Immunological status and virological suppression among HIV-infected adults on highly active antiretroviral therapy

The human immunodeficiency virus (HIV) pandemic continues to be a major public health threat in the world. Globally, more than 37.9 million people were living with HIV by the end of 2018. An estimated 70% of infections and deaths occur in the sub-Saharan region [1]. As a standard of care for HIV-infected individuals, the use of HAART reduces HIV-related morbidity and mortality [1, 2]. This treatment transforms HIV from rapidly fatal infection to a manageable chronic disease [3, 4]. The rapid scale-up of ART for treatment of HIV infection in resource-limited countries has been successfully saving the life of millions of people receiving HAART in low- and middle-income countries [5‐7].

Ethiopia has made substantial progress in terms of HIV prevention and control activities [8]. It has been implementing a number of programs, including universal access to ART, to reduce the burden of HIV/AIDS-related complications [9]. It has also adopted the WHO’s 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection which include treating all people living with HIV/AIDS (PLWHA) (“Test and Treat” approach). The expansion in healthcare service delivery in general and HIV-related clinical services in particular had resulted a significant decline in the annual new HIV infection and HIV/AIDS-related deaths in the country. As per the Ethiopian Federal Ministry of Health report, there were 426,472 PLWHA on ART by the year 2016 [10].

The rapid scale-up of ART in resource-limited setting could be accompanied by an increased risk of HIV drug resistance which in turn could compromise the performance of the national ART roll-out program [11, 12]. Coupled with the rapid scale-up of ART services in sub-Saharan Africa, the need for appropriate treatment response monitoring approaches had become indispensable [13‐15]. However, it becomes evident that monitoring of treatment response remains the key challenge for program managers and policymakers in Ethiopia due to sub-optimal access to HIV VL testing for routine follow-up of treatment [16‐18].

In clinical practice, plasma HIV ribonucleic acid (RNA) level and CD4 cell count are used to monitor HIV treatment response. The relationship between plasma VL and CD4 cell count in HIV disease is complex. CD4 cell count is a commonly used marker of HIV disease progression and the key for starting prophylaxis and monitoring ART in the absence of HIV VL testing service. Sustained response to HAART and suppression of HIV VL were associated with an increase in CD4 cell counts [19]. The immunological and virological response to ART can be measured by the ability to suppress viral replication, time to suppression, the durability of suppression, and level of immune reconstitution achieved with suppression. These immunological and virological responses vary at individual and population levels [20].

WHO treatment guideline recommends the use of VL testing by clinicians and researchers as a primary tool to monitor treatment response in HIV-infected individuals on HAART. Whereas CD4 cell counts can only be used to monitor clinical response to HAART where VL testing is not available [21]. Besides, it is recommended that VL measurements among people receiving HAART should be performed at 6 months after initiating ART, then at 12 months, and every year thereafter [22]. Furthermore, one of the goals of the Joint United Nations Programme on HIV/AIDS (UNAIDS), “90-90–90 initiative”, is achieving virological suppression in 90% of all people receiving ART by the year 2020 [23]. Identifying factors that affect the virological suppression and designing appropriate strategies to mitigate the problem would have a paramount importance in terms of achieving the stated goal. Different studies indicated that factors such as poor adherence, low baseline CD4 cell count, low BMI, rural residence, advanced disease stage, and duration of treatment negatively affect the immunologic status and virological suppression and hinder the achievement of the targeted treatment goal [24‐26].

In Ethiopia, immunologic and clinical parameters have been used to monitor HIV patients on ART. Recently, the government has implemented a VL testing in multiple testing centers across the regions; however, the viral suppression rate and immunological status are not well studied and even there is a need for locally generated data-driven evidence to inform policymakers and guide clinicians. Therefore, the aim of this study was to determine the immunologic and virological status and associated factors among adult PLWHA who were on HAART at the University of Gondar comprehensive specialized referral hospital.

The scale-up of ART service in Ethiopia has been one of the greatest achievements of the HIV program in the last one decade. HAART has been consistently reported to suppress HIV RNA to the level below the limit of detection, and has reduced the risk of clinical progression [30, 31]. Despite these successes, treatment failure due to drug resistance and poor adherence poses a challenge to the ART program. For this reason, the WHO recommends routine VL testing for monitoring ART.

In this study, 82% (95% CI 77.7, 86.1) of the study participants achieved virological suppression, indicating the success of the ART program and suggesting that the country is progressing towards achieving the third 90–90–90 target of the UNAIDS. Despite this achievement, there are still a considerable proportion of patients (18%) with high VL which needs monthly follow-up and repeated VL testing after 3–6 months of enhanced adherence support [10]. These groups of patients are classified as suspected virological failure because they are at higher risk of morbidity and mortality [15, 32]. Therefore, the finding of this study highlighted the importance of improved access to VL monitoring and prompt action to optimize treatment regimen for patients with high VL.

Even though the 82% of virological suppression in this study differs from previous studies, it is consistent with a study from Tanzania (79.1%) [27]. This result is lower than the finding from previous studies in Nepal (90%) [33], Addis Ababa, Ethiopia (90%) [34], Ghana (89.6%) [35], and South Africa (94%) [36]. Similarly, the Ethiopian Public Health Institute reported that 88.1% of patients on first-line treatment showed virological suppression in the country, with a regional variation [37]. In this study, HIV-infected adults enrolled to ART care in 2005, where ART service was started in the hospital, might have participated in the study. These participants could initiate ART medication at the advanced stage of the disease which affects the treatment response [38]. Remarkably, in our study, 57.2 % of study participants were initiated ART at WHO stage 3 or 4 defining conditions, whereas WHO recommends that earlier initiation of ART would improve treatment response and help countries to achieve the 2020 target for virological suppression [39].

