Background: Since the advent of HAART, there is a significant reduction in opportunistic Infections (OIs), morbidity, mortality and HIV transmission. However, the low antiretroviral Therapy (ART) coverage in resource-limited countries (42%) and the presence of globally 500-800 thousand patients on first-line having to required switch to second-line drugs in 2010 are some concerns. Other challenges related to HAART include: lifelong therapy, failed treatment response, optimal time to start treatment and switching regimens, drug interaction, toxicity, cardiovascular risks, drug resistance, lost to follow-up, immune reconstitution inflammatory syndrome (IRIS), early mortality, and lack of restoration of solid immunity against HIV. To achieve the goals of ART, national ART programmes focus on the vital patient monitoring systems including clinical, immunologic, virologic, adherence, lost to follow-up and mortality. Objectives: This review is aimed at addressing the profile of immunovirological responses to HAART and the factors associated with, with a special emphasis on the drawbacks of immunologic assessment to diagnose virologic failures. Main findings: WHO recommends clinical and immunological assessments as surrogates of plasma viral load (VL) to identify first-line treatment failures in resource-poor settings. However, immunological tools have poor sensitivity (20-30%) and specificity (86-90%) to identify virologic failures that may lead to continue with failed regimen or to unnecessary switch of regimen which could result in a more complex profile of resistance. There are three main types of immunovirologic responders in clinical practice: concordant responders (40-60%), concordant non-responders (12-27.3%), and discordant responders that include lack of CD4+ increases despite viral suppression (7-48%), and optimal CD4+ responses in the absence of viral suppression (5-23.8%), whereby the risk of morbidity and mortality is higher in the concordant non-responders and discordant responders. Conclusions: ART benefits a substantial number of HIV patients even in resource-poor settings. Since clinicoimmunological assessments have lower performance in diagnosing virologic failures, moving towards the availability of VL testing to confirm treatment failures, if not pre-HAART resistance testing, is a logical and timely approach for resource limited countries like Ethiopia where the long-term effect of the roll-out ART is not well investigated. However, the high cost and technical demand of VL testing, lack of experience of health professionals, weak infrastructure and health care system, the unavailability and high costs of second-line drugs could be the major challenges during expansion of VL testing. Moreover, longitudinal studies on long-term effects of HAART, and surveys focused on transmitted or acquired HIV drug resistance, and Early Warning Indicators are highly pertinent.