Healthcare utilization among persons living with hiv with attention to the influences of hepatitis

Chapter 5:
Conclusion

The studies presented in Chapters 2 and 3 each demonstrate that HBV and HCV are important drivers of hospitalizations among PLWH. Because hospitalizations represent a substantial component of total healthcare costs among PLWH, healthcare systems and providers that are caring for PLWH who are co-infected with HBV and/or HCV must be prepared to handle higher healthcare costs than those incurred by persons with HIV mono-infection.^4,5 Public funders may consider diverting scarce healthcare resources toward this more vulnerable patient population and managed care organizations may consider increasing capitation rates to providers caring for PLWH who are co-infected with viral hepatitis. Furthermore, research is needed to identify specific interventions that may attenuate the risk of hospitalization among PLWH who are co-infected with viral hepatitis.

The study presented in Chapter 2 provides some insight into potentially modifiable factors that contribute to the excess risk of hospitalization among PLWH with hepatitis co-infection. In this study, hospital admission for non-AIDS-defining infection was more common among PLWH with any hepatitis co-infection. Among such infections, pneumonia was most common. Routine pneumococcal and influenza vaccinations have been shown to decrease hospitalizations and are recommended for all PLWH in the United States.^6-9 These recommendations may be particularly important for PLWH who are co-infected with viral hepatitis.

Psychiatric hospitalizations were disproportionately common among HIV/HCV co-infected patients, with the most common admitting diagnosis being depression. Mood disorders and depression are common among PLWH, with studies reporting prevalence of 18-81% depending on the specific population and diagnostic methodology used.¹⁰ HIV/HCV co-infection is associated with higher prevalence and severity of neuropsychiatric disease than is HIV infection alone.^11,12 The successful management of mental health disorders among PLWH, and specifically those with HIV/HCV co-infection, can lead to improved quality of life, improved adherence to medication, and reduction of high-risk behaviors and suicidality.^13-16 One effective strategy to manage mental health disorders among this population includes integration of mental health and HIV care programs, which has been shown to improve clinical outcomes of HIV and psychiatric disease as well as decrease hospitalization costs.^17,18 HIV/HCV co-infected patients may benefit from targeted interventions to improve mental health, including co-location of services to care for HIV, hepatitis, and psychiatric disorders.

The study presented in Chapter 3 reinforces the importance of psychiatric disease as a driver of healthcare utilization among HIV/HCV co-infected patients by demonstrating their increased utilization of outpatient mental health services as compared to patients with HIV mono-infection. Furthermore, non-White PLWH were significantly less likely to utilize mental health services than were those reporting White race/ethnicity, potentially reflecting cultural barriers to care or other access issues that may require targeted intervention.¹⁹ Healthcare delivery systems caring for PLWH, and specifically those with HIV/HCV co-infection, must proactively address mental health issues in order to improve clinical outcomes and ultimately reduce total healthcare costs. It is unclear why utilization of mental health care services appears to be decreasing among both HIV mono-infected and HIV/HCV co-infected patients during the study interval from 2006 to 2011. This trend raises concern that funding limitations or other barriers may be limiting access to an important healthcare service in a population with particular need for mental health care. Providing access to mental health services should be a priority for all healthcare systems caring for PLWH and is especially important in the setting of HIV/HCV co-infection.

The study presented in Chapter 3 also demonstrated that utilization of outpatient primary HIV care services is decreasing over time and is not influenced by hepatitis serostatus. This decline is almost certainly due to updated professional society guidelines that recommend less frequent monitoring for patients with well-controlled HIV disease.^20-22 This observation may help to predict future needs for outpatient primary HIV care services, but the decline in number of visits per patient must also be balanced with the expectation that a greater number of patients will require services as a result of insurance and HIV screening changes brought about by the ACA.

The studies in Chapters 2 and 3 both raise questions about the potential role of therapies directed against HBV and HCV in decreasing healthcare utilization and, ideally, healthcare costs. Such therapies have been shown to decrease progression to cirrhosis among co-infected PLWH.²³ In Chapter 3, the observed association between higher FIB-4 score and increased hospitalization rates suggests that hepatocellular dysfunction may directly contribute to the risk of hospitalization in co-infected patients. It might therefore be inferred that reducing hepatic injury by treating the underlying viral hepatitis may reduce the risk of hospitalization. However, in this study, use of ART with activity against HBV by persons with HIV/HBV co-infection only modestly reduced the rate of primary HIV care visits and was associated with a non-significant trend towards fewer hospitalizations. Treatment of HBV is common among PLWH and over 70% of the HIV/HBV co-infected patients evaluated in Chapter 3 were prescribed such therapies. Conversely, prior studies have reported HCV treatment rates of only 20-40% for HIV/HCV co-infected patients, with less than half of these achieving sustained virologic response.^24,25 More effective and better tolerated therapies for HCV have recently been developed and could potentially transform HCV into a much more readily cured disease.^26-28 If these therapies decrease hospitalization rates, the associated cost savings could counterbalance the high cost of the newest medications used to treat HCV.^29,30 Further research on this topic is needed. Interestingly, one study evaluating the treatment of HIV/HCV co-infected patients with triple therapy against HCV did not show a resultant decline in the incidence of major depressive disorder, which we have already described as an important co-morbidity among persons with HIV/HCV co-infection.³¹

