Justification of the integrated approach to management of HIV-infected patients with comorbid pathology of the digestive system

Abstract

Introduction. Among the main strategic and operational goals of the State Strategy for Combating HIV / AIDS, Tuberculosis and Viral Hepatitis by 2030 in Ukraine is to ensure comprehensive access to HIV treatment, increase the effectiveness of monitoring and support of treatment of both opportunistic infections and other somatic conditions in HIV-infected patients. The key role of family physicians in the detection and treatment of many chronic gastrointestinal complications in HIV-infected patients is recognized.

Purpose of the study. To increase the efficiency of early diagnosis and tactics of integrated management of HIV-infected patients of family physicians (FP) by clarifying the peculiarities of HIV infection in the presence of comorbid pathology of the digestive system (DS) and creating an algorithm for providing medical care to these patients.

Material and methods. The research was conducted on the basis of five regional HIV / AIDS centers of Ukraine during 2017-2019. Randomly selected 342 adult HIV-infected patients were divided into two groups - with concomitant lesions and without concomitant gastrointestinal lesions. The following research methods were used: general clinical and laboratory biochemical, molecular genetic, immunological, enzyme-linked immunosorbent, instrumental (FGDS, chest radiography, abdominal ultrasound, computed tomography of the chest and / or abdominal cavity), analysis of primary medical records, consultations related specialists according to the indications, questionnaires, statistical methods.

Results and discussion. It was found that the incidence of gastrointestinal pathology in patients with II, III and IV clinical stages of HIV infection was significantly higher than in patients with stage I, significantly more often associated with tuberculosis, candidiasis, kidney disease and HIV encephalopathy and was combined. Manifestations of asthenovegetative and dyspeptic syndromes, weight loss, anemia and leukopenia, increased activity of liver enzymes, low levels of CD4 + lymphocytes and preservation of viral load on antiretroviral therapy were significantly more common in HIV-infected patients with gastrointestinal pathology. In the presence of pathology of the digestive system, replacements, breaks and side effects of antiretroviral therapy were significantly more frequent. The results of physicians survey analysis showed the role of family physicians in the current examination and management of HIV-infected people with comorbid pathology of the digestive system.

Conclusions. To detect diseases of the organs of the DS in HIV-infected people, it is necessary to conduct a comprehensive laboratory and instrumental examination, taking into account the possibility of combined pathology. The proposed algorithm of integrated management of HIV-infected patients with comorbid pathology of DS by FPs, taking into account the most informative clinical and laboratory criteria, allows to increase the effectiveness of early diagnosis and tactics of integrated management of HIV-infected by FPs.

Background

Among the main strategic and operational goals of the State Strategy for Combating HIV / AIDS, Tuberculosis and Viral Hepatitis by 2030 in Ukraine are to ensure comprehensive access to HIV treatment, increase the effectiveness of monitoring and support of the reatment of both opportunistic infections and other somatic conditions in HIV-infected patients [1]. The epidemic in Ukraine is estimated as the second-largest HIV epidemic in Eastern Europe and Central Asia. At the same time, in 2019, Ukraine was one of the few countries in the region that made progress in ensuring the effectiveness of ART and came significantly closer to the goal of “90% of PLHIV who know their status receive ART” [2].

The importance of expanding the provision and adherence to antiretroviral therapy (ART) with the inclusion of services aimed at treating co-infections and comorbidities in the range of services for the prevention, treatment, care, and support of HIV-infected patients is emphasized by the Strategy "On the Fast-Track to end AIDS" of the United Nations Program on HIV / AIDS (UNAIDS). The need to integrate medical care for HIV-infected patients with comorbid somatic diseases is emphasized. It is recognized that the best outcome for both the patient and the global goal of combating the HIV epidemic can be provided by patient-centered clinical monitoring of lifelong ART support [3-6]. A modern approach to prescribing ART to all people living with HIV with any number of CD4 cells, commonly known as "Test and Start", allows patients to receive ART immediately after diagnosis of HIV infection. This significantly improves treatment outcomes. Studies have shown a 53% reduction in HIV morbidity and mortality as a result of the early initiation of ART [7]. In 2019, Ukraine approved a new Clinical Protocol for the use of antiretroviral drugs for the treatment and prevention of HIV infection [8].

