A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population

A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging... Infect Dis Ther (2018) 7:183–195 https://doi.org/10.1007/s40121-018-0201-6 REVIEW A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population . . . . Anita Chawla Christina Wang Cody Patton Miranda Murray . . Yogesh Punekar Annemiek de Ruiter Corklin Steinhart Received: March 23, 2018 / Published online: May 14, 2018 The Author(s) 2018 central nervous system disorders, cardiovascular ABSTRACT disease, and liver disease. There remains limited evidence describing the economic burden of Human immunodeficiency virus (HIV) is a long-term ART. Overall, an aging HIV popula- chronic infectious disease currently requiring tion treated with long-term ART presents a lifelong antiretroviral therapy (ART). People scenario in which the clinical, humanistic, and living with HIV (PLWH) face an increased risk of economic burden for healthcare systems will comorbidities associated with aging, chronic demand thoughtful policy solutions that pre- HIV, and the toxicity arising from long-term serve access to treatment. Newer treatment ART. A literature review was conducted to regimens with fewer drugs may mitigate some identify the most recent evidence documenting of the cumulative toxicity burden of long-term toxicities associated with long-term ART, par- ART. ticularly among aging PLWH. In general, PLWH Funding: ViiV Healthcare. are at a greater risk of developing fractures, osteoporosis, renal and metabolic disorders, Keywords: Aging; Antiretroviral therapy; HIV/ Enhanced digital features To view enhanced digital AIDS; Toxicity; Two-drug regimen features for this article go to https://doi.org/10.6084/ m9.figshare.6170426. Electronic supplementary material The online INTRODUCTION version of this article (https://doi.org/10.1007/s40121- 018-0201-6) contains supplementary material, which is available to authorized users. Antiretroviral therapy (ART) has led to sub- stantial improvements in the life expectancy of A. Chawla  C. Wang  C. Patton (&) patients infected with human immunodefi- Analysis Group, Inc., Menlo Park, CA, USA ciency virus (HIV), which is now treated as a e-mail: cody.patton@analysisgroup.com chronic disease requiring life-long ART treat- ment [1–3]. Current ART regimens are generally M. Murray  Y. Punekar ViiV Healthcare, Brentford, Middlesex, UK well tolerated with fewer associated severe adverse events (AEs) that are life-threatening or A. de Ruiter that lead to disability or permanent damage in Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, UK the short term compared with older regimens; AE profiles that have been documented across C. Steinhart all classes of ART are reported in Table 1 [4, 5]. ViiV Healthcare, Research Triangle Park, NC, USA 184 Infect Dis Ther (2018) 7:183–195 Table 1 Frequent and severe AEs associated with ART by class. Adapted from EACS October 2017 guidelines [4] Class Frequent AEs (‡ 10% of patients) Severe AEs NRTI Steatosis, peripheral neuropathy, lipoatrophy, Ischemic heart disease, systemic hypersensitivity syndrome, dyslipidemia rhabdomyolysis, hyperlactatemia, pancreatitis, increased fracture risk, Fanconi syndrome NNRTI Depression, sleep disturbances, headache, Suicidal ideation, systemic hypersensitivity, rash dyslipidemia, lower plasma 25(OH) vitamin D PI Dry skin, nausea and diarrhea, hyperbilirubinemia, Hepatitis, ischemic heart disease, intracranial hemorrhage, nephrolithiasis, increase of abdominal fat, dyslipidemia dyslipidemia Boosting Lowering of eGFR None FI None Injection nodules INSTI Nausea, lowering of eGFR, sleep disturbance, Rhabdomyolysis, systemic hypersensitivity syndrome headache (\ 1%) CCR5i None None AE adverse event, CCR5i C–C chemokine receptor 5 inhibitor, eGFR estimated glomerular filtration rate, FI fusion inhibitor, INSTI integrase strand transfer inhibitor, NNRTI non-nucleoside reverse transcriptase inhibitor, NRTI nucleos(t)ide reverse transcriptase inhibitor, PI protease inhibitor There has been a decrease in the proportion of and mortality risk may contribute significantly patients switching or discontinuing treatment, to healthcare resource utilization and costs and fewer patients now discontinue ART com- associated with HIV treatment. Reducing the pared with a decade ago [6]. This decrease can number of ART agents that PLWH require may be attributed to factors including fewer AEs or have the potential to reduce cumulative toxici- intolerance with newer ART regimens as well as ties as well as the economic burden associated research showing that continuous use of ART is with long-term treatment. Novel ART strategies, superior to episodic use [6, 7]. such as two-drug regimens, are currently being Advances in ART have also led to significant explored. While not all two-drug regimens increases in survival among people living with studied to date have demonstrated efficacy and HIV (PLWH) [8]; however, the corollary of a safety results indicative of an alternative to longer lifespan is that PLWH are now faced with current regimens [11], certain regimens have an increased risk of developing comorbidities been shown to provide non-inferior viral sup- and chronic diseases associated with aging in pression along with reduced toxicity in viro- addition to chronic HIV. Approximately 45% of logically stable patients compared with three- PLWH are aged C 50 years, and by 2020 an drug regimens that are currently considered to estimated 70% of Americans with HIV are pro- be standard of care [12–16]. jected to be in this age group [9, 10]. Further- The objective of this review is to provide a more, PLWH are now using ART over a much synthesis of evidence documenting the toxicity longer period of time, and the resulting poten- implications arising from long-term ART use in tial cumulative toxicity that can emerge is not high-income settings, particularly as it relates to fully understood. Not only could such long- an aging population of PLWH. The economic term toxicity lead to poor health status and a burden of AEs resulting from long-term ART use diminished quality of life but ART-related AEs is also assessed. that ultimately result in increases in morbidity Infect Dis Ther (2018) 7:183–195 185 their uninfected peers; of these 13 medications, METHODS only 4 were ART agents [22]. Several harmful effects of polypharmacy in older patients have In this literature review, a combined approach been documented; these include drug–drug of targeted searches of published literature for interactions (DDIs) between ART and therapies pre-specified topics of interest was supple- prescribed to manage non-HIV conditions, with mented with searches to identify additional Category D (consider therapy modification) major studies and clinical guidelines. Searches DDIs reported in 70% of patients and Category were conducted in MEDLINE (via PubMed) X (avoid combination) DDIs reported in 11% of using keywords to identify studies reporting patients older than 60 years [22]. Additionally, a data on the AEs associated with long-term use of loss of treatment efficacy can often result from ART. Searches incorporated HIV-, AIDS-, treat- polypharmacy [23–25]. ment-, and economic-based terms (see supple- Common comorbidities that have known mentary material Table S1 and Table S2 for associations with long-term ART use and complete search strings). Identified studies were chronic HIV infection in older patients include assessed by the authors and those relevant to fracture risk and osteoporosis, renal and meta- the objectives of this review were included. This bolic disorders, central nervous system (CNS) article is based on previously conducted studies disorders, cardiovascular disease, and liver and does not contain any studies with human disease. participants or animals performed by any of the authors. Bone Disease RESULTS As PLWH age, they are at an increased risk for osteoporosis and fragility fractures, indepen- For PLWH, long-term ART use has the potential dent of long-term ART use [25–31]. In a cross- to increase the underlying risk of conditions or sectional study of 202 drug-naı¨ve and drug-ex- diseases associated with both aging and chronic perienced PLWH, age was associated with the HIV infection. Nearly half of PLWH aged risk of fractures [odds ratio (OR) for each C 50 years have at least one major medical year = 1.18; 95% confidence interval (CI): comorbidity, and PLWH have more age-associ- 1.03–1.25; P = 0.01]. Additionally, vertebral ated non-communicable comorbidities fracture was more prevalent among those aged (AANCCs) than age-matched non-infected 50–67 years compared with those aged 31–50 individuals [mean ± standard deviation (SD) (32% vs. 13%; P = 0.008) [32]. A stronger asso- number AANCCs: 1.3 ± 1.14 vs. 1.0 ± 0.95, ciation between HIV infection and major frac- respectively; P \ 0.001] [17, 18]. Furthermore, tures in patients C 59 years [hazard ratio the prevalence of comorbid conditions such as (HR) = 2.11; 95% CI 1.05–4.22; P = 0.035] cardiovascular disease (CVD), diabetes mellitus compared with patients \ 59 (HR = 1.35; 95% (DM), and osteoporosis among PLWH signifi- CI 0.88–2.07; P = 0.17) has similarly been cantly increases as PLWH age [19]. reported based on an analysis of medical records Chronic comorbidities also contribute to a of Spanish PLWH (n = 2489) [30]. Additionally, greater pill burden, often resulting in additional the prevalence of fractures was higher among complications [20, 21]. In an analysis of the PLWH compared with HIV-uninfected peers for Swiss HIV Cohort Study, the proportion of both men (P \ 0.001) and women (P = 0.002) in PLWH who were taking at least four non-HIV a population-based study conducted at a large co-medications was 5.2% among those aged US healthcare system (n = 8525 PLWH; 50–64 years compared with 14.2% for those n = 2,208,792 HIV-uninfected), and the differ- aged C 64 [19]. In a separate retrospective ences widened with increasing age [27]. chart review of 89 older (C 60 years) PLWH, the The progression of bone disease among aging median number of concomitant medications PLWH is further complicated by long-term was 13 (range 9–17) compared with only 6 for 186 Infect Dis Ther (2018) 7:183–195 toxicity concerns observed among patients sectional retrospective case–control study found treated with certain ART regimens. There is that PLWH had a higher prevalence of both evidence that certain nucleos(t)ide reverse renal failure and DM compared with HIV-un- transcriptase inhibitors (NRTIs) are associated infected controls, especially among those with declines in bone mineral density (BMD) aged [ 60 years (24.26% vs. 0.49% and 38.97% and an increased risk of fractures in some vs. 15.93%, respectively; both P \ 0.001) [29]. studies; however, the issue remains controver- Among PLWH in the John Hopkins HIV Clinical sial [33–36]. In an evaluation of HIV-infected Cohort who developed CKD (n = 284), the patients in the Veterans Health Administra- adjusted IRRs were 3.47 (95% CI 2.07–5.81; tion’s (VHA) Clinical Case Registry (n = 56,660), P \ 0.001) and 1.45 (95% CI 1.01–2.09; extended use of tenofovir disoproxil fumarate P = 0.044) for those [ 55 years and 45–55 years was associated with an increased risk of osteo- old, respectively, relative to PLWH \ 45 years of porotic fractures (yearly HR = 1.08; P \ 0.001), age [38]. although this finding was no longer significant Toxicity resulting from long-term ART use after multivariate adjustment for age, race, that affects renal and metabolic health may tobacco use, diabetes, chronic kidney disease further compound the overall disease burden in (CKD), hepatitis C virus (HCV), and body mass aging PLWH. Long-term use of ART has been index (HR = 1.06; P = 0.079) [35]. Recent results linked to an increased risk of CKD and DM. In from the EuroSIDA study (n = 20,854) showed particular, an analysis of over 10,000 patients that ever (vs. never), current (vs. no current demonstrated a 33% increased risk of CKD for use), and cumulative tenofovir disoproxil each additional year of tenofovir disoproxil fumarate use was associated with increased fumarate use (HR = 1.33; 95% CI 1.18–1.51; fracture risk among PLWH in a univariate P \ 0.0001) [39]. A similar analysis of 21,590 analysis; however, there was no association for HIV-infected men found that the overall 5-year any other ART investigated [36]. After multi- event rate of CKD in tenofovir disoproxil variate adjustment, the association between fumarate users compared with non-users was ever and current tenofovir disoproxil fumarate 7.7% versus 3.8%, respectively (overall adjusted use remained significant [adjusted incidence HR = 2.0; 95% CI 1.8–2.2) [40]. Based on find- rate ratio (IRR) = 1.40; 95% CI 1.15–1.70; ings from the EuroSIDA study, higher rates of P = 0.0008 and adjusted IRR = 1.25; 95% CI CKD have also been associated with a more 1.05–1.49; P = 0.012, respectively], while frequent use of atazanavir (annual IRR = 1.21, cumulative tenofovir disoproxil fumarate use P = 0.003) and lopinavir/ritonavir (annual (per 5 years additional exposure) did not remain IRR = 1.08; P = 0.030) [41]. Finally, in a significant (adjusted IRR = 1.08; 95% CI prospective study of 1524 HIV-infected women 0.94–1.25; P = 0.027) [36]. Recently, tenofovir with no evidence of DM, longer cumulative use alafenamide has been used in place of tenofovir of NRTIs was associated with an increased inci- disoproxil fumarate in ART regimens and has dence of DM over the study period (October demonstrated smaller reductions in hip and 2000 to March 2006) compared with no use of lumbar spine BMD compared with tenofovir NRTIs (0–3 years NRTI use relative HR = 1.81; disoproxil fumarate (P \ 0.0001) [4, 37]. How- 95% CI 0.83–3.93; C 3 years NRTI use relative ever, long-term data on potential toxicity asso- HR = 2.64; 95% CI 1.11–6.32) [42]. ciated with tenofovir alafenamide-containing regimens are lacking [4]. Central Nervous System Renal and Metabolic Disorders Data on the effect of aging on CNS function among PLWH are mixed, and are complicated Older PLWH are at an increased risk of devel- by potential synergistic effects of comorbid oping premature renal failure and DM com- conditions including mental illness, the natural pared with the general population [29]. A cross- aging process, and HIV infection, each of which Infect Dis Ther (2018) 7:183–195 187 may contribute to decline in cognitive function attempted or completed suicide (HR = 2.58; [43–46]. Furthermore, while there are various 95% CI 0.94–7.06; P = 0.065) with efavirenz use screening tools available, there is a lack of clear compared with non-efavirenz regimens [50]. consensus among care providers on how to However, there is conflicting evidence to sup- diagnose and manage HIV-associated neu- port this association; a retrospective analysis of rocognitive disorder [47, 48]. In a longitudinal data from the US Food and Drug Administration case–control study including 54 PLWH and 30 Adverse Event Reporting System found that HIV-uninfected individuals, the interaction of disproportionality scores for efavirenz were HIV and age significantly predicted longitudinal below the pre-determined threshold for a decline in verbal memory performance, sug- potential association for increased suicidality