Favorable immunologic status was observed among 52.9% (95% CI 47.4, 58.8) of the study participants. This finding is lower than reports from Nepal (62.83%) [33], southern Ethiopia (82.4%) [40], and Debre Markos, Ethiopia (79%) [41]. The variation in the immunologic status of the study participants with other studies might be attributable to the fact that other studies presented for comparison to our finding defined immunological recovery differently. In contrary, our finding is higher than study reports from Oromia, Ethiopia (32%) [42] and Tanzania (43.1%) [27]. Most patients in these two studies initiated treatment lately which can affect the immune reconstitution [43].

In this study, it is noted that there is a discrepancy between the immunological status (52.9%) and the virological suppression (82%). For some of the study participants, the HIV RNA plasma level is below the limit of detection, but the CD4⁺ cell count response is blunted. Some others exhibited a different pattern of discordant response characterized by a sustained CD4⁺ cell response despite persistent viremia. Similarly, studies also reported such type of results [44, 45]. The possible reason for discordant result might be late initiation of ART, HIV-related depletion of T cells, persistent immune activation and exhaustion of T cell due to microbial translocation, long-term impact of HIV on thymus function and its output, and lymph node fibrosis [44, 46].

Current age and CD4 cell count at VL measurement were associated with virological suppression. Accordingly, the odds of virological suppression among patients aged > 45 years old were nearly 6 times more likely compared with those aged < 30 years. This finding confirms the previous study from the rural part of South African describing that greater proportion of older adults (90.1%) had good virological response as compared with younger adults [47]. Probably, older patients might demonstrate better medication adherence which would positively influence to achieve optimal outcome of ART medication [48, 49]. Therefore, adherence assessment with different age categories is critical.

The other factors associated with virological suppression is CD4 cell count at the time of VL testing. The odds of virological suppression among patients who had a CD4 cell count of 350–499 and > 499 cells/mm³ were 2.56 and 7.71 more likely to respond compared with patients having CD4 count of < 350 cells/mm³, respectively. This is due to the fact that as the current CD4 count raises, the duration on ART increases and the VL is suppressed; HIV/AIDS-related mortality might also decline. Evidence also supports that the effect of CD4 count varied strongly by VL and duration of treatment [50]. Similarly, HIV VL needs to be controlled at a lower level to maintain favorable CD4 response while the patient is on HAART [51].

Favorable immunologic status was seen among those participants with high baseline CD4 cell count, urban residence, and age at enrollment within the range of 26–40 years. The odds of favorable immunologic status among patients who had a baseline CD4 cell count of 200–499 cells/mm³ and > 499 cells/mm³ were 2.7 and 9.6 times higher compared with patients who had a baseline CD4 cell count of < 200 cells/mm³. Other studies have also reported that high baseline CD4 cell count was positively associated with a better immunological response in HIV-infected patients taking HAART [52‐55]. This finding enlightened the benefits of earlier initiation of ART. For those patients who had a higher baseline CD4 cell count, it might be easier to reach the normal CD4 level within a short period after initiation of treatment. A study in sub-Saharan Africa has indicated an increment in CD4 cell count by 50–100 cells/mm³ 1 year after initiation of HAART [56]. The odds of favorable immunologic status among patients who were residing in urban areas was 1.9 times more likely as compared with patients residing in rural areas. This might be due to lifestyle differences like poor feeding practice, as such in the rural setting most of the time they are not feeding as recommended, and compliance barrier for prescribed ART drugs in the rural area [57].

The age of participants is another factor affecting the immunologic status. Those participants who were in the age range of 26–40 years old at enrollment were 47% less likely to have favorable immunologic status compared with those within the age of > 40 years old. A study aimed at exploring the effect of age on immunologic restoration reported that a younger age favors CD4 cell restoration because of preserved thymus function which was contrary to this study [58]. The discrepancy might be related with adherence problem, which is seen mostly in younger aged group of HIV-infected patients. In support of this argument, one study reported that the rate of poor adherence among young adults was twice as high as older individuals did [59].

Although this study was conducted with due diligence and scientific approaches, there were certain limitations. The level of adherence to ART was not assessed, which might have an effect on the outcome of interest. Furthermore, a single VL measurement was taken to estimate the virological suppression which might underestimate the proportion of patients with virological suppression since VL re-suppression could occur if the test is repeated after 3–6 months of enhanced adherence support.

This study revealed a sub-optimal level of virological suppression, indicating the need for strong commitment to achieve the third 90% target of the UNAIDS 90–90–90 targets by 2020. On the other hand, the immunological status was found to be low. Age > 45 years old and CD4 cell count ≥ 350 cells/mm³ were significantly associated with virological suppression. Age at enrollment between 26 and 40 years was negatively associated with immunological status, whereas urban residence and baseline CD4 cell count ≥ 200 cells/mm³ were positively associated. Therefore, early initiation of HAART at higher CD4 cell count level is vital to achieve the goal of HAART. For better treatment outcome, younger age groups and those with low baseline CD4 cell count need to be followed cautiously. This finding also generated evidence for tracking the progress towards achieving the third target of the 90–90–90 UNAIDS plan.