Non-communicable diseases among people living with HIV, Victoria Chitepo provincial hospital: A retrospective cohort study, a secondary data analysis (2013-2023)

doi:10.21203/rs.3.rs-4711585/v1

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Research Article

Non-communicable diseases among people living with HIV, Victoria Chitepo provincial hospital: A retrospective cohort study, a secondary data analysis (2013-2023)

https://doi.org/10.21203/rs.3.rs-4711585/v1

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Background

Non-communicable diseases (NCDs) associated with human immunodeficiency virus (HIV) are emerging as the leading cause of death globally. An in depth analysis of the burden of NCDs in Manicaland province has not been done. We analyzed the NCDs/HIV data at Victoria Chitepo provincial hospital.

Methods

We conducted a retrospective cohort study from October 2013 to September 2023 using secondary data. Five major groups of NCDs were selected which were hypertension (HPT), diabetes mellitus (DM), chronic kidney injury (CKD), cancers and chronic respiratory illness. Kaplan Meier analysis and Cox proportional hazard analysis were performed. Risk ratios and hazard ratios with 95% confidence intervals were generated.

Results

A total of 974 patient records were reviewed with a median age of 43 (Q₁₌35; Q₃ = 51) years. Number of years on antiretroviral therapy (ART) (HR = 5.99, 95% CI: p < 0.001), age (HR = 4.78, 95%CI: p < 0.001) and DM/HIV comorbidity (HR = 4.63, 95% CI: p < 0.001) were hazards to HPT while being on efavirenz based regimen had a lower risk (HR = 0.47, 95% CI: p = 0.01) of developing HPT. Number of years on ART (HR = 9.89, 95% CI: p < 0.001), being on PI based regimen (HR = 4.66, 95% CI: p < 0.001), age (HR = 3.86, 95% CI, p < 0.001) and being on WHO stage 3 or 4 (HR = 3.75, 95% CI: p < 0.001) were hazards to DM. In 2022, the prevalence rate was 12 per 1000 people per year.

Conclusion

HPT and DM are the common NCDs among people living with HIV in this cohort. To minimize complications related to NCD/HIV comorbidities, we recommend routine screening of NCDs at monthly basis for early diagnosis and treatment.

Non-communicable disease

Human immunodeficiency virus

ART

Manicaland province

People who are living with HIV (PLHIV) have an increased risk of developing non-communicable diseases (NCDs) (1, 2). NCDs associated with human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS) are emerging as the leading cause of death globally (equivalent to 74% of all deaths), with a doubled risk in the HIV positive population than the non-AIDS related population (3, 4). The gains in HIV care has led to an increase in older HIV patient cohorts associated with increased risk of NCDs (5). It is acceptable and feasible to integrate HIV and NCD services in resource limited settings (6).

The global goal is: “To reduce the preventable and avoidable burden of morbidity, mortality and disability due to non-communicable diseases by means of multi-sectoral collaboration and cooperation at national, regional and global levels, so that populations reach the highest attainable standards of health and productivity at every age and those diseases are no longer a barrier to well-being or socioeconomic development”(7). Annually; cardiovascular diseases, cancers, chronic respiratory diseases and diabetes mellitus account for 40%, 23%, 10% and 5% of NCD related deaths respectively globally (4).

Globally, the top ten cancers with highest mortality rates are cervical cancer, prostate cancer, breast cancer, liver cancer, esophageal cancer, colorectal cancer, Kaposi sarcoma, stomach cancer, ovarian cancer and lung cancer (5). Cervical cancer has the highest mortality rate among women in developing countries (22 per 100000 population) and Zimbabwe is among the top five African countries with high incidence rate of 57 per 100000 population (5).

In low and middle income countries; the NCD burden account for 80% of deaths with 30% of these deaths occurring before reaching 60 years (8). According to the 2022 World Health Organization (WHO) updates, NCDs in Africa caused 100000 to 400000 deaths annually (9). Zimbabwe has been experiencing a rise in NCDs in Africa with high age standardized disability adjusted life years (DALYs) (10). Another Zimbabwean study which used an individual multi-disease model evaluated that between 2015 and 2035, the most prevalent NCDs are chronic kidney injury (CKD), hypertension, depression and cancer with an estimation of 59% of PLHIV having at least one NCD by 2035 (11).