gesting that older age was associated with a [51]. The AEs associated with efavirenz may be greater decline in the HIV-positive group [43]. related to the dose of the drug; results from the Additionally, in a prospective study of 146 ENCORE-1 trial showed that a dose of 400 mg PLWH with normal neurocognitive function at efavirenz provided non-inferior efficacy and baseline, PLWH were nearly five times as likely had fewer AEs than the standard dose of 600 mg to have a neurocognitive disorder after efavirenz when combined with tenofovir plus 14 months follow-up than patients without emtricitabine in ART-naı¨ve patients [52]. Rilpi- HIV; however, a logistic regression analysis virine has been studied as an alternative treat- found no effect of age (B 40 or C 50 years) ment to efavirenz in combination with two among PLWH on incident neurocognitive dis- background NRTIs; this combination demon- orders over the same follow-up period strated a significantly lower incidence of neu- (P = 0.410) [44]. In contrast, in a cross-sectional rological AEs compared with efavirenz in HIV-1 study (n = 392), older PLWH were at a higher treatment-naı¨ve patients enrolled in the ECHO risk of exhibiting cognitive impairment com- and THRIVE trials [53, 54]. Improved neuro- pared with younger PLWH (OR = 2.28; 95% CI logical tolerability outcomes were also observed 1.35–3.82; P = 0.002), although the extent to in a study of patients switching from an efavir- which the cognitive impairment is enz-containing regimen to one containing ril- attributable solely to HIV or to an interaction pivirine [55]. between HIV infection and other age-related In addition to efavirenz-related toxicity, a diseases is not fully understood [45]. retrospective analysis evaluating patients with The potentially increased risk for impaired HIV who were treated with dolutegravir, ralte- CNS function among older PLWH is further gravir, and elvitegravir showed rates of neu- complicated by evidence of an association ropsychiatric AEs leading to discontinuation at between long-term ART and neurocognitive 12/24 months of 5.6/6.7%, 0.7/1.5%, and 1.9/ functioning. An analysis of neurocognitive 2.3%, respectively. In patients older than functioning in patients from the CNS HIV 60 years, the discontinuation rate due to neu- Antiretroviral Therapy Effects Research cohort ropsychiatric AEs for dolutegravir was nearly found that patients with long-term (median three-fold higher compared with younger 17.9 months) use of efavirenz had worse speed patients [56]. However, a recent analysis of five of information processing (P = 0.04), verbal phase 3 clinical trials involving patients treated fluency (P = 0.03), and working memory with dolutegravir-based regimens found that (P = 0.03) relative to patients using ritonavir- psychiatric symptoms were reported with low boosted lopinavir [49]. Additionally, efavirenz frequencies, were generally mild to moderate in has been shown to contribute to other serious intensity, and rarely necessitated dolutegravir long-term effects; a pre-specified retrospective discontinuation, similar to other commonly analysis of four AIDS Clinical Trial Group prescribed anchor drugs, including efavirenz, studies reported a higher risk of suicidality raltegravir, and darunavir [57]. (HR = 2.28; 95% CI 1.27–4.10; P = 0.006), defined as suicide ideation, attempted or com- pleted suicide, or a numerically higher risk of 188 Infect Dis Ther (2018) 7:183–195 Cardiovascular Disease treatment (adjusted RR = 1.98, 95% CI 1.72–2.29) [65, 69]. Rates of CVD mortality, acute MI risk, and ischemic stroke risk increase with age among Liver Disease PLWH, and the absolute risk for CVD is expec- ted to increase in parallel with age [58–61]. A Liver-related morbidity and mortality are major large US population-based cohort study showed concerns for PLWH, with liver disease account- that proportionate CVD mortality in PLWH ing for approximately 13% of all deaths among increased from 1.95% in 1999 to 4.62% in 2013 PLWH [70]. As a person ages, the regenerative (P \ 0.0001) [59]. By comparison, the general capacity of the liver declines. In addition, population saw a decrease in proportionate accelerated fibrogenesis has been observed in CVD mortality over the same 15-year time per- patients with HIV/HCV co-infection, although iod [59]. An analyses of male veterans direct acting antivirals have now been shown to (n = 76,835) found a higher risk for ischemic effectively treat and cure HCV infection in stroke among HIV-infected versus HIV-unin- patients with HIV/HCV co-infection at rates fected veterans (adjusted HR = 1.17, 95% CI similar to patients without HIV co-infection 1.01–1.36; P \ 0.04) [60]. A separate analysis of [71, 72]. However, there are limited data indi- 82,459 participants in the same cohort found cating that curing HCV in HIV/HCV co-infected that HIV-positive veterans had an increased risk patients reverses hepatic damage. Older age is of incident acute MI compared with uninfected also associated with increased risk of mito- veterans (adjusted HR = 1.48, 95% CI chondrial dysfunction, increased polyphar- 1.27–1.72) [61]. In addition, the mean (95% CI) macy, worse prognosis of alcoholic liver disease, rate of acute MI events per 1000 person-years greater severity of non-alcoholic fatty liver dis- increased with age in HIV-infected veterans ease, and an increased risk of liver cancer [73]. compared with uninfected veterans [2.0 Although nonalcoholic steatohepatitis (NASH) (1.6–2.4) vs. 1.5 (1.3–1.7) for those aged 40–- and nonalcoholic fatty liver disease (NAFLD) are 49 years; 3.9 (3.3–4.5) vs. 2.2 (1.9–2.5) for those frequently observed in PLWH, use of specific aged 50–59; and 5.0 (3.8–6.7) vs. 3.3 (2.6–4.2) ART agents and duration of ART have not been for those aged 60–69, respectively; P \ 0.05 for established as risk factors [74]. NASH and all] [61]. However, it is difficult to discern to NAFLD may be emerging comorbidities in this what extent the survival effect is leading to high population based on the association between rates of CVD in the aging HIV population. HIV and metabolic syndrome, which has a The increased risk for CVD among older reported prevalence in patients with HIV from PLWH may be exacerbated by cumulative toxi- 11.2% up to 45.4% [75]. city associated with ART. One study While the increased risk of liver disease (n = 23,437) of PLWH showed that the inci- among older PLWH is established, evidence dence of MI over more than 6 years of follow-up describing the association between long-term was higher in patients treated with PIs than ART use and liver-related toxicity is variable. In those not treated with PIs (6.01 per 1000 per- a study of 23,441 patients treated with NRTI- son-years vs. 1.53 per 1000 person years, based ART, increased liver-related mortality has respectively) [62]. After multivariate adjust- been observed with continuing use (annual ment, the relative rate of MI per year of PI use relative risk = 1.11; 95% CI 1.02–1.12, P = 0.02) was 1.16 (95% CI 1.10–1.23) [62]. The data [76]. However, a large study of 22,910 patients regarding any association between abacavir and without hepatitis virus co-infection over CVD risk are very mixed and the issue remains 114,478 person-years of follow-up (D.A.D. controversial [63–69]. Recently updated data cohort) found that there were 12 liver-related from the D:A:D cohort (n = 49,717) found that deaths resulting in an incidence of 0.10/1000 current abacavir use was associated with a 98% person-years [77]. Seven deaths were due to increase in the rate of MI among PLWH com- severe alcohol use and five were due to pared with PLWH