It should be noted that in Ukraine the diseases of the digestive system take 3rd place (9.8%) in the general structure of prevalence by classes of diseases among the whole population and 7th place (4.1%) in the structure of morbidity. Given that all age groups of our country suffer from these diseases, and most patients are in the working-age group, the medical and social relevance of digestive diseases increases. As well as a consideration of its impact on organizational strategies of the health care system [9,10]. Taking into account the frequency of comorbidity of HIV infection with diseases of the digestive system, an urgent issue is to study the possibilities of their early diagnosis to prevent the risk of complications, interruptions, or refusals to receive continuous antiretroviral therapy (ART) due to digestive diseases pathology. This is especially important given the fact that every third death of HIV-infected people in Ukraine was not related to the course of HIV infection, but was due to concomitant pathology. According to the analysis of the causes of death of HIV-infected people in Ukraine in 2019, in every second case (52%) they were directly related to HIV infection, in particular, 2977 people died of AIDS (half of them - from HIV co-infection / TB). It is worth noting that only 57% among this category of people received ART [2].

It is important to note that the expansion of the network of institutions and organizations that provide medical care to PLHIV has increased in recent years, mainly due to the opening of new sites based on outpatient health care facilities. HIV care is provided by 439 ART sites, the number of which has increased by a third since 2017. All this has a positive effect on the early diagnosis of HIV infection, the timely start of ART, the formation of adherence to treatment, and proper support [2].

It is emphasized that the active involvement of primary care workers in the treatment, spot testing, and use of streamlined hepatitis B and C management algorithms in patients at risk helps to improve the effectiveness of care for both the patient and the community in which they live [11]. International experience demonstrates the crucial role of family physicians in the detection and treatment of many chronic gastrointestinal complications in HIV-infected patients. Which is provided by monitoring the use of medications by patients that are often used in such pathologies and interact with antiretroviral drugs [12]. The importance of decentralization of HIV services to the level of primary care facilities on the basis of family medicine increases aimed to improve permanent access to continuous ART. General practitioners of family medicine are responsible for providing continuous, coordinated, and comprehensive integrated care for all categories of patients. They manage the numerous needs of patients in health care, regardless of the nosology of the disease, which is in line with international strategies to combat the HIV epidemic [13-15]. Taking into account that the primary care community is recognized as the cornerstone of ending the HIV epidemic, the emphasis is on improving the participation of primary care physicians in implementing effective HIV prevention and treatment technologies. This emphasis is also on developing standardized work processes for HIV risk assessment and prescribing therapy. For example, prevention of preexposure (PrEP), which reduces the risk of HIV infection by 97% in patients at high risk of HIV infection. PrEP was identified as part of the national strategy to combat the HIV epidemic in the United States until 2030, and in July 2019 PrEP received a recommendation from the US Preventive Services Task Force (NEJM JW Infect Dis Jun 2019 and JAMA 2019); 321: 2203) [16].

Thus, the problem of studying the features, ways to improve and form a modern integrated, patient-oriented approach to the management of HIV-infected patients with comorbid somatic pathology of the digestive system by family physicians becomes especially relevant.

Aim

To increase the effectiveness of early diagnosis and tactics of integrated management of HIV-infected patients by general practice family physicians by elucidating the peculiarities of the course of HIV infection with comorbid pathology of the digestive system and creating an algorithm for providing medical care to these patients.

Sample and methods

The research was conducted on the clinical basis of the Department of Infectious Diseases and the Educational and Scientific Center - Ukrainian Training Center for Family Medicine of the National Medical University named after O.O. Bogomolets, namely: Kyiv City Center for AIDS Prevention and Control of Kyiv City Clinical Hospital №5 and 4 regional HIV / AIDS centers of Odesa, Kherson, Mykolaiv and Dnipropetrovsk regions during 2017-2019. A randomized sample was used to select 342 patients who were registered with the HIV / AIDS Centers and had a confirmed diagnosis of HIV infection. The diagnosis of HIV infection was established and confirmed on the basis of existing recommendations and protocols [17].

