Inflammation May Hold Key to Noncommunicable Disease in HIV

The common link to many noncommunicable HIV-associated comorbidities appears to be inflammation.¹ HIV-associated cardiovascular disease (CVD), neurocognitive impairments, and non-AIDS-defining cancers may also be influenced by sex hormones that might activate inflammation and the immune system.¹

In low- and high-resource countries, the population aged >50 years with HIV is increasing, and researchers are noticing that more deaths among these individuals are not directly associated with communicable diseases.¹ The puzzling aspect in this age cohort is that individuals treated with antiretroviral therapy (ART) who have undetectable viral loads still exhibit systemic inflammation and immune activation.^1,2 As a result, there is a flurry of inquiry as to how inflammation and sex differences affect the trajectory of health outcomes for people living with HIV.

Cardiovascular Comorbidities of HIV

The CV risk for people with HIV is similar to that for those who have type 2 diabetes.³ Despite this, people with HIV are less likely to be screened and treated for CVD.

The common pathway to CV risk may be inflammation, which is responsible for plaque development that precipitates the accumulation of low-density lipoprotein (LDL) particles and insulin resistance.³ This CV risk may be attenuated by lifestyle changes, such as diet and exercise, as well as pharmacologic therapy.³ To mitigate CV risk in patients with HIV, clinicians should screen for hypertension, diabetes, dyslipidemia, and tobacco use.³

“What is clear from recent data is that patients with HIV appear to be less commonly screened for risk factors of [CVD] and as a result are less aggressively receiving primary prevention management compared with the general US population,” says Faisal Rahman, BM BCh, a research cardiologist from Johns Hopkins University School of Medicine in Baltimore, Maryland.

INTREPID was the first study to determine the efficacy of statins in reducing markers of immune activation and arterial inflammation in patients with HIV.⁴ Toribio and colleagues randomly assigned 252 HIV-infected patients on ART (median age, 50 years) to receive pitavastatin 4 mg or pravastatin 40 mg for 52 weeks. At the end of the study, patients in the pitavastatin group vs those in the pravastatin group had significant reductions in soluble CD14(-10.0 vs. 0.6%; P =.02), oxidized LDL (-26.9 vs -17.5%; P =.02), and lipoprotein-associated phospholipase 2 (-26.6 vs -15.5%; P =.005).⁴

The statins were chosen based on their minimal interactions with antiretroviral medications. Patients receiving darunavir were excluded from the study because of its interactions with pravastatin. There were no significant changes in the levels of inflammatory markers sCD163 or hsIL-6 with either statin in the study. In previous studies, both biomarkers had been implicated in activating plaque in people with HIV.⁴

“Clinicians may now be more aware of the potent effects of statins and in particular, pitavastatin, to reduce indices on monocyte activation in HIV,” notes Steven Grinspoon, MD, professor of medicine at Harvard Medical School in Boston, Massachusetts.

Janjua and colleagues found that women living with HIV (WLWHIV) had 2.5 times the risk for heart failure (HF) compared with women who were uninfected.⁵ Using data from a large insurer, researchers found that WLWHIV with HF vs uninfected women had higher rates of HF hospitalization (42 per 100 person-years vs 9 per 100 person-years; P <.0001), longer HF hospitalization (8 days vs 5 days; P <.0001), higher all-cause mortality (53% vs 21%; P <.001), and greater CV mortality (83% vs 33%; P <.006).⁵

When asked about potential sex differences in CV risk for HF in men with HIV, Tomas Neilan, MD, MPH, director of the cardio-oncology program at Massachusetts General Hospital, Boston, Massachusetts, responded: “The findings are similar in that both men and women in this larger cohort with HIV and HF are at a higher risk of hospitalization with HF. These patients are also at increased risk of CV death.”

