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Abstract

Background:

Cases of treatment failure in patients developing the R263K mutation have been previously reported. Here we present a patient who developed resistance to dolutegravir due to the R263K mutation during rifampicin treatment.

Case presentation:

A patient with human immunodeficiency virus (HIV) had a virological failure of HIV when he used dolutegravir (DTG, once a day) and rifampicin at the same time. After treatment failure the dose of dolutegravir was increased (50mg, twice daily), but expected response was not achieved. The R263K mutation was identified and rifampicin was stopped. The treatment regimen was changed to zidovudine combined with lamivudine and lopinavir/ritonavir. Along with the regimen changes, the HIV-RNA, CD4, and CD8 of the patient improved. Due to the DTG drug-drug interactions with rifampicin, the dose of DTG should be doubled when used with rifampicin. Otherwise the patient might be at risk of developing treatment failure and the INSTI drug resistance R263K mutation.

Conclusion:

This case report discusses a possibility of developing resistance to dolutegravir due to the R263K mutation during rifampicin treatment, stressing the importance of detailed medical history and adherence, as well as the problem of drug-drug interactions in the follow-up process.

Introduction

The resistance to antiretroviral therapy (ART) in patients with human immunodeficiency virus (HIV) is associated with virologic failure.1 Considering the role of integrase strand transfer inhibitors (INSTI) as a first-line regimen for the treatment of HIV type 1 (HIV-1) or as postexposure prophylaxis,2 the development of resistance to this therapy is a matter of concern.3

Dolutegravir (DTG) is a second-generation INSTI that is superior to efavirenz (EFV)-based regimen and non-inferior to raltegravir (RAL)-based regimen in efficacy.2 It is also reported to be safe, well-tolerated, and have a potential to reduce the pill burden in PLWH.2 Importantly, some mutations will reduce the sensitivity of RAL or elvitegravir (EVG), but DTG is still sensitive to these mutants, such as N155H, Y143C/R/H/K/S/G/A, G140A/S, and E138K/A/T.4,5 On the other hand, mutations like R263K and G118R alone can reduce susceptibility of DTG, and L74M and Q148 H/K/R/N can reduce DTG susceptibility in combination with other INSTI-resistance mutations.4,6,7 Additionally, DTG resistance is more often, but not exclusively, observed in patients with a history of RAL treatment (a first-generation INSTI).8 –10

The R263K mutation in the integrase gene leads to an intermediate resistance to DTG.11 It has been reported in treatment-naïve and treatment-experienced patients.8,12 In developed countries, R263K is mostly reported in patients with subtype B infection and a history of abacavir (ABC)/lamivudine (3TC)/DTG or DTG monotherapy. In developing countries, the R263K mutation is more common for patients who receive the same antiretroviral regimen for a long time despite failure, in patients who temporarily switched to other drugs due to the shortage of specific drugs, or in patients using undisclosed antiretrovirals.13 –15 Patients with poor adherence to DTG have also been reported to develop the R263K mutation.16 Furthermore, drug–drug interactions (DDIs) might affect the pharmacokinetics and pharmacodynamics of DTG.17,18

Invitro studies showed that the R263K mutation associated with resistance to DTG does not impact treatment because of the viral fitness cost.11,19,20 Still, some cases of treatment failure in patients developing the R263K mutation have been reported.21 Here, we discuss a case of DTG resistance developed due to the R263K mutation during RIF treatment. We believe that reporting such cases is important to monitor the evolution of HIV and potential problems in treatment.

Case Report

A treatment-naïve man who has sex with men, aged 46 years, was diagnosed with HIV-1 on October 12, 2019 at the Dongguan Ninth People’s Hospital. On September 30, 2019, the laboratory tests showed cluster of differentiation 4 (CD4) at 5 cells/µL and cluster of differentiation 8 (CD8) at 479 cells/µL (Table1). Blood routine examination, liver and kidney functions, HBsAg, HBsAB, HBeAg, HEeAb, HBcAb, hepatitis C antibody, syphilis, chest X-ray, and liver ultrasound were completed, and no obvious abnormalities were found. The values of blood lipids are shown in Table2.

Table1.