not currently on abacavir Infect Dis Ther (2018) 7:183–195 189 established ART-related toxicity, the latter of Potential for New Therapies to Improve Long-Term Outcomes which resulted in an ART-related mortality incidence of 0.04/1000 person-years. The increased risk of liver-related AEs, including Among PLWH, shifting from targeting an acute liver fibrosis, with use of specific NRTIs such as infection to managing a chronic disease didanosine is well known [78]. As a result of requires new approaches to treatment and drug these known AEs, current treatment guidelines regimens that ultimately achieve viral suppres- no longer recommend the use of didanosine sion while minimizing cumulative toxicities. [5, 79]. While continued improvements in ART cannot fully address issues related to chronic inflam- Economic Burden Associated with ART- mation and other comorbidities associated with HIV and long-term ART in aging patients, such Related Cumulative Toxicity regimens have the potential to improve patient adherence, reduce pill burden, and ultimately There is limited evidence describing the eco- lower the economic impact of cumulative toxi- nomic burden associated with cumulative toxi- cities. Novel approaches to treatment in certain city that results from long-term ART use in older patient populations include ART regimens PLWH. Nevertheless, short-term toxicity-related taken 4 days per week compared with continu- costs among PLWH who are treated with ART ous ART 7 days per week (QUATUOR trial) [84], have been documented, and there is an expec- the use of long-acting injectable formulations tation that healthcare costs will increase com- [85], and two-drug regimens [13, 16, 85–87]. mensurately as PLWH age. In a retrospective Assuming viral loads can be controlled with Medicaid claims analysis of PLWH treated with fewer drugs in a treatment regimen, the risk of ATV or darunavir (n = 2426), the mean ± SD toxicity associated with long-term ART may be per-patient per-month costs of all medically lowered. Recent head-to-head studies of two- attended AEs were US$3879 ± $6635 and drug regimens comparing either atazanavir–ri- $5354 ± $8127, respectively [80]. In another US tonavir plus lamivudine or rilpivirine plus boos- claims analysis of PLWH treated with NNRTIs ted darunavir to currently recommended three- (n = 2548), mean total healthcare costs or four-drug ART in virologically stable patients (12 months) were estimated to be have shown non-inferior efficacy and favorable $27,299 ± $37,170, and annual AE-associated AE profiles for two-drug regimens [13, 16]. Stud- costs were $608 ± $3897 [81]. Costs varied from ies investigating treatment switching from three- $586 for lipid disorders to $4434 for nausea/ or four-drug regimens to two- or one-drug regi- vomiting. A retrospective US case–control study mens in virologically stable patients have also found that for patients who had initiated ART demonstrated non-inferior efficacy and compa- within the last 12 months, the median differ- rable or a more favorable AE profile associated ence (episode with event of interest vs. without with regimens that include fewer drugs event of interest) in total all-cause healthcare [12, 14, 15, 85–87]; several switch studies are costs was $3310 for managing diabetes/insulin ongoing [88–91]. These recent head-to-head tri- resistance, $2792 for lipid disorders, $1389 for a als and switch studies are generally limited to a renal disorder event, $390 for rash, $357 for a duration of 1 year or less, and may therefore somnolence/sleep event, and $212 for a hepatic underestimate the benefits of initiating or disorder event [82]. Aging in the population of switching to simplified regimens that potentially PLWH is likely to add to the cost of HIV man- have fewer cumulative long-term toxicities. agement; between 1999 and 2011, the propor- tion of older PLWH increased from 9.6 to 25.4%, and proportional costs increased from LIMITATIONS 25 to 31% [83]. The findings reported in this literature review are subject to several limitations. The review 190 Infect Dis Ther (2018) 7:183–195 was non-systematic and thus did not identify the data in this study and take complete literature from a broad set of databases or responsibility for the integrity of the data and undergo dual-reviewer study screening and accuracy of the data analysis. evaluation. Additionally, while we attempted to Medical Writing and Editorial Assis- include impactful and meaningful studies, we tance. The authors thank Marcia Reinhart, did not conduct a formal quality assessment DPhil, of Analysis Group Inc., for providing and thus the quality of data reported may vary. medical writing and editorial support; Analysis Furthermore, not all included studies were Group received consultancy fees from ViiV case–control studies and caution should be used Healthcare for this support. when interpreting findings of excess comor- bidities among PLWH. Indeed, while not the Authorship. All named authors meet the focus of this review, lifestyle factors that affect International Committee of Medical Journal patients without HIV as well as PLWH and that Editors (ICMJE) criteria for authorship for this lead to age-related comorbidities may also article, take responsibility for the integrity of complicate treatment outcomes among PLWH. the work as a whole, and have given their Finally, the apparent lack of literature focusing approval for this version to be published. on the economic burden of long-term ART toxicities may be a result of the non-systematic Disclosures. Miranda Murray is an employee nature of the review, but may also highlight an of ViiV Healthcare. Yogesh Punekar is an important evidence gap and area of potential employee of ViiV Healthcare. Annemiek de future research. Ruiter was affiliated with Guy’s and St Thomas’ NHS Foundation Trust, during the conduct of this review. Annemiek de Ruiter is now an CONCLUSION employee of ViiV Healthcare, Brentford, Mid- dlesex, UK. Corklin Steinhart is an employee of Potential cumulative toxicity remains a concern ViiV Healthcare. Anita Chawla is an employee as more patients experience long-term treat- of Analysis Group, Inc. Cody Patton is an ment and are at greater risk for chronic diseases employee of Analysis Group, Inc. Christina associated with aging, despite recent advances Wang was an employee of Analysis Group, Inc., in ART that have significantly increased the life during the conduct of this review. Christina expectancy of PLWH and offer better safety Wang is now a medical student at University of profiles. Newer treatment regimens with fewer California, San Francisco, California, USA. drugs may help mitigate the clinical, humanis- Analysis Group, Inc., has received consultancy tic, and economic burden of cumulative toxic- fees from ViiV Healthcare to carry out this ity that emerges because of long-term use of research. ART. Together, aging and long-term treatment of HIV as a chronic disease imply the risk of Compliance with Ethics Guidelines. This greater economic burden for healthcare sys- article is based on previously conducted studies tems, which will demand thoughtful policy and does not contain any studies with human solutions that preserve access to innovative participants or animals performed by any of the ART. authors. Data Availability. All data generated or ACKNOWLEDGEMENTS analyzed during this study are included in this published article/as supplementary information files. Funding. Sponsorship for this study and article processing charges were funded by ViiV Open Access. 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A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population