The division of patients into groups was carried out depending on the presence or absence of pathology of the digestive system on the background of HIV infection. The main group (MG) consisted of 252 patients with pathology of the digestive system (140 men, 122 women), the average age was 42.7 ± 0.6 years. The control group (CG) consisted of 90 patients without signs of gastrointestinal disease (47 men and 43 women) with an average age of 38.7 ± 1.1 years. Patients with II, III, and, especially, with IV clinical stage of HIV infection predominated in MG, in CG - with I stage, p <0.05. The groups were comparable in age and sex, in both groups the men were slightly prevalent.

Examinations of patients were performed in compliance with the requirements of existing bioethical norms and scientific standards. The results of the following research methods were used: general clinical and laboratory biochemical, molecular-genetic, immunological, enzyme-linked immunosorbent, instrumental (fibrogastroduodenoscopy, chest X-ray, abdominal ultrasound, computed tomography of the chest and/or abdominal cavity), analysis of primary medical records consultations of related specialists on indications, questionnaires, statistical methods. Statistical processing of the study results was performed using software in the package EZR 1.41 (Saitama Medical Center, Jichi Medical University, Japan), which is an analytical tool with various parameters, including non-parametric statistical methods and graphical visualization of results.

Results and discussion

Comparison of MG and CG was performed on the nature of concomitant pathology, frequency of clinical manifestations and changes in hematological, biochemical, immunological and virological parameters. Tuberculosis (p <0.01), candidiasis (p <0.05), kidney disease (p <0.001) and HIV encephalopathy (p <0.01) were significantly more common in patients of MG than of CG. Using the criterion χ2, the relationship between the detection of pathology of the digestive system and the presence of concomitant disease as a factor that increases the likelihood of this pathology was calculated. The significance of the relationship was considered to be proven in cases where the confidence interval was outside the absence of an effect, which is equal to 1 (Table 1).

Table 1. The odds ratio of detecting pathology of the digestive system in the presence of comorbidities

Factor	Odds ratio	Standard odds error	Confidence interval (odds ratio) 95%
Candidiasis	2.055	0.262	1.229-3.436
Tuberculosis	1.961	0.302	1.086 - 3.541
HIV encephalopathy	4.471	0.447	1.860-10.747
Kidney disease	3.696	0.489	1.418-9.631

According to the data obtained, the presence of candidiasis and tuberculosis in HIV-infected patients doubled the chance of detecting diseases of the digestive system, and the presence of HIV encephalopathy and kidney disease - 4.5 and 3.7 times, respectively.

Among the digestive system lesions in HIV-infected patients, hepatitis of various etiologies was the most often detected - in 220 (87.3%) patients of MG, among them chronic hepatitis C (CHC) - 128 (50.8%), chronic hepatitis B (CHB) - 9 (3.6%), CHC + CHB - 9 (3.6%), chronic hepatitis of unknown etiology - 74 (29.4%) patients. The second most common lesion of digestive system was chronic pancreatitis, which was found in 116 (46.0%) patients of MG. Lesions of the gastro-duodenal zone in 88 (34.9%) patients of MG were found both in isolation and in various combinations. Among them gastroduodenitis was the most frequent and was diagnosed in 47 (53.4%) persons, gastritis - in 14 (15.9%) persons, peptic ulcer disease - in 4 (4.5%) patients. In the remaining 23 (26.1%) of the examined patients, the pathology of the gastro-duodenal zone was combined. Chronic cholecystitis was found in 74 (29.4%) patients of MG, of which 66 (89.2%) were non-calculous and 8 (10.8%) were calculous. Candidal esophagitis was observed in 13 (5.2%) of the examined patients and was observed only in HIV-infected patients with clinical stage IV. Colitis was observed in 8 (3.2%) patients of MG. It is noteworthy that in the vast majority of examined patients - 150 (59.5%) persons a pathology of the digestive system was combined, i.e. damage to two or more organs revealed at the same time.