Laboratory test of the patient

Date	CD4 count (cells/μL)	CD8 count (cells/μL)	HIV viral load (copies/mL)	ART regimen	Anti-TB regimen	Genotype mutations	Drug resistance
September 30, 2019	5	479	–	TDF, 3TC, and EFV	–	–	–
January 7, 2020	23	580	–	TDF, 3TC, and EFV	–	–	–
April 30, 2020	20	498	385,762	TDF, 3TC, and EFV	–	–	–
June 22, 2020	–	–	293,000	TDF, 3TC, and EFV	–	NRTI resistance mutations: L74LIV and M184V NNRTI resistance mutations: V106M, V179D, and F22FL	High-level resistance: ABC, FTC, 3TC, NVP, and EFV Potential resistance: ETR and RPV
June 30, 2020	–	–	–	TDF, 3TC, and DTG (50 mg)	–	–	–
August 15, 2020	–	–	–	TDF, 3TC, and DTG (50 mg once daily)	RIF, ethambutol hydrochloride, clarithromycin, enteric-soluble capsule of diamine glycyrrhizinate, and Chinese patent medicine	–	–
October 12, 2020	51	355	175,000	TDF, 3TC, and DTG (50 mg twice daily)	RIF, ethambutol hydrochloride, clarithromycin, enteric-soluble capsule of diamine glycyrrhizinate, and Chinese patent medicine	–	–
January 11, 2021	56	426	221,000	TDF, 3TC, and DTG (50 mg twice daily)	RIF, ethambutol hydrochloride, clarithromycin, enteric-soluble capsule of diamine glycyrrhizinate, and Chinese patent medicine	–	–
January 19, 2021	–	–	–	TDF, 3TC, and DTG (50 mg twice daily)	RIF, ethambutol hydrochloride, clarithromycin, enteric-soluble capsule of diamine glycyrrhizinate, and Chinese patent medicine	NRTI resistance mutations: L74LIV and M184V NNRTI resistance mutations: V106M, V179D, and F22FL INSTI resistance mutations: G118R, E138K, and R263K PI resistance mutations: None	High-level resistance: ABC, DDI, FTC, 3TC, DOR, EFV, NVP, BIC, DTG, EVG, and RAL Low-level resistance: TDF Potential resistance: RPV and ETR
January 28, 2021	–	–	–	AZT, 3TC, and LPV/r	Ethambutol hydrochloride, clarithromycin, enteric-soluble capsule of diamine glycyrrhizinate, and Chinese patent medicine	–	–
February 18, 2021	100	465	458	AZT, 3TC, and LPV/r	–	–	–
March 6, 2021	115	806	609	AZT, 3TC, and LPV/r	–	–	–
April 6, 2021	1,125	726	799	AZT, 3TC, and LPV/r	–	–	–
July 17, 2021	128	720	770.1	AZT, 3TC, and LPV/r	–	–	–

CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; HIV, human immunodeficiency virus; ART, antiretroviral therapy; TB, tuberculous; TDF, tenofovir; 3TC, lamivudine; EFV, efavirenz; DTG, dolutegravir; AZT, zidovudine; LPV/r, lopinavir/ritonavir; ABC, abacavir; DDI, didanosine; FTC, emtricitabine; DOR, doravirine; NVP, nevirapine; BIC, bictegravir; EVG, elvitegravir; RAL, raltegravir; RPV, rilpivirine; ETR, etravirine; RIF, rifampicin; NRTI, nucleos(t)ide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; INSTI, integrase strand-transfer inhibitor; PI, protease inhibitor.

Table2.

Changes in blood lipids

	Triglycerides (mmol/L)	Total cholesterol (mmol/L)	Low-density lipoprotein cholesterol (mmol/L)	How-density lipoprotein cholesterol (mmol/L)
October 17, 2019	2.51	10.13	7.20	1.75
November 14, 2019	3.75	8.55	5.65	1.29
December 10, 2019	4.77	6.74	4.13	1.00
January 7, 2020	6.89	5.80	3.74	0.89

On October 21, 2019, the patient received tenofovir (TDF) + 3TC + EFV. The patient was followed-up on November 14, 2019, December 10, 2019, and January 7, 2020. During these periods, the patient reported taking medicine on time and in sufficient quantity, without omissions or supplements. The blood routine examinations, liver and kidney functions, myocardial enzymes, and other indicators showed no abnormalities.

On January 7, 2020 (i.e., after 3 months of treatment), CD4 was 23 cells/µL, and CD8 was 580 cells/µL. The patient continued TDF + 3TC + EFV without complaining or obvious discomfort. On April 30, 2020 (i.e., after 6 months of antiviral treatment), HIV-RNA was 385,762 copies/mL, CD4 was 20 cells/µL, and CD8 was 498 cells/µL. On June 22, 2020, HIV-RNA was 293,000 copies/mL. The drug resistance test showed that the drug resistance sites were L74LIV and M184V for the nucleoside drug resistance sites, and V106M, V179D, and F22FL for the non-nucleoside resistance sites. These mutations suggested high-level resistance to abacavir, emtricitabine, 3TC, nevirapine, and EFV, and potential resistance to etravirine (ETR) and rilpivirine. No integrase inhibitors (INI)-related drug-resistant mutations were found in this test.