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Abstract

Infect Dis Ther (2018) 7:183–195 https://doi.org/10.1007/s40121-018-0201-6 REVIEW A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population . . . . Anita Chawla Christina Wang Cody Patton Miranda Murray . . Yogesh Punekar Annemiek de Ruiter Corklin Steinhart Received: March 23, 2018 / Published online: May 14, 2018 The Author(s) 2018 central nervous system disorders, cardiovascular ABSTRACT disease, and liver disease. There remains limited evidence describing the economic burden of Human immunodeficiency virus (HIV) is a long-term ART. Overall, an aging HIV popula- chronic infectious disease currently requiring tion treated with long-term ART presents a lifelong antiretroviral therapy (ART). People scenario in which the clinical, humanistic, and living with HIV (PLWH) face an increased risk of economic burden for healthcare systems will comorbidities associated with aging, chronic demand thoughtful policy solutions that pre- HIV, and the toxicity arising from long-term serve access to treatment. Newer treatment ART. A literature review was conducted to regimens with fewer drugs may mitigate some identify the most recent evidence documenting of the cumulative toxicity burden of long-term toxicities associated with long-term ART, par- ART. ticularly among aging PLWH. In general, PLWH Funding: ViiV Healthcare. are at a greater risk of developing fractures, osteoporosis, renal and metabolic disorders, Keywords: Aging; Antiretroviral therapy; HIV/ Enhanced digital features To view enhanced digital AIDS; Toxicity; Two-drug regimen features for this article go to https://doi.org/10.6084/ m9.figshare.6170426. Electronic supplementary material The online INTRODUCTION version of this article (https://doi.org/10.1007/s40121- 018-0201-6) contains supplementary material, which is available to authorized users. Antiretroviral therapy (ART) has led to sub- stantial improvements in the life expectancy of A. Chawla  C. Wang  C. Patton (&) patients infected with human immunodefi- Analysis Group, Inc., Menlo Park, CA, USA ciency virus (HIV), which is now treated as a e-mail: cody.patton@analysisgroup.com chronic disease requiring life-long ART treat- ment [1–3]. Current ART regimens are generally M. Murray  Y. Punekar ViiV Healthcare, Brentford, Middlesex, UK well tolerated with fewer associated severe adverse events (AEs) that are life-threatening or A. de Ruiter that lead to disability or permanent damage in Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, UK the short term compared with older regimens; AE profiles that have been documented across C. Steinhart all classes of ART are reported in Table 1 [4, 5]. ViiV Healthcare, Research Triangle Park, NC, USA 184 Infect Dis Ther (2018) 7:183–195 Table 1 Frequent and severe AEs associated with ART by class. Adapted from EACS October 2017 guidelines [4] Class Frequent AEs (‡ 10% of patients) Severe AEs NRTI Steatosis, peripheral neuropathy, lipoatrophy, Ischemic heart disease, systemic hypersensitivity syndrome, dyslipidemia rhabdomyolysis, hyperlactatemia, pancreatitis, increased fracture risk, Fanconi syndrome NNRTI Depression, sleep disturbances, headache, Suicidal ideation, systemic hypersensitivity, rash dyslipidemia, lower plasma 25(OH) vitamin D PI Dry skin, nausea and diarrhea, hyperbilirubinemia, Hepatitis, ischemic heart disease, intracranial hemorrhage, nephrolithiasis, increase of abdominal fat, dyslipidemia dyslipidemia Boosting Lowering of eGFR None FI None Injection nodules INSTI Nausea, lowering of eGFR, sleep disturbance, Rhabdomyolysis, systemic hypersensitivity syndrome headache (\ 1%) CCR5i None None AE adverse event, CCR5i C–C chemokine receptor 5 inhibitor, eGFR estimated glomerular filtration rate, FI fusion inhibitor, INSTI integrase strand transfer inhibitor, NNRTI non-nucleoside reverse transcriptase inhibitor, NRTI nucleos(t)ide reverse transcriptase inhibitor, PI protease inhibitor There has been a decrease in the proportion of and mortality risk may contribute significantly patients switching or discontinuing treatment, to healthcare resource utilization and costs and fewer patients now discontinue ART com- associated with HIV treatment. Reducing the pared with a decade ago [6]. This decrease can number of ART agents that PLWH require may be attributed to factors including fewer AEs or have the potential to reduce cumulative toxici- intolerance with newer ART regimens as well as ties as well as the economic burden associated research showing that continuous use of ART is with long-term treatment. Novel ART strategies, superior to episodic use [6, 7]. such as two-drug regimens, are currently being Advances in ART have also led to significant explored. While not all two-drug regimens increases in survival among people living with studied to date have demonstrated efficacy and HIV (PLWH) [8]; however, the corollary of a safety results indicative of an alternative to longer lifespan is that PLWH are now faced with current regimens [11], certain regimens have an increased risk of developing comorbidities been shown to provide non-inferior viral sup- and chronic diseases associated with aging in pression along with reduced toxicity in viro- addition to chronic HIV. Approximately 45% of logically stable patients compared with three- PLWH are aged C 50 years, and by 2020 an drug regimens that are currently considered to estimated 70% of Americans with HIV are pro- be standard of care [12–16]. jected to be in this age group [9, 10]. Further- The objective of this review is to provide a more, PLWH are now using ART over a much synthesis of evidence documenting the toxicity longer period of time, and the resulting poten- implications arising from long-term ART use in tial cumulative toxicity that can emerge is not high-income settings, particularly as it relates to fully understood. Not only could such long- an aging population of PLWH. The economic term toxicity lead to poor health status and a burden of AEs resulting from long-term ART use diminished quality of life but ART-related AEs is also assessed. that ultimately result in increases in morbidity Infect Dis Ther (2018) 7:183–195 185 their uninfected peers; of these 13 medications, METHODS only 4 were ART agents [22]. Several harmful effects of polypharmacy in older patients have In this literature review, a combined approach been documented; these include drug–drug of targeted searches of published literature for interactions (DDIs) between ART and therapies pre-specified topics of interest was supple- prescribed to manage non-HIV conditions, with mented with searches to identify additional Category D (consider therapy modification) major studies and clinical guidelines. Searches DDIs reported in 70% of patients and Category were conducted in MEDLINE (via PubMed) X (avoid combination) DDIs reported in 11% of using keywords to identify studies reporting patients older than 60 years [22]. Additionally, a data on the AEs associated with long-term use of loss of treatment efficacy can often result from ART. Searches incorporated HIV-, AIDS-, treat- polypharmacy [23–25]. ment-, and economic-based terms (see supple- Common comorbidities that have known mentary material Table S1 and Table S2 for associations with long-term ART use and complete search strings). Identified studies were chronic HIV infection in older patients include assessed by the authors and those relevant to fracture risk and osteoporosis, renal and meta- the objectives of this review were included. This bolic disorders, central nervous system (CNS) article is based on previously conducted studies