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Comparison of Three Different Anti-retroviral Regimens in Terms of Immunological and Virological Response/Uc Farkli Anti-retroviral Tedavi Rejiminin Immunolojik ve Virolojik Acidan Karsilastirilmasi.

Introduction

Human immunodeficiency virus (HIV) infection is an important infectious disease caused by HIV [1]. Acquired Immune Deficiency Syndrome (AIDS) is a syndrome where opportunistic infections may occur due to immune system insufficiency. Although the prevalence of HIV is low (< 1%) in Turkey, an increase in the number of newly diagnosed cases through years is remarkable [2].

In 1987, first generation antiretroviral agents (ART) were introduced and by 1996 new generation anti-HIV drugs with different mechanism of actions -namely highly active antiretroviral treatment (HAART) consisting at least three drugs in combination- were introduced. HAART provides significant decrease in viral load and increase in CD4+ T cell counts, thus the mortality of AIDS have decreased and life quality of patients have improved [3,4].

Currently, there are more than 25 anti-HIV drugs that grouped in six major classes [5]. Most of these drugs are used in combinations to receive maximum efficiency. Various studies have shown that, if one of a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitors (PI) or integrase inhibitors (INI) is combined with two potent nucleoside reverse transcriptase inhibitors (NRTI), the treatment is found effective in naive cases [5]. Factors such as co-morbidities, viral load, drug sensitivity of the virus, adverse events, dose intervals, drug-drug interactions, patient compliance and drug access should be taken into account while deciding on the most appropriate drug choice [6].

Viral load and CD4+ T cell count are the two important markers of ART responses and HIV disease progression that have been used for decades to manage and monitor HIV infection.

Viral load is a marker of response to ART. A patient's pre-ART viral load level and the magnitude of viral load decline after initiation of ART provide prognostic information about the probability of disease progression [7].

HIV infects CD4+ T cells and CD4+ T cell count drops gradually, which weakens the immune system. Therefore, it is important to monitor CD4+ T cell count and percentage in HIV/AIDS cases during follow-up.

In terms of treatment follow up, viral load and CD4+ T cell counts should be monitored in all HIV cases. Since HIV drug options are limited in our country and there are not enough studies that compare drug regimens in Turkish patients, we aimed to compare immunological and virological responses to three different anti-retroviral regimens by using NNRTI, PI or INI in combination with NRTI.

2. Material and methods

2.1. Patient group

Naive HIV/AIDS cases over 18 years of age were included in this study. Pregnant women, treatment experienced patients, patients without compliance and/or who left follow-up were excluded.

2.2. Methods

In this study, data of the HIV/AIDS patients who treated with different ART regimens between 2011-2017 were analyzed, retrospectively. All patients were treated with NRTI+NNRTI (NNRTI group) or NRTI+PI (PI group) or NRTI+INI (INI group) regimens at least for one year. ART combinations were included; zidovudin/lamivudine or tenofovir disoproxil fumarate/emtricitabine and abacavir/lamivudine in NRTI class, nevirapine or efavirenz in NNRTI class, lopinavir/ritonavir or darunavir/ritonavir in PI class, raltegravir, dolutegravir or elvitegravir/cobicistat in INI class [5].

Ethics committee approval had been received at the Tepecik Training and Research Hospital on 02.05.2016 with serial number "1". Patients' data were analysed at 1st month, 3rd month, 6th month and 12th month, CD4+ T cell counts and HIV RNA levels were recorded. An adequate immunological response was defined as 50 - 150 cells/[mm.sup.3] increase in CD4+ T cell counts, per year [5, 8]. In addition, stable HIV RNA level <200 copies/mL was defined as virological response [5].

2.3. Laboratory measurements

HIV RNA were measured as copies/mL by real time polymerase chain reaction performed on Roche COBAS[R] AmpliPrep/COBAS[R] TaqMan[R] HIV-1 Test, v2.0 device (Roche Molecular Systems, Branchburg, USA). Minimum level of detection for this device was 20 copies/mL. CD4 cell count ([mm.sup.3]/mL) was measured by Becton-Dickinson FACSCalibur Flow Cytometer device (San Jose, USA).

