Effectiveness and safety of combination antiretroviral therapy schemes for acute HIV infection

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Introduction

Statistical data on the spread of HIV infection in the Russian Federation show a worsening of the epidemic situation, with 0.8% of the country's population affected [1]. At the same time, it is known that one of the main sources of HIV transmission (about half of all cases) is acute infection caused by the human immunodeficiency virus [2]. In this regard, early initiation of antiretroviral therapy (ART) plays an important role in preventing the spread of the disease [3], reducing the size of the latent HIV reservoir [4; 5], slowing the clinical progression of the disease, and contributing to the prevention of AIDS. Foreign scientists have proven that the early (acute) stage of infection, due to the high viral load determined before the appearance of antibodies to HIV, is a priority for prescribing therapy [6] to prevent transmission of the virus during the highly infectious period. The immunological effect that occurs at this time is associated with a decrease or normalization of systemic inflammation markers [7].

According to the Russian classification of HIV infection, the acute stage of the disease may be asymptomatic, or it may develop with or without secondary manifestations⁵. The diagnosis of the disease is carried out comprehensively: based on the presence of clinical symptoms, epidemiological history data, and laboratory test results, including a positive ELISA and immunoblot (IB) reaction with the detection of antibodies to HIV and its antigens [8–11].

In 2014–2016, a multicenter randomized study was conducted at the Novosibirsk Regional Clinical Hospital No. 1 to investigate the efficacy and safety of elsulfavirin in combination therapy for acute HIV infection [12].

The study involved 57 treatment-naive patients who were prescribed ART within 7 days before receiving the final result of the IB reaction. All patients were divided into three groups. Patients in the first group received first-line therapy: lamivudine + tenofovir + efavirenz; patients in the second group received an alternative first-line regimen: lamivudine + tenofovir + lopinavir/ritonavir; and patients in the third group received lamivudine + tenofovir + elsulfavir. The effectiveness of treatment was monitored by measuring the reduction in viral load after 4weeks of antiretroviral therapy. The results were most effective in the third group of patients receiving ART with elsulfavirine, where there was high adherence to ART, no adverse events, and a reduction in viral load to undetectable levels. Based on the data obtained, the following conclusion was made: early initiation of combination therapy in patients in the acute stage of HIV infection rapidly reduces high viral load.

The literature contains examples of a number of studies that describe ART regimens including phosphazide, which cause the least change in laboratory parameters indicating the occurrence of adverse reactions [13–14].

The aim of the study is to conduct a comparative study of the efficacy and safety of treatment with nucleoside reverse transcriptase inhibitors (NRTIs) – phosphazide and tenofovir– in patients with acute HIV infection.

Materials and Methods

The work was carried out at the Perm Regional Center for the Prevention and Control of AIDS and Infectious Diseases, a state-funded healthcare institution in the Perm Territory, between 2017 and 2019. In accordance with Russian clinical protocols for the dispensary observation and treatment of HIV-infected patients (2019), first-line regimens were used for ART. Phosphazide and tenofovir were used in combination with lamivudine and efavirenz in standard doses. Thus, when prescribing therapy in accordance with the recommendations, less toxic treatment regimens with fixed doses of drugs were used [17]. It should be noted that phosphazide is a domestic single-component drug with a minimum of side effects and undesirable effects [18–20].

Our study involved 28 patients with acute HIV infection prior to confirmation of diagnosis by IB, who were divided into two groups: the first (observation group) – 15 people (8 men and 7 women aged 25–56) received ART with phosphazide, the second (comparison group) – 13 people (7 men and 6 women aged 18–58) – with tenofovir. Depending on clinical manifestations in the group of patients receiving phosphazide, two patients were diagnosed with stage 2a, three with stage 2b, and ten with stage 2c HIV infection. In the group of individuals who used tenofovir, 2 patients were diagnosed with stage 2a, 3 with stage 2b, and 8 with stage 2c of the disease. Phosphazide was prescribed at a dose of 400 mg twice daily, tenofovir, lamivudine, and efavirenz were prescribed at standard therapeutic doses.

When diagnosing HIV infection in the acute stage, the following diagnostic methods were used:

• IB – NEW LAVE Blot-1 ser. 9G1361, 9H0363;
• ELISA for detecting antibodies to HIV-1 type Jenskren Ultra HIV Ag/At;
• Determination of HIV-1 DNA concentration by polymerase chain reaction (PCR) using Amplisense HIV-96 DNA test systems from Interlabservice;
• determination of HIV-1 RNA levels in blood plasma using PCR with Amplisense RNK HIV Monitor FRT test systems from Interlabservice with a sensitivity threshold of less than 250 copies/ml;
• Cellular immunity parameters (number of CD+ lymphocytes) were determined using monoclonal antibodies from BD Tritest (USA) by flow cytometry on a BD FACS Calibur cytometer.