The frequency of detection of digestive system pathology increased with the progression of HIV infection: in patients with II, III, and clinical stages it was observed significantly more often than in patients with clinical stage I - in 43 (45.7%) patients with clinical stage I, p> 0.05, in 30 (83.3%) with the II clinical stage (p <0.05), in 69 (90.8%) with the III (p <0.05) and in 115 (81.0%) with a clinical-stage, p <0,05. Features of the clinical course of HIV infection in patients with comorbid pathology of the digestive system and without it are presented in Table 2.

Table 2. Clinical symptoms in HIV-infected patients of MG and CG

Symptoms	MG		CG		р
		n	%	n	%
Weakness	123	48.8	17	18.9	<0.001
Weight loss	66	26.2	9	10.0	<0.01
Temperature rise	63	25.0	8	8.9	<0.01
Cognitive disorders and neurological symptoms	54	29.0	6	8.9	<0.01
Decreased appetite	67	26.6	7	7.8	<0.001
Nausea	45	17.9	2	2.2	<0.001
Pain in the epigastrium	49	19.4	7	7.8	<0.05
Itchy skin	24	9.5	1	1.1	<0.01

Other manifestations of astheno-vegetative syndrome (headache, pallor), dyspeptic syndrome (vomiting, heartburn, diarrhea, bloating), as well as cough and rash, etc. were observed in patients of MG and CG with the same frequency, p> 0.05.

In the analysis of hematological parameters, it was found that anemia was observed in 94 (48.5%) patients of MG, and 11 (34.5%) patients of CG, p <0.05, leukopenia was detected in 59 of 193 patients of MG, which is 30,6% and in 4 of 28 patients of CG, which is 14.3%, p <0.05, and leukocytosis, on the contrary, was significantly more common in CG - in 6 (21.4%), compared with MG - in 8 (4.2%), p <0.05. There was no statistical difference in the frequency of erythrocyte sedimentation rate in 95 patients of MG and CG, p> 0.05. When comparing the mean values ​​of the main hematological parameters - the level of hemoglobin, erythrocytes, and erythrocyte sedimentation rate – there was found no statistically significant difference, p> 0.05, and the average level of leukocytes in MG was statistically significantly higher than in CG, p <0.05.

In MG, biochemical analysis of blood was performed in 117 patients, which is 46.4% of the group size, in CG - 42 patients (46.7% of the group), p> 0.05. There was no statistical difference in the frequency of reduction of total protein and hypoalbuminemia, and p>0.05. Increased levels of alanine transaminase (ALT) and gamma-glutamine transpeptidase (GGT), as well as urea and creatinine, p <0.05 were significantly more common in MG patients. When comparing the average values ​​of total protein, albumin, urea, and creatinine between MG and CG, no statistically significant difference was found, p> 0.05, but the average levels of ALT, AST, and GGT were statistically higher in MG, p <0.05.

Studies of the immunological status of HIV-infected patients of MG and CG showed that normal CD4 lymphocyte quantity indicators were observed in 75 (32.1%) versus 37 (52.1%) in CG, p<0.05, a moderate decrease in 96 (41.0%) of the examined patients of MG and in 25 (35.2%) in CG, p> 0.05, and the level of CD4 lymphocytes, which corresponds to the state of advanced immunodeficiency, was found in MG in 63 (26.9%) versus 9 (12.7%), p<0.01. That is, patients of MG were statistically significantly more likely to have advanced immunodeficiency and less likely to have normal CD4 quantity indicators.

The average CD4 quantity indicator in MG was 418.96 ± 18.26 cells / μl (Me = 394, Mo = 190) and is statistically significantly lower than in CG - 548.7 ± 40.15 cells / μl (Me = 525, 5, Mo = 808), p <0.01.

