Incidence and predictors of LTFU among adults with TB/HIV co-infection in two governmental hospitals, Mekelle, Ethiopia, 2009–2016: survival model approach

From infectious diseases’ statistics, Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) are the leading causes of death globally. Despite many efforts have been made to control and prevent the dual occurrences of the diseases, yet TB is the leading cause of mortality and morbidity in People Living with HIV (PLHIV) [1].

Above one third of the world population is infected with Tuberculosis (TB) and 5–10% of them develop active TB. The reactivation of Latent TB infection (LTBI) to active TB diseases is pronounced among PLHIV by approximately 20 times on average. Globally, approximately one million PLHIV co-infected with TB in 2017. TB is the leading cause of death among PLHIV attributable to 300,000 HIV-associated TB deaths in 2017 in which Africa accounted for the largest shares (84%). Moreover, PLHIV faces the threat of drug-resistant TB. If diagnosis is delayed there is increased risk of mortality from multi-drug resistant and extensively drug-resistant TB [2].

Studies from SSA have also shown that the cumulative incidence of attrition after 3 years of follow-up can be up to 35%. A declined from 86% at 6 months to 77% by 36 months after ART initiation in SSA [3, 4]. Thus, attrition remains a major challenge among adults with HIV and TB in resource limited setting of Low and Middle Income Countries (LMICs) as a result of scarce data on Lost to Follow-Up (LTFU) [5, 6].

Currently, quality of HIV health care services and Anti-Retroviral Therapy (ART) coverage are significantly increasing from time to time. However, LTFU rate is still high and many people drop out at various phases of the treatment pathway. Because of the reasons why people LTFU are not clearly investigated, a poor adherence to treatment is achieved that results in undesired treatment outcomes [7].

LTFU minimizes the benefits of ART in PLHIV which can enhance the occurrence of Opportunistic Infections (OI/s) including TB as a result of immune suppression. Therefore, it intensifies the TB/HIV or Acquired Immune Deficiency Syndrome (AIDS) related negative consequences – morbidity, mortality, and hospitalizations – as a result of dual burdens of the two infections. Moreover, LTFU in HIV or TB/HIV co-infected adults has also adverse consequences such as drug toxicity, treatment failure, and drug resistance that ultimately shorten the survival of patients [8–10].

Different literatures have been shown that LTFU attributes to an increased mortality globally and approximately 1 death every 3 LTFUs (40%) in the SSA region particularly [11–14]. In addition, many studies in the region identified risk factors associated with increased LTFU are mainly: under-nutrition, reduced baseline CD4 count, co-infection with OI/s including active TB, advanced clinical staging, adverse drug reactions, gaps in services, and low access to ART services [3, 13, 15, 16].

Early screening and treatment of TB are on the other hand important to reduce the dual burdens of TB and HIV, reactivation from Latent TB infection (LTBI) to active TB disease, and prevent the transmissions of HIV and TB. Ethiopia has adopted the World Health Organization (WHO) Stop TB strategy which currently is being used as a guideline for the anti TB treatment regimen in almost all health facilities throughout the country since Directly Observed Therapy Short Course (DOTS) full implementation coverage in 2000. Nationally, however, the utilization was yet restricted to approximately 92% due to the low health coverage and poor health access [17].

Generally, LTFU is more common in resource poor setting countries as a result of poor adherence and low health care seeking behavior of people. In an ART in LMICs study, the LTFU after 1 year of ART initiation is greater than 40% that is mainly associated with advanced WHO clinical stage (AIDS) and very low baseline CD4 as a result of late initiation. Though the first 6 months of ART initiation are very important to reduce the LTFU rate, the health care seeking behavior of people remains a major challenge yet to increase retention rate [18, 19].

In Ethiopia, ART was begun in 2003 and free ART was launched in 2005. An estimated 739, 000 Ethiopians are currently living with HIV and all of them eligible to initiate ART irrespective of their baseline CD4 cell count. However, the ART coverage is approximately 76% in adult HIV patients [20]. Despite the high LTFU related negative consequences, little was known even on TB and HIV related LTFU rate in adults in Ethiopia and thus, the incidence and predictors of LTFU are unknown. Thus, this study was aimed at partly filling the gap that will contribute its own role in reducing negative consequences of LTFU among people co-infected with TB and HIV in the country in general and the study setting in particular.

The current study was investigated to determine the incidence and predictors of LTFU among adults with TB/HIV co-infection in the study setting. Thus, the incidence rate was found to be 4.5 new LTFU cases per 100 PYs with a median follow up time of 3.1 years (IQR: 0.8–5.3 years). Up on running our final cox model, statistically significant predictors of LTFU are: baseline hemoglobin level, adverse drug events, history of OI/s, TB treatment completion, and IPT (Table 4).