Africa is facing the highest burden of diabetes mellitus, with Zimbabwe being amongst the countries with a high age standardized death rate of diabetes mellitus among females of 20–35 per 100000 population (5). African countries have also high prevalence of hypertension ranging from 24–34% among adults; with 82% of them being neither aware nor on treatment (5). A review on monitoring progress of the African region in achieving national commitments towards NCDs has been slowest (12).

The risk of contracting NCDs include HIV infection, the ART regimens, aging, physical inactivity, use of tobacco, air pollution, unhealthy diets, dyslipidemia and alcohol abuse (4, 13, 14). The response to NCDs is anchored on early detection and screening combined with palliative care and treatment (4). The increased burden of the NCDs in Africa demands dependable estimation of the NCDs epidemiology to develop appropriate prevention and control measures (14).

In high HIV burden settings, multimorbidity has been increasing among the adolescents and younger people with an increased risk of developing HIV related NCDs (15, 16). A South African study reported that initial HIV response is more focused on mothers and children more than in older adults as they are assumed to be at a lower risk which increases the challenges in the management of NCDs and HIV in elderly people (17). In Uganda one in five HIV positive people had an NCD in 2018 (18).

The control of the HIV/NCD burden requires the sensitization of the population through some of the HIV programs such as community engagement and defaulter tracing (19). The existence of more than one chronic disease in a person has been lacking adequate integrated healthcare which is a major health system challenge (20).

At Victoria Chitepo Provincial Hospital (VCPH) an in depth analysis of the burden of NCDs has not been done. The burden of PLHIV developing NCDs has been on the rise globally but this has not been evaluated in the cohort managed at VCPH, which is the referral facility for Manicaland Province. We therefore analyzed the data of NCDs among PLHIV at VCPH from 2013 to 2023.

Research Question

What are factors associated with development of NCDs among PLHIV at VCPH over the past ten years?

Broad Objective:

To determine the risk factors associated with development of NCDs among PLHIV at VCPH from 2013 to 2023.

Specific Objectives:

To determine the demographic factors associated with development of NCDs among PLHIV at VCPH from 2013 to 2023.

To determine the clinical factors associated with development of NCDs among PLHIV at VCPH from 2013 to 2023.

To determine the prevalence of NCDs among PLHIV by ART regimen at VCPH from 2013 to 2023.

To describe outcomes of HIV/NCDs comorbidity (alive, lost to follow up, dead) among PLHIV at VCPH from 2013 to 2023.

To determine the trends of cumulative NCDs among PLHIV at VCPH from 2013 to 2023.

Study Design

A retrospective cohort study of PLHIV initiated on ART from October 2013 to September 2023, using secondary data was carried out.

Study setting

The study was conducted at Victoria Chitepo Provincial Hospital (VCPH). VCPH is situated in Mutare City 3.4km north of Mutare town along the Mutare-Harare highway. Mutare is the third biggest city in Zimbabwe (after Harare and Bulawayo) and VCPH is the biggest government hospital in eastern Zimbabwe. VCPH is located in Mutare City which is in Manicaland province. It is a referral hospital for all the seven (7) districts of the province. The hospital serves a population of two million people in the province. By December 2022, 132755 people were on ART, in Manicaland Province (DHIS2).

Study population

Study participants were records of all PLHIV, enrolled on ART with case based data entered into the ePMS and patient booklets at VCPH for the cohorts from 2013 to 2023. Key informants were drawn from health care workers who work in the opportunistic infection department at VCPH.

Sample size calculation

Sample size was calculated using the Dobson formula n = z²p (1-p)/d², with sensitivity analysis based on a study by Cheza et al (2019) on incidence of non-communicable diseases in HIV patients on ART in a developing country: Case of Zimbabwe’s Chitungwiza central hospital-A retrospective cohort study with a prevalence of 63% on being a female; and in another study by Pangmekeh et al (2019) on association between highly active antiretroviral therapy (HAART) and hypertension in persons living with HIV/AIDS at the Bamenda regional hospital, Cameroon with a prevalence of hypertension in PLHIV on ART of 36.44% ; at 95% confidence interval, precision (d²) of 5% and a non-response rate of 10%. The minimum sample size for the patients’ records was 394.

Sampling

To increase the power of the study; all the 974 records of PLHIV initiated on ART who presented at VCPH from October 2013 to September 2023 were enrolled into the study using ePMS and patient booklets.

