Impact of Advanced HIV Disease on Quality of Life and Mortality in the Era of Combined Antiretroviral Treatment

Currently, AIDS or severe immunodeficiency remains as a challenge for people with HIV (PWHIV) and healthcare providers. Our purpose was to analyze the impact of advanced HIV disease (AHD) on mortality, life expectancy and health-related quality of life (HRQoL). We reviewed cohort studies and meta-analyses conducted in middle- and high-income countries. To analyze HRQoL, we selected studies that reported overall health and/or physical/mental health scores on a validated HRQoL instrument. AIDS diagnosis supposes a higher risk of mortality during the first six months, remaining higher for 48 months. It has been reported that cancer and cardiovascular disease persist as frequent causes of mortality in PWHIV, especially those with previous or current AHD. PWHIV who initiate combination antiretroviral therapy (cART) with CD4 < 200 cells/µL have significantly lower estimated life expectancy than those with higher counts. AHD is associated with lower HRQoL, and a worse physical health or mental health status. AIDS and non-AIDS defining events are significant predictors of a lower HRQoL, especially physical health status. AHD survivors are in risk of mortality and serious comorbidities, needing special clinical attention and preventive programs for associated comorbidities. Their specific needs should be reflected in HIV guidelines.


Introduction
In the early years of the human immunodeficiency virus (HIV) pandemic, acquired immunodeficiency syndrome (AIDS) was a fatal condition accompanied by severe opportunistic diseases, with physical symptoms such as wasting, diarrhea, fever, and a short-time mortality. In addition, people living with HIV (PWHIV) suffered social isolation, internalized stigma, problems related to drug abuse, depression, anxiety, and other psychosocial conditions [1]. With the advent of high-activity antiretroviral therapy (HAART) in 1996, AIDS mortality decreased dramatically, although serious adverse events secondary to the new antiretroviral drugs began to surface. The HIV population who survived to AIDS, known as long-term survivors [2], frequently suffer a constellation of medical, psychological, and emotional disorders, and low quality of life related to health (HRQoL) [3,4].
Despite improvements in early HIV diagnosis and global efforts to deliver combination antiretroviral therapy (cART), many patients are still at risk of advanced HIV disease (AHD). The Joint United Nations Program on HIV/AIDS (UNAIDS) reported that at the end of 2018, around 770,000 (uncertainty bounds, 570,000-1.1 million) people died from AIDSrelated illnesses worldwide [5]. In 2017, the European Centre for Disease Control reported 3130 AIDS diagnoses in the 28 European Union/European Economic Area (EU/EEA) countries, giving a crude rate of 0.7 cases per 100,000 of the population [6].
AHD continues to have a negative impact among some PWHIV, despite antiretroviral therapy [7]. Currently, surviving to AHD can be a real challenge for some PWHIV and their healthcare providers. Our aim is to review the impact of AHD on mortality and HRQoL in PWHIV living in countries with easy access to cART.

Methodology
Our population of interest was people diagnosed with AHD. We used the stage 3 definition of HIV disease from the Centers for Disease Control and Prevention (CDC), which includes those PWHIV with AIDS or CD4 < 200 cells/µL [8]. For the objectives of this article, we reviewed the scientific literature in PubMed and Google Scholar in English language journals before July 2020, with the condition that most of the study should have been carried out during the 21st century and started after the availability of HAART (1996). We selected cohort studies and meta-analyses conducted in middleand high-income countries with universal access to cART and to healthcare. To identify independent determinants of mortality, loss of life expectancy, and perceived HRQoL, articles had to report appropriate statistics, especially a multivariate regression analysis on the association between AHD and the corresponding endpoint variables. Moreover, to analyze HRQoL, we selected cross-sectional and longitudinal studies that reported overall health and/or physical/mental health scores on a validated HRQoL instrument.
We searched for the terms "mortality", "life expectancy", "cancer", "cardiovascular disease" and "health-related quality of life". Each term was crossed with "AIDS diagnosis" or "advanced HIV disease" or "CD4 cells".
The main reasons to exclude articles were: (1) did not strictly comply with inclusion criteria; (2) did not include patients with AHD or CD4+ lymphocyte counts below 200/µL; and (3) did not include multivariable analysis about the subject of researching. We decided not to review liver disease due to hepatitis C virus (HCV), because the currently available high-active antiviral agents against HCV are decreasing the incidence, morbidity and mortality of serious liver disease in PWHIV.

Factors Associated to AHD or Progression to AIDS
Studies conducted in high-income countries showed that the populations most likely to present for care with AHD are men, heterosexuals, older people, people who inject drugs, migrants, people suffering socioeconomic inequalities, and people with lower educational levels [9,10].

