Evaluation of the efficiency of tenofovir + lamivudine + lopinavir/ritonavir regimen in hiv/aids patients with first line treatment failure in Hai Phong (6/2012 - 6/2019)

T¹p chÝ y - d−îc häc qu©n sù sè 8-2020 116 EVALUATION OF THE EFFICIENCY OF TENOFOVIR + LAMIVUDINE + LOPINAVIR/RITONAVIR REGIMEN IN HIV/AIDS PATIENTS WITH FIRST LINE TREATMENT FAILURE IN HAI PHONG (6/2012 - 6/2019) Tran Thi Thoa1, Nguyen Minh Nam2, Hoang Tien Tuyen2 SUMMARY Objectives: To evaluate the efficiency and safety of tenofovir + lamivudine + lopinavir/ritonavir regimen in HIV/AIDS patients with first-line treatment failure. Subjects and methods: Retrospective and prospective cohort studies on 55 patients with virological failure of first-line regimens (ZDV + 3TC + NVP or ZDV + 3TC + EFV), switched to TDF +3TC + LPV/r at Viet Tiep Hospital from June 2012 to June 2019. Results: Virologic failure (HIV-RNA > 1,000 copies/mL): was not well etablished at 6, 12 and 24 months after the end of therapy. Mean CD4 cell count increased significantly in W24 (368 ± 102 cell/mm3) compared with W0 (150 ± 136 cell/mm3). The most common side effect of TDF + 3TC + LPV/r was mild to moderate: diarrhea (29.1%), fatigue (18.2%). Dyslipidemia occurred at all times and the proportion of patients with dyslipidemia after treatment was higher than starting. Conclusions: TDF + 3TC + LPV/r showed clinical, virological and immunological effectiveness in patients with first-line treatment failure. * Keywords: ARV; First-line regimen; HIV/AIDS; Treatment failure. INTRODUCTION Since 2011, the 1c/1d regimen: AZT + 3TC + NVP/EFV was one of the initial ARV regimens recommended by the Ministry of Health for treating naive HIV/AIDS patients. However, some patients with prolonged treatment appeared treatment failure, of which viral failure was the leading cause. Second-line ARV regimen: TDF + 3TC + LVP/r was an alternative regimen [1]. To evaluate the efficacy, as well as the side effects of TDF + 3TC + LVP/r regimen, we conducted this study: To evaluate the efficacy and determine the side effects of TDF + 3TC + LPV/r regimen in HIV/AIDS patients with virological failure with 1c/1d regimen. 1Department of Infectious Diseases, Hai Phong University of Medicine and Pharmacy 2Department of Infectious Diseases, Military Hospital 103, Vietnam Military Medical University Corresponding author: Hoang Tien Tuyen (hoangtuyena5@gmail.com) Date received: 14/8/2020 Date accepted: 14/10/2020 T¹p chÝ y - d−îc häc qu©n sù sè 8-2020 117 SUBJECTS AND METHODS 1. Subjects, place and time of study Our study included 55 HIV/AIDS patients who had virological treatment failure with first-line regimens (ZDV + 3TC + NVP) or 1d (ZDV + 3TC + EFV), then were switched to second line regimen (TDF + 3TC + LPV/r) and treated at Outpatient Clinic, Viet Tiep Friendship Hospital, Hai Phong from 6/2012 - 6/2019. * Inclusion criteria: - HIV/AIDS patients who had virological treatment failure according to the criteria of the Ministry of Health (2015) [2]. The plasma viral load was > 5,000 copies/mL (patients had been treated before 2016); more than 1,000 copies/mL of plasma (patients have been treated since 2016) on two consecutive viral tests 3 months apart in patients who have been on ARV for at least 6 months. - Age from 18 - 60. * Exclusion criteria: - Patients did not cooperate and comply with treatment. - Pregnant women. - Renal diseases (glomerular filtration rate < 10 mL/minute). - Uncontrolled hypertension. * Research materials: - Tenofovir disoproxil fumarate (TDF): 300 mg tablets, 1 capsule/day. - Lamivudine (3TC): 150 mg capsule, take 2 capsules daily, 1 pill in the morning, 1 pill in the evening, 12 hours apart. - Aluvia (lopinavir/ritonavir) (LPV/r): 200 mg/50 mg tablets, take 4 capsules/day, 2 pills in the morning, 2 pills in the evening, 12 hours apart. - Drugs were provided by the PEPFAR program, manufactured in India. 