All the patients included in the study received antiretroviral therapy, and one of the efficiency criteria was the virological response. According to the results of the virological examination, it was found that the vast majority of HIV-infected patients (174 (69.0%) in MG and 79 (87.8%) in CG) affected by ART achieved a virological response with a viral load of fewer than 40 copies/ml, p<0.05. However, there were 78 (31.0%) patients in MG, who had the viral load higher than the level, which is not determined, which is statistically significantly higher than in CG - 11 (12.2%), p<0.05.

The untreated comorbid diseases of the digestive tract in HIV infection may have been a factor influencing the effectiveness of ART. ART substitutions and breaks, as well as the frequency of side effects, in the MG, were significantly more frequent than in the CG, p<0,05. Among the side effects that required correction of therapy, the most common were the lack of immune response, hematotoxic effects, manifested by the development of anemia, leukopenia, thrombocytopenia or pancytopenia, lipodystrophy, a severe dyspeptic syndrome in the form of nausea, vomiting, abdominal pain. Among patients who showed side effects of ART, patients of MG exceeded statistically significantly: hematotoxicity in 18 (81.8%) patients of MG, against 4 (18.2%) patients with CG, p<0.05; lack of immunological response in 20 (90.9%) against 3 (13.6%), p<0.05; lipodystrophy 6 (27.3%) against 1 (4.6%), p<0.05, dyspeptic syndrome in 9 (100%) against 0, p<0.05.

Based on the study of observation materials of HIV-infected patients, the following markers were identified – risk factors for the development of digestive system pathology, namely:

• Manifestations of the astheno-vegetative syndrome (weakness, headache, paleness, fever, weight loss).
• Manifestations of a dyspeptic syndrome (anorexia, abdominal pain).
• Stage of HIV infection (III, IV).
• Concomitant diseases (tuberculosis, candidiasis, kidney disease).
• HIV encephalopathy (cognitive impairment, neurological symptoms).
• Changes in laboratory parameters (anemia, leukopenia, increased ALT).
• Low levels of CD4 + lymphocytes (below 500 cells / μl).
• No virological response to ART (viral load> 40 copies / μl).

It should be noted that this is especially relevant in the context of the current practice of primary care when family doctors are responsible for providing medical care to patients with HIV and their concomitant somatic pathology, directly related to the provision of primary care. Thus, in their current practice, primary care institutions have already successfully carried out seroepidemiological monitoring of the spread of HIV, officially registered cases of HIV infection among citizens, including the structure of HIV transmission routes, as well as new deaths among HIV-infected people, according to the order of the Ministry of Health of Ukraine № 180 from 05.03.2013 [18].

At the same time, the practice of family physicians in ensuring the timely detection, monitoring, and treatment of typical diseases of the digestive system in HIV-infected patients is expanding.

To study the role of general practitioners in family medicine in the examination and management of HIV-infected persons with concomitant pathology of the digestive system, a survey of 492 physicians was conducted, including 200 general practice family physicians and 292 specialists, which included physicians, gastroenterologists, surgeons, anesthesiologists-reanimatologists, phthisiologist, obstetricians-gynecologists, dentists, etc. A group of 53 infectious disease physicians was singled out, as in most cases these specialists are directly involved in the treatment and monitoring of HIV-infected patients.

According to the results of the survey, certain problems of the current medical practice regarding the detection of comorbid digestive system pathology in HIV-infected patients and the tactics of management of such patients by specialists and doctors of general practice were studied out. The role of general practice and family physicians in the current examination and management of HIV-infected people with concomitant pathology of the digestive system was clarified.

Taking into account the large-scale study of routes and trends in the dropout of HIV-positive patients from the healthcare system of Ukraine, eight stages of providing medical care to HIV-infected people in our country, the following structural and functional scheme of HIV-infected patients management in health care facilities at the primary and secondary levels of care was developed. Thus, the role of general practice and family physicians in the examination and management of HIV-infected people with concomitant pathology of the digestive system, which is currently carried out, can be demonstrated (Figure 1):

Figure 1. Scheme of current management of HIV-infected patients with comorbid pathology of the digestive system in the practice of family medicine

There was no feedback on the follow-up of patients who were referred by primary medical care centers to the private counseling room “Dovira” or AIDS center. It was also found that there is no feedback from the AIDS Centers to the primary medical care centers at the stages of registration, examination, appointment, and retention on ART, as well as regular medical supervision, especially at the outpatient stages of medical care. This is important because the loss of people at all stages of HIV counseling and testing and medical care to HIV-infected patients in health care facilities of various profiles may be greater at the outpatient stage of treatment than inpatient treatment.

