Background
There is a persistent life expectancy gap of 8–9 years between people living with HIV (PLWH) and the general population [
1,
2]. Reasons may include an increased risk for atherosclerotic cardiovascular disease (ASCVD) [
3,
4], non-AIDS defining cancers [
5], osteoporosis, and accelerated liver fibrosis [
6] which have been summarized as HIV-associated non-AIDS comorbidity and carry, along with non-AIDS-defining infections, a higher attributable mortality in PLWH [
7,
8]. Hyperlipidemia and premature cardiovascular disease in PLWH were first reported in 1997 [
9] and 1998 [
10] as a presumed side effect of lifesaving antiretroviral therapy (ART). Physicians, staying true to ‘
primum nil nocere’, have since monitored serum lipid levels and frequently prescribed lipid-lowering therapy (LLT). This practice continued even after it became apparent that rising serum cholesterol after initiation of highly active antiretroviral therapy (HAART) represent a return to pre-infection levels [
11] and that HIV infection itself is a key contributor to ASCVD risk [
3,
4].
Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are a major tool for ASCVD prevention in the general population. In PLWH, statins have also been shown to exert beneficial immunomodulatory effects, as suggested by decreased cancer incidence [
5], progression of liver fibrosis [
12], or chance of HIV virologic rebound [
13]. Yet only their lipid-lowering efficacy [
14] and not their effectiveness to prevent ASCVD events, has been demonstrated. Since statin use has been linked to greater than 50% reductions in all-cause mortality in several HIV cohorts [
15‐
17], an expanded indication could conceivably contribute to bridging of the life expectancy gap. However, other analyses have either failed to show a statin-associated mortality benefit [
17,
18] or found it comparable to the general population [
19]. Also, large beneficial statin-attributed treatment effects in some observational studies have been identified as the result of methodological flaws [
20]. Given this uncertainty about the true extent of their benefit, statins remain substantially underutilized in PLWH [
21] (based on the 2013 AHA/ACC Cholesterol treatment guidelines [
22]).
The question whether all PLWH should receive statins may be answered by a large multinational trial of pitavastatin in PLWH aged 40–75 years with low to moderate ASCVD risk, scheduled to conclude by 2023 [
23,
24]. But its effect size may not apply to real-world patients with higher cardiovascular and all-cause mortality risk for whom a placebo-controlled trial was not ethically or practically feasible. As these patients may already struggle with polypharmacy and poor ART adherence, a clinician’s enthusiasm to promote statins will be best informed by an accurate estimate of the population-specific clinical benefit.
The US Veterans Affairs (VA) HIV Clinical Case Registry (CCR) was a racially diverse virtual cohort of all HIV-infected US-veterans until 2012, based on the VA’s electronic medical records, including its Pharmacy Benefits Management database [
25]. VA-pharmacies are the exclusive source for prescription medications for most US veterans and require very low or no medication co-pays. Their detailed inpatient and outpatient prescription and refill records lend themselves to the creation of granular day-to-day medication exposure models. This allowed for a comprehensive analysis of clinical effectiveness of preventive medications.
Discussion
Prior HIV cohort analyses have reported a disproportionately large statin-associated mortality benefit of > 50% [
15‐
17] which resembles reports of ≥40% reduced mortality among statin users in other populations with altered immunity [
33‐
35], inherently increased (cardiovascular) mortality risk [
36‐
39], or old age (25% mortality reduction in men > 75 years) [
40]. Decreased mortality had never been observed in primary NS-LLT prevention trials but has recently been reported when icosapent-ethyl (fish oil component) or alirocumab (PSK-9 inhibitor) was added to statins in high-risk populations [
41,
42].
The relationship between density of longitudinal LLT exposure and clinical effectiveness is incompletely understood. It could hinge on magnitude of cumulative exposure, consistency of exposure, and recency of use. To capture optimal exposures, “consistent use” in our multi-level exposure model required both > 91% adherence for ≥1 year and use within 30 days. To our knowledge, LLT effectiveness has not been analysed this way in high-risk populations.
