Determinants of Virologic Failure among Adult HIV Patients on First-Line Antiretroviral Therapy at Waghimra Zone, Northern Ethiopia: A Case-Control Study

Introduction. (e primary goal of antiretroviral therapy (ART) is to reduce the viral load in HIV-infected patients to promote quality of life, as well as to reduce HIV-related morbidity and mortality. A high rate of virologic failure was reported inWaghimra Zone, Northwest Ethiopia, in viral load assessment conducted among HIV-infected patients on ART in the Amhara region. However, there is limited evidence on the determinants of virological failure in the study area. (is study aimed to identify the determinants of virological failure among HIV-infected patients on antiretroviral therapy in Waghimra zone, Northern Ethiopia, 2019. Methods. An institutional-based unmatched case-control study was conducted from May 21 to June 30, 2019. Cases were people living with HIV (PLHIV) on ARTwho had already experienced virological failure; controls were those without virological failure. Data were extracted from 92 cases and 184 controls through chart review using a pretested and structured checklist. (e data were entered using Epi Info version 7 and exported to SPSS version 20 for analysis. A multivariate logistic regression analysis was carried out to identify factors associated with virological failure, and variables with a P value <0.05 were considered statistically significant. Results. (is study revealed that poor adherence to ART (adjusted odds ratio (AOR)� 4.24, 95% confidence interval (CI): 2.17, 8.31), taking ARTfor longer than five years (AOR� 3.11, 95% CI: 1.17, 8.25), having drug toxicity (AOR� 3.34, 95% CI: 1.54, 7.23), age of PLHIV≥ 35 years (AOR� 2.45, 95% CI: 1.29,4.64), and recent CD4 count <200 cells/mm3 (AOR� 3.06, 95% CI: 1.52, 6.13) were factors associated with virologic failure. Conclusion and Recommendation. (is study showed that poor adherence to treatment, longer duration on ART, experiencing drug toxicity, older age, and recent CD4 <200 cell/mm3 are factors that increase the risk of virologic failure.


Introduction
Since the start of the human immunodeficiency virus (HIV) epidemic, 74.9 million people have been infected, and 32 million people have died from acquired immunodeficiency syndrome-(AIDS-) related illnesses. In 2018, 37.9 million people were living with HIV/AIDS globally, from which 95% were adults. About 1.7 million people became newly infected, and one million died from AIDS-related illness. Of all people living with the human immunodeficiency virus (PLHIV), 62% were accessing treatment and 53% were virally suppressed in 2018 [1]. Africa contains most of the disease and is largely affected by the epidemic. In Eastern and Southern Africa, 20.6 million people were living with HIV in 2018, which accounts for 54% of global total HIV infection. From all PLHIV in this region, 67% had access to antiretroviral therapy (ART) [1].
In Ethiopia, the prevalence of HIV among adults was 0.9% and varying across regions with the highest prevalence observed in Gambella 4.8% followed by Addis Ababa 3.4% in 2016 [2]. In Amhara regional state, there were about 187,975 PLHIV, contributing to 30% of the PLHIV population of the country [3]. ART was introduced in Ethiopia in 2003, and in 2005, the Ethiopian Government launched free access for ART in different health sectors to improve the quality of life of PLHIV [4]. e primary goal of ART is to achieve long-term durable suppression of HIV replication, which gives immunologic and clinical benefits, and in turn leads to a reduction in morbidity and mortality and improved quality of life. Unable to suppress HIV viral replication results in treatment failure and development of antiretroviral (ARV) drug resistance [5]. e World Health Organization (WHO) recommends the use of routine HIV viral load (VL) testing as the preferred approach for PLHIV on ART to monitor treatment response and diagnose treatment failure. While routine virologic monitoring is the standard of care in industrialized countries, targeted VL testing is still practiced in some resource-limited settings to confirm immunologic and/or clinical failure before switching to second-line treatment [5].
According to the National Consolidated Guidelines for Comprehensive HIV Prevention, Care, and Treatment of Ethiopia, the recommended first-line regimens for adults are TDF + 3TC + DTG, AZT + 3TC + EFV/NVP, TDF + 3TC + EFV/NVP, or ABC + 3TC + EFV/NVP, and the second-line regimens could be TDF + 3TC + LPV/r or ATV/r or AZT + 3TC + LPV/r or ATV/r depending on the regimen type used in the first-line [20]. e government of Ethiopia has adopted the global goal to attain the 90-90-90 targets: 90 percent of PLHIV know their status, 90 percent of PLHIV who know their status are on treatment (ART), and 90 percent of PLHIV on treatment have attained viral suppression. In Ethiopia, as of May 2018, 79% of PLHIV knew their status; 71% of eligible PLHIV are on ART, and 87% of those on ART have attained viral suppression [3]. A VL assessment that was conducted in 2018 in the Amhara region by the regional health bureau revealed that 18% of PLHIV on first-line ART in Waghimra Zone had a virologic failure [21], which is the highest in the region.
erefore, this study aimed to determine factors related to virologic failure among adult PLHIV in the Waghimra zone.