The data obtained were compared with the standard set by the Federal Research Center for AIDS Prevention and Treatment (V.V. Pokrovsky, 2001), according to which the CD4 lymphocyte count is 800–1400 cells/μl (28–60%).

Treatment monitoring was based on CD4+ lymphocyte count tests prior to ART initiation and at 12, 24, 36, and 48 weeks of therapy; HIV DNA and/or RNA viral load indicators, with HIV RNA determined at baseline and then at 2–4–12–24–36–48 weeks of treatment.

The research results were processed using the built-in analysis package of the Excel® MSO spreadsheet processor (© Microsoft, 2013). The average group values of the characteristics were presented as medians and quartiles (Me, Q₁–Q₃). The Mann–Whitney U test was used to assess the statistical significance of differences. Differences were considered significant at a significance level of p < 0.05.

Results and Discussion

Virological efficacy. The level of HIV RNA viral load (VL) before the start of therapy in group 1 ranged from 109,660 to more than 10,000,000 (6.5 log10), and in group 2 from 56,436 to more than 10,000,000 (6.3 log10) copies/ml. To assess the dynamics of RNA viral load, the reduction rates (%) were calculated using the formula:

$P_{pr}=\frac{Current week\text{'}s VL level}{Previous week\text{'}s VL level}\times 100-100$.

In patients of the observation group, the rate of viral load reduction was higher than in HIV-infected patients in the comparison group at week 2 of ART (P_pr=–31.7% versus –21.7%) and the fourth week (Ppr = –29.4% versus –28.0%), respectively. At week 12, the rate of decline was slightly higher in the comparison group (–27.5% versus –18.6% inthe observation group). The further decline in VL levels was virtually identical in both groups (Fig. 1).

 

Fig. 1. HIV RNA viral load indicators in the dynamics of different treatment periods

 

Immunological efficacy. The initial number (Me) of CD4+ lymphocytes in the observation group was 485 cells/μl, and in the comparison group it was 490.0 (U = 66.0; p = 0.547). Against the background of ART, starting from week 24, the level of CD4+ cells became higher in patients in the first group (table).

 

The number (Me) of CD4+ lymphocytes (abs./%) at different periods of treatment

Group	Before ART	12 weeks	24 weeks	36 weeks	48 weeks
1	485,0/16,0	590,0/31,0	720,0/31,0*	785,0/30,5*	785,0/32,0*
2	490,0/20,0	620,0/28,5	600,0/34,0	740,0/34,0	740,0/38,5

Note: * – significant differences between patient groups (p < 0.05).

 

A comparison of the dynamics of the increase in cellular immunity indicators showed that it corresponded to a decrease in HIV RNA viral load levels in both groups.

The results obtained in terms of a sustained reduction and maintenance of viral load levels below the detection threshold ( < 250 copies/ml) against a background of stable CD4+ lymphocyte growth and the absence of clinical signs of HIV/AIDS progression indicate the effectiveness of both ART regimens for the treatment of patients in the acute stage of infection.

Safety and tolerance. Throughout the study period, no side effects of therapy were reported in patients in either group.

In the group receiving phosphazide, only mild anemia was noted, which was not an indication for discontinuation of therapy. Thus, at week 12 of treatment, two patients had a decrease in hemoglobin to 118 g/L, and at week 24, one patient had a decrease to 119g/L, which was insignificant, since during further therapy, hemoglobin parameters returned to normal levels (Fig. 2, a).

 

Fig. 2. Median values in treatment dynamics: a – hemoglobin (g/L); b – red blood cells (· 10¹²/L)

 

The adverse events that occurred were considered mild and did not lead to discontinuation of treatment.

Against the background of ART, the group of patients treated with phosphazide showed a decrease in red blood cell count starting from week 12 (in 7 patients) to (3.3–3.9) × 10¹²/L (mean = 3.8), and by week 24 (in 6 patients) to (3.1–3.6) × 10¹²/L (mean = 3.5), at 36 weeks (in 3 patients) to (3.2–3.5) × 10¹²/L (Me = 3.7), at 48 weeks – in 3 patients to (3.3–3.5) × 10¹²/L (Me = 3.5) (Fig. 2, b).

No side effects were reported in the group using tenofovir during 48 weeks of ART.