2. Methods * Study design: Descriptive case study, including 46 retrospective patients from 2012 and 9 prospective patients from February to June 2019. All patients were registered according to the unified form * Research targets: + Average age, age group; clinical symptoms before and after each month of treatment. + The viral load was measured with Roche Diagnostic Firm COBAS® AmpliPre/COBAS® TaqMan® HIV, performed at the Department of Microbiology, Bach Mai Hospital. Detection threshold ≥ 40 copies/mL. + The number of lymphocytes TCD4 was performed with Cyflow SL3 at Viet Tiep Friendship Hospital, according to the flow cell counting principles. The tests were done at the time of before and the end of 6, 12, 18, 24 months of treatment. - Criteria for evaluating treatment failure: + Viral failure: HIV-RNA load > 1,000 copies/mL at 6 months of treatment. + Immunological failure: The number of TCD4 at the time of testing was equal to or lower than the number of TCD4 before treatment with ARV or the number of lymphocytes TCD4 were less than 100 cells/mm3 at two consecutive tests (6 months apart) and no recent etiology of infection caused a decrease in TCD4. + Clinical failure: New onset or relapse of clinical stage 4 after at least 6 months of treatment with ARV. * Data processing: By SPSS software version 20.0. T¹p chÝ y - d−îc häc qu©n sù sè 8-2020 118 RESULTS Table 1: Some clinical and subclinical characteristics of pre-treatment. Targets n = 55 Age (X̅ ± SD; min - max) (years) 41.3 ± 7.6 (18 - 60) Age group from 31 - 50 (n, %) 49 (89.1) Male (n, %) 40 (72.7) BMI (X̅ ± SD; min - max) (kg/m2) 19.3 ± 2.4 (13.68 - 24.46) 1 35 (63.6) 2 2 (3.7) 3 6 (10.9) Clinical stage (n, %) 4 12 (21.8) Hb < 120 g/L (n, %) 29 (52.7) ALT > 1.25 ULN (n, %) 9/29 (31.1) Creatinin > 120 µmol/L (n, %) 0 (0.0) Cholesterol > 6.2 mmol/L (n, %) 1 (1.8) TCD4 (X̅ ± SD; min - max) (cells/mm3) 150 ± 136 (11 - 375) HIV-RNA > 1,000 copies/mL (n,%) (X̅ ± SD; min - max) (copies/mL) 55 (100.0) 131,262 ± 225,536 (1,100 - 812,000) The average BMI was in the low limit of normal values (19.3 ± 2.4 kg/m2), clinical stage 4 was only available in 21.8% of patients; 100% of patients had viral load more than 1,000 copies/mL, the lowest viral load was 1,100 copies/mL, the average number of TCD4 was low (150 ± 136 cells/mm3), the lowest TCD4 was 11 cells/mm3. Table 2: Clinical response during the treatment. Time of treatment Targets T0 (a) (n = 55) T6 (b) (n = 55) T12 (c) (n = 45) T24 (d) (n = 36) pb,c,d-a BMI (kg/m2) (X̅ ± SD) 19.3 ± 2.4 21.2 ± 2.6 21.3 ± 1.9 21.7 ± 2.1 < 0.05 1 35 (63.6) 44 (80.0) 41 (91.4) 34 (94.9) 2 2 (3.7) 0 (0.0) 0 (0.0) 0 (0.0) 3 6 (10.9) 3 (5.5) 2 (3.3) 0 (0.0) Clinical stage (n, %) 4 12 (21.8) 8 (14.5) 2 (3.3) 2 (5.1) < 0.05 The average BMI improved to the high limit of normal range at the end of 6 months of treatment and remained stable at the end of 12 and 24 months of treatment. The difference between before and after treatment was statistically significant with p < 0.05. Similar to the clinical stage of the disease, there was a clear improvement at the time T6. At the time T24, there were 94.9% of patients in the clinical stage 1 and 5.1% of patients still in the clinical stage 4. T¹p chÝ y - d−îc häc qu©n sù sè 8-2020 119 Table 3: Virological response during the treatment. HIV-RNA (VL) (copies /mL) T0 (n = 55) T6 (n = 55) T12 (n = 45) T24 (n = 36) p24-0 Below the threshold VL ≤ 40 0 (0.0) 42 (76.4) 39 (86.7) 33 (91.7) 40 < VL ≤ 1,000 0 (0.0) 13 (23.6) 6 (13.3) 2 (5.6) > 1,000 55 (100.0) 0 (0.0) 0 (0.0) 1 (2.8) < 0.05 The virological response (VL < 1,000 copies/mL plasma) occurred in 100% of patients at the end of 6 months of treatment, of which 76.4% were below the detection threshold. There were no patients with viral failures at T12 and T24. Figure 1: Immune response during the treatment. The average number of CD4 cells improved after 6 months and increased significantly at the end of 24 months after treatment (368 ± 102 cells/mm3), the difference was statistically significant with p < 0.05. Table 4: Clinical side effects in patients treated with TDF + 3TC + LPV/r. Time of treatment Symptoms T0 T6 T12 T24 Total (n = 55) Percentage (%) Diarrhea 0 16 0 0 16 29.1 Fatigue 0 10 0 0 10 18.2 Nausea, vomiting 0 10 0 0 10 18.2 Headache 0 4 0 0 4 7.3 Abdominal pain 0 5 0 0 5 9.1 Skin rash 0 2 0 0 2 3.6 The most common symptom was diarrhea (29.1%), time of appearance was 28.4 ± 26.7 days. Fatigue, nausea, skin rash, headache occured with incidence of less than 20% and appeared within the first week of treatment. T¹p chÝ y - d−îc häc qu©n sù sè 8-2020 120 Table 5: Side effects in patients treated with TDF + 3TC + LPV/r. Time of treatment Symptoms (n, %) T0 (a) T6 (b) T12 (c) T24 (d) pb,c,d-a Hb < 120 g/L 29/55 (52.7) 19/55 (34.5) 6/45 (13.3) 2/36 (5.6) < 0.05 Creatinin > 120 µmol/L 