Life Expectancy and Mortality in AHD Patients
Life expectancy in PWHIV on cART has improved worldwide, but an important gap remains compared with the general population [15]. PWHIV at higher risk of mortality in Western countries include people who inject drugs, people living in resourceconstrained settings, and people who are highly stigmatized or who face other barriers such as depression and other mental disorders, access to health services, unemployment, family responsibilities, and so on [5,11,15,16].
In our review, we included 14 studies (Table 1): three analyzed life expectancy, and 11 explored mortality associated with AIDS defining-events (ADEs) and non-AIDS defining-events (NADEs). All of them were cohort studies and were mainly conducted in high-income Western countries (Europe and North America), but one included patients from Israel and Argentina.
Cohort studies are quite homogeneous in this regard. Results from longitudinal cohort studies published during the 21st century demonstrate that even on cART, patients with AHD have an increased risk of mortality related with AIDS and non-AIDS events. PWHIV who initiate cART with CD4 < 200 cells/µL have significantly lower estimated life expectancies [16][17][18] and a higher risk of mortality by ADEs and NADEs than those with higher counts [19][20][21][22]. Patients presenting for care with AIDS have a higher risk of mortality during the first six months, and it persists higher during the 48 months after AIDS diagnosis compared with those without previous AIDS [23,24]. After surviving five years with cART, the mortality of patients who started cART with a low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts [25]. In addition, most of the cohort studies agree that starting cART with higher CD4 counts decrease mortality in PWHIV [26][27][28][29]. These results are independents of gender, age, and type or number of comorbidities (Table 1).

Cancer Incidence and Related Mortality in PWHIV with AHD
Excess of mortality in PWHIV, comparing with the general population of the same sex and age, has been observed in non-AIDS cancer, cardiovascular disease, respiratory diseases, liver diseases, drug abuse, suicide, and other external causes [15]. The more frequent NADEs driving to mortality with previous AIDS or <200 CD4/µL are malignancies, cardiovascular and end-stage liver disease [19,27,28] (Table 1).
Cancers in PWHIV are classified as either AIDS-defining cancers (ADC) or non-AIDS defining cancers (NADC) that includes those related to virus infections (NADCI). We analyzed eight studies on the impact of AHD on cancer development; five were large cohort studies, two were extracted from a Cancer National Registry, and one was a metaanalysis. All of them separately analyzed ADC and NADC in people with previous AIDS or CD4 < 200/cells/µL. Data from these studies demonstrate the strong association between AHD and increased cancer risk in PWHIV (Table 2).
Low CD4 cell count is an independent predictor of developing ADC and NADCI: Kaposi sarcoma, non-Hodgkin lymphoma [30][31][32][33], anal cancer and Hodgkin lymphoma [34][35][36][37]. Data from the ATHENA cohort associate cumulative exposure to CD4 < 200 cells/µL during cART with increased risk of NADCI [37]. Previous AIDS diagnosis is also a risk factor of cancer, compared with those with non-AIDS [36]. Results on the association between AHD and NADC are discordant ( Table 2). Some studies show an association between AHD and lung cancer, colorectal and oral cavity/pharynx cancer [31,35], while other studies find no associations [30].  Regarding mortality, Patel et al. [35] from the HIV Outpatient Study (HOPS) cohort reported that factors associated with all-cause mortality among persons with ADC were a nadir CD4 cell count < 200 cells/mm 3 and HIV RNA ≥ 400 copies/mL. Among persons with NADCI, no associated factors were identified. Among persons with NADC, factors associated with increased mortality were older age at cancer diagnosis, non-white race, nadir CD4 cell count < 200 cells/mm 3 , viral load ≥ 400 copies/mL, and prior or current history of tobacco use.