On June 30, 2020, the antiviral therapy was switched to TDF + 3TC + DTG (50 mg once daily). On July 20, 2020, the patient developed a cough, sputum, hemoptysis, night sweat, and weight loss (3 kg in 1 month). On August 15, 2020, after comprehensive anti-tuberculosis, anti-infection, and immunity-boosting treatments in a local hospital, cough and sputum were reduced, and hemoptysis had disappeared. The TDF + 3TC + DTG (50 mg once daily) regimen was continued during these treatments.

From August 20 to October 12, 2020, the patient received both rifampicin (RIF) and DTG. On October 12, 2020, HIV-RNA was 1.75 × 10⁵ copies/mL, CD4 was 51 cells/µL, and CD8 was 355 cells/µL. Therefore, to retain the original anti-tuberculosis regimen, the anti-HIV regimen was adjusted to TDF + 3TC + DTG (50 mg twice daily).

On January 11, 2021, HIV-RNA was 2.21 × 10⁵ copies/mL, CD4 was 56 cells/µL, and CD8 was 426 cells/µL. Considering the poor efficacy of the antiviral therapy, a DTG blood concentration test was conducted to understand the patient’s medication compliance, and the results showed that blood DTG reached effective concentrations (Ctrough: 2.45 µg/mL; C2: 3.2 µg/mL).

On January 19, 2021, both RNA and DNA drug resistance reports indicated nucleoside reverse transcriptase-related mutations at L74LI and M184MV (The drug resistance report suggests that it may be highly resistant to abacavir, didanosine (ddI), emtricitabine, and 3TC, and low resistance to TDF.), non-nucleoside reverse transcriptase-related mutations at V106M, V179D, and F227L (The drug resistance report suggests that it may be highly resistant to doravirine, EFV, and nevirapine, and potential drug resistance to rilpivirine and ETR.), INSTI mutation sites at G118R, E138K, and R263K (The drug resistance report suggests that it may be highly resistant to bictegravir, DTG, EVG, and RAL.), and no protease inhibitor resistance mutations. Therefore, on January 28, 2021, considering the drug resistance, the treatment was changed to zidovudine + 3TC and lopinavir/ritonavir. At the same time, considering the 5-month duration of anti-tuberculosis treatment, RIF was discontinued, while ethambutol and clarithromycin were continued.

On February 18, 2021, HIV-RNA was 458 copies/mL, CD4 was 100 cells/µL, and CD8 was 465 cells/µL, and the patient stopped using anti-tuberculosis drugs. On March 6, 2021, HIV-RNA was 609 copies/mL, CD4 was 115 cells/µL, and CD8 was 806 cells/µL. There was no obvious cough, sputum, or other discomforts, and the weight increased by 0.5 kg.

On April 6, 2021, HIV-RNA was 799 copies/mL, and CD4/CD8 was 1,125/726 cells/µL. The patient had no obvious discomfort and gained 0.5 kg in weight. On July 17, 2021, HIV-RNA was 770.10 copies/mL, and CD4/CD8 was 128/720 cells/µL. The patient had no complaints and gained 2 kg. At the time of writing this report, the patient still insists on regularly returning for follow-ups. At the follow-up on January 22, 2022, HIV-RNA was 133 copies/mL.

Laboratory Analyses

HIV-RNA was extracted from plasma using SUPBIO Nucleic Acid Extraction or Purification Kits. The HIV-1 RNA Quantitative PCR Kit (SUPBIO, Guangzhou, China) was used for quantitating HIV-RNA. The linear quantification range of the HIV-1 RNA Quantitative PCR Kit was 12 to 6.0 × 10⁶ copies/mL.

In samples with viral load ≥1,000 copies/mL, HIV drug resistance (HIVDR) genotyping was performed at WHO Accreditation Laboratory of National Center for AIDS/STD Control and Prevention of the Chinese Center for Disease Control and Prevention by using an in-house method. The main steps include the following: (1) extracting HIV-1 RNA from plasma and HIV-1 DNA from blood cells; (2) amplification of HIV-1 pol region gene (including reverse transcriptase region, protease region, and integrase region) by PCR; (3) sequencing the amplified products by the Sanger sequencing method; (4) analyze and explain the results of HIV-1 RNA and HIV-1 DNA genotypic drug resistance detection by using Stanford University drug resistance database, and judge low drug resistance (L), moderate drug resistance (I), and high drug resistance (H) as drug resistance.