2.4. Statistical analysis

SPSS 18.0 (IBM Corporation, Armonk, New York, United States) software were used for data analysis. Quantitative data were shown as mean [+ or -] SD (standard deviation) and median (maximum-minimum), while categorical data were presented as n (number) and percentage (%). The distributions of qualitative variables were presented as frequency and percentages in cross tables. For comparison of independent categorical data with each other, Pearson Chi-Square test and Fisher's Exact test were applied. For all tests the margin of error was determined as a: 0.05 and tested bidirectionally. The confidence level of 95% was selected and p value below 0.05 was accepted as statistically significant.

3. Results

Of sixty-three naive HIV/AIDS patients, eight were women (13%), 55 were men (87%). Seventy-two patients who did not fullfill the inclusion criteria were excluded from the study. Mean age of patients were 43 [+ or -] 13 (19-66) years (standard deviation, minimum-maximum), respectively. Mean follow-up time of the patients was 4 (1-14) years (minimum-maximum). Totally fourteen patients were treated with NRTI+INI (22.2%), 18 with NRTI+PI (28.6%) and 31 with NRTI+NNRTI (49.2%). Backbone NRTI were as follows; tenofovir disoproxil fumarate/emtricitabine (88.9%), zidovudin/lamivudine (9.5%) and abacavir/lamivudine (1.6%).

Baseline median CD4+ T cell counts of patients were 370 [+ or -] 391 (4-2469) cells/[mm.sup.3] (standard deviation, minimum-maximum), and the median HIV RNA levels were 100.000 (743-10.000.000) copies/mL (minimum-maximum). The age, median CD4+ T cell counts and HIV RNA levels of the patients for each group are presented in Table-1.

When all three groups were compared in terms of immunological response (>50 cell/[mm.sup.3] increase in CD4+ T cell counts in consecutive measurements), at the end of 12 months; PI group was the most successful and NNRTI group was the most unsuccessful group. Despite the high CD4+ T cell counts at the beginning of the treatment, INI group had significant increase especially in the first 3 months. Immunological response of INI group found to be significantly higher than NNRTI group in this period (p: 0.046). However, there was no other statistically significant difference between the three treatment groups at the end of 12 months and consecutive measurements. Among all groups total immunological response rate was 82.5% at the end of 12 months. Immunological responses are presented in Table-2 and Table-3.

When patients were evaluated in terms of the virological responses, it was found that the patients in INI group had a significant advantage over the other groups in the first 3 months. In patients that were in INI group, 85.7% achieved virological response at 3 months of treatment, while 50% (PI vs INI, p: 0.039) in the PI group and only 38.7% (NNRTI vs INI, p = 0.009) in the NNRTI group. Superiority of the INI group continues in the 6th and 12th months of treatment. While all patients had virological response in INI group, it reached to over 80% at 6th month and over 90% at 12th month in both of the other treatment groups (p>0.05). The patients in PI and NNRTI treatment groups had similar virological response rates and no significant difference was found at any time of treatment. Total virological response in all patients receiving any treatment were found to be 85.7% at 6 months and 93.7% at 12 months of treatment. Virological responses in three treatment groups are presented in Table - 4, Table - 5 and Graph - 1.

4. Discussion

In this retrospective study, three different ART groups were compared immunologically and virologically. The efficacy of all three drug regimens in terms of immunological response at the end of 12 months of treatment was found to be similar. INI group had significant advantage over NNRTI group in the first 3 months. Virological response rates were also similar in all groups at 6th month and 12th month of therapy, but INI group was superior than other groups in the first 3 months.

Currently, some of the drugs in our study are considered to be alternative in recent guidelines with the introduction of single tablet combinations and potent new agents [9]. These alternative agents can still be used in developing countries such as Turkey, where there is limited access to all drugs. This data suggests that treatment success still can be achieved by ensuring treatment compliance and management of side effects.

