The appropriate timing to initiate antiretroviral therapy (ART) in human immunodeficiency infection type 1 (HIV-1) infected patients is a long-standing debate among clinicians all across the globe. Primary goal of ART is to reduce plasma viral loads and AIDS-associated illnesses in HIV-1 infected patients on long-term therapy. Guidelines suggesting when to start ART in virus infected patients are constantly changing and are largely rely on CD4 T cell counts and the status of AIDS defining illnesses. During the progression of the disease, CD4 counts are rapidly declined in HIV infected patients to very low levels. Though initial guidelines recommended by various organizations and commissions set a threshold of 200 CD4+ counts as ART initiation point, later modified to 350 counts and is now on the verge of initiating therapy in everyone living with HIV at any CD4 T cell counts, which is lately revised by WHO. Recent evidence provided by two of the human randomized trials with the focus on benefits and risks of initiation of ART in patients with higher CD4 T cells counts (≥ 500 cells per mm3) during asymptomatic HIV infection support these guidelines. Recent studies from International Network for strategic Initiatives in Global HIV Trials (INSIGHT) Strategic Timing of Antiretroviral Therapy (START) study group and TEMPRANO ANRS 12136 trial demonstrated that HIV infected patients with more than 500 CD4 T cell counts per cubic millimeter benefit from early ART initiation over delayed start in patients with lower CD4 counts. The major benefits of early initiation of ART include, lower risk of AIDS related, non-AIDS related deaths, bacterial infections and gradual increase in CD4 T cell counts suggesting that early ART increases improves immune functions and decreases the mortality rate in HIV-1 infected patients. 

Keywords: HIV; AIDS; early ART; early initiation of antiretroviral therapy; INSIGHT; START; TEMPRANO ANRS 12136; CD4 counts; CD4 recovery; AIDS associated illnesses; non-AIDS associated illnesses.

Introduction of highly active antiretroviral therapy (ART) in mid 1990s, changed the face of the human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS) epidemic. If the HIV-1 infected patients are not treated with ART, most of them eventually develop severe immunodeficiency due to gradual loss of vital CD4+ T immune cells, opportunistic secondary infections, AIDS defining illnesses and premature death. The primary goal of ART is to prevent HIV-associated mortality and morbidity, which is accomplished by suppression of viral replication to undetectable levels in plasma of treated patients. In general, optimal suppression of plasma viremia is defined as a viral load persistently below the level of detection (HIV RNA <20-75 copies/mL, depending on the assay used) (1). However, isolated blips or transient detection of viral RNAs at low levels, typically <400 copies/mL are frequently observed even in successfully treated patients and are not predictive of virologic or treatment failure [1,2].  

 
According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2015 report, currently 36.9 million people are living with HIV infections. 2 million became newly infected, and 1.2 million died of AIDS related illnesses. More than 15 million people have received lifesaving ART including low-income and middle income countries by March 2015. Since 2000, availability of ART and AIDS awareness prevented more than 30 million new HIV infections and nearly 8 million AIDS related deaths [3]. Overall, from the year 2000 to 2014, new HIV infections have fallen from 3.1 to 2 million a drop of 35% and AIDS related deaths by 41% (UNAIDS report). The major reduction was also seen in children became infected from 36000 to 4800, a drop of 87% and this change is mainly attributed to availability of ART. From past 14 years, 40% of all people living with HIV had access to ART [3].

 
Currently, the time to initiate ART is largely based on the total number of CD4+ T cell counts observed in infected patients. In healthy individuals, CD4+ counts range from 500 to 1200 cells per cubic millimeter. Loss of body CD4+ T cells is a hallmark of immune compromise caused by human immunodeficiency viral infection [4]. HIV-associated complications and rate of death of infected patients increases with decrease in total number of CD4 T cell counts in peripheral blood (. It has been general practice to postpone the initiation of antiretroviral therapy in patients with a CD4+ T cell counts above 200-350 CD4+ T cells/cubic millimeter. For the first 6 years of this century, the Department of Health and Human Services (DHHS) recommended- on the basis of clinical-trial evidence-that ART be initiated when the CD4+ count dropped to less than 200-250 cells per cubic millimeter [5].

 
Surprisingly however, recommended time to initiate ART in the patients based on observed threshold CD4+ T cell count differed among various guidelines [6]. Most of the earlier studies have focused primarily on the risks and damaging effects of acquired immunodeficiency syndrome (AIDS) and death but fail to address various benefits of initiating antiretroviral therapy in patients with high CD4+ T cell count. One of the possible reasons is that the complications and death are largely attributed to non-AIDS related events in these patients [7, 8]. Since patients on antiretroviral therapy frequently experience drug induced toxicities, some of the studies were also focused on adverse effects of antiretroviral drugs on cardiovascular and renal diseases [9,10], which is an additional parameter to consider before initiation of ART in HIV-1 infected patients with major complications. Short-term risk for death and development of AIDS-causing illnesses are fairly low in individuals with high CD4 T cell counts and for the same reasons, the health care professionals postpone the initiation of the therapy in these patients [11]. However, it is alarming to know that the patients who start treatment with CD4+ counts <350 cells/mm3 never achieve counts >500 cells/mm3 even up to 6 years on ART [12]. In recent past, the recommendations to initiate ART in patients with high CD4 T cell counts are considerably changed due to growing body of evidence on various complications in untreated HIV infections and patients with uncontrolled viremia [5,13]. Cardiovascular (CVD), kidney, liver and lung diseases, neurologic complications, and malignancies are common non-AIDS related diseases observed in patients with high CD4 T cell counts [14]. With this perspective, the decision to initiate ART should always include considering patient’s condition, willingness, available resources and readiness to initiate therapy. In case of developed countries, following the development of effective and customized therapies, 2012 DHHS recommended treatment for anyone living with HIV infection [5]. Whereas, current trend of delay in treating patients with threshold CD4 counts in developing and poor countries needs to be reconsidered based on two of the most recent studies to increase the survival rate and improve quality of living [15,16]. However, another major obstacle to reach this goal is the availability of resources and funding and increase in current funding and concerted efforts might solve these problems.  