The study presented in Chapter 4 demonstrated that hospitalization rates were higher among PLWH with elite control of HIV as compared to persons whose virus was medically controlled with ART. Because elite control is a rare phenomenon, representing less than 1% of PLWH, excess hospitalizations among this group do not represent a large contributor to the total healthcare costs associated with HIV infection.³² The more important inference that may be drawn from the data presented is that the clinical outcomes of elite control may be worse than the outcomes associated with successful virologic control using ART. This is important for at least two reasons. First, individual elite controllers may experience a benefit from initiation of ART. Second, elite control may be a suboptimal model for the functional cure of HIV.

The notion that elite controllers may benefit from ART initiation is supported by a growing body of evidence. It has previously been shown that elite control is associated with chronic immune activation and low-grade inflammation beyond the levels seen among PLWH who are medically controlled with ART.^33-35 This may place elite controllers at higher risk of clinical events that are sequelae of chronic immune activation and inflammation, such as cardiovascular events. Prior studies have demonstrated a higher burden of coronary atherosclerosis among elite controllers than among medically controlled PLWH and HIV-uninfected comparators.^36,37 Consistent with this observation, the data presented in Chapter 4 demonstrate that cardiovascular disease was the most common reason for hospitalization among elite controllers, accounting for about one-third of all hospitalizations. Risk of hospitalization for cardiovascular disease remained elevated among elite controllers as compared to those with medically controlled HIV after adjusting for other clinical factors, although data on known cardiovascular risk factors such as dyslipidemia and hypertension were not included in the statistical models. If cardiovascular events among elite controllers occur as a result of chronic inflammation and immune activation, then it is possible that elite controllers could benefit from interventions to reduce this inflammation and immune activation. ART has been shown to reduce low-level viral replication measured by ultrasensitive assays among spontaneous controllers of HIV and also reduces markers of T cell activation in blood and the gut of these patients.³⁸ Adjunctive therapy with anti-inflammatory agents such as non-steroidal anti-inflammatory drugs and HMG-CoA reductase inhibitors should also be investigated.

Elite control has often been looked to as a model for HIV remission, given the presumed value of viral suppression without lifelong ART. While ART has successfully transformed HIV into a chronic disease, its use is complicated by toxicities, the need for lifelong adherence and the constant threat of emerging drug-resistance.^39-41 Even among PLWH who are successfully treated with ART, some immunologic dysfunction persists.^42-45 Therefore, it remains desirable to develop curative approaches that confer durable virologic control, delay disease progression, restore immunologic function and decrease morbidity without a requirement for perpetual ART. Evidence suggests that elite control does not meet these objectives and is inferior to ART. Viral replication occurs among elite controllers at levels that are often higher than those seen among PLWH who are well-controlled on ART.^46,47 Despite virologic control, some elite controllers still experience CD4 decline and progression to AIDS.³⁵ Elite controllers have evidence of immune dysfunction and inflammation that is higher than that seen among PLWH who are well-controlled on ART.^35,48,49 Now, the data presented in Chapter 4, indicate that clinical outcomes represented by the need for hospitalization are worse among elite controllers than among PLWH who are well-controlled on ART. This suggests that interventions designed to induce a state similar to elite control may not be as desirable as other strategies to achieve HIV remission that may more closely reproduce or exceed the beneficial effects of ART.

The research presented in this dissertation provides valuable insight into factors contributing to healthcare utilization and healthcare costs. It clearly demonstrates that hepatitis co-infection is an important driver of healthcare utilization. Interventions to decrease the rate of costly hospitalizations in co-infected patients must be investigated and implements. Known strategies to prevent infectious causes of hospitalization, such as pneumococcal and influenza vaccinations, must be recognized by providers and prioritized by third-party payors. Similarly, evidence-based interventions to improve the mental health of PLWH, particularly those with HIV/HCV co-infection, must be implemented in order to improve clinical outcomes and reduce total healthcare costs. Third-party payors should be aware of the trends in healthcare utilization over time as they plan for future healthcare needs. As the HIV-infected population ages, chronic hepatitis co-infection is likely to play an even greater role in the long-term morbidity of PLWH. Clinicians must be prepared to address the needs associated with the long-term care of co-infected individuals. Clinicians must also recognize the potential benefit of ART use among elite controllers. Further investigation is needed to prospectively evaluate the influence of ART use and anti-inflammatory agents among elite controllers. Tremendous strides in the management of HIV have been achieved over the last 30 years and additional successes may soon be seen in linking a greater number of PLWH to life-saving medical care. With an understanding of the factors contributing to healthcare costs, policy-makers and third-party payors may be able to design systems to achieve more cost-effective care for PLWH. With an understanding of the clinical outcomes and underlying physiology involved in the spontaneous control of HIV, we may someday identify an intervention to achieve HIV remission.