In this review, the summary incidence of mortality among adult HIV infected patients after taking HAART in Ethiopia was 5 deaths per 100 person years of observation (95% CI: 4–5/100pyo). The pooled incidence of mortality has decreased from 8 deaths per 100 pyo in 2010 to 4 deaths per 100 pyo in 2018. This indicated that there is an improvement in reduction of mortality among HIV infected patients through times. This might be due to improvement in health care delivery systems; commitments from the government and stakeholders to achieve the global target; improved quality of life of the patients due to treatment, care and support.
Pooled incidence of mortality in this review was low compare to Central African Republic (9.1/100pyo, South Sudan 8.2/100pyo, Côte d’Ivoire 7.5/100pyo, Cameroon 7.2/100pyo, Chad 7.1/100pyo and Nigeria 6.5/100pyo done via systematic review and meta-analysis (34). The variation may be due to difference in study setting, difference in their culture, economic status, and difference in the level of awareness and educational background of the patients between these populations.
However, this result is high compared to study done on 200 000 patients in Botswana National Program from 2002–2012 indicated that lower incidence of mortality rate which was 2.06 deaths per 100 person years of observation over a total follow up period (35). This difference might be difference in the follow up period, early detection and diagnosis of the infection and then early rapid scale up of ART before CD4 deterioration and development of advanced WHO clinical stage starting from 2002 in Botswana may explain the attributable difference in the estimation.
This review demonstrated trends of reduced death rates from 8 per 100 pyo in the year group 2005–2010 to 4 per 100 pyo in the year group 2015–2018. This result is similar with the trend analysis of mortality among ART treated HIV infected adult in Asia-pacific region between 1999 to 2017 indicated that the overall incidence rate of mortality during follow up period was 0.28 per 100 pyo. Moreover, the incidence rates of AIDS – related deaths have been decreased from 0.51/100 PYS in the year groups 2003–2007 to 0.09/100 PYS in the year group 2013–2017 (p < 0.001) in Asia – pacific region (35) and from 7–2% in Botswana in the year 2002–2012 (34,35). The improvements in the reduction of mortality through time have been related with the introduction of effective free HAART to all HIV infected patients before the deterioration of CD4 cell count and development of advanced AIDS stages, which extends the time to AIDS deaths and decrease the total number of AIDS death itself
Patients presented with advanced WHO clinical stage, low CD4 cells count, low body weight, low hemoglobin level, presence of TB co-infection, non – working functional status, improper medication adherence, lack of cotrimoxazole preventive therapy, male sex and older age at the initiation of HAART were significantly associated with increased mortality.
The hazards of dying among HIV infected adult patients presented with WHO clinical stage III and IV at the initiation of HAART were almost three times more likely than those patients with WHO clinical stage I and II. This finding is the same as studies done in LMIC (low and Middle income countries) and Tanzania with OR of 2.3 (95% CI, 1.0–5.5) that the vast majority of the patients who were died had advanced HIV disease stage (36,37). People presented with advanced HIV disease are at high risk of opportunistic infections and increased incidence of death, even after starting HAART. Severe immune suppression has frequently shown to be associated with increased risk of fatal advanced HIV disease. Early initiation of treatment before the development of advanced WHO clinical stage of the disease will reduce morbidity and prevent the high mortality rate occurred among patients with advanced WHO clinical stage of the disease (36, 37,38).
Patients who had low CD4 cells counts at initiation of HAART was almost twice more likely to experience hazard of death than patients with higher CD4. This is a similar finding to the systematic review and meta-analysis conducted by Anglemyer et al (39), study at Iran (40), Botswana (35), Tanzania (37) and In trend mortality analysis in Asia – pacific region (36). Immediate HAART Initiation to all HIV infected patients at higher CD4 cells counts has been associated with several health benefits. These may include reduce the risk of mortality, slow progression of the infection to AIDS stage, can improve the likelihood of immunological recovery (CD4 T – Cells counts reaching 800cells/mm3 or more after HAART), can increase the percentage of individuals who achieved rapid viral suppression, prolongs survival of the patients and quality of life (36, 37,41).
Patients presented with non – working functional status at the initiation of HAART in Ethiopia were four times more likely to experience death than those patients with working functional status. A study done in Maryland, USA to examine the association between physical performance and mortality on HIV infected patients indicated that reduced physical performance among HIV infected individuals had been associated with increased mortality (hazard ratio 2.52, 95% CI: 1.59–4.00) (42). HIV infected individuals frequently exposed to physical performance impairment because of loss of muscle mass, altered body composition, decrease physical function, frailty, and disability. These predisposing causes may restrict the day to day activities of the patients especial during advanced HIV diseases and increased the likelihood of mortality (39).