 
There is a strong evidence and agreement that patients with CD4+ counts below 200 cells per cubic millimeter are at increased risk for AIDS related events and death and therefore need immediate initiation of ART [14]. In a later trial in Haiti showed that reduced morbidity and mortality among persons in whom ART was initiated at a CD4+ count of 350 cells per cubic millimeter, as compared with those in whom therapy was deferred [17,18]. More recently, a randomized trial to examine the effect of ART on HIV infected persons with CD4+ counts of more than 500 cells per cubic millimeter and with noninfectious and non-AIDS complications of HIV infection [15]. The spectrum of AIDS varies across the globe because of differences in exposures, viral subtypes, diagnostic measures and therapeutic strategies. To achieve results from a larger study group, International Network for strategic Initiatives in Global HIV Trials (INSIGHT) Strategic Timing of Antiretroviral Therapy (START) study groups followed around 4685 patients from 35 countries and distributed equal numbers either into immediate ART group with a median CD4+ count of 651 cells per cubic millimeter or deferred ART with a median CD4+ count of 408 cells per cubic millimeter. They demonstrated that though the initial median plasma viremia in deferred ART initiation group was 3 fold higher than immediate ART initiation group, both of the groups achieved complete viral suppression by 12 months (>97%) [15]. One of the most noticeable differences was gradual increase in CD4+ counts in Immediate-ART-initiation group following ART treatment as compared to deferred-ART-initiation group. During the first year of ART treatment, while CD4+ counts were markedly increased in the first group a declined kinetics were observed in later group, which were stabilized or slightly increased in following years. This directly shows that CD4 T cells and associated immune functions are possibly restored when the therapy is initiated at a stage when the patients maintain higher CD4 T cell numbers (>500 cells per cubic millimeter) as observed in this study and earlier studies. Since patients who recover their CD4 counts to normal levels tend to show clinical improvement and may have lifespan equivalent to uninfected individuals [19,20], the observed trend of increased CD4 T cell counts in immediate ART-initiation group in INSIGHT START study is predicted to improve the quality of their life and provide normal lifespan over deferred-ART initiation setting [15]. There may be many reasons for increased CD4 counts during early initiation ART and previous studies have demonstrated that increase in thymic output, redistribution from lymphoid organs to systemic circulation [21-23] This study and previous studies reiterate the fact that HIV infected patients with lower CD4 T cell numbers (<250 cells per cubic millimeter) may not show complete CD4 T cell recovery upon ART to an extent that was observed in immediate-ART-initiated group of patients with higher CD4 T cell counts at the beginning of the therapy and more or less the damage is irreparable.

 
ART may have additional benefits other than viral suppression in HIV-1 infected patients. Reduced risk of acquiring herpes simplex virus type 2 infection was observed in ART treated patients [24]. Lundgren et al have demonstrated that estimation of risk of death due to a serious AIDS-related event (72%), a serious non-AIDS related event (62%) and because of both (57%) were higher in the deferred-ART-initiation group as compared to immediate-ART-initiation group [15]. Even in the whole study group, death caused by any cause also was 42% higher in deferred-ART-initiation group. In immediate-ART-initiation group, severe cardiovascular disease and non-AIDS-defining cancers were 14% and 2% higher than deferred ART initiation group respectively. Whereas, 6% lower tuberculosis associated deaths were noticed in immediate –ART-initiation group as compared to deferred-initiation group. In a separate study in African cohort (TEMPRANO ANRS 12136 trial), early initiation of ART showed similar benefits over deferred-ART initiation groups of HIV-1 infected patients [25].  

 
There are several obstacles to achieve the final goal of ending AIDS in future years. One, there is still more than 30 percent of HIV infected patients lack access to ART [26]. Two, a larger group of individuals with HIV who are unaware of their infection status because of their avoidance of HIV testing due to stigma and discrimination in the society is one of the major obstacles to control disease in early stages of infection. Three, late diagnosis of HIV infection in resource limited settings. Four, limited funding to treat all of the HIV-1 infected individuals across the globe. Overcoming these obstacles, bring us closer to end the AIDS by 2030 as predicted by UNAIDS.

 
 
Acknowledgements: We thank Anthony Podany for critical input and Courtney Fletcher for support and encouragement. 

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