Incidence and predictors of virological failure among adult HIV patients on first-line antiretroviral therapy in Amhara regional referral hospitals; Ethiopia: a retrospective follow-up study

Globally, it has been estimated that out of 36.9 million people living with HIV, 59% of them received Anti-retroviral Therapy (ART) [1]. Ethiopia is one of the sub- Saharan African countries most affected by the HIV epidemic and as estimated 610,335 people were living with HIV in 2018 [2]. A Highly Active Anti-retroviral Therapy (HAART) decreased HIV related morbidity and mortality associated with chronic HIV infection at a low cost of drug toxicity and increased patient survival [3, 4]. Nonetheless, the major challenge in ART treatment was reducing virological failure and increasing the occurrence of drug resistance, while most of the patients were experienced treatment failure [5]. Routine viral load monitoring can be carried out at 6 months on ART, at 12 monthsand then every 12 months thereafter if the patient is stable on ART to synchronizewith routine monitoring and evaluation reporting [6]. Virological failure, the most informative biomarker of treatment failure, [6, 7] has become a common public health problem among HIV patients on ART [6, 8]. For example, according to the World Health Organization (WHO) 2016 global report, 70% of patients experienced virological failure [9]. In sub- Saharan African countries, viral load suppression rate was 40.2–77.4% [10], and 24% of the adult patients on first-line ART experienced virological failure within 12 months of ART initiation [11]. In the Ethiopian public health facilities, virological failure was estimated to be 11.9% [12]. Ethiopia has adopted the UNAIDS 90–90-90 treatment target by 2020 [13], and other countries have planned to reach 90% viral suppression among all people receiving ART [5]. However, evidence indicated that more than 10% of patient plasma viral load was not suppressed after 6 months of the first-line ART treatment [14‐17]. Studies indicated that there was a high incidence of virological failure. For example, in Tanzania, 14.9% [18], southeast Uganda 8.67 events per person-year follow up (PYFU) [19], and in india10.7 per 100 PYFU [20], and various factors were associated with virological failure. Accordingly, poor adherence [17, 20‐26], lower CD4 count at baseline [17, 19, 25‐31], age [17, 21, 25, 32], TB/HIV co-infection [28], and non-disclosure status [33] were associated with virological failure.

Identifying and handling the determinants of virological failure and reducing its incidence is used to realize the 90–90-90 treatment target and achieve sustainable development goal 3. To create an HIV free generation and stop HIV epidemic, early detection of virological failure on first-line ART patients is very important for better preservation of the efficacy of second-line regimens. Maintaining a low viral load is important for patients to prevent the progression of AIDS and associated co-infections; yet, there is only limited evidence on the incidence of virological failure and its predictors. Therefore, this study aimed to estimate the incidence of virological failure and identify its predictors among adult HIV patients on first-line ART in Amhara regional referral hospitals.

This study investigated the incidence and predictors of virological failure among adult HIV/AIDS patients on first-line ART in northwest Amhara referral hospitals.

The overall incidence rate of virological failure in this follow up was 4.9 events per 1000 PM observations (95%CI: 3.86–6.38). This result was higher than that of a retrospective study done in Adama, Ethiopia [24] 2.1 events per 1000 PM observations. This could be due to differences in a longer duration of ART, and a lower proportion of patients were observed in poor adherence status (11% vs 16%) compared to what is noted in this study. Furthermore, in our study higher proportion (11% vs 8%) of patients were on NVP based first-line ART regimen [35] compared to the report in Adama. Similarly, our study was higher than that done in Thailand [21] with 2.33 events per 1000 PM observations and a retrospective cohort study conducted in Myanmar [29] with 2.7 cases per 1000 PM observations. The discrepancy might be due to the duration of ART and different cut-off points used to define virological failure. Evidence illustrated a short duration of ART increased the risk of virological failure [19, 24]. This is justified by due to early in the initiation of ART, the likelihood of interrupting ARV drugs and developing resistance associated with drug side effects and non-compliance [6, 36] might lead to virological failure. Besides, patients in the Thailand study had good ART adherence (95.7% Vs 84%) compared to our study and this could reduce the burden of other opportunistic infections and prevents viral replication. In Myanmar, virological failure was considered when two consecutive viral load measurements are above 5000 copies/ml, contributing to a low incidence of virological failure. This could increase the incidence of virological failure.

The incidence of virological failure in this study was slightly higher than that of an observational cohort study conducted in South Africa [37] (3.8 events per 1000 PM observations). This can be justified as follows. The study in South Africa was based on a longer duration of ART and used different cut off points to state virological failure. As patients have a longer duration on ART, awareness about the importance of taking ART could increase, and the common, early and severe adverse drug reactions might also decrease [38, 39].

This, in turn, will lead to an increase in the possibility of adherence and boosted immunity which increases viral suppression. In South Africa, treatment failure was declared when the patient viral load on two consecutive measurements was greater than 5000 copies/ml; this might underestimate the incidence rate of virological failure.

The finding of this study was in line with that of a study done in northwestern Uganda [19] with 4.83 events per 1000 PM observations. This similarity could be due to a similar duration of ART and with a similar cut off points of viral load to define virological failure.

Furthermore, this work reported a lower incidence of virological failure than the study conducted somewhere else [20, 40]. The study done in India reported that the overall incidence rate was 8.92 events per 1000 PM observations. This might be due to variations in ART treatment durations, exclusion criteria used and the definition of virological failure. Regarding the exclusion criteria, the study done in India excluded patients with a high baseline CD4 count. CD4 count has an inverse relationship with viral load in that high baseline CD4 count prevents the replication of the virus thereby increasing patient immunity which in turn reduces virological failure [39]. The shorter duration of ART treatment in India and the viral load measurement used to define virological failure on two consecutive samples (above 400 copies/ml) were the reasons for the differences.