Different studies reported that patients with non – adherence to treatment had been associated with increased risk of mortality than those who adhere to their treatment. HAART will work best for patients who adhere to their medication and these patients have increased chance of survival. Poor adherence is associated with the risk of early treatment failure and rapid development of drug resistance (43,44). The hazard of death among adult HIV infected patients with poor medication adherence at initial enrollment to chronic care had nearly five times higher than those patients with good medication adherence.
In this analysis, patients diagnosed with TB at initiation of HAART were three times more likely to die than those patients without TB. This finding is in line with study done in assessing determinants of mortality in South Africa (45), Iran (40) and a meta-analysis study at LMIC (36). This might be due to HIV infected patients co-infected with TB are prone to develop advanced AIDS stage easily as their immune system have been deteriorated. TB and HIV have vicious cycle. Innovative approaches to reduce TB infection should be implemented and scaling up of TB prevention strategy including routine INH provision to all HIV infected adults, rapid TB detection and diagnosis methods and immediate treatment should be strengthened (36,37).
In this review, HIV infected patients with severe anemia at initiation of HAART had two times risk of dying than those patients without anemia. This finding is similar with the finding from Tanzania showed that severe anemia had been associated with increased mortality with odds ratio of 6.6 (95% CI, 3.4–12.9) (37). Another study at LMIC indicated that anemic patients with hemoglobin level < 8 gm/dl have experienced the greatest risk of mortality. Anemia among HIV infected individuals are easily exposed to chronic diseases like chronic heart failure that may be fatal to the patients could be the best explanation for the finding (35,36).
HIV infected patients who did not take a cotrimoxazole preventive therapy before or at the initiation of HAART were 53% more risk to die than patients who took cotrimoxazole preventive therapy. The finding is similar with systematic review and meta-analysis conducted at LMIC, patients who had taken CPT in their course of therapy had a 58% reduced incidence of mortality among HIV infected adults (46). This might be CPT has been recommended for all HIV infected patients developing advanced AIDS stage III & IV and patients with WHO stage I & II whose CD4 counts < 350cells/µl. Cotrimoxazole is safe, well tolerated, widely available and inexpensive which is used to prevent opportunistic infections which can be developed when the immune system of the body is compromised due to HIV infection (40).
Patients with low body weight at the initiation of HAART had 59% higher risk of death than those patients with normal range of body weight. A systematic review and meta-analysis conducted in LMIC among adult patients initiating HAART showed that low Body Mass Index/ body weight was independently associated with early mortality (36). In the trend mortality at Asia – Pacific region, lower BMI was a significant determinant associated with increased mortality in which underweight patients with BMI value < 18.5 had three times more hazard of death than patients who were in the normal BMI range of 18.5–24.9 (HR = 3.33, 95% CI: 2.31–4.81) (36). This may be due to the underlying effects of poor nutrition which may result in low body weight and hence associated with early mortality. Loss of appetite, inability to eat/ difficulty to swallow foods and stress associated with HIV/AIDS make the immune system to weaken and easily vulnerable to advanced AIDS stage. Body weight was used as a proxy indicator of nutritional status of a person.
In this analysis, being male had 41% higher risk of death due to HIV/AIDS related cause than female after the initiation of HAART in Ethiopia. This finding is consistent with a national ART study conducted at Botswana that predicted women had a lower risk of mortality (about 46% of reduction) due to AIDS related causes when compared with men (odds ratio = 0.64; 95% CI 0.60–0.69) (35). In Tanzania one study indicated that being male had almost two times higher odds of death than females (odds ratio = 1.8, 95% CI: 1.1–3.0) (37) and a systematic review and meta-analysis in LMIC revealed that male sex was an independent risk factor associated with early mortality in about 30 (60%) of the included studies (35). The reasons why males were in general more likely to die early in the course of therapy than females may be due to the difference in health seeking behavior, biological differences in ART response resulting in poorer adherence in males, difference in HIV treatment outcomes.
In this study older ages above 40 years had 21% higher hazard of dying from HIV/AIDS when compared to patients below the age of 40 years. This result is in line with a study done at LMIC, Botswana and China indicated that older age above 40 years had been strongly associated with increased odds of AIDS related mortality (34, 35,47). This is probably due to the fact that older people would experience to have poor adherence to ARV drugs because of low level of education and their desire to reduce the burden and stigma on their family associated with HIV/AIDS, older people may be underserved by public health care facility and has been associated with late presentation, diagnostic delays, poorer CD4 immune reconstitution may also explain the finding as is was mentioned in these studies.
Limitation of the Study
Patients who died at home without registered were considered as alive or loss to follow up which result in underestimation of incidence of mortality. Similarity, patients who died at health facility and recorded in the ART registry were considered as death due to HIV related causes as the exact cause of death was not differentiated routinely and this may overestimate the incidence of mortality.
This review and analysis may not include all the eligible studies because of lack of access to the databases. Only free databases (Pubmed, Google Scholar, Scopus, Cochrane and DOAJ) have been accessed for searching studies.