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) ALT > 40 U/L 9/29 (31.1) 9/24 (37.5) 10/27 (37.0) 11/29 (37.9) > 0.05 Triglycerid > 4.5 mmol/L 4/55 (7.3) 7/55 (12.7) 9/45 (20.0) 5/36 (13.8) > 0.05 Cholesterol > 6.2 mmol/L 1/55 (1.8) 6/55 (10.9) 8/45 (17.8) 4/36 (11.1) > 0.05 The number of anemia patients decreased significantly following the time of treatment. The number of patients with triglyceride > 4.5 mmol/L and cholesterol > 6.2 mmol/L increased by the time of treatment, but there was no statistical significance between the time points. DISCUSSION In Hai Phong, Vietnam-Czech Hospital had a lot of HIV/AIDS patients managed, monitored and treated with ZDV + 3TC + NVP/EFV regimen, many of whom had viral treatment failure and were transferred to TDF + 3TC + LPV/r regimen. To accurately assess the therapeutic effect and undesirable effects of TDF + 3TC + LPV/r, we selected 55 patients who met the study criteria. On the basis of statistical data, the average age of patients was 41.3 ± 7.6 (18 - 60), the age group from 31 - 50 accounted for 89.1%; 63.6% of patients in clinical stage 1, 52.7% of patients with moderate anemia, the average viral load was 131,262 ± 225,536 (1,100 - 812,000), the average number of TCD4 was 150 ± 136 cells/mm3 (11 - 375 cells/mm3). Pham Ba Hien's study (2018) on 393 patients who failed with first-line regimens and were transferred to second-line regimens in Hanoi showed that: The average age was 32.74 ± 7.49, the age group 31 - 50 accounted for the majority (60.3%). Among 43 patients treated with second- line regimens, only 6.9% of patients was in clinical stage 1 and had an average TCD4 count of 100 ± 6.3 cells/mm3 (12 - 317 cells/mm3) [4]. In terms of data differences, we found that the patients adhered to counseling and treatment. The data in our study of viral treatment failure with first line regimen were similar to Pham Ba Hien’s findings. Assessing the effectiveness of the TDF + 3TC + LVP/r regimen at 6, 12, 24 months after treatment, the results showed that: The virological response was found in 100% of patients at all times, below the detection threshold was 76.4%, 86.7% and 91.7%, respectively. Similarly, 100% of patients had an immune response and increased over time, specifically, the average number of TCD4 was 231, 298, 368 cells/mm3, respectively. Clinical response increased: After 6 months of treatment, there was up to 80.0% of patients in clinical stage 1, and 94.9% after 24 months. Unfortunately, there was 5.1% of patients did not show any improvement in clinical response even despite of the virological response. Pham Ba Hien’s research T¹p chÝ y - d−îc häc qu©n sù sè 8-2020 121 (2018) showed that the viral responses at the respective times were 100%, 100% and 97.6%. Research by Laurent F (2010) in Cambodia showed that the average number of TCD4 cells were 197, 258 and 372 cells/mm3, respectively [6]. This result allows confirming the effectiveness of the regimen if the patient adheres to therapy Evaluation of side effects of TDF + 3TC + LPV/r regimen, we found that: Diarrhea accounted for the highest 29.1%, followed by fatigue 18.2%, headache 7.3%, nausea, vomiting 18.2%, abdominal pain 9.1%, skin rash 3.6%. According to Nguyen The Tien (2015): Diarrhea (29.3%), nausea (13.8%), fatigue (13.8%), headache (10.3%), abdominal pain and vomiting (8.6% and 5.2%) [5]. Hypercholesterolemia disorders ranged from 4.6% - 15.3%, triglyceride hyperactivity ranged from 10.8% - 18.4%. Our research results were similar to Nguyen The Tien’s findings, the rate of hyper-triglyceridemia during treatment ranged from 17.2% - 28.2%, hyper- cholesterolemia during treatment ranged from 5.7% - 17.7% [5]. Our adverse effects were also completely consistent with the warning of the Ministry of Health [3]. CONCLUSION - TDF + 3TC + LVP/r regimen was a highly effective ARV regimen. Specifically: 100% of patients had a virological response, improved immune response at the time of evaluation, 92.7% patients had clinical response at the end of 24 months of treatment. - TDF + 3TC + LVP/r regimen caused some side effeccts such as diarrhea, headache, fatigue, nausea, and abdominal pain. Increasing cholesterol, triglycerides - metabolic disorders occured in some patients and increased by the time of treatment. REFERENCES 1. Bộ Y tế. 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