Clinical Effectiveness

The treatment regimens used demonstrated the same clinical efficacy of ART drugs. None of the patients experienced progression of HIV infection. By week 48 of therapy, the acute stage of the disease had been replaced by the third latent stage of the disease.

Conclusions

1. Early diagnosis and treatment of the acute stage of HIV infection is of significant epidemiological importance in preventing the spread of the disease by rapidly reducing high levels of viremia.
2. The results of a comparative study conducted over 48 weeks showed high virologic and immunologic efficacy of phosphazide in combination of antiretroviral therapy with lamivudine and efavirenz, comparable to that of tenofovir. In patients in both groups, after 48 weeks of treatment, the HIV RNA viral load was less than 250 copies/ml. With a higher baseline VL in the phosphazide group (from 109,660 to over 10,000,000 copies/mL), the rate of HIV RNA reduction by week 4 was higher than in the comparison group. The average increase in CD4+ lymphocyte count over12–48 weeks in the first group was +75.0cells/μL, compared with 62.5 cells/μL in the second group (p=0.049).
3. Both treatment regimens were safe. The development of mild anemia in individual patients was not an indication for discontinuation of the prescribed drugs.
4. The absence of HIV infection progression by week 48 of ART in all patients indicates the clinical efficacy of the treatment.

Thus, the study makes it possible to recommend the use of phosphazide in combination with lamivudine and efavirenz as first-line therapy for HIV-infected patients.

Further optimization of antiretroviral therapy for HIV infection based on phosphazide involves the creation of new dosage forms in the form of fixed-dose combinations administered once daily for the treatment of HIV/AIDS.

Funding. The study had no external funding.

Conflict of interest. The authors declare no conflict of interest.

Author contributions:

Ivanova E.S. – writing the article.

Sheludko V.S. – statistical processing of the material.

Vorobyova N.N. – final editing and approval of the version for publication.

Okishev M.A. – compilation of graphs and tables.

Nikolenko V.V. – development of the concept and design of the study.

Sumlivaya O.N. – analysis of information, interpretation of research results.

Semerikov V.V. – analysis of literature data.

Teterin V.Yu. – preparation of the article summary and translation into English.

All authors approved the final version of the article.

Study limitations. The study complies with the standards of the Declaration of Helsinki and has been approved by the Ethics Committee of the Ye.A. Vagner Perm State Medical University, protocol No. 5 dated June 26, 2025. Before the start of the study, all patients confirmed their participation by signing a written informed consent form.

About the authors

E. S. Ivanova

Perm Regional Center for Prevention and Control of AIDS and Infectious Diseases

Email: okishev_mikhail@mail.ru
ORCID iD: 0000-0001-8756-9854

PhD (Medicine), Head of the Department of Medical Care

Russian Federation, Perm

V. S. Sheludko

Ye.A. Vagner Perm State Medical University

Email: okishev_mikhail@mail.ru
ORCID iD: 0000-0002-7080-9142

PhD (Medicine), Specialist of the Department of Research Activities

Russian Federation, Perm

N. N. Vorobjeva

Ye.A. Vagner Perm State Medical University

Email: okishev_mikhail@mail.ru
ORCID iD: 0000-0001-5384-5910

DSc (Medicine), Professor, Head of the Department of Infectious Diseases

Russian Federation, Perm

M. A. Okishev

Ye.A. Vagner Perm State Medical University

Author for correspondence.
Email: okishev_mikhail@mail.ru
ORCID iD: 0000-0002-9461-7145

PhD (Medicine), Associate Professor of the Department of Infectious Diseases

Russian Federation, Perm

V. V. Nikolenko

Ye.A. Vagner Perm State Medical University

Email: okishev_mikhail@mail.ru

DSc (Medicine), Professor of the Department of Infectious Diseases

Russian Federation, Perm

O. N. Sumlivaya

Ye.A. Vagner Perm State Medical University

Email: okishev_mikhail@mail.ru
ORCID iD: 0000-0003-0498-4900

DSc (Medicine), Professor of the Department of Infectious Diseases

Russian Federation, Perm

V. V. Semerikov

Perm Regional Clinical Infectious Diseases Hospital

Email: okishev_mikhail@mail.ru
ORCID iD: 0000-0002-5346-8104

DSc (Medicine), Head of the Department of Epidemiology

Russian Federation, Perm

V. Yu. Teterin

Ye.A. Vagner Perm State Medical University

Email: okishev_mikhail@mail.ru
ORCID iD: 0009-0007-2162-8111

PhD (Medicine), Associate Professor of the Department of Infectious Diseases

Russian Federation, Perm

References

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