Neurocognitive Impairment

Before the advent of ART, neuropathy and encephalopathy were major consequences of late-stage HIV.⁶ Now, rates of HIV-associated neurocognitive disorders are increasing, especially milder forms of impairment such as mild neurocognitive disorder and asymptomatic neurocognitive impairment, even when patients with HIV have access to ART.⁶

Researchers are examining the use of the cerebrospinal fluid biomarker neopterin, which is elevated in patients who have HIV-associated dementia, to potentially provide early detection of cognitive impairment. Another biomarker, neurofilament light chain, signals axonal injury that can predict severity and survival in neurocognitive disorders. Much of the research in neurocognitive studies seeks to address the relevance of early initiation of ART and whether it can prevent poor neurologic outcomes in patients with HIV.⁶

To test the biomarker hypothesis in neurocognitive disorders of HIV, Imp and colleagues measured the biomarkers soluble CD163 (sCD163), soluble CD14 (sCD14), C-reactive protein, interleukin-6, and a gut microbial translocation marker (intestinal fatty acid binding protein) in 253 women, 73% of whom were infected with HIV.⁷ High levels of certain biomarkers were associated with distinct types of neurologic impairments. Higher sCD163 levels correlated with poor overall performance and worse verbal learning, verbal memory, executive function, psychomotor speed, and fine motor skills (P <.05 for all comparisons). Elevated sCD14 levels were linked to worse verbal learning, verbal memory, executive function, and psychomotor speed (P <.05 for all comparisons).

Non-AIDS-defining cancers

While the incidence of cancers such as Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer is well established in patients with HIV, scientists are still determining how non-AIDS-defining cancers occur in people infected with HIV.⁸ In an 18-study meta-analysis of 625,716 HIV-infected men and women, Shiels and colleagues found 4797 non-AIDS cancers. The standardized incidence ratio (SIR) for infection-associated cancers included anal (SIR, 28; 95% confidence limit [CL], 21-35); liver (SIR, 5.6; 95% CL, 4.0-7.7); Hodgkin lymphoma (SIR, 11; 95% CL, 8.8-15); smoking-related, such as lung (SIR, 2.6; 95% CL, 2.1-3.1); kidney (SIR, 1.7; 95% CL, 1.3-2.2); and laryngeal (SIR, 1.5; 95% CL, 1.1-2.0). The researchers theorized that immune suppression may be implicated in the cancers.⁸

Future studies on immune activation and inflammation in patients with HIV will need to examine multiple mechanisms implicated in cancer, liver disease, renal disease, neurocognitive decline, and osteoporosis.²

“Providers are coming to recognize that suppressing HIV-1 RNA is only the first step in caring for people aging with HIV infection,” explains Amy C. Justice, MD, PhD, professor of medicine and public health at the Yale School of Public Health in New Haven, Connecticut. “Increasing consideration needs to be given to how to optimize the balance between addressing ongoing health concerns, including inflammation, and avoiding polypharmacy.”

Summary and Clinical Applicability

As the population of people living with HIV is growing older, there is greater interest in their morbidity and mortality, particularly for noncommunicable diseases. Inflammation is thought to play a role in comorbidities such as CVD, neurocognitive impairment, and non-AIDS-related cancers. More research is warranted to better understand how clinicians can manage patients with HIV, who appear to be at higher risk for these diseases.

References

1. Raghavan A, Rimmelin DE, Fitch KV, Zanni MV. Sex differences in select non-communicable HIV-associated comorbidities: exploring the role of systemic immune activation/inflammation. Curr HIV/AIDS Rep. 2017;14(6):220-228
2. Justice AC, Erlandson KM, Hunt PW, Landay A, Miotti PG, Tracy RP. Can biomarkers advance HIV research and care in the antiretroviral therapy era? J Infect Dis. 2018;217(4):521-528.
3. Rahman F, Martin SS, Whelton SP, Mody FV, Vaishnav J, McEvoy JW. Inflammation and cardiovascular disease risk: a case study of HIV and inflammatory joint disease [published online December 18, 2017]. Am J Med. doi: 10.1016/j.amjmed.2017.11.034
4. Toribio M, Fitch KV, Sanchez L, et al. Effects of pitavastatin and pravastatin on markers of immune activation and arterial inflammation in HIV. AIDS. 2017;31(6):797-806.
5. Janjua SA, Triant VA, Addison D, et al. HIV infection and heart failure outcomes in women. J Am Coll Cardiol. 2017;69(1):107-108.
6. Farhadian S, Patel P, Spudich S. Neurological complications of HIV infection. Curr Infect Dis Rep. 2017;19(12):50.
7. Imp BM, Rubin LH, Tien PC, et al. Monocyte activation is associated with worse cognitive performance in HIV-infected women with virologic suppression. J Infect Dis. 2017;215(1):114-121.
8. Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr. 2009;52(5):611-622.