Cardiovascular Disease-Related Mortality in PWHIV with AHD
The effect of AHD on the pathogenesis of cardiovascular disease (CVD) is not well established. Traditional cardiovascular risk factors seem to play the main role in this condition. However, some data suggest that AHD may influence the incidence and outcome of CVD and strokes. Authors from the NA-ACCORD cohort analyzed the incidence of type 1 (atherothrombotic) myocardial infarction (T1MI) and risk attributable to traditional and HIV-specific factors. The multivariable analysis showed that lower CD4 counts were significatively associated with higher risk T1MI. The adjusted incidence rate ratios (aIRR) for CD4 counts < 100 cells/µL were: 2.19 (95% CI: 1.44-3.33); 100-199 cells/µL: 1.60 (95% CI: 1.09-2.34); and 200-349 cells/µL: 1.37 (95% CI: 1.01-1.86) [38]. In a systematic review and meta-analysis, Eyawo et al. [39] found that CD4 count < 200 cells/µL was associated with higher MI risk compared with ≥200 cells/µL in three studies and HIV VL ≥ 100,000 copies/mL was associated with increased MI risk compared with <100,000 copies/mL in two studies. However, Feinstein et al. reported that significant mortality predictors for T1MI in PWHIV were only high HIV viral load (HIV-VL), renal dysfunction, and older age; and for a type 2 (supply-demand mismatch) MI, low body-mass index and detectable HIV [40].
In a nationwide inpatient sample from the United States, PWHIV with previous AIDS were significantly more likely than uninfected patients to die during hospitalization after admission for MI (OR: 3.03; 95% CI, 1.71-5.38), or stroke (OR: 2.59; 95% CI, 1.97-3.4) [41]. In the same way, in a retrospective cohort study about the outcomes of MI and cardiogenic shock in PWHIV, AIDS was also associated with higher in-hospital mortality compared with HIV people without previous AIDS (28.8% vs. 21.1%; aOR: 4.12 [95% CI: 1.89-9.00]) [42].
The authors of a Taiwanese study reported cytomegalovirus end-organ disease as an independent risk factor for incident all-cause stroke, and particularly ischemic stroke, in PWHIV [43]. Lastly, data from a meta-analysis including 724 cases of intracerebral hemorrhage linked AIDS diagnosis and low CD4 with higher incidence of this event [44].
All these data suggest the high vulnerability and risk of dying after an AHD diagnosis. Mortality related with NADEs could be prevented with the treatment of traditional risk factors such as smoking, elevated total cholesterol, hypertension, and chronic HCV infection [45]. Exhaustive screening of traditional risk factors is necessary to reduce mortality in PWHIV with previous or current AHD.

AHD and Health-Related Quality of Life
We reviewed 11 articles that analyzed the impact of AHD on HRQoL and that complied with the inclusion criteria (Table 3). These articles were heterogeneous, with different populations and different study designs. They used a variety in measurement tools, including generic and HIV-specific ones. Generic HRQoL measures are those applicable across types and severities of disease, across different medical treatments or health interventions, and demographic and cultural subgroups. Disease-specific measures are those that assess specific diagnosis groups or patient populations such as PWHIV. Six of the reviewed articles were cross-sectional studies, and five had a longitudinal design. All studies were conducted in high-income countries, mostly in North America. Sample sizes ranged from 744 to 2508 PWHIV in the cross-sectional studies, and from 265 to 1000 PWHIV in the longitudinal studies.
All the studies found an association between CD4 count and HRQoL. Some associated low CD4 counts with lower overall HRQoL scores or self-perception of health [46][47][48], while others linked low CD4 count to worse physical health status [49] or mental health status [50,51]. A cross-sectional study using a multidimensional HIV-specific HRQoL measure showed that PWHIV with the lowest CD4 counts had the lowest scores in several HRQoL domains, including physical health status [48]. Longitudinal studies found that lower CD4 count predicted worse physical health status and worse mental health status [52][53][54][55][56].
In addition to clinical and biological markers, the studies we reviewed consistently associated several socio-demographic and psychosocial factors with worse HRQoL in PWHIV. These factors included ageing, housing, depression, social support, employment, and HIV-related stigma.     • Ageing led to a longitudinal reduction in PHS.

Discussion and Conclusions
Despite the efficacy and safety of current cART, PWHIV presenting for care with AHD or who progress to AIDS are at higher risk of mortality by new ADEs or NADEs. Longitudinal cohort studies and meta-analyses performed during the cART era demonstrate that AHD is associated with a higher risk of developing ADC and NADC, especially NADCI. Traditional cardiovascular risk factors, exposure to some antiretroviral drugs, and persistent HIV viremia are associated with CVD in PWHIV. However, data from cohort studies suggest that AHD could be associated with stroke, CVD, and related mortality. Patients with previous cytomegalovirus end-organ disease or lower nadir CD4 are at risk of developing ischemic strokes. AHD also leads to worse HRQoL. Most of the studies about HRQoL presented in this review are cross-sectional studies. Unfortunately, longitudinal studies evaluating the quality of life in patients previously diagnosed with AHD are scarce. Of those presented in this review, most include a large number of patients, strengthening the results. These studies agree that lower CD4 and previous AIDS diagnosis are associated with lower HRQoL scores, regardless of the questionnaire used or other known variables associated with worse HRQoL. We need more longitudinal studies that analyze the HRQoL for longer periods of time after an AHD diagnosis. Antiretroviral Treatment guidelines from the World Health Organization (WHO) [57] and from the British HIV Association (BHIVA) [58] consider the AHD as a special issue, but both guidelines focus their interest on the treatment and prevention of opportunist diseases. Our study highlights the need to define AHD as a special state in the spectrum of HIV disease. The high incidence of NADEs and mortality found in AHD patients could be lowered with interventions on traditional risk factors; hence, the importance of screening for risk factors, improving prevention, and creating sustainable care models to implement these interventions during follow-up. We need more longitudinal studies that analyze the HRQoL for longer periods of time after an AHD diagnosis. In our opinion, HIV guidelines should consider AHD patients as a special population whose needs are different from PWHIV who present for care soon after HIV infection.