In the current study, 45 of 305 (14.8%) TB/HIV co-infected patients developed the event of interest (LTFU). The incidence rate was found to be 4.5 per 100 PYs collectively among TB/HIV co-infected adults. The incidence of LTFU was lower as compared to other studies conducted in India, Vietnam, South Africa (Johannesburg), and SSA region [3, 11, 22, 23]. To the contrary, the LTFU rate was higher as compared to other studies conducted in Vietnam, South Africa, Cameroon, Zambia, and Liberia [24–28]. However, the LTFU rate is similar to a prospective study conducted in Ethiopia [29] . The high incidence rate in the current study may be due to the duel burden of TB and HIV might be triggered the risk of LTFU as compared to the majority of other studies in which their study subjects were HIV or TB patients alone. Thus, this finding strengthens the idea that LTFU remains a major challenge among adults with TB and HIV in resource limited setting of LMICs such as Ethiopia as a result of scarce data [5, 6] and retention of patients in care remains a major challenge to the health care providers and program mangers [18, 19].

In this study, LTFU was significantly affected by the baseline hemoglobin level where the incidence of LTFU is roughly twice among the anemic groups than their normal counterpart (AHR = 2.660; 95%CI: 1.459–4.848). Finding of the current study is consistent with a study conducted in Myanmar, India though that has estimated Odds Ratio (OR) instead of HR and the study subjects were HIV patients than TB/HIV co-infected [30]. However, another study that has been done in Central Tigray, Ethiopia reported the non-predictive effect of baseline hemoglobin to LTFU among HIV Patients under ART [21]. In fact, multiple medications for TB, HIV and Anemia as well may lead to LTFU of the patient from ART follow up due to multiple burdens.

Moreover, patients who have been reported any adverse drug events during the course of their treatment were experienced low risk of LTFU (AHR = 0.451; 95% CI: 0.216–0.941). Though literatures on this study variable were scarce, a facility based case control study has been revealed that presence of drug side effect among HIV/AIDS patient was significant risk factor of LTFU in which patients with adverse drug side effect had approximately 12 times the odds of developing LTFU than those in the control group [31]. The unusual findings observed in this study can be seen from the side that the high health care seeking behavior of the patients may contribute for high adherence to treatment and thus, they might report adverse events if they were experienced which in turn leads to replacement by the safest medication by their doctors’ that may tend to decrease the LTFU rate. On the other hand, patients who did not report any drug side effects might be negligent about the adverse effects irrespective of the consequences of LTFU such as morbidity, hospitalization and eventually death. Moreover, the degree of Scaling up LTBI treatment using IPT was higher among those with adverse drug events that could possibly both increase adherence and decrease LTFU related mortality among adults (18.6% IPT coverage among those with adverse events as compared to 14.1% among those did not report it).

Any history of OI/s was also statistically positively associated with LTFU among TB/HIV co-infected adults. Controlling the effect of other predictors, TB/HIV adults who have been diagnosed with at least one OI during the course of their treatment were approximately 4 times more likely to experience LTFU than those who did not (Table 4). It is possibly justifiable that the multiple burdens of diseases may affect the psychological curability and diminish the immune status of the patient and eventually which may result in LTFU from their regular course of treatment.

Successfully completing TB treatment had also a protective effect over LTFU among TB/HIV co-infected adults (AHR =0.121; 95% CI: 0.057–0.254). It is evidenced that both TB and HIV have bidirectional and synergistic relation-ships and thus, the presence of either infection has its own significant contribution for the occurrence of other. The strong association between the two infections will be broken up on the successful completion of TB treatment that may reduce the dual burdens proportionally through TB treatment success rate. Therefore, the health status would be improved, and the incidence of LTFU on the other hand will be decreased as a result of treatment success for TB.

In the current study, majority (84.3%) of the patients were off IPT prophylaxis (Table 3). Regarding the statistical association, on IPT adults had low risk of LTFU than those of off IPT one (Table 4). The finding of the current study is consistent with a facility based retrospective cohort and follow up studies, and another case control study conducted in Mizan Aman, Southern Ethiopia, and Wukro (all in Ethiopia), respectively that have been revealed all off IPT is a potential risk factor of LTFU among HIV patients [31–33]. This could be related to preventing LTBI reactivation by IPT is simpler than treating active TB disease using full regiment of TB treatment so that people tend to LTFU as a result of dual burdens of both diseases and dual follow ups as well.

The cause and effect relationship of TB and HIV (was TB or HIV come first) is in fact unclear and considered as TB/HIV co-infected regardless of their temporal relationship. Literatures are also scarce and majority of the literatures are LTFU about HIV patients than TB/HIV co-infected. Moreover, some HIV adults who were on IPT initially tend to develop active TB and thus, started anti TB regimen that may mislead to that IPT was given to active TB co-infected adults.

Overall, 1 in approximately seven of TB/HIV co-infected adults had experienced of LTFU with an incidence rate 4.5 LTFUs per 100 PYs. TB/HIV co-infected adults diagnosed with anemia at base line, and diagnosed with any OI/s have been strengthened the occurrence of LTFU. Conversely, being on IPT, Completing TB treatment, and developing adverse drug events had protective effect against LTFU among TB/HIV co-infected adults. Therefore, it is advisable to treat anemia and active TB, and preventing the occurrence of OIs including reactivation of latent TB using IPT to reduce the incidence of LTFU among TB/HIV co-infected adults.