Similarly, the result of this study was lower than that of a study done in Jinia, southeast Uganda with the incidence rate of 7.23 events per 1000 PM observations. The higher incidence of virological failure in Uganda could be due to methodological differences (randomized equivalence trial). RCT by itself increases the attrition rate of the patients but the method of analysis used in the Southeast Uganda study was intended to treat. Intent to treat analysis considers all patients assigned at the beginning of an event despite the follow-up time with the first viral load result which is greater than 500 copies/ml. Regarding cut off points of virological failure, in Southeast Uganda, virological failure was defined as viral load above 500 copies/ml, and a high proportion (78% Vs 10.82%) of patients have treated in NVP based regimen [35].

The other possible reason might be the inclusion criteria used. For example, the study participants in Southeast Uganda were WHO stage IV or late-stage III disease or CD4 count below 200 cells/mm³.

Also, higher sample size was used in Southeast Uganda compared to this study. When the sample size increases, the probability of getting a high number of events also increases. Thus, all these differences could overestimate the incidence rate of virological failure in southeast Uganda.

According to the Weibull regression model, non-user CPT, fair/poor ART adherence, NVP based first-line regimen, and baseline lower CD4 count (<=200 cells/mm³ and 201–350 cells/mm³) were significant predictors of virological failure.

This study showed that patients who were on CPT had a lower chance of developing virological failure by 45%. This can be justified by the fact that CPT boosts the immune status of patients in that CPT directly prevents opportunistic infections, and leads to the reduction in the incidence of virological failure associated with different causes. This has been supported by daily co-trim oxazole prophylaxis was associated with reduced morbidity and mortality and had beneficial effects on CD4-cell count and viral load. CPT increases CD4 count and reduces viral loads on ART patients. On the other hand, viral load increases before the introduction of CPT but decreases during taking CPT [34].

Poor adherence was also found to be the other predictor of virological failure. The risk of developing virological failure of patients with poor adherence was 5 times more than t that of patients with good adherence. The result was consistent with those of studies in Thailand [21], Mozambique [41], Rwanda [30], Kenya [42], Harare [33], rural Uganda [23], Tanzania [43], Adama [24], Tigray [17], Dessie [26] and Gondar [25]. It is a common agreement that adherence issues are the most important point for ART users and that is why poor adherence increases the risk of virological failure. Evidence showed that when the adherence level is below 95%, patients are prone to develop drug resistance and low immunity [44], and in poor adherent patients CD4 count significantly decreases and leads to immunological failure [45]. This creates an appropriate condition for viral replication and leads to virological failure.

This study reported that the hazards of developing virological failure among patients who were treated in the NVP based first-line ARV drug regimen were three and half times higher than that of patients who were treated in EFV based regimen. This was supported by studies done in South Africa [22, 27, 37], AIDS relief site countries (Kenya, Nigeria, and Zambia) [31] and Uganda [46]. NVP’s favor for the development of drug resistance and the pill burden associated with concomitant treatments could lead to reduced immunity and decreased adherence [47]. Studies indicated that in resource-limited settings, anti-retroviral drug regimens mostly consisted of non-nucleoid reverse transcriptase inhibitors typically NVP. Hence, 18% of the patients who started in the NVP based first-line ART regimen were prone to treatment failure due to drug toxicity [48]. According to the recommendations of the Ethiopian Federal Ministry of Health in January 2019, NVP based regimen has to be phased out as of September 2019 due to drug-drug interaction, toxicity and lower genetic barrier against ART resistance [35]. This could accelerate viral replication by enhancing immunological and clinical failures and significantly increasing virological failure.

Another important predictor of virological failure was baseline CD4 count in which patients with a CD4 count of (<=200 cells/mm³) and (201–350 cells/mm³) were nearly four times at higher hazard of developing virological failure compared to patients with more than 500 cells/mm³ CD4 count. This result was similar to those of studies done in Myanmar [29], Kenya [42], AIDS relief site countries (Kenya, Nigeria and Zambia) [31], Nigeria [28], Swaziland [49], rural Gabon [50], south Africa [51],Tigray [17], Dessie [26] and Gondar [25]. It is known that viral replication has an inverse relationship with CD4 count, and lower CD4 count increases the risk and occurrence of opportunistic infections and high an attrition rate [52]. Patients with drug resistance or interruption have immunological failure and may reflect viral replication [53]. There appears to be a consistent relationship between current low CD4 count and the hazard of virological failure. Besides, patients with compromised immunity are more susceptible to different opportunistic infections that ultimately lead to increased virological failure [44].

The limitation of this study was based on secondary data, and follow up data (CD4 count and T-staging) was incomplete and didn’t incorporated as a predictors and also didn’t studied behavioral characteristics like smoking, alcohol and psychosocial, emotional factors like stigma, depression and anxiety.

The incidence rate of virological failure was high among HIV patients on the first line ART at northwest Amhara referral hospitals, Northwest, Ethiopia. Non users of CPT, poor adherence, NVP based regimen and lower CD4count (<=200 cells/mm³ and 201–350 cells/mm³⁾ were independent predictors associated with increased risk of virological failure. Patients with this condition need to be carefully observed during the follow up time. Furthermore, since NVP based regimen is associated with virological failure. This is very important to facilitate shifting NVP based regimen to the recommended drug (DTG based).