Study Design and
Setting. An institutional-based unmatched case-control study was conducted from May 21 to June 30, 2019, in the Waghimra zone. Waghimra zone is a special administrative zone in Amhara regional state. Sekota is the administrative capital of the Waghimra zone and is located 715 km far from Addis Ababa, the capital of Ethiopia, and 560 km from Bahir Dar, the capital city of Amhara regional state. Waghimra zone has 31 health centers and 3 district hospitals and provides health care services for more than 600,000 residents. Currently, 11 health centers and 1 district hospital provides comprehensive HIV care. e regional health bureau conducted a VL test for 512 PLHIV in 6 randomly selected health facilities (5 health centers and 1 primary hospital) in 2018. A total of 1,984 PLHIV were enrolled in these health facilities: 195 in Amdework Heath Center (HC), 163 in Chila HC, 278 in Asketema HC, 166 in Hamusit HC, 292 in Tsisika HC, and 890 in Tefera Hailu Hospital.

Population and Sample.
e sample size of the study was calculated by Epi Info ™ 7 software Statcalc program using the following assumptions: key predictor of virological failure (age) from a previous study, proportion of controls exposed 47.7%, odds ratio 2.52 [11], 5% level of significance, 80% power of the study, and 1 : 2 case to control ratio. erefore, the calculated sample size was 197 (66 cases and 131 controls). However, to improve the power of the study, all of the cases (92) and comparable controls (184) were included in the study. Controls were selected by using simple random sampling techniques. All adult PLHIV aged ≥15 years who have at least two VL measurements after initiation of first-line ART in the Waghimra zone were included in the study. PLHIV who have taken the first-line ART for less than 6 months were excluded. All HIV-infected adults whose plasma VL is ≥ 1,000 copies/mL in two consecutive VL measurements within a 3-month interval with adherence support between measurements were defined as cases (virologic failure), while study participants with a VL level of <1,000 copies/mL were considered as controls [5]. All 92 cases found from 5 health centers and 1 primary hospital were included in the study. e case of virologic failure distributions were 9 from Amdework HC, 8 from Chila HC, 15 from Asketema HC, 6 from Hamusit HC, 14 from Tsisika HC, and 40 from Tefera Hailu Hospital.

Data Collection Tools and
Procedure. Data were extracted from the clients' medical records using a pretested structured checklist adapted from the Ethiopian Federal Ministry of Health ART clinic intake and follow-up form. e data were collected by 5 trained health professionals. e principal investigator and supervisors closely monitored the whole data collection process.

Assessment of Drug Toxicity and Adherence.
When drug toxicity is suspected, the clinical condition is assessed to identify whether it is due to ARV toxicities, other drugs, or other illness including new opportunistic infections. e responsible ARV drug will be identified, and the severity of toxicity will be assessed using the toxicity grading matrix. en, drug regimens or single-agent substitutions may be required [20]. In our study, we have included all the recorded toxicities irrespective of the severity.
Adherence status was assessed based on the reported number of pills taken in the last one month divided by the number of prescribed pills multiplied by 100%. Clients who reported an intake of ≥95% of the prescribed medication were considered good adherent; those with a reported intake of <95% were classified as poor adherent [20].

Data
Processing and Analysis. Data were entered using Epi Info version 7 and exported to Statistical Package for Social Sciences (SPSS) version 20 software for analysis. Descriptive statistics, including frequencies and percentages, were used to describe demographic, clinical, hematologic, and medication-related characteristics of the study participants. Bivariate analysis was carried out for all independent variables with an outcome variable, and variables with P value ≤0.2 were entered into a multivariable logistic regression model to identify the independent determinants of virological failure. Finally, the adjusted odds ratio with 95% CI was determined, and variables with P value <0.05 were considered significant.

Sociodemographic Characteristics.
A total of 276 HIVpositive individuals (92 cases and 184 controls) who have at least 6 months ART follow-up participated in the study. More than half (55.1%) of the study participants were females. Two-thirds, 122(66.3%) of controls and 44 (44.6%) of cases, were under the age of 35 years. Over half (57.1%) of controls and 40.2% cases were married. More than half (58.7%) of cases and 52.2% controls were urban dwellers. e majority of cases (57.6%), as well as controls (64.1%), have no formal education (Table 1).

