that many of these administration strategies are off-label and should be performed with pharmacist involvement and documentation, particularly when enteral feeding tubes or drug–nutrient interactions may affect absorption.

Newer intravenous formulations are currently under investigation.⁴¹ Among those being investigated are semzuvolimab (UB-421), an IV anti-CD4 antibody in Phase II trials (NCT05582694) and a subcutaneous (SC) form in a Phase I trial (NCT04620291).⁴² Pirmitegravir (STP0404) is a new allosteric HIV-1 integrase inhibitor being investigated as an intraperitoneal injection (NCT05869643).⁴³ Furthermore, IV/SC long acting broadly neutralizing antibodies (VH3810109) with intramuscular long-acting cabotegravir are also currently being investigated in phase II trials (NCT05996471).⁴⁴ These formulations might be able to expand our arsenal of parenteral agents. However, as of now, oral agents remain the backbone of ART.

Limitations

As this is a scoping review, the information is not systematic which affects interpretation of findings and their generalizability. It is also prone to bias. To combat this, we implemented an extensively inclusive search, blinded the reviewers and critically appraised all findings. We also included data that does not support use of alternative methods of some pill forms to maximize transparency and minimize bias. Besides, usage might differ between a wide-bore G-tube vs a fine-bore NG tube, such as different risk of clogging with clumps, as is the case with Tenofovir.

Another limitation is that some of the evidence comes from case reports and case series, which are considered lower quality of evidence, included due to the scarcity of publications on this topic, making this manuscript a scoping review.

Another limitation in scoping reviews is the lack of rigorous methodology, for which we adopted the systematic PRISMA approach and made the methodology section very clear to make sure our findings are reproducible.

Conclusion

Some antiretroviral agents and combinations may be crushed, dissolved, or administered enterally when swallowing is not possible. While manufacturer labels often advise against crushing, clinical outcomes suggest that viral suppression can be maintained. However, it is important to stay mindful about need for water or lipid dependence for successful administration. A pharmacist involvement is advised in such situations for proper guidance of these nuances. This review may encourage further research in alternative methods of administering ART pills or push for formulations that bypass the need of active and conscious swallowing in specific settings.