disorders, cardiovascular disease, and liver and does not contain any studies with human disease. participants or animals performed by any of the authors. Bone Disease RESULTS As PLWH age, they are at an increased risk for osteoporosis and fragility fractures, indepen- For PLWH, long-term ART use has the potential dent of long-term ART use [25–31]. In a cross- to increase the underlying risk of conditions or sectional study of 202 drug-naı¨ve and drug-ex- diseases associated with both aging and chronic perienced PLWH, age was associated with the HIV infection. Nearly half of PLWH aged risk of fractures [odds ratio (OR) for each C 50 years have at least one major medical year = 1.18; 95% confidence interval (CI): comorbidity, and PLWH have more age-associ- 1.03–1.25; P = 0.01]. Additionally, vertebral ated non-communicable comorbidities fracture was more prevalent among those aged (AANCCs) than age-matched non-infected 50–67 years compared with those aged 31–50 individuals [mean ± standard deviation (SD) (32% vs. 13%; P = 0.008) [32]. A stronger asso- number AANCCs: 1.3 ± 1.14 vs. 1.0 ± 0.95, ciation between HIV infection and major frac- respectively; P \ 0.001] [17, 18]. Furthermore, tures in patients C 59 years [hazard ratio the prevalence of comorbid conditions such as (HR) = 2.11; 95% CI 1.05–4.22; P = 0.035] cardiovascular disease (CVD), diabetes mellitus compared with patients \ 59 (HR = 1.35; 95% (DM), and osteoporosis among PLWH signifi- CI 0.88–2.07; P = 0.17) has similarly been cantly increases as PLWH age [19]. reported based on an analysis of medical records Chronic comorbidities also contribute to a of Spanish PLWH (n = 2489) [30]. Additionally, greater pill burden, often resulting in additional the prevalence of fractures was higher among complications [20, 21]. In an analysis of the PLWH compared with HIV-uninfected peers for Swiss HIV Cohort Study, the proportion of both men (P \ 0.001) and women (P = 0.002) in PLWH who were taking at least four non-HIV a population-based study conducted at a large co-medications was 5.2% among those aged US healthcare system (n = 8525 PLWH; 50–64 years compared with 14.2% for those n = 2,208,792 HIV-uninfected), and the differ- aged C 64 [19]. In a separate retrospective ences widened with increasing age [27]. chart review of 89 older (C 60 years) PLWH, the The progression of bone disease among aging median number of concomitant medications PLWH is further complicated by long-term was 13 (range 9–17) compared with only 6 for 186 Infect Dis Ther (2018) 7:183–195 toxicity concerns observed among patients sectional retrospective case–control study found treated with certain ART regimens. There is that PLWH had a higher prevalence of both evidence that certain nucleos(t)ide reverse renal failure and DM compared with HIV-un- transcriptase inhibitors (NRTIs) are associated infected controls, especially among those with declines in bone mineral density (BMD) aged [ 60 years (24.26% vs. 0.49% and 38.97% and an increased risk of fractures in some vs. 15.93%, respectively; both P \ 0.001) [29]. studies; however, the issue remains controver- Among PLWH in the John Hopkins HIV Clinical sial [33–36]. In an evaluation of HIV-infected Cohort who developed CKD (n = 284), the patients in the Veterans Health Administra- adjusted IRRs were 3.47 (95% CI 2.07–5.81; tion’s (VHA) Clinical Case Registry (n = 56,660), P \ 0.001) and 1.45 (95% CI 1.01–2.09; extended use of tenofovir disoproxil fumarate P = 0.044) for those [ 55 years and 45–55 years was associated with an increased risk of osteo- old, respectively, relative to PLWH \ 45 years of porotic fractures (yearly HR = 1.08; P \ 0.001), age [38]. although this finding was no longer significant Toxicity resulting from long-term ART use after multivariate adjustment for age, race, that affects renal and metabolic health may tobacco use, diabetes, chronic kidney disease further compound the overall disease burden in (CKD), hepatitis C virus (HCV), and body mass aging PLWH. Long-term use of ART has been index (HR = 1.06; P = 0.079) [35]. Recent results linked to an increased risk of CKD and DM. In from the EuroSIDA study (n = 20,854) showed particular, an analysis of over 10,000 patients that ever (vs. never), current (vs. no current demonstrated a 33% increased risk of CKD for use), and cumulative tenofovir disoproxil each additional year of tenofovir disoproxil fumarate use was associated with increased fumarate use (HR = 1.33; 95% CI 1.18–1.51; fracture risk among PLWH in a univariate P \ 0.0001) [39]. A similar analysis of 21,590 analysis; however, there was no association for HIV-infected men found that the overall 5-year any other ART investigated [36]. After multi- event rate of CKD in tenofovir disoproxil variate adjustment, the association between fumarate users compared with non-users was ever and current tenofovir disoproxil fumarate 7.7% versus 3.8%, respectively (overall adjusted use remained significant [adjusted incidence HR = 2.0; 95% CI 1.8–2.2) [40]. Based on find- rate ratio (IRR) = 1.40; 95% CI 1.15–1.70; ings from the EuroSIDA study, higher rates of P = 0.0008 and adjusted IRR = 1.25; 95% CI CKD have also been associated with a more 1.05–1.49; P = 0.012, respectively], while frequent use of atazanavir (annual IRR = 1.21, cumulative tenofovir disoproxil fumarate use P = 0.003) and lopinavir/ritonavir (annual (per 5 years additional exposure) did not remain IRR = 1.08; P = 0.030) [41]. Finally, in a significant (adjusted IRR = 1.08; 95% CI prospective study of 1524 HIV-infected women 0.94–1.25; P = 0.027) [36]. Recently, tenofovir with no evidence of DM, longer cumulative use alafenamide has been used in place of tenofovir of NRTIs was associated with an increased inci- disoproxil fumarate in ART regimens and has dence of DM over the study period (October demonstrated smaller reductions in hip and 2000 to March 2006) compared with no use of lumbar spine BMD compared with tenofovir NRTIs (0–3 years NRTI use relative HR = 1.81; disoproxil fumarate (P \ 0.0001) [4, 37]. How- 95% CI 0.83–3.93; C 3 years NRTI use relative ever, long-term data on potential toxicity asso- HR = 2.64; 95% CI 1.11–6.32) [42]. ciated with tenofovir alafenamide-containing regimens are lacking [4]. Central Nervous System Renal and Metabolic Disorders Data on the effect of aging on CNS function among PLWH are mixed, and are complicated Older PLWH are at an increased risk of devel- by potential synergistic effects of comorbid oping premature renal failure and DM com- conditions including mental illness, the natural pared with the general population [29]. A cross- aging process, and HIV infection, each of which Infect Dis Ther (2018) 7:183–195 187 may contribute to decline in cognitive function attempted or completed suicide (HR = 2.58; [43–46]. Furthermore, while there are various 95% CI 0.94–7.06; P = 0.065) with efavirenz use screening tools available, there is a lack of clear compared with non-efavirenz regimens [50]. consensus among care providers on how to However, there is conflicting evidence to sup- diagnose and manage HIV-associated neu- port this association; a retrospective analysis of rocognitive disorder [47, 48]. In a longitudinal data from the US Food and Drug Administration case–control study including 54 PLWH and 30 Adverse Event Reporting System found that HIV-uninfected individuals, the interaction of disproportionality scores for efavirenz were HIV and age significantly predicted longitudinal below the pre-determined threshold for a decline in verbal memory performance, sug- potential association for increased suicidality gesting that older age was associated with a [51]. The AEs associated with efavirenz may be greater decline in the HIV-positive group [43]. related to the dose of the drug; results from the Additionally, in a prospective study of 146 ENCORE-1 trial showed that a dose of 400 mg PLWH with normal neurocognitive function at efavirenz provided non-inferior efficacy and baseline, PLWH were nearly five times as likely had fewer AEs than the standard dose of 600 mg to have a neurocognitive disorder after efavirenz when combined with tenofovir plus 14 months follow-up than patients without emtricitabine in ART-naı¨ve patients [52]. Rilpi- HIV; however, a logistic regression analysis virine has been studied as an alternative treat- found no effect of age (B 40 or C 50 years) ment to efavirenz in combination with two among PLWH on incident neurocognitive dis- background NRTIs; this combination demon- orders over the same follow-up period strated a significantly lower incidence of neu- (P = 0.410) [44]. In contrast, in a cross-sectional rological AEs compared with efavirenz in HIV-1 study (n = 392), older PLWH were at a higher treatment-naı¨ve patients enrolled in the ECHO risk of exhibiting cognitive impairment com- and THRIVE trials [53, 54]. Improved neuro- pared with younger PLWH (OR = 2.28; 95% CI logical tolerability outcomes were also observed 1.35–3.82; P = 0.002), although the extent to in a study of patients switching from an efavir- which the cognitive impairment is enz-containing regimen to one containing ril- attributable solely to HIV or to an interaction pivirine [55]. between HIV infection and other age-related In addition to efavirenz-related toxicity, a diseases is not fully understood [45]. retrospective analysis evaluating patients with The potentially increased risk for impaired HIV who were treated with dolutegravir, ralte- CNS function among older PLWH is further gravir, and elvitegravir showed rates of neu- complicated by evidence of an association ropsychiatric AEs leading to discontinuation at between long-term ART and neurocognitive 12/24 months of 5.6/6.7%, 0.7/1.5%, and 1.9/ functioning. An analysis of neurocognitive 2.3%, respectively. In patients older than functioning in patients from the CNS HIV 60 years, the discontinuation rate due to neu- Antiretroviral Therapy Effects Research cohort ropsychiatric AEs for dolutegravir was nearly found that patients with long-term (median three-fold higher compared with younger 17.9 months) use of efavirenz had worse speed patients [56]. However, a recent analysis of five of information processing (P = 0.04), verbal phase 3 clinical trials involving patients treated fluency (P = 0.03), and working memory with dolutegravir-based regimens found that (P = 0.03) relative to patients using ritonavir- psychiatric symptoms were reported with low boosted lopinavir [49]. Additionally, efavirenz frequencies, were generally mild to moderate in has been shown to contribute to other serious intensity, and rarely necessitated dolutegravir long-term effects; a pre-specified retrospective discontinuation, similar to other commonly analysis of four AIDS Clinical Trial Group prescribed anchor drugs, including efavirenz, studies reported a higher risk of suicidality raltegravir, and darunavir [57]. (HR = 2.28; 95% CI 1.27–4.10; P = 0.006), defined as suicide ideation, attempted or com- pleted suicide, or a numerically higher risk of 188 Infect Dis Ther (2018) 7:183–195 Cardiovascular Disease treatment (adjusted RR = 1.98, 95% CI 1.72–2.29) [65, 69]. Rates of CVD mortality, acute MI risk, and ischemic stroke risk increase with age among Liver Disease PLWH, and the absolute risk for CVD is expec- ted to increase in parallel with age [58–61]. A Liver-related morbidity and mortality are major large US population-based cohort study showed concerns for PLWH, with liver disease account- that proportionate CVD mortality in PLWH ing for approximately 13% of all deaths among increased from 1.95% in 1999 to 4.62% in 2013 PLWH [70]. As a person ages, the regenerative (P \ 0.0001) [59]. By comparison, the general capacity of the liver declines. In addition, population saw a decrease in proportionate accelerated fibrogenesis has been observed in CVD mortality over the same 15-year time per- patients with HIV/HCV co-infection, although iod [59]. An analyses of male veterans direct acting antivirals have now been shown to (n = 76,835) found a higher risk for ischemic effectively treat and cure HCV infection in stroke among HIV-infected versus HIV-unin- patients with HIV/HCV co-infection at rates fected veterans (adjusted HR = 1.17, 95% CI similar to patients without HIV co-infection 1.01–1.36; P \ 0.04) [60]. A separate analysis of [71, 72]. However, there are limited data indi- 82,459 participants in the same cohort found cating that curing HCV in HIV/HCV co-infected that HIV-positive veterans had an increased risk patients reverses hepatic damage. Older age is of incident acute MI compared with uninfected also associated with increased risk of mito- veterans (adjusted HR = 1.48, 95% CI chondrial dysfunction, increased polyphar- 1.27–1.72) [61]. In addition, the mean (95% CI) macy, worse prognosis of alcoholic liver disease, rate of acute MI events per 1000 person-years greater severity of non-alcoholic fatty liver dis- increased with age in HIV-infected veterans ease, and an increased risk of liver cancer [73]. compared with uninfected veterans [2.0 Although nonalcoholic steatohepatitis (NASH) (1.6–2.4) vs. 1.5 (1.3–1.7) for those aged 40–- and nonalcoholic fatty liver disease (NAFLD) are 49 years; 3.9 (3.3–4.5) vs. 2.2 (1.9–2.5) for those frequently observed in PLWH, use of specific aged 50–59; and 5.0 (3.8–6.7) vs. 3.3 (2.6–4.2) ART agents and duration of ART have not been for those aged 60–69, respectively; P \ 0.05 for established as risk factors [74]. NASH and all] [61]. However, it is difficult to discern to NAFLD may be emerging comorbidities in this what extent the survival effect is leading to high population based on the association between rates of CVD in the aging HIV population. HIV and metabolic syndrome, which has a The increased risk for CVD among older reported prevalence in patients with HIV from PLWH may be exacerbated by cumulative toxi- 11.2% up to 45.4% [75]. city associated with ART. One study While the increased risk of liver disease (n = 23,437) of PLWH showed that the inci- among older PLWH is established, evidence dence of MI over more than 6 years of follow-up describing the association between long-term was higher in patients treated with PIs than ART use and liver-related toxicity is variable. In those not treated with PIs (6.01 per 1000 per- a study of 23,441 patients treated with NRTI- son-years vs. 1.53 per 1000 person years, based ART, increased liver-related mortality has respectively) [62]. After multivariate adjust- been observed with continuing use (annual ment, the relative rate of MI per year of PI use relative risk = 1.11; 95% CI 1.02–1.12, P = 0.02) was 1.16 (95% CI 1.10–1.23) [62]. The data [76]. However, a large study of 22,910 patients regarding any association between abacavir and without hepatitis virus co-infection over CVD risk are very mixed and the issue remains 114,478 person-years of follow-up (D.A.D. controversial [63–69]. Recently updated data cohort) found that there were 12 liver-related from the D:A:D cohort (n = 49,717) found that deaths resulting in an incidence of 0.10/1000 current abacavir use was associated with a 98% person-years [77]. Seven deaths were due to increase in the rate of MI among PLWH com- severe alcohol use and five were due to pared with PLWH not currently on abacavir Infect Dis Ther (2018) 