Hematological and Immunological Factors.
In this study, 65 (70.7%) of the cases and 113 (61.4%) of the controls had <200 cells/mm 3 CD4 count at baseline, while 40(43.5%) of the cases and 38 (20.7%) of the controls had current CD4 count of <200 cells/mm 3 . Baseline white blood cell (WBC) count of the majority of cases (67 (72.8%)) and controls (130 (70.7%)) was laid between 4 × 10 and 10.9 × 10 cells/mm 3 . e baseline hemoglobin level was greater than 12 g/dl for 52 (56.5%) of cases and 110 (59.8%) of controls (Table 2).  (Table 3).  (Table 4). e odds of developing virologic failure among PLHIV who had less than 200 cells/mm in recent CD4 count were 3 times (AOR � 3.06, 95% CI: 1.52,6.13) more likely as compared to clients with baseline CD4 count ≥ 200 cells/mm . Participants who stayed five years and above on first-line ART were also 3 times (AOR � 3.11, 95% CI: 1.17, 8.25) more likely to develop virologic failure as compared to those who stayed for less than five years. Clients who had experienced drug toxicity were 3.34 times (AOR � 3.34, 95% CI: 1.54, 7.23) more likely to have virologic failure as compared to those who had no history of drug toxicity. Clients who were not adherent to their ART drugs were 4 times (AOR 4.24, 95% CI: 2.17, 8.31) more likely to have virologic failure as compared to those who were adherent to their treatment (Table 5).

Discussion
is study aimed to assess the determinants of virological failure among adult PLHIV on first-line ART and showed that older age (≥35 years), low recent CD4 count (<200 mm 3 ), longer duration of stay on ART, having history of ART drug toxicity, and poor adherence to ART were found to have increased odds of virological failure.
is study revealed that PLHIV aged ≥35 years were 2.45 times more likely to develop virologic failure as compared with their younger counterparts. is finding is supported by studies conducted in Ethiopia [22], Mozambique [23], and the United States of America [24]. On the contrary, the odds of virological failure decreased with increased age as evidenced by the studies conducted in Uganda [18], Canada [25], and Gondar, Ethiopia [11]. e possible reasons for higher odds of virologic failure among older clients maybe that old PLHIV tend to develop drug toxicity and age-related kidney and liver function reduction, which may result in impaired drug elimination [26,27].

Advances in Public Health
In this study, PLHIV who had a recent CD4 count of fewer than 200 cells/mm had a 3-fold increased odds of developing virological failure as compared to those with higher CD4 count. is finding was consistent with studies conducted in Ethiopia [11,28] and Gabon [29]. is might be since clients with a low CD4 count are more likely to

Advances in Public Health
develop different opportunistic infections, and the added burden of these diseases further complicates their response. is likely increases the possibility of viral mutations and virological failure [30,31]. e current study also found that PLHIV who stayed for more than 5 years on ART were 3 times more likely to develop virologic failure as compared to those who had less than five years follow-up. is result is supported by different studies conducted in Ethiopia [11,32] and Swaziland [33]. e possible reason might be related to the persistent replication of the virus during ART, and longer time on ART could be associated with drug resistance mutations, which eventually leads to virological failure [29,34].
In this study, adherence to ART was an important determinant of virological failure. PLHIV with poor medication adherence were 4 times more likely to develop virologic failure as compared to clients with good adherence. A metaanalysis finding [35] supports our study, and similar findings were also reported in previous studies conducted in Ethiopia [11,28,36] and Zimbabwe [37]. Poor adherence to medication reduces viral suppression due to suboptimal drug concentration and subsequently increasing the viral load [5,38]. e current study found that PLHIV who had experienced drug toxicity were 3.34 times more likely to have virologic failure as compared to those who had not  experienced drug toxicity. is finding is consistent with a study conducted in Nigeria [39]. is might be due to the fact that clients who have experienced drug toxicity would interrupt ART and causes acquired drug resistance, which leads to virologic failure [5,40,41].

Limitation of the Study.
We used unmatched casecontrol study design, and differences in baseline between the cases and controls may lead to selection bias. Our study may also be affected by survivor bias since deaths and loss to follow-up were not accounted for and may compete with the outcome. e study was entirely based on secondary data, which may affect the reliability of the data.

Conclusion
is study showed that poor adherence to treatment, longer duration on ART, experiencing drug toxicity, older age, and recent CD4 < 200 cell/mm were important factors that increase the risk of virologic failure. erefore, identifying the cause of nonadherence and increasing adherence to ART would help to suppress viral replication. Special attention should be given to older clients, PLHIV with longer time on ART, and low recent CD4 count. Managing the drug toxicity and the use of a safer ART regimen is also an important strategy to prevent virologic failure, besides the promotion of adherence.