When our study was evaluated in terms of immunological response; it has been determined that PI group was the most successful and NNRTI group was the most unsuccessful group. But, there was no significant difference among all groups at the end of 12 months. In a study of 1397 naive patients, there was no significant difference immunologically and clinically, between protease inhibitors and non-nucleoside reverse transcriptase inhibitors after five years of follow-up [10]. In another study, the factors that rapidly increase the number of CD4 + T cells above 500 cells / [mm.sup.3] were found as; younger age, higher baseline CD4+ T cell counts, and initiation of a PI-based regimen instead of NNRTI-based regimen [11]. In our study PI group was also found to have highest immunological response rate. This may be due to the baseline lower CD4 + T cell counts in PI-based regimen group compared to other groups. PI agents are potent, but due to pill burden and availability of drugs with less side effects, some of them are recommended as alternative drugs [9].

INI group was relatively new in our country during the study period and according to the HIV guidelines, treatment was started regardless of the number of CD4+ T cell counts in the light of two major studies [12, 13]. This may be the reason of lower patient number and the higher baseline median CD4+ T cell counts. Although, highest baseline median CD4 + T cell counts were in the INI group, the highest immunological response rate was found in this group in the first three months. Difference was statistically significant versus NNRTI group between 0 - 3 months (p: 0.046).

In our study, INI group was found to be associated with faster virological response, however at the end of the 6 and 12 months there was no significant difference among all groups. In a study comparing raltegravir with efavirenz combined with tenofovir and lamivudine, virological suppression was significantly faster in raltegravir group, but no difference was observed in antiviral efficacy in the raltegravir and efavirenz arms at weeks 24 and 48, in concordance with our results [14]. INI group was also found to be associated with rapid virological response in another study [15].

We did not find any any difference in virological response rates between NNRTI and PI groups at the end of 12 months. In a major clinical trial, 1875 naive cases were treated with ritonavir-boosted atazanavir or efavirenz either with abacavir-lamivudine or tenofovir-emtricitabine [16]. At the end of 96 weeks, there was no significant difference in virological response between the groups, irrespective of the NRTI group. Virological success was achieved in 80% of cases.

In our study, there are three options as backbone; zidovudine/lamivudine, tenofovir/emtricitabine and abacavir/lamivudine. But the efficiency of these drugs is not compared separately. This can be described as a limitation, but in the study above-mentioned, it was shown that virological success was achieved in 80% of patients irrespective of used backbone NRTI [16]. Approximately 90% of the backbone regimen in our study was tenofovir/emtricitabine, thus it was considered that NRTI groups would not affect the outcome of treatment. In our study total virological response in all groups was found to be 85.7% at 6 months and 93.7% at 12 months of treatment.

In a study conducted in our country with 1306 naive patients, HIV transmitted drug resistance mutations were investigated and resistance to NRTI, NNRTI and PI was found as 8.1%, 3.3% and 2.3%, respectively [17]. Recent data has shown that INI resistance mutations were not found in naive HIV-1 infected patients in Turkey. But treatment experienced patients had major resistance mutations associated with raltegravir and elvitegravir [18]. This data shows that it is a rational approach to select an agent with high genetic resistance barrier such as PI or dolutegravir to obtain treatment success and prevent resistance development in patients with low CD4+ T cell counts until resistance test results are obtained or resistance testing is not available. In our study, lowest baseline median CD4+ T cell counts were in the PI group. This may be due the abovementioned reason.

Our study has some limitations: It was conducted with a small number of patients in a single center with retrospective design. Baseline CD4+ T cell count and viral load levels were not similar. The agents were evaluated as a group and drug resistance is not specified, impact of NRTI class was also not evaluated. But we have agreed that alternative agents can still be used in developing countries where single tablet regimens are not widely available. For this reason, selection of the appropriate drug for each patient is extremely important and drug compliance must be ensured.

As the number of HIV positive patients in Turkey is increasing, but there are only a very few studies exist showing the effectiveness of ART in Turkish patients, we believe our findings might be useful for further treatment strategies and researches that will be conducted in our country.

The authors report no conflicts of interest.