Blood samples were taken at Ctrough (>12 h postdose) and C2 (2 h postdose) for the measurement of DTG concentrations. Plasma was collected by centrifugation within 2 h after the specimen was collected, and the sample was extracted by the protein precipitation method and detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We mix 30 μL of plasma sample with 600 μL of internal standard containing isotope label-DTG-d₇¹⁵N (DTG-IS). After shaking at room temperature for 3 min, the supernatant was obtained by 14,000 rpm separation for 5 min. Before the LC-MS/MS analysis, a part of the supernatant was diluted with 50:50 methanol:water. DTG was eluted from a Varian Pursuit Diphenyl (2.1 × 50 mm, 3 mmparticle size) analytical column (Agilent Technologies, Santa Clara, CA, USA). An API-5000 triple quadrupole mass spectrometer (AB Sciex, Foster City, CA, USA) was used to detect analytes. For DTG, the precursor ion was 420 m/z, and the product ion was 277 m/z. For DTG-IS, the precursor ion was 428 m/z, and the product ion was 283 m/z. Data were collected using the AB Sciex Analyst Chromatography Software. The dynamic range of the assay was 20–20,000 ng/mL.

Discussion

With the increase in average age, there is a holistic shift in HIV medical management, related to the age-associated comorbidities.22 Therefore, patients are increasingly exposed to polypharmacy, while DDIs more often lead to clinically significant events.23 This case report discusses a possibility of developing resistance to DTG due to the R263K mutation during RIF treatment, stressing the importance of detailed medical history and adherence, as well as the problem of DDIs in the follow-up process. Presented data and results of sanger sequencing may be applicable to other HIV patients with virologic rebound or treatment failure.

A few previous case reports have drawn attention to using RIF together with DTG.24,25 Due to lowering DTG levels, when combined with RIF, DTG needs to be used twice daily,18 and in cases when patients’ compliance is poor, treatment failure and DTG resistance may occur.17 Pena etal.,24 while describing a similar resistance case in HIV patient with concomitant rifampin treatment ofstaphylococcal infection and selection of R263K + E157Q, discussed low plasma DTG levels and suspected lack of adherence to the ART as the most likely explanation. In this case, HIV was complicated with tuberculosis after 9 months of antiviral treatment, and for 5 months, the patient received both RIF and DTG. We trust the compliance of the patient's self-report relatively because his blood concentration test shows that the blood DTG reaches the effective concentration after the dosage of DTG is doubled. Of course, it does not rule out that the patient has inadvertently missed taking the medicine, but these factors are difficult to trace back to the source. Looking back on the diagnosis and treatment process of this patient, the biggest risk occurred during the period when he used RIF and DTG once a day. Although it is not certain whether there was a drug-resistant mutation of DTG in these months, according to the previously published research data, the probability of insufficient blood concentration of DTG during this period is very high. The biggest hint for us is that when evaluating the risk of DDI, we should not only evaluate the DDI between known drugs but also guard against the risk of drug-drug interaction (DDI) caused by patients taking drugs outside the hospital. Especially for patients with low CD4, it is necessary to strengthen the monitoring after medication because they are more prone to opportunistic infections. In this case, the patients were co-infected but received anti-tuberculosis treatment in different hospitals, which led to the failure of clinicians to find the risk of DDI in time.

According to the Chinese AIDS Diagnosis and Treatment Guidelines (2021 edition), in patients with ART failure, ART regimen should be adjusted according to the HIV drug resistance test results. The principle of drug regimen selection is to replace at least two ART drugs: in this case, we choose three new drugs with antiviral activity and observed gradual decrease in HIV-RNA; patient had no obvious discomfort and gained weight, which implies at least partial efficacy.

In fact, the risk of DDI in both DTG and 3TC is very low, but the risk of DDI cannot be absolutely zero. Therefore, even if the patients have achieved virological inhibition, it is necessary for them to follow-up regularly and monitor their co-infection status. In addition, this case also suggests that the stigma of our patients is accompanied by the treatment process of patients. Even patients who are actively treating HIV infection will tend to hide their HIV infection status when they visit other hospitals. Perhaps the elimination of stigma can also help reduce the risk of DDI.

Funding: None.

Conflict of Interest: The authors declare no competing interest.

Authors’ Contribution: JL and SY had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, as well as involved in the study design. ZW and YC involved in the data collection. JL involved in making draft of the manuscript.

Footnotes

Acknowledgments

None.

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