Still, the magnitude of the mortality benefit during consistent statin-free LLT use was unexpected and sharply contrasted with only moderately reduced mortality risk for inconsistent use – for which no reduced ASCVD risk was observed. Increased intra-individual (visit-to-visit) serum cholesterol variability has recently been identified as an important ASCVD and mortality risk factor [
43,
44]. Although not yet biologically understood, this phenomenon could potentially offset beneficial LLT effects in patients with low adherence and may even play a role in randomized controlled trials of LLT. For statins, the mortality difference between consistent and inconsistent use was much smaller. This may reflect their sustained immunomodulatory properties, as evidenced by reduced infection and cancer risk even for inconsistent, respectively remote users.
Multi-level time-updated drug exposure models have been tested [
45], can address frailty bias [
28], and are not subject to immortal time bias [
20,
46]; both of which are known to lead to inflated treatment effects [
20,
28]. The lack of a mortality benefit for remote LLT use argues against healthy user bias [
47] and the lack of any benefit for consistent antihypertensive or aspirin use against healthy adherer bias [
48] as explanations for the apparent mortality benefit of ongoing LLT use. Our mortality model met consistency, positivity, and correctness of weight-generation criteria of marginal structural models [
49]. Similar reductions for overall ASCVD risk during consistent statin-free LLT and coronary risk during consistent statin-only LLT provide biologic plausibility for the reduced mortality risk. Yet after IPW and multi-level adjustment, consistent use of antihypertensives and aspirin remained associated with increased mortality and other adverse outcomes which indicates residual indication bias. This “stubborn” residual bias [
50] was directed against patients taking CV medications and would have affected statins similarly. As statins are arguably the most important preventive CV drug class, this residual bias may explain why they appeared less effective than statin-free LLT in reducing mortality. Yet, the lack of a cerebrovascular effect during consistent statin monotherapy is also noteworthy.
The current HAART era is characterized by high adherence to single tablet regimens, sustained virologic suppression, and durable immune restoration. We included patients only after achieving virologic suppression but continued to follow them regardless of virologic failure to avoid informative censoring. We further approximated contemporary conditions in contrasting subgroup analyses and observed comparable results. Consistent combination LLT use remained associated with significantly reduced mortality in all examined subgroups including patients with sustained virologic suppression and immune reconstitution and patients with low ASCVD risk. A notable exception were patients taking TDF containing HAART for whom the mortality impact of consistent LLT was attenuated. TDF (but not tenofovir alafenamide fumarate [
51]) has well documented lipid lowering properties [
52] and was the only ARV component independently associated with reduced mortality. Importantly, it is no longer used in most modern single-tablet HAART regimens.
There was no apparent association between absolute serum LDL levels and clinical outcomes within the same LLT exposure levels. But if the decreasing mortality risk from remote to consistent LLT exposures is interpreted as “dose-response relationship”, our study would fulfil most of the Bradford-Hill criteria [
53] for causal inference between LLT use and mortality risk in PLWH. The REPRIEVE trial [
23,
24] will provide the ultimate guidance on statin use in PLWH. But as unmeasured or uncontrolled confounding is unlikely a major explanation for our findings, extensive use of lipid lowering therapy in HIV-infected US-veterans - including those not virologically suppressed - could have saved thousands of lives.
The major strengths of our study are its comprehensiveness, its detailed drug exposure models, and its statistical approach. Others include cohort size and diversity, length of follow-up, and the reliance on uniform data collection on exposures and outcomes across the entire US-VA system. Limitations include an extreme male predominance, the lack of differentiation between different daily doses and the absence of cause of death. Before the publication of the 2013 AHA/ACC Cholesterol guidelines [
22], non-statin lipid lowering agents were commonly combined with or substituted for statins in order to target risk-specific cholesterol goals [
54]. While its remote timeframe is the major limitation of our study, it also allowed a comprehensive and unique analysis of statin and non-statin LLT effectiveness in PLWH.
Acknowledgements
The authors acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin (
http://www.tacc.utexas.edu) for providing high performance computing resources that have contributed to the research results reported within this paper.
We also would like to thank all the staff of the Dallas VA ID section for their support, particularly our founder, Dr. James Smith, and our two long time physician assistants, Diana Turner and Teresa Moore. We also like to thank the members of the former Veteran’s Affairs Center for Quality Management in Public Health in Palo Alto, CA for compilation and dissemination of the CCR data.
Parts of this study were presented at the 25th Conference for Retroviruses and Opportunistic Infections 2019 in Seattle WA, USA, and the 17th European AIDS Conference 2019 in Basel, Switzerland.
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