7:183–195 189 established ART-related toxicity, the latter of Potential for New Therapies to Improve Long-Term Outcomes which resulted in an ART-related mortality incidence of 0.04/1000 person-years. The increased risk of liver-related AEs, including Among PLWH, shifting from targeting an acute liver fibrosis, with use of specific NRTIs such as infection to managing a chronic disease didanosine is well known [78]. As a result of requires new approaches to treatment and drug these known AEs, current treatment guidelines regimens that ultimately achieve viral suppres- no longer recommend the use of didanosine sion while minimizing cumulative toxicities. [5, 79]. While continued improvements in ART cannot fully address issues related to chronic inflam- Economic Burden Associated with ART- mation and other comorbidities associated with HIV and long-term ART in aging patients, such Related Cumulative Toxicity regimens have the potential to improve patient adherence, reduce pill burden, and ultimately There is limited evidence describing the eco- lower the economic impact of cumulative toxi- nomic burden associated with cumulative toxi- cities. Novel approaches to treatment in certain city that results from long-term ART use in older patient populations include ART regimens PLWH. Nevertheless, short-term toxicity-related taken 4 days per week compared with continu- costs among PLWH who are treated with ART ous ART 7 days per week (QUATUOR trial) [84], have been documented, and there is an expec- the use of long-acting injectable formulations tation that healthcare costs will increase com- [85], and two-drug regimens [13, 16, 85–87]. mensurately as PLWH age. In a retrospective Assuming viral loads can be controlled with Medicaid claims analysis of PLWH treated with fewer drugs in a treatment regimen, the risk of ATV or darunavir (n = 2426), the mean ± SD toxicity associated with long-term ART may be per-patient per-month costs of all medically lowered. Recent head-to-head studies of two- attended AEs were US$3879 ± $6635 and drug regimens comparing either atazanavir–ri- $5354 ± $8127, respectively [80]. In another US tonavir plus lamivudine or rilpivirine plus boos- claims analysis of PLWH treated with NNRTIs ted darunavir to currently recommended three- (n = 2548), mean total healthcare costs or four-drug ART in virologically stable patients (12 months) were estimated to be have shown non-inferior efficacy and favorable $27,299 ± $37,170, and annual AE-associated AE profiles for two-drug regimens [13, 16]. Stud- costs were $608 ± $3897 [81]. Costs varied from ies investigating treatment switching from three- $586 for lipid disorders to $4434 for nausea/ or four-drug regimens to two- or one-drug regi- vomiting. A retrospective US case–control study mens in virologically stable patients have also found that for patients who had initiated ART demonstrated non-inferior efficacy and compa- within the last 12 months, the median differ- rable or a more favorable AE profile associated ence (episode with event of interest vs. without with regimens that include fewer drugs event of interest) in total all-cause healthcare [12, 14, 15, 85–87]; several switch studies are costs was $3310 for managing diabetes/insulin ongoing [88–91]. These recent head-to-head tri- resistance, $2792 for lipid disorders, $1389 for a als and switch studies are generally limited to a renal disorder event, $390 for rash, $357 for a duration of 1 year or less, and may therefore somnolence/sleep event, and $212 for a hepatic underestimate the benefits of initiating or disorder event [82]. Aging in the population of switching to simplified regimens that potentially PLWH is likely to add to the cost of HIV man- have fewer cumulative long-term toxicities. agement; between 1999 and 2011, the propor- tion of older PLWH increased from 9.6 to 25.4%, and proportional costs increased from LIMITATIONS 25 to 31% [83]. The findings reported in this literature review are subject to several limitations. The review 190 Infect Dis Ther (2018) 7:183–195 was non-systematic and thus did not identify the data in this study and take complete literature from a broad set of databases or responsibility for the integrity of the data and undergo dual-reviewer study screening and accuracy of the data analysis. evaluation. Additionally, while we attempted to Medical Writing and Editorial Assis- include impactful and meaningful studies, we tance. The authors thank Marcia Reinhart, did not conduct a formal quality assessment DPhil, of Analysis Group Inc., for providing and thus the quality of data reported may vary. medical writing and editorial support; Analysis Furthermore, not all included studies were Group received consultancy fees from ViiV case–control studies and caution should be used Healthcare for this support. when interpreting findings of excess comor- bidities among PLWH. Indeed, while not the Authorship. All named authors meet the focus of this review, lifestyle factors that affect International Committee of Medical Journal patients without HIV as well as PLWH and that Editors (ICMJE) criteria for authorship for this lead to age-related comorbidities may also article, take responsibility for the integrity of complicate treatment outcomes among PLWH. the work as a whole, and have given their Finally, the apparent lack of literature focusing approval for this version to be published. on the economic burden of long-term ART toxicities may be a result of the non-systematic Disclosures. Miranda Murray is an employee nature of the review, but may also highlight an of ViiV Healthcare. Yogesh Punekar is an important evidence gap and area of potential employee of ViiV Healthcare. Annemiek de future research. Ruiter was affiliated with Guy’s and St Thomas’ NHS Foundation Trust, during the conduct of this review. Annemiek de Ruiter is now an CONCLUSION employee of ViiV Healthcare, Brentford, Mid- dlesex, UK. Corklin Steinhart is an employee of Potential cumulative toxicity remains a concern ViiV Healthcare. Anita Chawla is an employee as more patients experience long-term treat- of Analysis Group, Inc. Cody Patton is an ment and are at greater risk for chronic diseases employee of Analysis Group, Inc. Christina associated with aging, despite recent advances Wang was an employee of Analysis Group, Inc., in ART that have significantly increased the life during the conduct of this review. Christina expectancy of PLWH and offer better safety Wang is now a medical student at University of profiles. Newer treatment regimens with fewer California, San Francisco, California, USA. drugs may help mitigate the clinical, humanis- Analysis Group, Inc., has received consultancy tic, and economic burden of cumulative toxic- fees from ViiV Healthcare to carry out this ity that emerges because of long-term use of research. ART. Together, aging and long-term treatment of HIV as a chronic disease imply the risk of Compliance with Ethics Guidelines. This greater economic burden for healthcare sys- article is based on previously conducted studies tems, which will demand thoughtful policy and does not contain any studies with human solutions that preserve access to innovative participants or animals performed by any of the ART. authors. Data Availability. All data generated or ACKNOWLEDGEMENTS analyzed during this study are included in this published article/as supplementary information files. Funding. Sponsorship for this study and article processing charges were funded by ViiV Open Access. 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Infectious Diseases and TherapySpringer Journals

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