Data capture and analysis

Data which was captured from the ePMS and patient booklets which includes the age, sex, follow up status, CD4 count, ART regimen, ART start date, attendance records and the NCDs of the PLHIV. The five major groups of NCDs were selected from the records which are hypertension (HPT), diabetes mellitus (DM), chronic kidney injury (CKD), cancers and respiratory infections. Univariate analysis was performed through the calculation of proportions, means, medians and frequencies. Kaplan Meier analysis was performed using the same software, measuring against the event of interest: development of NCDs. The time to event was measured in months. Risk ratios and hazard ratios with 95% confidence intervals were generated and recorded from analysis. Cleaning of data was done before analysis. The Kaplan Meier and Logrank tests were used for survival analysis of the different groups of NCDs among PLHIV.

Ethical considerations

Permission to carry out the study was obtained from Manicaland Provincial Medical Directorate, Victoria Chitepo provincial hospital and Health Studies Office (HSO). Confidentiality of the patient records and study participants was maintained. No names were included on the key informant guide.

A total of 974 patient booklets were successfully reviewed. The demographic and clinical characteristics are shown in Table 1. Majority of the reviewed records constituted of females 565 (58.0%). Median age of the patients in years was 43 (Q₁₌35; Q₃ = 51). Out of the 159 (16.3%) who developed NCDs, 59.1% of them had hypertension.

Table 1

Demographic and clinical characteristics of HIV/NCD cases, Victoria Chitepo Provincial Hospital, October 2013 – September 2023
Variable	Category	Frequency n (%)
Sex	Male	409 (42.0)
Sex	Female	565 (58.0)
Case classification	Hypertension Diabetes mellitus Cancers Chronic kidney disease Respiratory infections	94 (9.7) 76 (7.8) 9 ((0.9) 6 (0.6) 3 (0.3)
Outcome status	Alive Lost to follow up Dead	864 (88.7) 87 (8.9) 23 (2.4)
WHO stage	Stage 1 Stage 2 Stage 3 Stage 4	400 (41.2) 331 (34.1) 217 (22.3) 24 (2.5)
Age in years	Median age (Q₁; Q₃)	43 (Q₁₌35;Q₃ = 51)
Period of years on ART	< 5 years ≥ 5 years	486 (49.9) 488 (50.1)
Type of current regimen	Nevirapine based Efavirenz based Dolutegravir based Protease inhibitor based	85 (8.7) 514 (52.8) 917 (94.2) 54 (5.5)

In this study, PLHIV who were 40 years or older had 5.41 times risk of developing diabetes mellitus compared to those who were less than 40 years and it was statistically significant p < 0.001. Those who were initiated on dolutegravir had 1.12 times risk of developing diabetes mellitus compared to those who did not take dolutegravir and it was not statistically significant p = 0.82. PLHIV on WHO stage 3 or 4 (advanced HIV disease) had 2.72 times risk of developing diabetes mellitus compared to those who were on WHO stage 1 or 2. This was statistically significant (p < 0.001). HIV positive patients who were 40 years or older had 4.81 times risk of developing hypertension compared to those who were less than 40 years and this was statistically significant (p < 0.001).

The probability of developing DM in PLHIV at 40 years and above was higher than in those below 40 years and it was statistically significant (p < 0.001). The probability of developing diabetes mellitus in PLHIV increased with increasing years on ART and it was statistically significant (p < 0.001). The probability of developing diabetes mellitus among PLHIV was not different among DTG users and DTG non-users and it was not statistically significant (p = 0.43). The probability of developing diabetes mellitus among PLHIV initiated on EFV based regimen is lower among EFV based regimen users than EFV based regimen non-users and it is statistically significant (p = 0.001). The probability of developing diabetes mellitus among PLHIV initiated on PI based regimen is higher among PI based regimen users than PI based regimen non-users and it was statistically significant (p < 0.001).

The probability of developing hypertension among PLHIV increased with increasing number of years on ART and it statistically significant (p < 0.001). The probability of developing hypertension in PLHIV at 40 years and above was higher than in those below 40 years and it was statistically significant (p < 0.001). The probability of developing hypertension in PLHIV was higher in females than males but it was not statistically significant (p = 0.37).

Controlling for gender and other variables (Fig. 1 and Table 2); the hazard for hypertension was 5.99 times higher in patients who had 5 or more years on ART compared to those who were on ART for less than 5 years and it was statistically significant (p < 0.001). Other hazards were being 40 years and above and being diabetic. There was approximately 53% lower risk of developing hypertension in the patients on efavirenz based regimen compared to non-users of efavirenz based regimen.