Thus, it is expedient to introduce mandatory feedback from primary care centers to monitor the admission of patients who came from the family physicians to the private counseling room “Dovira” or AIDS center and to identify those who did not come, to find them, including through social workers when appropriate. As well as the introduction of feedback from primary medical care centers and at the stage of regular medical supervision of HIV-infected patients, especially with the presence of concomitant pathology of the digestive system in AIDS centers.

Based on the analysis and established markers that may indicate the presence of comorbid pathology of the digestive system in HIV-infected patients, it is proposed to make the following changes to the 6-8 stages of the above scheme (Figure 2).

We have developed and proposed for implementation an Algorithm for integrated management of HIV-infected patients with comorbid pathology of the digestive system for the convenience of regular outpatient medical care and to ensure the continuity of coordinated medical care by primary care facilities in integration with secondary care facilities, namely AIDS Prevention and Control Centers, as well as to prevent patients from dropping out of the system of continuous antiretroviral treatment due to pathology.

The algorithm assumes that general practice and family physicians provide comprehensive, extended, coordinated, and patient-oriented medical care. This Algorithm will promote the formation and provision of integrated medical services for the diagnosis and treatment of pathology of the organs of the digestive system to HIV-infected patients also on the basis of primary care facilities (Figure 3).

This algorithm will contribute to the formation and provision of integrated medical services for the diagnosis and treatment of pathology of the organs of the digestive system to HIV-infected patients on the basis of the primary medical center. However, further development of mechanisms for the exchange of information on these issues between health care facilities of primary medical care and AIDS facilities is needed, which will allow assessing measures at all stages of referral of an HIV-positive person to a medical facility. To ensure the continuity of HIV services, it is important to introduce a social order for social support services for identified HIV-positive people before taking them under medical supervision in AIDS facilities and forming a commitment to ART in them.

Conclusion

1. To detect diseases of the digestive system organs in HIV-infected patients, it is necessary to conduct a comprehensive laboratory-instrumental examination taking into account the possibility of combined pathology by implementing an algorithm of joint action of general practitioners and specialists involved in the management of HIV-infected patients with digestive system comorbidities.
2. The proposed algorithm of integrated management of HIV-infected patients with comorbid pathology of digestive system takes into account the most informative clinical and laboratory criteria for early diagnosis of digestive system pathology in HIV-infected patients and subsequent individualization of management of these patients by general practice and family physicians: manifestations of astheno-vegetative and dyspeptic syndromes, stage III-IV of HIV infection, the level of CD4 + lymphocytes below 500 cells / μl, the comorbidities (tuberculosis, candidiasis, kidney disease), signs of HIV encephalopathy, anemia, dysfunction due to the cytolysis syndrome, the lack of virological response to ART. It allows increasing the effectiveness of early diagnosis and tactics of integrated management of HIV-infected patients by general practitioners - family medicine.
3. It is considered very necessary to raise the awareness of general practice family physicians about screening and modern approaches to the management of HIV-infected patients with pathology of the digestive system. The interdisciplinary approaches of working in a team of general practice family physicians and doctors - narrow specialists who are involved in the management of HIV-infected patients with concomitant pathology of the digestive system need to be improved.

Conflict of interests

The study is a fragment of the research work of NMU named after O.O. Bogomolets "Development of a system to combat the spread of socially dangerous hemocontact viral infections at the level of primary health care in the context of public health in Ukraine", funding from the Ministry of Health of Ukraine from the State Budget of Ukraine (state registration No. 0118U001212).