5. References

[1.] http://www.unaids.org/sites/default/files/media_asset/AIDS_by_the_numbers_2015_en.pdf (Accessed on April 30, 2016)

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[5.] https://aidsinfo.nih.gov/guidelines. (Accessed on March 01, 2018)

[6.] Selcuk Kaya, Gurdal Yilmaz, Sukru Erensoy, Mustafa Arslan, Iftihar Koksal. HIV/AIDS'li 36 Olgunun Retrospektif Analizi. Klimik Dergisi 2011; 24(1): 11-6.

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[12.] Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fatkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD.; INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015 Aug 27;373(9):795-807.

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[14.] Markowitz M (1), Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H; Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr.2007;46:125-133.

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Ufuk Sonmez (1), Sabri Atalay (2), Hazal Albayrak (2), Melda Turken (2), Sukran Kose (2)

(1) Izmir Bozyaka Education and Research Hospital, Infectious Diseases and Clinical Microbiology

(2) Izmir Tepecik Education and Research Hospital, Infectious Diseases and Clinical Microbiology

Corresponding author: Assoc. Prof. Dr. Sabri ATALAY (Izmir Tepecik Education and Research Hospital, Infectious Diseases and Clinical Microbiology, Turkey. E-mail address: drsatalay@gmail.com, telephone: +905308490955
Table-1: Baseline characteristics of the patients

Treatment group  Patient number  Mean age  Median CD4+ T cell
                                 (years)   count
                                           (cells/[mm.sup.3])

PI               18              41        262
NNRTI            31              42        418
INI              14              46        578
Total            63              43        370

Treatment group  Median HIV RNA
                 levels (copies/mL)


PI               164.133
NNRTI            100.000
INI              231.000
Total            100.000

Table -2: Immunological response rates (>50 cells/[mm.sup.3] increase
in CD4+ T cell counts on consecutive measurements)

                INI                      PI
Time            n:14       %             n:18         %

0 - 1.months    10         71.4%         14           77.8%
0 - 3. months   13         92.9%         14           77.8%
1 - 3. months    9         64.3%         10           55.6%
3 - 6. months    6         42.9%          7           38.9%
6 - 12. months   7         50.0%          7           38.9%
0 - 12. months  12         85.7%         17           94.4%

                NNRTI         Total
Time            n:31   %      n:63   %

0 - 1.months    14     45.2%  38     60.3%
0 - 3. months   20     64.5%  47     74.6%
1 - 3. months   17     54.8%  36     57.1%
3 - 6. months   19     61.3%  32     50.8%
6 - 12. months  16     51.6%  30     47.6%
0 - 12. months  23     74.2%  52     82.5%

Table - 3: Comparison of treatment groups in terms of immunological
response

p values

Time            INI vs PI  INI vs NNRTI  PI vs NNRTI

0 - 1. months   0.496      0.189         0.054
0 - 3. months   0.255      0.046         0.516
1 - 3. months   0.892      0.789         0.961
3 - 6. months   0.821      0.408         0.223
6 - 12. months  0.788      0.920         0.573
0 - 12. months  0.404      0.327         0.079

Table - 4: Virological response (<200 copies/mL)

           INI           PI           NNRTI         Total
Time       n:14  %       n:18  %      n:31   %      n:63   %

1. month    6     42.9%   1     5.6%   2      6.5%   9     14.3%
3. month   12     85.7%   9    50.0%  12     38.7%  33     52.4%
6. month   14    100.0%  15    83.3%  25     80.6%  54     85.7%
12. month  14    100.0%  17    94.4%  28     90.3%  59     93.7%

Table - 5: Comparison of the regimens in terms of virological response

p values

Time       INI vs PI  INI vs NNRTI  PI vs NNRTI

1. month   0.017      0.007         0.698
3. month   0.039      0.009         0.638
6. month   0.165      0.090         0.567
12. month  (a)        (a)           0.530

(a) No statistics are computed
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Title Annotation:Arastirma makalesi-research article
Author:Sonmez, Ufuk; Atalay, Sabri; Albayrak, Hazal; Turken, Melda; Kose, Sukran
Publication:Mediterranean Journal of Infection, Microbes and Antimicrobials
Article Type:Report
Date:Jan 1, 2018
Words:3670
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