Table 2

Cox proportional hazards for development of hypertension
Variable	Hazard ratio	p value
ART period (≥ 5, < 5)	5.99	< 0.001
Age group (≥ 40, < 40)	4.78	< 0.001
Diagnosed DM (yes, no)	4.63	< 0.001
WHO stage (3 or 4, 1 or 2)	2.08	0.09
NVP based (yes, no)	0.92	0.34
PI based (yes, no)	0.69	0.38
DTG based (yes, no)	0.66	0.40
EFV based (yes, no)	0.47	0.01
Sex (male, female)	0.69	0.09

The risk of developing DM was 9.89 times higher in patients who had 5 or more years on ART compared to those who had less than 5 years and this was statistically significant (p < 0.001). The other hazards to development of DM were being on PI based regimen, being greater than 40 years, being at WHO stage 3 or 4 and having hypertension. The hazard for diabetes mellitus was less for nevirapine based and efavirenz based regimens. However, there was no statistical significance between dolutegravir use and development of DM (Fig. 2 and Table 3).

Table 3

Cox proportional hazards for development of diabetes mellitus
Variable	Hazard ratio	p value
ART period (≥ 5,<5)	9.89	< 0.001
PI based (yes, no)	4.66	< 0.001
Age group (≥ 40,<40)	3.86	< 0.001
WHO stage (3 or 4, 1 or 2)	3.75	< 0.001
Diagnosed of HPT (yes, no)	3.52	< 0.001
DTG (yes, no)	1.70	0.34
EFV based (yes, no)	1.03	0.91
NVP based (yes, no)	0.93	0.87
Sex (male, female)	0.98	0.94

Majority of PLHIV in this study had hypertension 94 (9.7%) and diabetes mellitus 76 (7.8). In our study, with total records reviewed of PLHIV of 974 and 159 NCDs, the prevalence rate was approximately 17 per 100 people per year in Manicaland province. A total of 6 (0.6%) PLHIV died from HPT/HIV comorbidity, 7 (0.7%) from DM/HIV comorbidity, 1 (0.1%) from cervical cancer/HIV comorbidity and 1 (0.1%) from CKD/HIV comorbidity in this cohort. A total of 15 NCD/HIV deaths out of the 159 PLHIV who developed NCDs gave an approximate case fatality rate of 1 per 10 PLHIV with NCDs per year.

The highest NCD among PLHIV in this cohort was hypertension (HPT). This hypertension results from prothrombotic changes and inflammation caused by HIV as evidenced by Chastain et al (21). Aging in PLHIV was directly associated with development of hypertension as the exposure to HIV also increased. Similarly, Chastain et al and Daniel et al evidenced that the time on ART, the various types of regimens and the duration of HIV diagnosis have been associated with hypertension (21, 22).

The survival of PLHIV with HPT/HIV comorbidity reduced with age as they deteriorated more over time with aging and immunosuppression thereby shortening their lifespan. Similarly, in another study in Poland, the increase in duration with HIV disease and aging has been directly associated with CVD risk (23). As PLHIV were mostly screened on the yearly routine hospital visit, it delayed the diagnosis and treatment of the hypertension among other NCDs. Delayed diagnosis and treatment of hypertension can be linked to the high morbidity and mortality among these PLHIV as previously evidenced in an American study (21).

A high case fatality rate was evidenced in diabetics in this retrospective cohort study compared to other NCDs. Management of both type 1 and type 2 diabetes mellitus can be critical as they both depend on the dietary and exercise lifestyle other than medication. Moreover, the risk of developing diabetes mellitus increased with age and years on ART from our study. A previous study in Iran by Hadavandsiri et al supported that glucose tolerance impairment increased with age (24). However, Bujuma et al also evidenced that exposure to ART and increasing years on ART was significantly associated with development of diabetes mellitus. In contrary, PLHIV on efavirenz or nevirapine in our study had higher chances of survival from developing diabetes mellitus compared to those on other regimens. This could be due to the lower influence on metabolic syndrome of non-nucleoside reverse transcriptase inhibitors (NNRTI) compared to other ART classes leading to reduced risk of hyperglycemia, dyslipidemia and hypertension related, as previously evidenced by Nguyen et al (25).

WHO stage 3 or 4 also increased the risk of developing diabetes mellitus due to the HIV immunocompromised state. Switching of regimens is thereby recommended to monitor glucose metabolism (21, 26, 27). The potential risk of developing hyperglycemia due to various ART switches and HIV metabolic syndrome reduced the survival of PLHIV as evidenced in our study. In contrary to our study findings, patients who were on WHO stage 1 had higher risk of developing diabetes mellitus compared to other clinical stages in an Ethiopian study (28). However, in another study in Kenya, WHO staging had no significant association with development of NCDs (29).

The immune suppression due to cervical cancer/HIV comorbidity resulted in death of one of the PLHIV in the study. We have noted a low number of cancer/NCD cases in this cohort and this has also been reported by Cheza et al in Zimbabwe that cancers have the lowest incidence rate compared to other NCDs (8). Early cervical cancer screening and the human papilloma virus vaccine reduced the cancer incidence thereby reducing the cervical cancer/HIV related mortality (30).

Our study had an HIV positive patient who also suffered chronic kidney disease and died. This could be attributed to poorly controlled HIV and exposure to other ART regimens which causes cytopathic effect to the glomerular filtration leading to renal failure as supported by Alfano et al, Naicker et al and other researchers (31–34).

Although our study reported the least number of PLHIV with respiratory illnesses such as asthma, all of them were in WHO stage 3 in ART initiation which is characterized by HIV/AIDS due to the weakened immunity. The use of ART has been evidenced to reduce respiratory infections/HIV related mortality (35–37).

Dolutegravir has been hypothesized to cause insulin resistance through the chelation of its cofactor, the magnesium ions, thereby increasing the risk of hyperglycemia. However, our study evidenced that there was no statistical significance between DTG use and development of diabetes mellitus. DTG was combined with other regimens giving better cardio metabolic profile, with DTG associated with high viral load suppression and the other regimens in the combination controlling metabolism. Moreover, our study constituted a 94% coverage of DTG users which could make the non-diabetic DTG users override the diabetic DTG users in analysis. Supporting evidence of using combined regimens to control metabolism has been reported by Tripathi et al (38).

Protease inhibitor based regimen was a hazard to diabetes mellitus in this study group. This follows as PI based regimens produce enzymes that catalyze human proteins involved in homeostasis, metabolism and cell growth thereby inducing impaired glucose tolerance (39, 40). This increases the risk of developing hyperglycemia. Hughes et al also evidenced that longer duration on protease inhibitors increased the risk of developing diabetes mellitus (41).

In our study, one in five PLHIV had an NCD. Similarly, in Uganda one in five HIV positive people had an NCD (18). The similar study findings could be due to similar country policies which are against gays and lesbians. Moreover, the economic settings in Zimbabwe and Uganda are similar as both are low resource settings. In Zimbabwe, just like other Sub-Saharan Africa countries; multimorbidity has been increasing among the adolescents and younger people with an increased risk of developing HIV related NCDs (15, 16).

Limitations

On updating the patient booklets, some of the files were disposed with information of interest such as previous ART history and patients who deceased five or more years ago, thereby eliminating some PLHIV from the cohort study. Some patients who were lost to follow up and could not be determined their interval when they were out of the study.

Recommendations and conclusion

Hypertension and diabetes mellitus are the common NCDs among PLHIV due to the metabolic syndrome from HIV and the various ART regimens, causing high morbidity and mortality in this cohort. To minimise complications related to these NCD/HIV comorbidities, we recommend routine screening of NCDs at monthly basis for early diagnosis and treatment.

Competing interests

The authors declare that they have no competing interests both financial and non-financial.

Author Contribution

Authors’ contributions KC: conception, design, acquisition, analysis and interpretation of data and drafting the manuscript. MM: conception, design, acquisition, analysis and interpretation of data and drafting the manuscript. TJ: conception, design, data collection, analysis, interpretation and reviewing of several drafts of the manuscript for important intellectual content. AC: conception, design, data collection, analysis, interpretation and reviewing of several drafts of the manuscript for important intellectual content. GS: conception, design, data collection, analysis, interpretation and reviewing of several drafts of the manuscript for important intellectual content. NG: conception, design, data collection, analysis, interpretation and reviewing of several drafts of the manuscript for important intellectual content. MT: conception, design, data collection, analysis, interpretation and reviewing of several drafts of the manuscript for important intellectual content. All authors read and approved the final manuscript.

Acknowledgements

The authors acknowledge the Manicaland Provincial Medical Directorate for their support in conducting this study. The authors are also thankful to the Zimbabwe MPH-FETP program and Centers for Disease Control and Prevention (CDC) Zimbabwe for technical assistance.

Data Availability

Data availability statement"The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request."

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Non-communicable diseases among people living with HIV, Victoria Chitepo provincial hospital: A retrospective cohort study, a secondary data analysis (2013-2023)

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